**Meet the editor**

Dr. Stefan Danilla was born in Chile in 1979. He obtained his medical degree at the Universidad de los Andes in the year 2001. After that he graduated with honours, obtaining his Masters Degree on Clinical Epidemiology (University of Chile), starting his research career applying evidence-based medicine concepts to his work and teaching. In 2003, he started his General Sur-

gery training at the Military Hospital of Santiago (Universidad de los Andes) and finished his Plastic Surgery Residence in 2009 at the Universidad de Chile. As a plastic surgeon and researcher, Dr Danilla has worked on reconstructive and cosmetic surgery, performing randomized controlled trials in order to obtain reliable evidence for common procedures, useful for patients and surgeons. His research work is now dedicated to providing reliable outcomes, and measuring results in cosmetic surgery.

Contents

**Preface IX** 

**for Skin Cancer 3** 

Stefanos Tsourvakas

Alessandro Bonanno

Chapter 5 **Acellular Dermal Matrix** 

Ron Israeli

Chapter 6 **Consequences of Radiotherapy** 

Chapter 7 **Reconstruction of Perineum** 

**Part 1 Basic Topics in Reconstructive Surgery 1** 

Chapter 1 **Scar Revision and Secondary Reconstruction** 

Chapter 2 **Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 17** 

Chapter 3 **The Social Limits of Reconstructive Surgery:** 

**Part 2 Topographic Reconstruction Strategies 59** 

**Implant-Based Breast Reconstruction: Primary and Revisionary Procedures 93** 

Chapter 4 **Head and Neck Reconstructive Surgery 61**  J.J. Vranckx and P. Delaere

**for Optimizing Outcomes in** 

**for Breast Reconstruction 113**  Nicola S. Russell, Marion Scharpfenecker, Saske Hoving and Leonie A.E. Woerdeman

**and Abdominal Wall 141**  J.J. Vranckx and A. D'Hoore

**Stigma in Facially Disfigured Cancer Patients 45** 

Michael J. Brenner and Jennifer L. Nelson

### Contents

#### **Preface XI**


J.J. Vranckx and A. D'Hoore

X Contents

#### **Part 3 New Technologies and Future Scope in Plastic Surgery 161**

Chapter 8 **Stem Cell Research: A New Era for Reconstructive Surgery 163**  Qingfeng Li and Mei Yang

#### Chapter 9 **Three Dimensional Tissue Models for Research in Oncology 175**  Sarah Nietzer, Gudrun Dandekar, Milena Wasik and Heike Walles

Chapter 10 **Mathematical Modeling in Rehabilitation of Cleft Lip and Palate 191**  Martha R. Ortiz-Posadas and Leticia Vega-Alvarado

#### Chapter 11 **Advanced 3-D Biomodelling Technology for Complex Mandibular Reconstruction 217**  Horácio Zenha, Maria da Luz Barroso and Horácio Costa

### Preface

Plastic Surgery is a fast evolving surgical specialty. Although best known for cosmetic procedures, plastic surgery also involves reconstructive and aesthetic procedures, which very often overlap, aiming to restore functionality and normal appearance of organs damaged due to trauma, neoplasm, ageing tissue or iatrogenesis.

First reconstructive procedures were described more than 3000 years ago by Indian surgeons that reconstructed nasal deformities caused by nose amputation as a form of punishment. Nowadays, many ancient procedures are still used like the Indian forehead flap for nasal reconstruction, but as with all fields of medicine, the advances in technology and research have dramatically affected reconstructive surgery.

Recent developments and discoveries in vascular anatomy, imaging, advanced wound dressing, tissue engineering and robotic prosthetics have lead to moving frontiers in reconstructive surgery. These developments expand the limits of reconstruction and lead to achieving outcomes that would not have been possible ten years ago.

This book comprises three sections. First section is dedicated to general concepts of plastic surgery such as infection control, local flaps and sociological perspective of plastic surgery. The second section consists of highly detailed and reproducible reconstructive strategies used in several surgical problems. The final section provides the surgeons with easy-to-read articles about new technologies than can be applied in practically any field of plastic surgery.

I sincerely hope that this book will help plastic surgeons, residents and researchers to provide the best care for their patients worldwide.

> **Dr Stefan Danilla**  Plastic Surgeon Master of Science (Clinical Epidemiology) Hospital Clinic University of Chile Hospital Clínica Alemana de Santiago Santiago Chile

**Part 1** 

**Basic Topics in Reconstructive Surgery** 

## **Part 1**

## **Basic Topics in Reconstructive Surgery**

**1** 

*USA* 

**Scar Revision and Secondary** 

Michael J. Brenner1,2 and Jennifer L. Nelson2 *1Director of Facial Plastic & Reconstructive Surgery 2Division of Otolaryngology, Department of Surgery Southern Illinois University School of Medicine* 

**Reconstruction for Skin Cancer** 

Late wound management requires not only mastery of the techniques involved in scar revision, but a thorough understanding of facial anatomy, wound healing, and the psychological factors associated with traumatic injury. Treatment of a patient for scar revision requires the surgeon to understand that a patient's perception of a scar is often influenced by emotionally charged circumstances and possible self-critical evaluation. This chapter addresses the etiology, evaluation, and treatment of traumatic wounds in the

Unsightly scar formation and impaired wound healing may arise from a variety of factors related to trauma, surgery, or inflammation.(1) While the stigmata of trauma often appear isolated to the skin, many deformities also involve deeper injury to muscle, bone, or other underlying deep tissues. This distinction is of paramount importance because failure to appropriately identify a structural defect in the scaffolding and supporting tissue that is deep to the skin will almost certainly result in an unfruitful attempt at revision. Furthermore certain types of injuries, such as gunshot wounds, avulsions, and full thickness burns are

Several additional factors also adversely affect healing. Infection in the wound bed will exacerbate the degree of injury and will likely to cause added delay in revision. Infected wounds are characterized by greater tissue loss and destruction, as well as increased collagen deposition, impaired vascular supply, and worse scarring. Blunt injuries tend to cause more diffuse soft tissue injury than sharp injuries. Crush injuries that produce stellate tears, irregular lacerations, and diffuse underlying soft tissue destruction may result in particularly severe scarring. Host factors, such as skin thickness, predisposition to keloid formation or hypertrophic scars, skin pigmentation, prior injury, poor nutritional status, sun

The initial management of a traumatic wound heavily impacts the need for revision.(2) Wound closure is often performed by personnel with limited experience in plastic surgical

exposure, and smoking history will all also affect healing and scar formation.

**1. Introduction** 

delayed setting with emphasis on scar revision.

**2. Pathogenesis of scar formation** 

associated with significant tissue loss.

### **Scar Revision and Secondary Reconstruction for Skin Cancer**

Michael J. Brenner1,2 and Jennifer L. Nelson2 *1Director of Facial Plastic & Reconstructive Surgery 2Division of Otolaryngology, Department of Surgery Southern Illinois University School of Medicine USA* 

### **1. Introduction**

Late wound management requires not only mastery of the techniques involved in scar revision, but a thorough understanding of facial anatomy, wound healing, and the psychological factors associated with traumatic injury. Treatment of a patient for scar revision requires the surgeon to understand that a patient's perception of a scar is often influenced by emotionally charged circumstances and possible self-critical evaluation. This chapter addresses the etiology, evaluation, and treatment of traumatic wounds in the delayed setting with emphasis on scar revision.

#### **2. Pathogenesis of scar formation**

Unsightly scar formation and impaired wound healing may arise from a variety of factors related to trauma, surgery, or inflammation.(1) While the stigmata of trauma often appear isolated to the skin, many deformities also involve deeper injury to muscle, bone, or other underlying deep tissues. This distinction is of paramount importance because failure to appropriately identify a structural defect in the scaffolding and supporting tissue that is deep to the skin will almost certainly result in an unfruitful attempt at revision. Furthermore certain types of injuries, such as gunshot wounds, avulsions, and full thickness burns are associated with significant tissue loss.

Several additional factors also adversely affect healing. Infection in the wound bed will exacerbate the degree of injury and will likely to cause added delay in revision. Infected wounds are characterized by greater tissue loss and destruction, as well as increased collagen deposition, impaired vascular supply, and worse scarring. Blunt injuries tend to cause more diffuse soft tissue injury than sharp injuries. Crush injuries that produce stellate tears, irregular lacerations, and diffuse underlying soft tissue destruction may result in particularly severe scarring. Host factors, such as skin thickness, predisposition to keloid formation or hypertrophic scars, skin pigmentation, prior injury, poor nutritional status, sun exposure, and smoking history will all also affect healing and scar formation.

The initial management of a traumatic wound heavily impacts the need for revision.(2) Wound closure is often performed by personnel with limited experience in plastic surgical

Scar Revision and Secondary Reconstruction for Skin Cancer 5

Long, linear scars are usually more problematic than shorter scars with more segments because their regular appearance is readily discerned. The human eye has more difficulty detecting a scar's full extent if there is intervening normal tissue or irregularity to the scar. In addition, it is common for long scars to have a bowstring effect over sites such as the medial canthus or mandible to the neck, where webbing can occur due to concavity of these areas. In addition, muscle action can exaggerate a linear deformity, as in the example of

Deeper injuries induce greater scar formation than shallow injuries as a result of the correspondingly greater soft tissue contracture and volume loss. The underlying mechanism involves the melding of superficial and deep scar, resulting in tethering and visible depression. Multiple depths of injury will multiply the extent of scaring, with stellate or crushing injuries resulting in worse injury. Avulsion of tissue will further complicate healing, making it impossible to align skin edges at time of initial injury. Deep, beveled injuries maximize the amount of dermal trauma due to the correspondingly greater area of tissue traversed and the tendency of oblique contracture of the dermis to cause one skin edge to slide over the other. This pattern of scarring may cause either a pin cushioned appearance or a heaped appearance. In such cases, the surgeon may either debulk the

Relaxed skin tension lines (RSTLs) run perpendicular to the direction of maximal underlying tension within the skin (Figure 1). Those scars that are unfavorably positioned relative to RSTLs are most likely to require revision. Often the approach to scar revision is based upon how the scar can be reoriented to fall within these lines. The ability to align scars in this manner is often the difference between an excellent and mediocre result because placement within RSTLs improves camouflage and enables the contractile forces on the skin to approximate wound edges, rather than distracting the edges apart. The lines of maximum extensibility (LMEs) run perpendicular to the RSTLs and are usually parallel to muscle fibers. Lines of maximum extensibility are important to consider when recruiting tissue

Relaxed skin tension lines generally lie perpendicular to the underlying muscle fibers; but, this rule is not absolute. The RSTLs reflect tension on the skin that arises not only from muscle forces but also from stretch by soft tissue or rigid bone/cartilage. Similarly, wrinkle lines do not always accurately reflect the positions of the RSTLs. For example, the lines between the lower lip and mentum run parallel to the orbicularis oris muscle. Most of the RSTLs are parallel to 4 main facial lines: the facial median, the nasolabial, the facial marginal, and the palpebral lines. The facial median line spans from the alar facial groove to the columella and lip and then inferiorly to the mentum. The nasolabial line runs from the alar facial groove inferolaterally to form the nasolabial fold, traverses lateral to the oral commissure, and then extends inferiorly to form marionette lines. The facial marginal line

elevated skin and place bolster sutures or fully excise the affected area.

**3.1.4 Relation to relaxed skin tension lines (RSTLs)** 

from adjacent areas for flap reconstruction.

**3.1.2 Scar length** 

**3.1.3 Scar depth** 

curved scars that form a trapdoor deformity.

technique and wound management. As a result, wounds may be inadequately cleansed, with devitalized tissue and foreign body contamination predisposing to infection and inflammation. Conversely, overzealous debridement may result in an uneven or irregular wound. The wound closure may be inadequate or traumatic, and widened scars occur over sites of excess tension. Depressed scars occur if wound edges are not appropriately everted. When wounds are not covered with an occlusive dressing or appropriate ointment, desiccation will impair wound healing. Last, those, wounds that are situated at sites of repeated motion are prone to widening and delayed repair.

#### **3. Evaluation of late wounds**

Successful late wound management is predicated upon a thorough history and evaluation of the patient considering both the location and characteristics of the wound as well as the goals and expectations of the patient.(3) Preoperative photography plays an important role in documenting the extent of disfigurement. Patients need to be reminded that while treatments may camouflage pathologic wound healing, most interventions will exchange one type of scar or deformity for another, lesser one.(4) The indications for delayed wound management relate to an unacceptable appearance or a functionally problematic healing outcome.(5) Evaluation is influenced by anatomic site, mechanism of injury, extent of the deformity, and likelihood of pathologic healing.

#### **3.1 Characteristics of disfiguring scars**

Scars are perceived as unsightly when their surface characteristics differ markedly from the surrounding skin such that they are poorly camouflaged by the surrounding surface skin anatomy. Whereas scars that fall into shadows generally appear hidden, scars that traverse a smooth convexity such as the chin or malar eminence will be readily noticeable. Abnormal color, contour, and texture make scars more conspicuous and unsightly. Scars that are widened, long, and linear will similarly draw attention, particularly when they are unfavorably oriented relative to relaxed skin tension lines or disrupt an aesthetic subunit. Not uncommonly, cosmetically disfiguring scars are also associated with functional problems, such as contracture, distortion, stenosis, or fistula formation. Some examples are ectropion, entropion, or webbing of the eyelids; disruption of salivary ducts; and deformity of the nasal alae, ears, or lips.

#### **3.1.1 Scar color, contour, and texture**

Poor color match results from hyperpigmentation or hypopigmentation. Hyperpigmented scars have a deep red hue from inflammation or have darkening from increased melanin. Hypopigmentation reflects a loss of melanocytes and tend to be irreversible. Traumatic tattooing occurs when dirt, asphalt, graphite, or other foreign material is embedded within the skin. These particles can be particularly difficult to remove because they tend to be distributed across several different skin layers. Scars that are hypertrophied, elevated, depressed, or that have other poor contour are also difficult to mask, especially when accompanied by webbing or pin cushioned appearance. Unacceptable appearance also results from poor texture, such as a scar that is too shiny or too smooth.

#### **3.1.2 Scar length**

4 Selected Topics in Plastic Reconstructive Surgery

technique and wound management. As a result, wounds may be inadequately cleansed, with devitalized tissue and foreign body contamination predisposing to infection and inflammation. Conversely, overzealous debridement may result in an uneven or irregular wound. The wound closure may be inadequate or traumatic, and widened scars occur over sites of excess tension. Depressed scars occur if wound edges are not appropriately everted. When wounds are not covered with an occlusive dressing or appropriate ointment, desiccation will impair wound healing. Last, those, wounds that are situated at sites of

Successful late wound management is predicated upon a thorough history and evaluation of the patient considering both the location and characteristics of the wound as well as the goals and expectations of the patient.(3) Preoperative photography plays an important role in documenting the extent of disfigurement. Patients need to be reminded that while treatments may camouflage pathologic wound healing, most interventions will exchange one type of scar or deformity for another, lesser one.(4) The indications for delayed wound management relate to an unacceptable appearance or a functionally problematic healing outcome.(5) Evaluation is influenced by anatomic site, mechanism of injury, extent of the

Scars are perceived as unsightly when their surface characteristics differ markedly from the surrounding skin such that they are poorly camouflaged by the surrounding surface skin anatomy. Whereas scars that fall into shadows generally appear hidden, scars that traverse a smooth convexity such as the chin or malar eminence will be readily noticeable. Abnormal color, contour, and texture make scars more conspicuous and unsightly. Scars that are widened, long, and linear will similarly draw attention, particularly when they are unfavorably oriented relative to relaxed skin tension lines or disrupt an aesthetic subunit. Not uncommonly, cosmetically disfiguring scars are also associated with functional problems, such as contracture, distortion, stenosis, or fistula formation. Some examples are ectropion, entropion, or webbing of the eyelids; disruption of salivary ducts; and deformity

Poor color match results from hyperpigmentation or hypopigmentation. Hyperpigmented scars have a deep red hue from inflammation or have darkening from increased melanin. Hypopigmentation reflects a loss of melanocytes and tend to be irreversible. Traumatic tattooing occurs when dirt, asphalt, graphite, or other foreign material is embedded within the skin. These particles can be particularly difficult to remove because they tend to be distributed across several different skin layers. Scars that are hypertrophied, elevated, depressed, or that have other poor contour are also difficult to mask, especially when accompanied by webbing or pin cushioned appearance. Unacceptable appearance also

results from poor texture, such as a scar that is too shiny or too smooth.

repeated motion are prone to widening and delayed repair.

**3. Evaluation of late wounds** 

deformity, and likelihood of pathologic healing.

**3.1 Characteristics of disfiguring scars** 

of the nasal alae, ears, or lips.

**3.1.1 Scar color, contour, and texture** 

Long, linear scars are usually more problematic than shorter scars with more segments because their regular appearance is readily discerned. The human eye has more difficulty detecting a scar's full extent if there is intervening normal tissue or irregularity to the scar. In addition, it is common for long scars to have a bowstring effect over sites such as the medial canthus or mandible to the neck, where webbing can occur due to concavity of these areas. In addition, muscle action can exaggerate a linear deformity, as in the example of curved scars that form a trapdoor deformity.

#### **3.1.3 Scar depth**

Deeper injuries induce greater scar formation than shallow injuries as a result of the correspondingly greater soft tissue contracture and volume loss. The underlying mechanism involves the melding of superficial and deep scar, resulting in tethering and visible depression. Multiple depths of injury will multiply the extent of scaring, with stellate or crushing injuries resulting in worse injury. Avulsion of tissue will further complicate healing, making it impossible to align skin edges at time of initial injury. Deep, beveled injuries maximize the amount of dermal trauma due to the correspondingly greater area of tissue traversed and the tendency of oblique contracture of the dermis to cause one skin edge to slide over the other. This pattern of scarring may cause either a pin cushioned appearance or a heaped appearance. In such cases, the surgeon may either debulk the elevated skin and place bolster sutures or fully excise the affected area.

#### **3.1.4 Relation to relaxed skin tension lines (RSTLs)**

Relaxed skin tension lines (RSTLs) run perpendicular to the direction of maximal underlying tension within the skin (Figure 1). Those scars that are unfavorably positioned relative to RSTLs are most likely to require revision. Often the approach to scar revision is based upon how the scar can be reoriented to fall within these lines. The ability to align scars in this manner is often the difference between an excellent and mediocre result because placement within RSTLs improves camouflage and enables the contractile forces on the skin to approximate wound edges, rather than distracting the edges apart. The lines of maximum extensibility (LMEs) run perpendicular to the RSTLs and are usually parallel to muscle fibers. Lines of maximum extensibility are important to consider when recruiting tissue from adjacent areas for flap reconstruction.

Relaxed skin tension lines generally lie perpendicular to the underlying muscle fibers; but, this rule is not absolute. The RSTLs reflect tension on the skin that arises not only from muscle forces but also from stretch by soft tissue or rigid bone/cartilage. Similarly, wrinkle lines do not always accurately reflect the positions of the RSTLs. For example, the lines between the lower lip and mentum run parallel to the orbicularis oris muscle. Most of the RSTLs are parallel to 4 main facial lines: the facial median, the nasolabial, the facial marginal, and the palpebral lines. The facial median line spans from the alar facial groove to the columella and lip and then inferiorly to the mentum. The nasolabial line runs from the alar facial groove inferolaterally to form the nasolabial fold, traverses lateral to the oral commissure, and then extends inferiorly to form marionette lines. The facial marginal line

Scar Revision and Secondary Reconstruction for Skin Cancer 7

The time course of scar maturation is approximately 12 to 18 months, during which a complex sequence of histological changes associated with wound healing occurs.(6) A general guideline is that scar revision is considered appropriate after 6 to 12 months, when type I collagen has largely replaced type III collagen and the general extent of scar formation is apparent.(7) Earlier scar revision may be considered in unfavorable scars in order to positively influence aesthetic and functional outcomes while also alleviating the patient's psychological distress. Unfavorable scars typically cross cosmetic subunits, do not fall within relaxed skin tension lines, and have more conspicuously disfiguring appearance. In contrast, scars that do not disrupt cosmetic subunits and that have favorable orientation relative to relaxed skin tension lines may have a satisfactory appearance at 1 year without

Patients who opt to pursue scar revision often have persistent psychological trauma associated with the original traumatic event, even if a significant period of time has elapsed between the original injury and the time of surgical consultation. The surgeon must therefore be attentive to the patient's concerns and ensure that the patient has realistic goals. The surgeon should impress upon the patient that complete elimination of scars is seldom, if ever, achieved, although improvement is often possible.(8) It is also important to stress the role for planned secondary procedures as part of the treatment. For example, scar revision with excision is often followed by steroid injection or contour correction with dermabrasion. Similarly, scar revision by serial excision involves

In cases of significant psychological trauma, a specialist with relevant expertise may be consulted. When domestic violence has occurred, camouflaging may be particularly helpful as an interim strategy prior to definitive surgical therapy. Inquiring about the patient's social support system may afford the surgeon insights regarding potential factors that might adversely affect postoperative care. The patient should also understand the significant

A wide range of techniques are available for scar revision. Among these approaches are simple or serial excision, either with or without tissue expansion; irregularization through zplasty, w-plasty, m-plasty, or broken line closure; resurfacing with dermabrasion and lasers; minimally invasive approaches such as fillers and paralytic agents; and adjunctive techniques involving steroids, silicone sheeting, and cosmetics.(9) Each of these approaches

Atraumatic tissue handling, always important in surgery, assumes critical importance in revision surgery, where the wound edges are likely to have baseline vascular compromise. Toothed tissue forceps should be used, and tissue handling should be minimized. Use of skin hooks may diminish the need for traumatic tissue manipulation. Damp sponges may be used to help hydrate the skin edges, an approach that is of special value when using more

**3.3 Timing and psychological considerations** 

any surgery, despite initial erythema and discoloration.

sequential procedures.

**4. Surgical treatment** 

**4.1 General principles** 

period of time required for healing.

is discussed in detail in the following section.

starts at the hairline, travels anterior to the tragus, and descends along the posterior margin of the mandible, across the submandibular triangle, and to the hyoid. The palpebral line extends from the superolateral dorsum to the medial canthus and then proceeds to the lateral canthus to the cheek and submental area.

Fig. 1. Relaxed Skin Tension Lines.

#### **3.2 Relative contraindications to scar revision**

While many patients will benefit from surgical scar revision, several considerations must be taken into account including medical co-morbidities and the prospects for achieving a favorable visible outcome. It is preferable to avoid operating on immature scar, and the surgeon must use judgment when a patient presses for an inappropriately timed surgical intervention. Consideration must also be given to the psychological preparedness of the patient with attention to any unrealistic expectations that the patient may not have disclosed initially. Cigarette smoking should be discontinued at least 2 weeks prior to surgery. Use of nonsteroidal anti-inflammatory agents, Vitamin E, and herbal preparations that may impair wound healing should also be discontinued perioperatively.

#### **3.3 Timing and psychological considerations**

6 Selected Topics in Plastic Reconstructive Surgery

starts at the hairline, travels anterior to the tragus, and descends along the posterior margin of the mandible, across the submandibular triangle, and to the hyoid. The palpebral line extends from the superolateral dorsum to the medial canthus and then proceeds to the

While many patients will benefit from surgical scar revision, several considerations must be taken into account including medical co-morbidities and the prospects for achieving a favorable visible outcome. It is preferable to avoid operating on immature scar, and the surgeon must use judgment when a patient presses for an inappropriately timed surgical intervention. Consideration must also be given to the psychological preparedness of the patient with attention to any unrealistic expectations that the patient may not have disclosed initially. Cigarette smoking should be discontinued at least 2 weeks prior to surgery. Use of nonsteroidal anti-inflammatory agents, Vitamin E, and herbal preparations that may impair

lateral canthus to the cheek and submental area.

Fig. 1. Relaxed Skin Tension Lines.

**3.2 Relative contraindications to scar revision** 

wound healing should also be discontinued perioperatively.

The time course of scar maturation is approximately 12 to 18 months, during which a complex sequence of histological changes associated with wound healing occurs.(6) A general guideline is that scar revision is considered appropriate after 6 to 12 months, when type I collagen has largely replaced type III collagen and the general extent of scar formation is apparent.(7) Earlier scar revision may be considered in unfavorable scars in order to positively influence aesthetic and functional outcomes while also alleviating the patient's psychological distress. Unfavorable scars typically cross cosmetic subunits, do not fall within relaxed skin tension lines, and have more conspicuously disfiguring appearance. In contrast, scars that do not disrupt cosmetic subunits and that have favorable orientation relative to relaxed skin tension lines may have a satisfactory appearance at 1 year without any surgery, despite initial erythema and discoloration.

Patients who opt to pursue scar revision often have persistent psychological trauma associated with the original traumatic event, even if a significant period of time has elapsed between the original injury and the time of surgical consultation. The surgeon must therefore be attentive to the patient's concerns and ensure that the patient has realistic goals. The surgeon should impress upon the patient that complete elimination of scars is seldom, if ever, achieved, although improvement is often possible.(8) It is also important to stress the role for planned secondary procedures as part of the treatment. For example, scar revision with excision is often followed by steroid injection or contour correction with dermabrasion. Similarly, scar revision by serial excision involves sequential procedures.

In cases of significant psychological trauma, a specialist with relevant expertise may be consulted. When domestic violence has occurred, camouflaging may be particularly helpful as an interim strategy prior to definitive surgical therapy. Inquiring about the patient's social support system may afford the surgeon insights regarding potential factors that might adversely affect postoperative care. The patient should also understand the significant period of time required for healing.

#### **4. Surgical treatment**

A wide range of techniques are available for scar revision. Among these approaches are simple or serial excision, either with or without tissue expansion; irregularization through zplasty, w-plasty, m-plasty, or broken line closure; resurfacing with dermabrasion and lasers; minimally invasive approaches such as fillers and paralytic agents; and adjunctive techniques involving steroids, silicone sheeting, and cosmetics.(9) Each of these approaches is discussed in detail in the following section.

#### **4.1 General principles**

Atraumatic tissue handling, always important in surgery, assumes critical importance in revision surgery, where the wound edges are likely to have baseline vascular compromise. Toothed tissue forceps should be used, and tissue handling should be minimized. Use of skin hooks may diminish the need for traumatic tissue manipulation. Damp sponges may be used to help hydrate the skin edges, an approach that is of special value when using more

Scar Revision and Secondary Reconstruction for Skin Cancer 9

choose both the angle and the orientation for the Z-plasty that will most effectively align

Fig. 3. With wider angle Z-plasty configurations, rotation and the lengthening both increase

The double-opposing Z-plasty, unequal triangle Z-plasty, and planimetric Z-plasty are other variants of the basic Z-plasty. The double opposing Z-plasty involves use of overlying Z-

the scar with the RSTLs.

Fig. 2. Depiction of Z-plasty.

labor intensive approaches, such as geometric broken line closures. Subdermal undermining lateral to wound margins is essential to achieving a tension free closure. Skin flap undermining is performed sharply, while elevating the flap atraumatically with skin hooks or toothed forceps. Layered closure is performed with tension placed upon the deep sutures to facilitate hypereversion.(10)

Adequate hemostasis is a prerequisite for successful scar revision. Collections of blood under a flap will predispose to infection and more visible scar. A bipolar cautery is preferred to monopolar cautery due to decreased thermal injury. Meticulous subcutaneous closure minimizes dead space and ensures a stable foundation for the overlying skin surface. Beveling of the skin incision can be used to improve wound margin eversion. For deep tissue and deep dermal closure on the face, 5-0 and 6-0 absorbable sutures are preferred (PDS or vicryl). For the skin, non-absorbable sutures (6-0 or 7-0 prolene or ethilon) are best due to their low tissue bioreactivity; however, these may be cumbersome to remove in hair-bearing areas. Absorbable suture, such as fast absorbing gut, is an acceptable alternative. Of note, the needle on ethilon suture can be too rough for use on delicate tissues such as eyelids or facial tissue in infants

#### **4.2 Surgical methods of irregularization**

A variety of methods are available for irregularization of scars, so as to camouflage scars. The eye is naturally attracted to straight lines, as such lines seldom appear in nature. Therefore, introducing irregularity affords significant benefit in making scars less conspicuous.

#### **4.2.1 Z-plasty**

The classic Z-plasty involves the transposition of two adjacent undermined triangle flaps, usually with angles of the Z measuring approximately 60 degrees. Classic Z-plasty and its variations are used for a variety of purposes, including to:


The simple Z-plasty is composed of 3 limbs, as shown in Figure 2. After transposition of the two triangle flaps, the middle limb is reoriented approximately 90 degrees if the Zplasty is 60 degrees. The extent of rotation and the lengthening both diminish with tighter Z-plasty configurations, as shown in Figure 3. The lengthening in one axis corresponds to shortening in the other axis with associated tissue distortion. As shown, a 30 degree Zplasty results in a 25% increase in length; a 45 degree Z-plasty results in a 50% increase in length; and a 60 degree Z-plasty results in a 75% increase in length. A Z-plasty with a higher angle tends to create a standing cone deformity, whereas a Z-plasty with <30 degree angles has more risk of necrosis of the tips. The use of serial Z-plasty or compound Z-plasty can achieve effective scar lengthening with less tissue distortion and improved camouflage. The compound Z-plasty minimizes the number of incisions required for scar revision. Because a given scar can be reoriented in either of 2 directions, the surgeon must choose both the angle and the orientation for the Z-plasty that will most effectively align the scar with the RSTLs.

Fig. 2. Depiction of Z-plasty.

8 Selected Topics in Plastic Reconstructive Surgery

labor intensive approaches, such as geometric broken line closures. Subdermal undermining lateral to wound margins is essential to achieving a tension free closure. Skin flap undermining is performed sharply, while elevating the flap atraumatically with skin hooks or toothed forceps. Layered closure is performed with tension placed upon the deep sutures

Adequate hemostasis is a prerequisite for successful scar revision. Collections of blood under a flap will predispose to infection and more visible scar. A bipolar cautery is preferred to monopolar cautery due to decreased thermal injury. Meticulous subcutaneous closure minimizes dead space and ensures a stable foundation for the overlying skin surface. Beveling of the skin incision can be used to improve wound margin eversion. For deep tissue and deep dermal closure on the face, 5-0 and 6-0 absorbable sutures are preferred (PDS or vicryl). For the skin, non-absorbable sutures (6-0 or 7-0 prolene or ethilon) are best due to their low tissue bioreactivity; however, these may be cumbersome to remove in hair-bearing areas. Absorbable suture, such as fast absorbing gut, is an acceptable alternative. Of note, the needle on ethilon suture can be too rough for use on delicate tissues

A variety of methods are available for irregularization of scars, so as to camouflage scars. The eye is naturally attracted to straight lines, as such lines seldom appear in nature. Therefore,

The classic Z-plasty involves the transposition of two adjacent undermined triangle flaps, usually with angles of the Z measuring approximately 60 degrees. Classic Z-plasty and its

The simple Z-plasty is composed of 3 limbs, as shown in Figure 2. After transposition of the two triangle flaps, the middle limb is reoriented approximately 90 degrees if the Zplasty is 60 degrees. The extent of rotation and the lengthening both diminish with tighter Z-plasty configurations, as shown in Figure 3. The lengthening in one axis corresponds to shortening in the other axis with associated tissue distortion. As shown, a 30 degree Zplasty results in a 25% increase in length; a 45 degree Z-plasty results in a 50% increase in length; and a 60 degree Z-plasty results in a 75% increase in length. A Z-plasty with a higher angle tends to create a standing cone deformity, whereas a Z-plasty with <30 degree angles has more risk of necrosis of the tips. The use of serial Z-plasty or compound Z-plasty can achieve effective scar lengthening with less tissue distortion and improved camouflage. The compound Z-plasty minimizes the number of incisions required for scar revision. Because a given scar can be reoriented in either of 2 directions, the surgeon must

introducing irregularity affords significant benefit in making scars less conspicuous.

Reorient a scar to lie in a more favorable position relative to cosmetic subunits

Orient a skin incision away from an underlying scar to avoid a depressed scar

to facilitate hypereversion.(10)

such as eyelids or facial tissue in infants

**4.2.1 Z-plasty** 

**4.2 Surgical methods of irregularization** 

Reorient a scar to lie parallel to RSTLs

variations are used for a variety of purposes, including to:

Increase scar length to lengthen a site of contracture

Irregularize a scar by breaking a single line into segments

Fig. 3. With wider angle Z-plasty configurations, rotation and the lengthening both increase

The double-opposing Z-plasty, unequal triangle Z-plasty, and planimetric Z-plasty are other variants of the basic Z-plasty. The double opposing Z-plasty involves use of overlying Z-

Scar Revision and Secondary Reconstruction for Skin Cancer 11

Fig. 5. Comparison of W-plasty versus serial Z-plasty

The geometric broken line closure is a variant of the W-plasty, in which a linear scar is rendered irregular by use of a mixture of triangles, squares, rectangles, and/or circles (Figure 6).(12) The geometric broken line closure is more labor intensive to construct than the W-plasty given its varied design but yields a less visually perceptible result. The geometric shapes are intended to have a random sequence that interlocks on upper and lower sides. When the rectangles or squares within the geometric broken line closure are perpendicular to RSTLs, use of extra triangles may minimize any unfavorable appearance.

**4.2.3 Geometric broken line closure** 

plasties in reverse orientation. This method can be used to redistribute volume and avoid placing multiple layers of closure over a single line of tension. This approach has been most widely applied in cleft palate surgery, although it has also found application for treatment of cervical webs, using the platysma for the deep Z-plasty and the skin and subcutaneous fat for the superficial opposing Z-plasty. The unequal triangle Z-plasty involves a Z with nonparallel limbs and is useful when it is desirable to transpose unequal tissue areas. Planimetric Z-plasty entails excising the excess elevated tissue (dog ears) that is produced with standard Z-plasty on a flat surface. It is used for scar irregularization and limited skin elongation on planar surfaces.

#### **4.2.2 W-plasty**

The W-plasty (Figure 4) is most useful in changing a linear scar into an irregular scar .(11) It can also be useful in converting a curvilinear scar into an irregular scar that might otherwise be predisposed to a trap-door type deformity. The length of the limbs in W-plasty should be less than 6 mm. When using a curved W-plasty, the triangles of the outer limb must be wider than those of the inner limb in order that the tissue edges interlock properly. One advantage of the W-plasty is that it avoids the scar lengthening seen with Z-plasty. In addition, this W-plasty may be more amenable to orientation of the scar within RSTLs. However, the repetitive zig-zag pattern of W-plasty is often more readily discernible to the eye than more irregular Z-plasty. Figure 5 compares a curved serial Z-plasty against a curved W-plasty.

plasties in reverse orientation. This method can be used to redistribute volume and avoid placing multiple layers of closure over a single line of tension. This approach has been most widely applied in cleft palate surgery, although it has also found application for treatment of cervical webs, using the platysma for the deep Z-plasty and the skin and subcutaneous fat for the superficial opposing Z-plasty. The unequal triangle Z-plasty involves a Z with nonparallel limbs and is useful when it is desirable to transpose unequal tissue areas. Planimetric Z-plasty entails excising the excess elevated tissue (dog ears) that is produced with standard Z-plasty on a flat surface. It is used for scar irregularization and limited skin

The W-plasty (Figure 4) is most useful in changing a linear scar into an irregular scar .(11) It can also be useful in converting a curvilinear scar into an irregular scar that might otherwise be predisposed to a trap-door type deformity. The length of the limbs in W-plasty should be less than 6 mm. When using a curved W-plasty, the triangles of the outer limb must be wider than those of the inner limb in order that the tissue edges interlock properly. One advantage of the W-plasty is that it avoids the scar lengthening seen with Z-plasty. In addition, this W-plasty may be more amenable to orientation of the scar within RSTLs. However, the repetitive zig-zag pattern of W-plasty is often more readily discernible to the eye than more irregular Z-plasty. Figure 5 compares a curved serial Z-plasty against a

elongation on planar surfaces.

**4.2.2 W-plasty** 

curved W-plasty.

Fig. 4. W-plasty

Fig. 5. Comparison of W-plasty versus serial Z-plasty

#### **4.2.3 Geometric broken line closure**

The geometric broken line closure is a variant of the W-plasty, in which a linear scar is rendered irregular by use of a mixture of triangles, squares, rectangles, and/or circles (Figure 6).(12) The geometric broken line closure is more labor intensive to construct than the W-plasty given its varied design but yields a less visually perceptible result. The geometric shapes are intended to have a random sequence that interlocks on upper and lower sides. When the rectangles or squares within the geometric broken line closure are perpendicular to RSTLs, use of extra triangles may minimize any unfavorable appearance.

Scar Revision and Secondary Reconstruction for Skin Cancer 13

Usually 2 expanders are required to achieve the desired degree of skin expansion. The major risks of tissue expanders are infection and unintended trauma to the skin from distention.(13) A V to Y advancement flap (Figure 8) allows for recruitment of excess tissue from laterally and proximally into an area that has been shortened by contracture. This method is also useful when a soft tissue defect needs to be reconstructed. It is sometimes preferable to excise an

Each area of the head and neck has distinctive features with corresponding implications for the approach to scar revision. The various facial subsites differ in terms of RSTL orientation, solar exposure, skin thickness, pilosebaceous density, and muscle movement. The forehead, eyebrows, cheeks, nasolabial fold, and mentum are discussed below because of the special

While simple fusiform excision yield favorable results in the upper forehead, at the junction of the forehead and glabella the RSTLs are virtually perpendicular. This orientation corresponds to the perpendicular orientation of corrugator and frontalis fibers. Scar revision in this area may require a combination a Z-plasty to reorient scars and irregularization with

entire cosmetic subunit before proceeding with reconstruction using a local flap.(14)

Fig. 8. V to Y advancement

**4.4.1 Forehead** 

**4.4 Special considerations related to subsite** 

considerations that come into play for these areas.

W-plasty. Botulinum toxin may attenuate the wrinkles of this area.

Fig. 6. Geometric Broken Line Closure

#### **4.2.4 M-plasty**

The M-plasty (Figure 7) minimizes the loss of surrounding healthy tissue at the site of a scar and also can minimize the length of the scar. When compared to the simple ellipse excision, the loss of healthy, normal tissue is decreased by approximately 50%. The price paid for this preservation of healthy tissue is having two limbs at each pole of the M-plasty. The M-plasty is constructed by diminishing the distance from the midpoint of the wound to the lateral extents of the excision. By advancing the lateral triangles of tissue into the wound in a V-Y advancement fashion, the scar is shortened.

Fig. 7. M-plasty

#### **4.3 Other surgical methods of scar revision**

A variety of other surgical approaches are also useful in scar revision. Serial excision of scar is a logical extension of simple excision of ellipses in RSTLs. In this approach, a wound that would not readily close following complete excision is excised in multiple separate sittings to avoid undue stretch on the skin. Tissue expansion followed by excision may circumvent the need for serial excision if a sufficient area of skin for closure is created by the expander.

The M-plasty (Figure 7) minimizes the loss of surrounding healthy tissue at the site of a scar and also can minimize the length of the scar. When compared to the simple ellipse excision, the loss of healthy, normal tissue is decreased by approximately 50%. The price paid for this preservation of healthy tissue is having two limbs at each pole of the M-plasty. The M-plasty is constructed by diminishing the distance from the midpoint of the wound to the lateral extents of the excision. By advancing the lateral triangles of tissue into the wound in a V-Y

A variety of other surgical approaches are also useful in scar revision. Serial excision of scar is a logical extension of simple excision of ellipses in RSTLs. In this approach, a wound that would not readily close following complete excision is excised in multiple separate sittings to avoid undue stretch on the skin. Tissue expansion followed by excision may circumvent the need for serial excision if a sufficient area of skin for closure is created by the expander.

Fig. 6. Geometric Broken Line Closure

advancement fashion, the scar is shortened.

**4.3 Other surgical methods of scar revision** 

**4.2.4 M-plasty** 

Fig. 7. M-plasty

Usually 2 expanders are required to achieve the desired degree of skin expansion. The major risks of tissue expanders are infection and unintended trauma to the skin from distention.(13) A V to Y advancement flap (Figure 8) allows for recruitment of excess tissue from laterally and proximally into an area that has been shortened by contracture. This method is also useful when a soft tissue defect needs to be reconstructed. It is sometimes preferable to excise an entire cosmetic subunit before proceeding with reconstruction using a local flap.(14)

Fig. 8. V to Y advancement

#### **4.4 Special considerations related to subsite**

Each area of the head and neck has distinctive features with corresponding implications for the approach to scar revision. The various facial subsites differ in terms of RSTL orientation, solar exposure, skin thickness, pilosebaceous density, and muscle movement. The forehead, eyebrows, cheeks, nasolabial fold, and mentum are discussed below because of the special considerations that come into play for these areas.

#### **4.4.1 Forehead**

While simple fusiform excision yield favorable results in the upper forehead, at the junction of the forehead and glabella the RSTLs are virtually perpendicular. This orientation corresponds to the perpendicular orientation of corrugator and frontalis fibers. Scar revision in this area may require a combination a Z-plasty to reorient scars and irregularization with W-plasty. Botulinum toxin may attenuate the wrinkles of this area.

Scar Revision and Secondary Reconstruction for Skin Cancer 15

concentrations over the counter or 4% concentrations by prescription, with stronger concentrations being more effective but more prone to local skin irritation. Azelaic acid and kojic acid are two other effective depigmentation agents. Depressed scars may be ameliorated with use of fat/dermis grafts or allograft dermal matrix grafts. CO2 and Erbium lasers are also used for resurfacing. Lasers induce collagen reorganization and can thereby enhance camouflage, although variable depth of thermal damage and the potential for hypopigmentation are risks.(16) Intense pulsed light, KTP laser, and ND:YAG are among

Noninvasive resurfacing can be achieved using fillers. Improved symmetry can be achieved with administration of botulinum toxin to weaken one side of the face if the contralateral side is weak or paralyzed. Plucking of brows may also camouflage irregularities. Cosmetics, hairstyling, and hair replacement have all been used to enhance results. Makeup, tattoos, and prosthetics also can find useful application. Aestheticians are particularly helpful in the postoperative period, both to improve appearance during healing and to prevent erythema from sun exposure. Aestheticians also may treat

Hypertrophic scars and keloids are generally accepted to occur more commonly in young, darkly pigmented individuals. Clinically, hypertrophic scars exhibit excessive deposition within the scar, whereas keloid scars overgrow the original margins of an incision to involve adjacent tissues. Ultrastructurally, hypertrophic scars have parallel alignment of collagen sheets, whereas keloids have disorganized sheets. Keloids also demonstrate a greater

Although a variety of nonsurgical treatments have been investigated for management of hypertophic scars and keloids, the most common approach is primary excision with serial injection of steroid. Other approaches have included serial excision, carbon dioxide laser excision, and use of skin grafting. Topical application of silicone sheeting over sites of keloid formation has been shown to be beneficial in some series, although the mechanism by which sheeting may improve scar outcomes remains uncertain.(19) Benefit may be related to the improved hydration of tissues associated with this approach, as nonsilicone gel dressings may have similar efficacy.(20) Pulsed-dye lasers have been found effective for hypertrophic scars.(21) Other methods, including creams/vitamins, pressure dressings, and interferons have also been suggested. Thus there are a variety of options for treatment of scars. The role of compression garments, silicone sheets, scar massage

Late wound management after trauma includes surgical camouflaging of the aesthetically unacceptable scar and correction of functional impairments related to aberrant wound healing. The surgeon must remember that patients undergoing these procedures may harbor a significant emotional component to their injury. Optimal results are achieved through an in depth understanding of the mechanisms of scar formation and application of the optimal surgical technique, taking into consideration the characteristics of the site.

the techniques that have been used for vascular and pigmentary irregularities.(17;18)

**4.5.2 Minimally invasive treatments** 

irregularities that are not amenable to surgical revision.

and ultrasound should also be considered.

**6. Concluding remarks** 

**5. Special considerations: Hypertrophic and keloid scars** 

increase in collagenase and proline hydroxylase than do hypetrophic scars.

#### **4.4.2 Eyebrow**

The eyebrow region is a frequent area of unfavorable scarring that also warrants special consideration. Due to the prominence of the supraorbital rim, this site is prone to trauma in continuity with the forehead. Blunt trauma to this area may results in the underlying bone cutting the skin from beneath, as when the impact of a boxer's glove causes skin to shear against the underlying bone. This extensive soft tissue trauma predisposes to a significantly widened scar. While vertical incisions are commonly used elsewhere in scar revision, a beveled incision is needed in the eyebrow. The shafts of hair follicles are oriented obliquely; therefore, incisions made perpendicular to the skin are more likely to result in alopecia than beveled incisions that run parallel to the hair follicles. W-plasty is useful in camouflaging long, linear scars. Care must be taken to align the hairs when the eyebrow is divided by a scar.

#### **4.4.3 Cheek, nasolabial fold, and mentum**

The cheek, nasolabial fold, and mentum are also important areas in scar revision. The RSTLs of the cheek run from the zygoma to the mandible in a curved fashion. Many scars in this area run opposite the RSTLs and therefore require the use of a serial Z-plasty approach. When scars run parallel to the direction of RSTLs, a W-plasty will achieve excellent cosmesis. A terminal Z-plasty may achieve further irregularization.

The nasolabial fold is extremely useful in scar camouflage, and Z-plasty can be used to excellent advantage to reorient scars along the RSTLs. Only one of the two possible combinations of Z-plasty will yield an optimal cosmetic result, with the lateral limbs nearest the direction of the RSTLs. Scars along the mentum are effectively managed with W-plasty or Z-plasty for scars running parallel and oblique to RSTLs, respectively.

#### **4.5 Adjunctive treatments**

A variety of adjunctive techniques are available to assist in late wound management and scar camouflage. Many of these approaches are most effective when used as part of a surgical regimen, although some may prove useful alone. An important aspect of scar minimization is optimal postoperative care. This includes wound compression immediately following the procedure (such as using silicone sheets or micropore tape), UV protection (especially important in the first year after the procedure), and smoking cessation.

#### **4.5.1 Dermabrasion and lasers**

Dermabrasion and Laser skin resurfacing can be used to correct skin contour irregularities. Dermabrasion is useful to level a scar, to modify the texture of a scar, or to improve camouflage through blending with surrounding skin. It is typically performed approximately 6 to 8 weeks after W-plasty, Z-plasty, or geometric broken line closure.(15) Preoperative treatment with Retin-A will alleviate scarring, and antiviral therapy is indicated for patients with a history of herpetic infection. Care must be taken to avoid deep penetration into the reticular dermis, as excessive depth of dermabrasion is associated with risk of melanocyte loss and resulting permanent hypopigmentation. The adverse effects of dermabrasion on pigmentation are less significant in individuals with fairer skin. An occlusive dressing and moist ointment with regular cleansing will facilitate reepithelization. Hyperpigmented areas can be addressed with depigmentation agents, including hydroquinone, which blocks the production of melanin. This is available in 2% concentrations over the counter or 4% concentrations by prescription, with stronger concentrations being more effective but more prone to local skin irritation. Azelaic acid and kojic acid are two other effective depigmentation agents. Depressed scars may be ameliorated with use of fat/dermis grafts or allograft dermal matrix grafts. CO2 and Erbium lasers are also used for resurfacing. Lasers induce collagen reorganization and can thereby enhance camouflage, although variable depth of thermal damage and the potential for hypopigmentation are risks.(16) Intense pulsed light, KTP laser, and ND:YAG are among the techniques that have been used for vascular and pigmentary irregularities.(17;18)

#### **4.5.2 Minimally invasive treatments**

14 Selected Topics in Plastic Reconstructive Surgery

The eyebrow region is a frequent area of unfavorable scarring that also warrants special consideration. Due to the prominence of the supraorbital rim, this site is prone to trauma in continuity with the forehead. Blunt trauma to this area may results in the underlying bone cutting the skin from beneath, as when the impact of a boxer's glove causes skin to shear against the underlying bone. This extensive soft tissue trauma predisposes to a significantly widened scar. While vertical incisions are commonly used elsewhere in scar revision, a beveled incision is needed in the eyebrow. The shafts of hair follicles are oriented obliquely; therefore, incisions made perpendicular to the skin are more likely to result in alopecia than beveled incisions that run parallel to the hair follicles. W-plasty is useful in camouflaging long, linear scars. Care must be taken to align the hairs when the eyebrow is divided by a scar.

The cheek, nasolabial fold, and mentum are also important areas in scar revision. The RSTLs of the cheek run from the zygoma to the mandible in a curved fashion. Many scars in this area run opposite the RSTLs and therefore require the use of a serial Z-plasty approach. When scars run parallel to the direction of RSTLs, a W-plasty will achieve excellent

The nasolabial fold is extremely useful in scar camouflage, and Z-plasty can be used to excellent advantage to reorient scars along the RSTLs. Only one of the two possible combinations of Z-plasty will yield an optimal cosmetic result, with the lateral limbs nearest the direction of the RSTLs. Scars along the mentum are effectively managed with W-plasty

A variety of adjunctive techniques are available to assist in late wound management and scar camouflage. Many of these approaches are most effective when used as part of a surgical regimen, although some may prove useful alone. An important aspect of scar minimization is optimal postoperative care. This includes wound compression immediately following the procedure (such as using silicone sheets or micropore tape), UV protection

Dermabrasion and Laser skin resurfacing can be used to correct skin contour irregularities. Dermabrasion is useful to level a scar, to modify the texture of a scar, or to improve camouflage through blending with surrounding skin. It is typically performed approximately 6 to 8 weeks after W-plasty, Z-plasty, or geometric broken line closure.(15) Preoperative treatment with Retin-A will alleviate scarring, and antiviral therapy is indicated for patients with a history of herpetic infection. Care must be taken to avoid deep penetration into the reticular dermis, as excessive depth of dermabrasion is associated with risk of melanocyte loss and resulting permanent hypopigmentation. The adverse effects of dermabrasion on pigmentation are less significant in individuals with fairer skin. An occlusive dressing and moist ointment with regular cleansing will facilitate reepithelization. Hyperpigmented areas can be addressed with depigmentation agents, including hydroquinone, which blocks the production of melanin. This is available in 2%

(especially important in the first year after the procedure), and smoking cessation.

**4.4.2 Eyebrow** 

**4.4.3 Cheek, nasolabial fold, and mentum** 

**4.5 Adjunctive treatments** 

**4.5.1 Dermabrasion and lasers** 

cosmesis. A terminal Z-plasty may achieve further irregularization.

or Z-plasty for scars running parallel and oblique to RSTLs, respectively.

Noninvasive resurfacing can be achieved using fillers. Improved symmetry can be achieved with administration of botulinum toxin to weaken one side of the face if the contralateral side is weak or paralyzed. Plucking of brows may also camouflage irregularities. Cosmetics, hairstyling, and hair replacement have all been used to enhance results. Makeup, tattoos, and prosthetics also can find useful application. Aestheticians are particularly helpful in the postoperative period, both to improve appearance during healing and to prevent erythema from sun exposure. Aestheticians also may treat irregularities that are not amenable to surgical revision.

#### **5. Special considerations: Hypertrophic and keloid scars**

Hypertrophic scars and keloids are generally accepted to occur more commonly in young, darkly pigmented individuals. Clinically, hypertrophic scars exhibit excessive deposition within the scar, whereas keloid scars overgrow the original margins of an incision to involve adjacent tissues. Ultrastructurally, hypertrophic scars have parallel alignment of collagen sheets, whereas keloids have disorganized sheets. Keloids also demonstrate a greater increase in collagenase and proline hydroxylase than do hypetrophic scars.

Although a variety of nonsurgical treatments have been investigated for management of hypertophic scars and keloids, the most common approach is primary excision with serial injection of steroid. Other approaches have included serial excision, carbon dioxide laser excision, and use of skin grafting. Topical application of silicone sheeting over sites of keloid formation has been shown to be beneficial in some series, although the mechanism by which sheeting may improve scar outcomes remains uncertain.(19) Benefit may be related to the improved hydration of tissues associated with this approach, as nonsilicone gel dressings may have similar efficacy.(20) Pulsed-dye lasers have been found effective for hypertrophic scars.(21) Other methods, including creams/vitamins, pressure dressings, and interferons have also been suggested. Thus there are a variety of options for treatment of scars. The role of compression garments, silicone sheets, scar massage and ultrasound should also be considered.

#### **6. Concluding remarks**

Late wound management after trauma includes surgical camouflaging of the aesthetically unacceptable scar and correction of functional impairments related to aberrant wound healing. The surgeon must remember that patients undergoing these procedures may harbor a significant emotional component to their injury. Optimal results are achieved through an in depth understanding of the mechanisms of scar formation and application of the optimal surgical technique, taking into consideration the characteristics of the site.

**2** 

*Greece* 

Stefanos Tsourvakas

**Local Antibiotic Therapy in the Treatment** 

Bone and soft tissue infections are serious problems in orthopedic and reconstructive surgery. Especially, chronic osteomyelitis is a difficult infection to treat and eradicate. Long term parenteral antibiotics with multiple surgical debridements are often required for effective therapy (Cierny & Mader, 1984). Therefore, it is understandable that continuous efforts are being made and complete one or other element in the treatment of

There is a long history of local antibiotic use for the treatment of bone and soft tissue infections. During World War I, Alexander Fleming observed that locally applied antiseptics failed to sterilize chronically infected wounds, but they did reduce the burden of bacteria (Fleming, 1920). In 1939, the instillation of sulfanilamide crystals, along with thorough debridement, hemostasis, primary closure and immobilization, resulted in a reduced infection rate for open fractures (Jensen et al, 1939). As additional systemic antimicrobial agents became available, interest in the topical treatment of wounds waned, but the management of established osteomyelitis remained problematic. In the 1960s, the method of closed wound irrigation-suction was popularized as a method which could be used to deliver high concentrations of an antibiotic after debridement (Dombrowski & Dunn, 1965). An alternative method for delivering high concentrations of an antibiotic to sites of lower

The delivery of local antibiotics for the treatment of musculoskeletal infection has become increasingly popular for a variety of reasons. The basis for developing and using local antibiotic delivery systems in the treatment of bone and soft tissue infection is either to supplement or to replace the use of systemic antibiotics. High local levels of antibiotics facilitate delivery of antibiotics by diffusion to avascular areas of wounds that are inaccessible by systemic antibiotics and in many circumstances the organisms that are resistant to drug concentrations achieved by systemic antibiotic are susceptible to the

The local use of antibiotics to prevent and treat bone and soft tissue infections was revived in Germany with the widespread use of prosthetic joint replacement, a situation in which infections were not anticipated consequence of trauma or sepsis but a devastating complication of elective surgery (Buchholz & Engelbrecht, 1970). However, it is from the

extremity osteomyelitis was isolation and perfusion (Organ, 1971).

extremely high local drug concentrations provided by local antibiotic delivery.

**1. Introduction** 

bone and soft tissue infections.

 **of Bone and Soft Tissue Infections** 

*Orthopedic Department, General Hospital of Trikala* 

#### **7. References**


### **Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections**

Stefanos Tsourvakas

*Orthopedic Department, General Hospital of Trikala Greece* 

#### **1. Introduction**

16 Selected Topics in Plastic Reconstructive Surgery

[1] Kaplan B, Potter T, Moy RL, Kaplan B, Potter T, Moy RL. Scar revision. Dermatologic

[2] Zakkak TB, Griffin JE, Jr., Max DP, Zakkak TB, Griffin JEJ, Max DP. Posttraumatic scar

[3] Thomas JR, Ehlert TK, Thomas JR, Ehlert TK. Scar revision and camouflage.

[4] Kokoska MS, Thomas JR. Scar Revision. In: Papel ID, editor. Facial Plastic and

[5] Schweinfurth JM, Fedok F, Schweinfurth JM, Fedok F. Avoiding pitfalls and unfavorable outcomes in scar revision. Facial Plastic Surgery 2001; 17(4):273-278. [6] Goslen JB, Goslen JB. Wound healing for the dermatologic surgeon. Journal of

[7] Thomas JR, Prendiville S, Thomas JR, Prendiville S. Update in scar revision. Facial Plastic

[8] Moran ML, Moran ML. Scar revision. Otolaryngologic Clinics of North America 2001;

[9] Thomas JR, Mobley SR. Scar Revision and Camouflage. In: Cummings CW, Flint PW,

[11] Kelleher JC, Kelleher JC. W-plasty scar revision and its extended use. Clinics in Plastic

[12] Harnick DB, Harnick DB. Broken geometrical pattern used for facial scar revision.

[13] Mostafapour SP, Murakami CS, Mostafapour SP, Murakami CS. Tissue expansion and serial excision in scar revision. Facial Plastic Surgery 2001; 17(4):245-252. [14] Clark JM, Wang TD, Clark JM, Wang TD. Local flaps in scar revision. [Facial Plastic

[15] Harmon CB, Zelickson BD, Roenigk RK, Wayner EA, Hoffstrom B, Pittelkow MR et al.

[16] Alster T, Zaulyanov-Scanlon L, Alster T, Zaulyanov-Scanlon L. Laser scar revision: a review. [Review] [46 refs]. Dermatologic Surgery 2007; 33(2):131-140. [17] Cassuto D, Emanuelli G, Cassuto D, Emanuelli G. Non-ablative scar revision using a

[18] Westine JG, Lopez MA, Thomas JR, Westine JG, Lopez MA, Thomas JR. Scar revision.

[20] de Oliveira GV, Nunes TA, Magna LA, Cintra ML, Kitten GT, Zarpellon S et al. Silicone

[21] Bradley DT, Park SS, Bradley DT, Park SS. Scar revision via resurfacing. Facial Plastic

Facial Plastic Surgery Clinics of North America 2005; 13(2):325-331. [19] Katz BE, Katz BE. Silicone gel sheeting in scar therapy. Cutis 1995; 56(1):65-67.

Dermabrasive scar revision. Immunohistochemical and ultrastructural evaluation.

long pulsed frequency doubled Nd:YAG laser. Journal of Cosmetic & Laser

versus nonsilicone gel dressings: a controlled trial. Dermatologic Surgery 2001;

Harker LA, Haughey BH, Richardson MA, Robbins KT et al., editors. Cummings Otolaryngology Head & Neck Surgery. Philadelphia: Elsevier, 2005: 572-581. [10] Zide MF, Zide MF. Scar revision with hypereversion. Journal of Oral & Maxillofacial

Otolaryngologic Clinics of North America 1990; 23(5):963-973.

Reconstructive Surgery. New York: Thieme, 2002: 55-60.

Dermatologic Surgery & Oncology 1988; 14(9):959-972.

Surgery Clinics of North America 2002; 10(1):103-111.

revision: a review and case presentation. Journal of Cranio-Maxillofacial Trauma

**7. References** 

Surgery 1997; 23(6):435-442.

1998; 4(1):35-41.

34(4):767-780.

Surgery 1996; 54(9):1061-1067.

Laryngoscope 1984; 94(6):841-842.

Dermatologic Surgery 1995; 21(6):503-508.

Surgery 1977; 4(2):247-254.

Surgery 2001; 17(4):295-308.

Therapy 2003; 5(3-4):135-139.

Surgery 2001; 17(4):253-262.

27(8):721-726.

Bone and soft tissue infections are serious problems in orthopedic and reconstructive surgery. Especially, chronic osteomyelitis is a difficult infection to treat and eradicate. Long term parenteral antibiotics with multiple surgical debridements are often required for effective therapy (Cierny & Mader, 1984). Therefore, it is understandable that continuous efforts are being made and complete one or other element in the treatment of bone and soft tissue infections.

There is a long history of local antibiotic use for the treatment of bone and soft tissue infections. During World War I, Alexander Fleming observed that locally applied antiseptics failed to sterilize chronically infected wounds, but they did reduce the burden of bacteria (Fleming, 1920). In 1939, the instillation of sulfanilamide crystals, along with thorough debridement, hemostasis, primary closure and immobilization, resulted in a reduced infection rate for open fractures (Jensen et al, 1939). As additional systemic antimicrobial agents became available, interest in the topical treatment of wounds waned, but the management of established osteomyelitis remained problematic. In the 1960s, the method of closed wound irrigation-suction was popularized as a method which could be used to deliver high concentrations of an antibiotic after debridement (Dombrowski & Dunn, 1965). An alternative method for delivering high concentrations of an antibiotic to sites of lower extremity osteomyelitis was isolation and perfusion (Organ, 1971).

The delivery of local antibiotics for the treatment of musculoskeletal infection has become increasingly popular for a variety of reasons. The basis for developing and using local antibiotic delivery systems in the treatment of bone and soft tissue infection is either to supplement or to replace the use of systemic antibiotics. High local levels of antibiotics facilitate delivery of antibiotics by diffusion to avascular areas of wounds that are inaccessible by systemic antibiotics and in many circumstances the organisms that are resistant to drug concentrations achieved by systemic antibiotic are susceptible to the extremely high local drug concentrations provided by local antibiotic delivery.

The local use of antibiotics to prevent and treat bone and soft tissue infections was revived in Germany with the widespread use of prosthetic joint replacement, a situation in which infections were not anticipated consequence of trauma or sepsis but a devastating complication of elective surgery (Buchholz & Engelbrecht, 1970). However, it is from the

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 19

provide a context for their current clinical use and to discuss the emerging investigate and

**2. Criteria for the production of a local delivery system for antimicrobial agents**  Despite the reduction in the risk of contamination due to improved material, implant, and clean room technique as well as peri-operative antibiotic prophylaxis, infections still remain a feared complication in orthopedic and reconstructive surgery (Taylor, 1997). In many surgical disciplines, topical administration of antibacterial drug is not possible or practicable, and achieving of a sufficient antibacterial dose by systemic delivery may lead to adverse reactions negatively influencing overall patient's c by conditions. Especially the use of specific antibiotics may be limited by their high cumulative cell and organ toxicity (Ruszczak & Friess, 2003). Moreover, insufficiency in local blood supply due to posttraumatic or post-operative tissue damage as well as inadequate tissue penetration or bacterial resistance increase the local ineffectiveness of systemic antibiotic therapy, both in terms of preventive or curative drug administration (Mehta et al, 1996). This dilemma can be

The ideal local drug delivery system has been a pursuit of scientists and physicians for the past fifty years. The concept of delivering drugs locally to the area of disease rather than through the systemic circulation without the concomitant secondary systemic complications is appealing both physiologically and psychologically (Nelson, 2004). The ideal local antibiotic delivery system would produce high antibiotic levels at the site of infection and safe drug levels in the systemic circulation. Antibiotic levels would need to be controlled to allow the systemic to be either therapeutic, bellow the toxic level, or absent, and to allow these features to be controlled independently from each other. Furthermore, the antibiotic elution curves, the factors that influence elution, and the most suitable local delivery system for the environment into which the material is to be placed, would need to be known. These materials would need to be easily placed, easily removed or changed, patient friendly and inexpensive. According to Hanssen, the ideal local antibiotic delivery system "would provide a more efficient delivery of higher levels of antibiotics to the site of infection and yet minimize the risks of systemic toxicity associated with traditional methods of intravenous antibiotics" (Hanssen, 2005).

The consequent need for local drug delivery has been recognized since many years. During the last decades, different forms of local antibiotic delivery have been used. The most common and simple way was to spread the drug in a powder form over the wound area after an extensive debridement and before wound closure (Rushton, 1997). Consequently, high local concentrations for a short period of time are achieved which potentially result in tissue damage. Another approach was to applied antibiotics in liquid form by injection or irrigation or, to extend the effectiveness by continuous perfusion. However, this method is labor intensive and requires experienced nursing staff to avoid leakage and drain blockage. Furthermore, the use of implantable pumps which can be refilled percutaneously is described (Perry & Pearson, 1991). An additional method used was to soak the cotton gauze or linen operative material with the antibiotic and leave it in the wound until the final closure. This procedure is still in use in many countries to minimize the post-operative risk

developmental directions of these biomaterials.

resolved by local delivery of antibiotics.

**2.1 Carrier materials for local antibiotic delivery** 

of infection, e.g. in dirty abdominal wounds or in trauma patients.

year 2000 that research on local delivery of antibiotics to bone has gained considerable attention. Note that the numbers of publications in the last five years are double and decuple published in earlier decades (Soundrapandian et al, 2009).

Bacterial infection in orthopedic and reconstructive surgery can be devastating, and is associated with significant morbidity and poor functional outcomes (Haddad et al, 2004). Operative treatments (excision of infected and devascularized tissues, obliteration of dead space, restoration of blood supply and soft tissue coverage, stabilization and reconstruction of the damaged bone), removal of all foreign bodies and systemic antimicrobial therapy are three crucial components of the treatment of these cases (Lazzarini et al, 2004). A long-term course of systemic antibiotherapy has been considered essential, but these prolonged therapies can result in side effects or toxicity. In order to achieve therapeutic drug concentration in the affected area, high systemic doses are generally required which can further worsen toxic side effects (Nandi et al, 2009). Antibiotic treatment may be inadequate or ineffective in patients with poorly vascularized infected tissues and osteonecrosis, which is often present in cases of osteomyelitis. Moreover, normal doses of systemic antibiotics may be insufficient to breach the glycocalyx or biofilm produced by the infecting bacteria (El-Husseiny et al, 2011). Despite intensive therapy, advances in surgical techniques, and development of new antimicrobials, relapse rate are still significant and treatment of bone and soft tissue infections remain challenging.

New methods such as local delivery of antibiotics have evolved in an attempt to improve the prognosis of patients with musculoskeletal infections. The use of local antibiotic delivery system has become an accepted treatment method that continues to evolve for a variety of reasons. There has been an explosion of new technologies that are designed to facilitate the delivery of local antibiotics in new and creative ways. The primary reason for using these local antibiotic delivery vehicles is the ability to achieve very high local concentrations of antibiotics without associated systemic toxicity. In the typical infected wound environment, which frequently has zones of avascularity, the ability to achieve high levels of antibiotics in these otherwise inaccessible areas is highly desirable (Cierny, 1999). Additional reasons for use of these delivery vehicles include the desire to treat remaining plactonic organisms and sessile organisms in biofilms more effectively with high concentrations of antibiotics (Hanssen et al, 2005). Because bone regeneration often is required as a part of the treatment plan, a recent trend has been simultaneously to provide a frame work of osteoinductive and osteoconductive materials along with antibiotics (Gitelis & Brebach, 2002).

Despite the rapid acceptance of these antibiotic delivery vehicles, there are many unanswered questions related to their use, particularly when viewed within the environment of biofilms. Considerable investigation and development still are required to develop the necessary data to help determine a number of unknown variables associated with the use of local antibiotic delivery systems. In the application of a local antibiotic therapy for bone and soft tissue infections the following aspects should be considered: a) delivery technique; b) type of antibiotic that can be used; c) pharmacokinetics; d) possibility of application to a coating and to fillers; e) possibility of combination with osteoconductive and osteoinductive factors; f) use as prophylaxis and/or therapy; g) drawbacks.

This review introduces bone and soft tissue infection-its present options for drug delivery systems and their limitations, and the wide range of carrier materials and effective drug choices. Also, I will describe and contrast the different local antibiotic delivery vehicles to

year 2000 that research on local delivery of antibiotics to bone has gained considerable attention. Note that the numbers of publications in the last five years are double and

Bacterial infection in orthopedic and reconstructive surgery can be devastating, and is associated with significant morbidity and poor functional outcomes (Haddad et al, 2004). Operative treatments (excision of infected and devascularized tissues, obliteration of dead space, restoration of blood supply and soft tissue coverage, stabilization and reconstruction of the damaged bone), removal of all foreign bodies and systemic antimicrobial therapy are three crucial components of the treatment of these cases (Lazzarini et al, 2004). A long-term course of systemic antibiotherapy has been considered essential, but these prolonged therapies can result in side effects or toxicity. In order to achieve therapeutic drug concentration in the affected area, high systemic doses are generally required which can further worsen toxic side effects (Nandi et al, 2009). Antibiotic treatment may be inadequate or ineffective in patients with poorly vascularized infected tissues and osteonecrosis, which is often present in cases of osteomyelitis. Moreover, normal doses of systemic antibiotics may be insufficient to breach the glycocalyx or biofilm produced by the infecting bacteria (El-Husseiny et al, 2011). Despite intensive therapy, advances in surgical techniques, and development of new antimicrobials, relapse rate are still significant and treatment of bone

New methods such as local delivery of antibiotics have evolved in an attempt to improve the prognosis of patients with musculoskeletal infections. The use of local antibiotic delivery system has become an accepted treatment method that continues to evolve for a variety of reasons. There has been an explosion of new technologies that are designed to facilitate the delivery of local antibiotics in new and creative ways. The primary reason for using these local antibiotic delivery vehicles is the ability to achieve very high local concentrations of antibiotics without associated systemic toxicity. In the typical infected wound environment, which frequently has zones of avascularity, the ability to achieve high levels of antibiotics in these otherwise inaccessible areas is highly desirable (Cierny, 1999). Additional reasons for use of these delivery vehicles include the desire to treat remaining plactonic organisms and sessile organisms in biofilms more effectively with high concentrations of antibiotics (Hanssen et al, 2005). Because bone regeneration often is required as a part of the treatment plan, a recent trend has been simultaneously to provide a frame work of osteoinductive and

Despite the rapid acceptance of these antibiotic delivery vehicles, there are many unanswered questions related to their use, particularly when viewed within the environment of biofilms. Considerable investigation and development still are required to develop the necessary data to help determine a number of unknown variables associated with the use of local antibiotic delivery systems. In the application of a local antibiotic therapy for bone and soft tissue infections the following aspects should be considered: a) delivery technique; b) type of antibiotic that can be used; c) pharmacokinetics; d) possibility of application to a coating and to fillers; e) possibility of combination with osteoconductive

This review introduces bone and soft tissue infection-its present options for drug delivery systems and their limitations, and the wide range of carrier materials and effective drug choices. Also, I will describe and contrast the different local antibiotic delivery vehicles to

osteoconductive materials along with antibiotics (Gitelis & Brebach, 2002).

and osteoinductive factors; f) use as prophylaxis and/or therapy; g) drawbacks.

decuple published in earlier decades (Soundrapandian et al, 2009).

and soft tissue infections remain challenging.

provide a context for their current clinical use and to discuss the emerging investigate and developmental directions of these biomaterials.

#### **2. Criteria for the production of a local delivery system for antimicrobial agents**

Despite the reduction in the risk of contamination due to improved material, implant, and clean room technique as well as peri-operative antibiotic prophylaxis, infections still remain a feared complication in orthopedic and reconstructive surgery (Taylor, 1997). In many surgical disciplines, topical administration of antibacterial drug is not possible or practicable, and achieving of a sufficient antibacterial dose by systemic delivery may lead to adverse reactions negatively influencing overall patient's c by conditions. Especially the use of specific antibiotics may be limited by their high cumulative cell and organ toxicity (Ruszczak & Friess, 2003). Moreover, insufficiency in local blood supply due to posttraumatic or post-operative tissue damage as well as inadequate tissue penetration or bacterial resistance increase the local ineffectiveness of systemic antibiotic therapy, both in terms of preventive or curative drug administration (Mehta et al, 1996). This dilemma can be resolved by local delivery of antibiotics.

The ideal local drug delivery system has been a pursuit of scientists and physicians for the past fifty years. The concept of delivering drugs locally to the area of disease rather than through the systemic circulation without the concomitant secondary systemic complications is appealing both physiologically and psychologically (Nelson, 2004). The ideal local antibiotic delivery system would produce high antibiotic levels at the site of infection and safe drug levels in the systemic circulation. Antibiotic levels would need to be controlled to allow the systemic to be either therapeutic, bellow the toxic level, or absent, and to allow these features to be controlled independently from each other. Furthermore, the antibiotic elution curves, the factors that influence elution, and the most suitable local delivery system for the environment into which the material is to be placed, would need to be known. These materials would need to be easily placed, easily removed or changed, patient friendly and inexpensive. According to Hanssen, the ideal local antibiotic delivery system "would provide a more efficient delivery of higher levels of antibiotics to the site of infection and yet minimize the risks of systemic toxicity associated with traditional methods of intravenous antibiotics" (Hanssen, 2005).

#### **2.1 Carrier materials for local antibiotic delivery**

The consequent need for local drug delivery has been recognized since many years. During the last decades, different forms of local antibiotic delivery have been used. The most common and simple way was to spread the drug in a powder form over the wound area after an extensive debridement and before wound closure (Rushton, 1997). Consequently, high local concentrations for a short period of time are achieved which potentially result in tissue damage. Another approach was to applied antibiotics in liquid form by injection or irrigation or, to extend the effectiveness by continuous perfusion. However, this method is labor intensive and requires experienced nursing staff to avoid leakage and drain blockage. Furthermore, the use of implantable pumps which can be refilled percutaneously is described (Perry & Pearson, 1991). An additional method used was to soak the cotton gauze or linen operative material with the antibiotic and leave it in the wound until the final closure. This procedure is still in use in many countries to minimize the post-operative risk of infection, e.g. in dirty abdominal wounds or in trauma patients.

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 21

beads containing gentamicin have been approved for use in treatment of osteomyelitis in Europe (Klemm, 2001; Seligson et al, 1993). Antibiotic-loaded bone cement represent the current gold standard for local antibiotic delivery in orthopedic surgery (Nelson, 2004). This product has been proven to be efficacious but suffers from the major drawback of requiring subsequent operation to remove the bone cement beads at the completion of

In recent years, various biodegradable delivery systems have been developed and evaluated for local delivery of antibiotics in the treatment of bone and soft tissue infections (Garvin et al, 1994b; Gursel et al, 2000). One of the primary advantages of a biodegradable system is the avoidance of secondary surgical procedures to remove foreign materials, such as bone cement, once antibiotic elution has ceased. Biodegradable implants could provide high local bactericidal concentrations in tissue for the prolonged time needed to completely eradicate the infection and the possibility to match the rate of implant biodegradability according to the type of infection treated (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Biodegradation also makes surgical removal of the implant unnecessary. The implant can also be used initially to obliterate the dead space and, eventually to guide its repair. Additional possibilities with the use of biodegradable systems include variation in the magnitude and duration of antibiotic delivery as well as the potential for purposely adjusting the wound environment with breakdown products of some biodegradable

Additional methods have included adding antibiotics to bone graft and to bone substitutes (Li & Hu, 2001; Shinto et al, 1992; Witso et al, 2000) or other naturally occurring polymers (Kawanabe et al, 1998) whereby the antibiotic is adsorbed to the surface of these materials and is then released into the wound environment. These materials can be include to the

The major drawback associated with non-biodegradable systems is the need to remove from the application site upon completion of their task. This removal surgery is usually more difficult than the implantation because of local tissue scaring and adhesion and may lead to postoperative infection due to both the patient local and systemic condition. In addition, the second procedure poses the risk of additional pain, anesthetic complications, and inferring extra costs. Recently, a Dutch group of scientists has found that despite of antibiotic release, cement beads act as a biomaterial surface at which bacteria preferentially adhere, grow and

In order to select the appropriate antibiotic, an understanding of the microbiology of bone and soft tissue infections is imperative. Normal bone is highly resistant to infection, which can only develop as a result of trauma, very large inocula, or due to the presence of foreign material. Irrespective of the advancement in making surgeries and prosthesis, available sterile, and achieving aseptic conditions in operation theatres , infection associated with major trauma or surgeries are still unavoidable. Due to their application for prophylaxis and therapeutic antibiotics need to be applied to bone in every case of trauma or surgery, in addition to cases of bone and soft tissues infections. When the microbial load has crossed a critical density, they form biofilms that are quite hard for antibiotics to penetrate, often resulting in relapse of infection (Fux et al, 2005). Very high concentrations of antibiotics are

antibiotics release.

materials (Hanssen, 2005).

**2.2 Antibiotic selection** 

biodegradable antibiotic carriers.

potentially develop antibiotic resistant (Neu et al, 2001).

Although the ideal local antibiotic delivery system has not been discovered, several promising materials are present in modern research. The most common carrier systems of antibiotics that successfully release the drug according to prescribed dosage are listed in Table 1.


Table 1. Carriers used for local delivery of antibacterial agents

Drug delivery carriers developed for local delivery of antibiotics can be divided into nonbiodegradable and biodegradable carriers (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Non-biodegradable delivery systems such as polymethylmethacrylate (PMMA) beads containing gentamicin have been approved for use in treatment of osteomyelitis in Europe (Klemm, 2001; Seligson et al, 1993). Antibiotic-loaded bone cement represent the current gold standard for local antibiotic delivery in orthopedic surgery (Nelson, 2004). This product has been proven to be efficacious but suffers from the major drawback of requiring subsequent operation to remove the bone cement beads at the completion of antibiotics release.

In recent years, various biodegradable delivery systems have been developed and evaluated for local delivery of antibiotics in the treatment of bone and soft tissue infections (Garvin et al, 1994b; Gursel et al, 2000). One of the primary advantages of a biodegradable system is the avoidance of secondary surgical procedures to remove foreign materials, such as bone cement, once antibiotic elution has ceased. Biodegradable implants could provide high local bactericidal concentrations in tissue for the prolonged time needed to completely eradicate the infection and the possibility to match the rate of implant biodegradability according to the type of infection treated (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Biodegradation also makes surgical removal of the implant unnecessary. The implant can also be used initially to obliterate the dead space and, eventually to guide its repair. Additional possibilities with the use of biodegradable systems include variation in the magnitude and duration of antibiotic delivery as well as the potential for purposely adjusting the wound environment with breakdown products of some biodegradable materials (Hanssen, 2005).

Additional methods have included adding antibiotics to bone graft and to bone substitutes (Li & Hu, 2001; Shinto et al, 1992; Witso et al, 2000) or other naturally occurring polymers (Kawanabe et al, 1998) whereby the antibiotic is adsorbed to the surface of these materials and is then released into the wound environment. These materials can be include to the biodegradable antibiotic carriers.

The major drawback associated with non-biodegradable systems is the need to remove from the application site upon completion of their task. This removal surgery is usually more difficult than the implantation because of local tissue scaring and adhesion and may lead to postoperative infection due to both the patient local and systemic condition. In addition, the second procedure poses the risk of additional pain, anesthetic complications, and inferring extra costs. Recently, a Dutch group of scientists has found that despite of antibiotic release, cement beads act as a biomaterial surface at which bacteria preferentially adhere, grow and potentially develop antibiotic resistant (Neu et al, 2001).

#### **2.2 Antibiotic selection**

20 Selected Topics in Plastic Reconstructive Surgery

Although the ideal local antibiotic delivery system has not been discovered, several promising materials are present in modern research. The most common carrier systems of antibiotics that successfully release the drug according to prescribed dosage are listed in

**Carrier System Antibiotic Released References** 

1. Bone cement Gentamicin Baker & Greenham, 1988;

2. Bone cement beads Gentamicin Buchholz et al, 1984;

McGarvey, 2003

2. Collagen-Sponge Gentamicin Ruszczak & Friess, 2003 3. Fibrin-sealant Cefazolin Tredwell et al, 2006

4. Hydroxyapatite blocks Vancomycin Shirtliff et al, 2002

implants Gentamicin Garvin et al, 1994b

8. Calcium Sulfate Tobramycin Nelson et al, 2000 9. Calcium phosphate cement Teicoplanin Lazarettos et al, 2004

1. Fibres Tetracycline Tonetti et al, 1998 2. Chitosan Vancomycin Chevher et al, 2006 3. Biomedical polyourethanes Gentamicin, Ciprofloxacin Schierholz et al, 1997

Drug delivery carriers developed for local delivery of antibiotics can be divided into nonbiodegradable and biodegradable carriers (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Non-biodegradable delivery systems such as polymethylmethacrylate (PMMA)

1. Plaster of Paris pellets Gentamicin Santschi &

6. Dilactate polymers Fluoroquinolones

7. Cancellous bone Vancomycin,

Table 1. Carriers used for local delivery of antibacterial agents

Buchholz et al, 1984

Mendel et al, 2005

Vancomycin Kuechle et al, 1990 Cefazolin Marks et al, 1976 Ciprofloxacin Tsourvakas et al, 2009

Tobramycin Seligson et al, 1993 Cefuroxime Mohanty et al, 2003 Vancomycin Chohfi et al, 1998

Teicoplanin Dacquet et al, 1992

Ciprofloxacin Tsourvakas et al, 1995

Vancomycin Calhoun & Mader, 1997

1999

Dounis et al, 1996; Kanellakopoulou et al,

Ciprofloxacin Koort et al, 2008

Ciprofloxacin Witso et al, 2000

Table 1.

**Non-biodegradable** 

**Biodegradable** 

**Miscellaneous**

5. Polylactide/polyglycolide

In order to select the appropriate antibiotic, an understanding of the microbiology of bone and soft tissue infections is imperative. Normal bone is highly resistant to infection, which can only develop as a result of trauma, very large inocula, or due to the presence of foreign material. Irrespective of the advancement in making surgeries and prosthesis, available sterile, and achieving aseptic conditions in operation theatres , infection associated with major trauma or surgeries are still unavoidable. Due to their application for prophylaxis and therapeutic antibiotics need to be applied to bone in every case of trauma or surgery, in addition to cases of bone and soft tissues infections. When the microbial load has crossed a critical density, they form biofilms that are quite hard for antibiotics to penetrate, often resulting in relapse of infection (Fux et al, 2005). Very high concentrations of antibiotics are

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 23

Antibiotic impregnated beads have been employed in the treatment of bone and soft tissue infections for nearly 30 years; their use is well established in many European centers (Jenny, 1988). For the first time, antibiotic-loaded bone cement was used as a prophylactic agent against deep bone infections in orthopedic endoprosthetic surgery in human patients (Buchholz et al, 1984). Since then antibiotic-loaded bone cement has been an effective method for providing sustained high concentrations of antibiotics locally when used in numerous types of bone and soft tissue infections (Calhoun & Mader, 1989; Josefsson et al, 1990). Polymethylmethacrylate (PMMA) exist in two forms: that of antibiotic-impregnated bone cement applied in arthroplasties and antibiotic-impregnated bead chains for musculoskeletal infections (Henry & Galloway, 1995). The success of these carriers depend on two factors: PMMA does not usually trigger any immune response from the host and the form of a bead confers a wide surface area, allowing rapid release of

Several factors influence the elution of antibiotics from PMMA cement. In addition to the type of antibiotic used, the type of cement also influences elution (Marks et al, 1976). Factors that increase the porosity of the cement (such as the addition of dextran or higher concentrations of antibiotic) also increase elution (Patzakis & Wilkins, 1989). Walenkamp in 1989, showed that the size of the bead influenced the amount of antibiotic that can be eluted. Small or mini beads provide better elution than larger beads, probably because of a more favorable surface to volume ratio (Holtom et al, 1998). Finally, the turnover of the fluid surrounding the beads will influence the local concentration as well as the maximum

Polymethylmethacrylate cement is available in various commercial and non-commercial brands and in-vitro elution of antibiotics from these varies between brands (Greene et al, 1998). Commercially available beads have a consistent diameter of 7mm and are available in stands of 10 or 30 (Nelson et al, 1992). Noncommercial preparations are generally prepared by the surgeons themselves. The main disadvantages associated with beads are improper mixing of antibiotic into the beads and a lack of the uniform size of bead, resulting in lower antibiotic availability (Nelson et al, 1992). Selection of antibiotic in commercially prepared beads depends on its stability at the high temperatures (up to 100ºC) at which polymerization of bone cement occurs. The aminoglycosides are heat stable and are thus extensively used in these preparations. It has been documented for human being and invitro studies that elution of antibiotics from PMMA is bimodal (Henry et al, 1991). Approximately 5% of the total amount of antibiotic is released within the first 24 hours from the surface of beads or rods, followed by a sustained elution of antibiotic that diminishes during subsequent weeks or months. Elution properties of polymethylmethacrylate bone cement depend on the type of PMMA, type and concentration of antibiotic and structural characteristics of the bead or rods (Henry et al, 1991). Gas sterilization does not affect the

properties of antibiotics or elution properties of PMMA (Henry et al, 1993).

There have been many in-vitro studies on the diffusion or elution of antibiotics from polymethylmethacrylate bone cement. Several different antimicrobial agents have been studied, including the aminoglycosides, primarily gentamicin but also tobramycin, amikacin and streptomycin (Greene et al, 1998; Masri et al, 1995; Wahlig et al, 1978),

**3.1 Antibiotic-loaded bone cement (PMMA)** 

the antibiotic.

amount of antibiotic eluted.

required to eradicate them, which could hardly be attained by conventional routes of delivery without serious side effects.

The most commonly described microbes to cause bone and soft tissue infections, especially chronic osteomyelitis, are staphylococcus aureus; Group A beta hemolytic streptococcus and gram-negative bacteria, particularly Enterobacteriaceae and Pseudomonas aeruginosa (Galanakis et al, 1997; Rissing et al, 1997).

Numerous of antibiotics are available for use in antibiotic impregnated carriers. Considering the above criteria and on bacteriological finding in bone and soft tissue infections, the most acceptable agents in local delivery systems are aminoglycosides and to a lesser extent various β-lactam agents and quinolones (Rushton, 1997). A combination therapy of antibiotics is useful to reduce the toxicity of individual agents, to prevent the emergence of resistance and to treat mixed infections involved in chronic osteomyelitis (Mader et al, 1993). However, specific characteristics should be considered before the antimicrobial agents selected for use in local delivery systems: the antibiotic should be stable at body temperature and water soluble to ensure diffusion from the carrier; be active against the most common bacterial pathogens involved in bone and soft tissue infections; be locally released at concentrations exceeding several times (usually 10 times) the minimum inhibitory concentration (MIC) for the concerned pathogens; be unable to enter in systemic circulation; have a low rate of allergic reaction; a low rate of primary resistance; not produce supra infection and be readily available in powder form (Kobayashi et al, 1992; Popham et al, 1991). The choice of different classes of antibiotics for clinical use must be made according to a microbiologic sensitivity test (Popham et al, 1991; Ueng et al, 1997).

Antibiotics in general are hydrophilic drugs, hardly exhibit stability problems (except a few as cephalosporins) making them suitable to load with any kind of composite. Release of antibiotics shall depend on various factors. Release of the antibacterial agent in such systems is governed by the rate of dissolution of the drug in its matrix allowing its penetration through the pores of the carrier. For highly soluble agents, e.g. β-lactams agents, the amount of released drug depends on the surface area of the carrier and on the initial concentration of the drug in the prepared system. For relatively insoluble agents, e.g. quinolones, the rate of drug release depends on the porosity of the matrix and on dissolution of the drug in the matrix (Allababidi & Shah, 1998). However, insufficient release of antibiotics on the basis of time and concentration could lead to development of resistant strains and growth of microorganisms on the surface of the scaffolds (Soundrapandian et al, 2009).

#### **3. Non-biodegradable systems**

Antibiotic-impregnated non-biodegradable beads mainly polymethylmethacrylate (PMMA) have been widely used for the local administration of antibiotics. Buchholz and Engelbrecht in 1970 proposed delivering antibiotics to an infected site via elution of antibiotics from antibiotic-impregnated cement placed adjacent to the site of infection. The use of antibioticimpregnated polymethylmethacrylate (PMMA) cement bead for the treatment of bone and soft tissue infections has many theoretical advantages. The beads, which release antibiotics by passive diffusion, combine with high local concentrations with low systemic levels of the antibiotic (Henry & Galloway, 1995), leading to more effective killing of the organisms and less risk of systemic toxicity. In addition, the beads can fill the dead space that may be left after debridement of infected tissue (Patzakis et al, 1993).

#### **3.1 Antibiotic-loaded bone cement (PMMA)**

22 Selected Topics in Plastic Reconstructive Surgery

required to eradicate them, which could hardly be attained by conventional routes of

The most commonly described microbes to cause bone and soft tissue infections, especially chronic osteomyelitis, are staphylococcus aureus; Group A beta hemolytic streptococcus and gram-negative bacteria, particularly Enterobacteriaceae and Pseudomonas aeruginosa

Numerous of antibiotics are available for use in antibiotic impregnated carriers. Considering the above criteria and on bacteriological finding in bone and soft tissue infections, the most acceptable agents in local delivery systems are aminoglycosides and to a lesser extent various β-lactam agents and quinolones (Rushton, 1997). A combination therapy of antibiotics is useful to reduce the toxicity of individual agents, to prevent the emergence of resistance and to treat mixed infections involved in chronic osteomyelitis (Mader et al, 1993). However, specific characteristics should be considered before the antimicrobial agents selected for use in local delivery systems: the antibiotic should be stable at body temperature and water soluble to ensure diffusion from the carrier; be active against the most common bacterial pathogens involved in bone and soft tissue infections; be locally released at concentrations exceeding several times (usually 10 times) the minimum inhibitory concentration (MIC) for the concerned pathogens; be unable to enter in systemic circulation; have a low rate of allergic reaction; a low rate of primary resistance; not produce supra infection and be readily available in powder form (Kobayashi et al, 1992; Popham et al, 1991). The choice of different classes of antibiotics for clinical use must be made according to

Antibiotics in general are hydrophilic drugs, hardly exhibit stability problems (except a few as cephalosporins) making them suitable to load with any kind of composite. Release of antibiotics shall depend on various factors. Release of the antibacterial agent in such systems is governed by the rate of dissolution of the drug in its matrix allowing its penetration through the pores of the carrier. For highly soluble agents, e.g. β-lactams agents, the amount of released drug depends on the surface area of the carrier and on the initial concentration of the drug in the prepared system. For relatively insoluble agents, e.g. quinolones, the rate of drug release depends on the porosity of the matrix and on dissolution of the drug in the matrix (Allababidi & Shah, 1998). However, insufficient release of antibiotics on the basis of time and concentration could lead to development of resistant strains and growth of

Antibiotic-impregnated non-biodegradable beads mainly polymethylmethacrylate (PMMA) have been widely used for the local administration of antibiotics. Buchholz and Engelbrecht in 1970 proposed delivering antibiotics to an infected site via elution of antibiotics from antibiotic-impregnated cement placed adjacent to the site of infection. The use of antibioticimpregnated polymethylmethacrylate (PMMA) cement bead for the treatment of bone and soft tissue infections has many theoretical advantages. The beads, which release antibiotics by passive diffusion, combine with high local concentrations with low systemic levels of the antibiotic (Henry & Galloway, 1995), leading to more effective killing of the organisms and less risk of systemic toxicity. In addition, the beads can fill the dead space that may be left

a microbiologic sensitivity test (Popham et al, 1991; Ueng et al, 1997).

microorganisms on the surface of the scaffolds (Soundrapandian et al, 2009).

delivery without serious side effects.

(Galanakis et al, 1997; Rissing et al, 1997).

**3. Non-biodegradable systems** 

after debridement of infected tissue (Patzakis et al, 1993).

Antibiotic impregnated beads have been employed in the treatment of bone and soft tissue infections for nearly 30 years; their use is well established in many European centers (Jenny, 1988). For the first time, antibiotic-loaded bone cement was used as a prophylactic agent against deep bone infections in orthopedic endoprosthetic surgery in human patients (Buchholz et al, 1984). Since then antibiotic-loaded bone cement has been an effective method for providing sustained high concentrations of antibiotics locally when used in numerous types of bone and soft tissue infections (Calhoun & Mader, 1989; Josefsson et al, 1990). Polymethylmethacrylate (PMMA) exist in two forms: that of antibiotic-impregnated bone cement applied in arthroplasties and antibiotic-impregnated bead chains for musculoskeletal infections (Henry & Galloway, 1995). The success of these carriers depend on two factors: PMMA does not usually trigger any immune response from the host and the form of a bead confers a wide surface area, allowing rapid release of the antibiotic.

Several factors influence the elution of antibiotics from PMMA cement. In addition to the type of antibiotic used, the type of cement also influences elution (Marks et al, 1976). Factors that increase the porosity of the cement (such as the addition of dextran or higher concentrations of antibiotic) also increase elution (Patzakis & Wilkins, 1989). Walenkamp in 1989, showed that the size of the bead influenced the amount of antibiotic that can be eluted. Small or mini beads provide better elution than larger beads, probably because of a more favorable surface to volume ratio (Holtom et al, 1998). Finally, the turnover of the fluid surrounding the beads will influence the local concentration as well as the maximum amount of antibiotic eluted.

Polymethylmethacrylate cement is available in various commercial and non-commercial brands and in-vitro elution of antibiotics from these varies between brands (Greene et al, 1998). Commercially available beads have a consistent diameter of 7mm and are available in stands of 10 or 30 (Nelson et al, 1992). Noncommercial preparations are generally prepared by the surgeons themselves. The main disadvantages associated with beads are improper mixing of antibiotic into the beads and a lack of the uniform size of bead, resulting in lower antibiotic availability (Nelson et al, 1992). Selection of antibiotic in commercially prepared beads depends on its stability at the high temperatures (up to 100ºC) at which polymerization of bone cement occurs. The aminoglycosides are heat stable and are thus extensively used in these preparations. It has been documented for human being and invitro studies that elution of antibiotics from PMMA is bimodal (Henry et al, 1991). Approximately 5% of the total amount of antibiotic is released within the first 24 hours from the surface of beads or rods, followed by a sustained elution of antibiotic that diminishes during subsequent weeks or months. Elution properties of polymethylmethacrylate bone cement depend on the type of PMMA, type and concentration of antibiotic and structural characteristics of the bead or rods (Henry et al, 1991). Gas sterilization does not affect the properties of antibiotics or elution properties of PMMA (Henry et al, 1993).

There have been many in-vitro studies on the diffusion or elution of antibiotics from polymethylmethacrylate bone cement. Several different antimicrobial agents have been studied, including the aminoglycosides, primarily gentamicin but also tobramycin, amikacin and streptomycin (Greene et al, 1998; Masri et al, 1995; Wahlig et al, 1978),

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 25

Favorable outcome (%)

Follow-up ( months)

application Patients

Table 3. Cumulative data from clinical trials with antibiotic-loaded PMMA bone cement

The primary basis for use of antibiotic-loaded polymethylmethacrylate bone cement as a prophylactic method to reduce the prevalence of deep periprosthetic infection has been the clinical experience obtained over the past three decades combined with data from several experimental studies (Jiranek et al, 2006). Gentamicin, cefuroxime and tobramycin have been the antimicrobials most commonly admixed into PMMA in clinical studies worldwide (Chiu et al, 2002; Engesaeter et al, 2003; Malchau et al, 1993). In United States, tobramycin has been used most commonly, primarily because the product is available in powdered form. Of the three antibiotics, gentamicin has been used most frequently and studied most

In a large retrospective study, data on 22170 primary total hip replacements from the Norwegian Arthroplasty Register during the period of 1987 to 2001 were analyzed (Engesaeter et al, 2003). Patients who received only systemic antibiotic prophylaxis had a 1.8 times higher rate of infection than patients who received systemic antibiotic prophylaxis combined with gentamicin-loaded bone cement. Another retrospective study, of 92675 hip arthroplasties listed in the Swedish Joint Registry, presented similar conclusions, with the use of antibiotic-loaded bone cement favored for both primary and revision hip

Recently, prosthesis of antibiotics loaded acrylic bone cement consisting of an acetabular cup filled with antibiotic loaded polymethylmethacrylate bone cement was developed for the treatment of infections at the site of total hip arthroplasty accompanied by the extensive loss of the proximal part of the femur (Younger et al, 1998). The antibiotic usually impregnated is tobramycin or vancomycin with an elution of the former at intraarticular concentrations between 4.35 and 123.88 mg/L and remains undetected in the latter (Masri et al, 1998). This has resulted in a success rate of 94% in 61 patients after an average follow-up of 43 months. Polymethylmethacrylate bone cement beads impregnated with vancomycin were successfully used for the treatment of osteomyelitis of the pelvis

hip arthroplasty 1688 99.2 60

infection 40 95 17

prosthesis 183 84.2 93

prosthesis 33 96.9 24

prosthesis 86 89.6 52

osteomyelitis 31 87 36

Study Purpose of

Josefsson et al, 1990 Prophylaxis in total

Garvin et al, 1994a Periprosthetic hip

Hanssen et al, 1994 Infected knee

Whiteside, 1994 Infected knee

Raut et al, 1995 Infected knee

Cho et al, 1997 Chronic

extensively overall (Hanssen, 2004).

arthroplasties (Malchau et al, 1993).

and of the hip (Ozaki et al, 1998).

cephalosporins including cefazoline, cefotaxime, ceftriaxone and ceftazidime (Alonge & Fashina, 2000; Tomczak et al, 1989; Wilson et al, 1988), vancomycin (Kuechle et al, 1991) and ciprofloxacin (Tsourvakas et al, 2009). All antimicrobial agents go through an initial phase during which the concentration of fluid surrounding the beads or cement spacers is very high, followed by a gradual decrease to sustained low levels for many weeks or months. Although there are differences in elution between each different antimicrobial agent, all seem to have adequate elution for the treatment of bone and soft tissue infection, but the length of time that the drug levels remain above the minimum inhibitory concentration for the target organism (usually Staphylococcus aureus) varies depending on the drug selected and the conditions of the experiment. Cumulative data on the in-vitro elution of antibiotics in polymethylmethacrylate bone cement are presented in table 2, where it is clearly shown that both aminoglycosides and quinolones are released at very high concentrations, but the peak of release occurs on the first day. As the viscosity of PMMA decreases, the amount of released antibiotic increases (Bunetel et al, 1990). The same first day peak was also documented for tobramycin and vancomycin (Brien et al, 1993); the release lasted for a total period of only one week.


Table 2. Characteristics of the in-vitro elution of different antibiotics from PMMA bone cement

To achieve adequate killing of bacteria, beads should not be used in combination with an irrigation system, and moisture should be excluded by artificial skin. With these precautions the amount of gentamicin releasd by the bone cement beads does not exceed 25% of the total amount implanted (Rushton, 1997). In chronic osteomyelitis, healing of the wound expected within 10 days but PMMA beads may remain implanted for up to 4 weeks, after his surgical removal is necessary followed by osseous reconstructive surgery. The need for removal is the major disadvantage of the beads, although in some patients small chains of beads be removed in the ward via a small skin incision (Walenkamp, 1997).

Antibiotic-loaded bone cement can be applied either in infected arthroplasties or as surgical prophylaxis during joint arthroplasties. Cumulative results of clinical studies involving its application for both purposes are given in table 3.

cephalosporins including cefazoline, cefotaxime, ceftriaxone and ceftazidime (Alonge & Fashina, 2000; Tomczak et al, 1989; Wilson et al, 1988), vancomycin (Kuechle et al, 1991) and ciprofloxacin (Tsourvakas et al, 2009). All antimicrobial agents go through an initial phase during which the concentration of fluid surrounding the beads or cement spacers is very high, followed by a gradual decrease to sustained low levels for many weeks or months. Although there are differences in elution between each different antimicrobial agent, all seem to have adequate elution for the treatment of bone and soft tissue infection, but the length of time that the drug levels remain above the minimum inhibitory concentration for the target organism (usually Staphylococcus aureus) varies depending on the drug selected and the conditions of the experiment. Cumulative data on the in-vitro elution of antibiotics in polymethylmethacrylate bone cement are presented in table 2, where it is clearly shown that both aminoglycosides and quinolones are released at very high concentrations, but the peak of release occurs on the first day. As the viscosity of PMMA decreases, the amount of released antibiotic increases (Bunetel et al, 1990). The same first day peak was also documented for tobramycin and vancomycin

Peak of release

(μg/ml) Study

(Brien et al, 1993); the release lasted for a total period of only one week.

release

PMMA (days) /day of peak

removed in the ward via a small skin incision (Walenkamp, 1997).

application for both purposes are given in table 3.

Gentamicin 56 318.6/1 Hoff et al, 1981 Tobramycin 220 >250/1 Mader et al, 1997 Clindamycin 220 >250/1 Mader et al, 1997 Vancomycin 12 >200/1 Mader et al, 1997 Cefazolin 28 250/1 Adams et al, 1992 Penicillin 91 199.5/1 Hoff et al, 1981 Ciprofloxacin 360 80.8/1 Tsourvakas et al, 2009 Amikacin 5 200/1 Kuechle et al, 1990

Table 2. Characteristics of the in-vitro elution of different antibiotics from PMMA bone

To achieve adequate killing of bacteria, beads should not be used in combination with an irrigation system, and moisture should be excluded by artificial skin. With these precautions the amount of gentamicin releasd by the bone cement beads does not exceed 25% of the total amount implanted (Rushton, 1997). In chronic osteomyelitis, healing of the wound expected within 10 days but PMMA beads may remain implanted for up to 4 weeks, after his surgical removal is necessary followed by osseous reconstructive surgery. The need for removal is the major disadvantage of the beads, although in some patients small chains of beads be

Antibiotic-loaded bone cement can be applied either in infected arthroplasties or as surgical prophylaxis during joint arthroplasties. Cumulative results of clinical studies involving its

Antibiotic-loaded Duration of

cement


Table 3. Cumulative data from clinical trials with antibiotic-loaded PMMA bone cement

The primary basis for use of antibiotic-loaded polymethylmethacrylate bone cement as a prophylactic method to reduce the prevalence of deep periprosthetic infection has been the clinical experience obtained over the past three decades combined with data from several experimental studies (Jiranek et al, 2006). Gentamicin, cefuroxime and tobramycin have been the antimicrobials most commonly admixed into PMMA in clinical studies worldwide (Chiu et al, 2002; Engesaeter et al, 2003; Malchau et al, 1993). In United States, tobramycin has been used most commonly, primarily because the product is available in powdered form. Of the three antibiotics, gentamicin has been used most frequently and studied most extensively overall (Hanssen, 2004).

In a large retrospective study, data on 22170 primary total hip replacements from the Norwegian Arthroplasty Register during the period of 1987 to 2001 were analyzed (Engesaeter et al, 2003). Patients who received only systemic antibiotic prophylaxis had a 1.8 times higher rate of infection than patients who received systemic antibiotic prophylaxis combined with gentamicin-loaded bone cement. Another retrospective study, of 92675 hip arthroplasties listed in the Swedish Joint Registry, presented similar conclusions, with the use of antibiotic-loaded bone cement favored for both primary and revision hip arthroplasties (Malchau et al, 1993).

Recently, prosthesis of antibiotics loaded acrylic bone cement consisting of an acetabular cup filled with antibiotic loaded polymethylmethacrylate bone cement was developed for the treatment of infections at the site of total hip arthroplasty accompanied by the extensive loss of the proximal part of the femur (Younger et al, 1998). The antibiotic usually impregnated is tobramycin or vancomycin with an elution of the former at intraarticular concentrations between 4.35 and 123.88 mg/L and remains undetected in the latter (Masri et al, 1998). This has resulted in a success rate of 94% in 61 patients after an average follow-up of 43 months. Polymethylmethacrylate bone cement beads impregnated with vancomycin were successfully used for the treatment of osteomyelitis of the pelvis and of the hip (Ozaki et al, 1998).

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 27

Biodegradation also makes surgical removal of the implant unnecessary. The implant can also be used initially to obliterate the dead space and, eventually, to guide its repair. Furthermore, secondary release of the antibiotic may occur during the degradation phase of the carrier, which could increase antibacterial efficacy compared to non-biodegradable

The biodegradable antibiotic delivery materials have been classified into four broad categories: bone graft and bone substitutes, protein-based materials (natural polymers), synthetic polymers and miscellaneous biodegradable materials (McLaren, 2004). Within these four categories there are several mechanisms of antibiotic release such as the first order kinetics associated with antibiotics attached by surface adsorption and variable antibiotic release rates that are observed with products whereby antibiotics are admixed within the substance of the biomaterial (Hanssen, 2005). In vitro and in vivo elution of

Study Carrier Antibiotic Duration of

release (days)

antibacterial agents from biodegradable materials are show in tables 4 and 5.

Witso et al, 2000 Bone-graft Vancomycin 7 Ciprofloxacin 7 Jia et al, 2010 Calcium Sulfate Teicoplanin 29

al, 1996 Collagen Sponge Gentamicin 4

Vancomycin 2

<sup>2009</sup>Fibrin-clot Ciprofloxacin 60

Garvin et al, 1994b Synthetic Polymers Clindamycin 38-50 Tobramycin 36-75 Vancomycin 38-51

al, 1999 Polylactate Ciprofloxacin 51-350

 Pefloxacin 56-295 Dounis et al, 1996 Polylactate Fleroxacin 56

McGarey, 2003 Plaster of Paris Gentamicin 14

Shinto et al, 1992 Hydroxyapatite Gentamicin 90

Table 4. Cumulative data from in-vitro studies with antibiotic-loaded in biodegradable

carriers (Nandi et al, 2009).

Wachol-Drewek et

Tsourvakas et al,

Kanellakopoulou et

Santschi &

materials

The primary concern regarding antibiotic-loaded acrylic bone cement include the potential for detrimental effects on the mechanical or structural characteristics of polymethylmethacrylate bone cement when antibiotic are admixed. The addition of >4.5g of gentamicin powder per 40g package of cement powder or the addition of liquid antibiotics causes a decrease in compressive strength to a level below American Society for Testing and Materials standards (Lautenschlager et al, 1976). The use of high-dose antibiotics in acrylic bone cement spacers (>2g of antibiotic powder per 40g of acrylic bone cement powder) implanted in staged revision procedures can lead to substantial cost savings to the hospital and improvement in patient care. However, the routine use of high-dose antibiotics in cement employed for fixation of prostheses is not supported by evidence (Jiranek et al, 2006).

Another basic concern regarding antibiotic-loaded polymethylmethacrylate bone cement include the potential for development of drug-resistant bacteria. Many of the bacterial pathogens involved in bone and soft tissue infections, particularly Staphylococcus epidermidis, produce a biofilm that limits the activity of antibiotics (Gracia et al, 1998). The biofilm, known as the extracellular slime of glycocalyx, is produced by strains of Staphylococcus aureus and Staphylococcus epidermidis, it also provides these strains with the capacity to adhere the foreign materials, such as the acrylic bone cement beads (Bayston & Rogers, 1990). Consequently, despite adequate killing of these micro-organisms by invitro elution of antibiotic in close proximity to the beads, the same micro-organisms survive on their surface (Kendall et al, 1996). This stable adherence might provide a mechanism of recurrence of the infection and of development of resistance, since small colony variants of Staphylococcus aureus resistant to gentamicin have been isolated from the wounds of patients with bone and soft tissue infections treated with gentamicin-impregnated acrylic bone cement beads (vonEiff et al, 1997). In a report from the Ohio State University Medical Center, the overall rate of infection decreased with the introduction and use of antibiotic-loaded acrylic bone cement; however, the prevalence of aminoglycosideresistant bacteria, particularly in Staphylococcus aureus and coagulase-negative staphylococcal infections, increased (Wininger & Fass, 1996). Because of the considerable data suggesting the potential for the development of bacterial antibiotic resistance, antibiotic-loaded polymethylmethacrylate bone cement should not be used routinely for prophylaxis. Rather, it should be used for prophylaxis only when there are clear indications, such as a high-risk primary procedure or a high-risk revision arthroplasty. Vancomycin should not be used as a primary agent for prophylaxis because of the emergence of resistant organisms and the need to reserve this antibiotic for patients who require it for treatment (Hanssen & Osmon, 1999).

#### **4. Biodegradable materials**

A variety of bone cement alternatives have been used experimentally and clinically as local antibiotic delivery vehicles and there are many additional products in development. Currently, there are no FDA-approved biodegradable materials available for use to treat established musculoskeletal infection (Nelson, 2004).

Biodegradable implants could provide high local bacteridical concentrations in tissue for the prolonged time needed to completely eradicate the infection and the possibility to match the rate of implant biodegradability according to the type of infection and the possibility to match the rate of implant biodegradability according to the type of infection treated.

The primary concern regarding antibiotic-loaded acrylic bone cement include the potential for detrimental effects on the mechanical or structural characteristics of polymethylmethacrylate bone cement when antibiotic are admixed. The addition of >4.5g of gentamicin powder per 40g package of cement powder or the addition of liquid antibiotics causes a decrease in compressive strength to a level below American Society for Testing and Materials standards (Lautenschlager et al, 1976). The use of high-dose antibiotics in acrylic bone cement spacers (>2g of antibiotic powder per 40g of acrylic bone cement powder) implanted in staged revision procedures can lead to substantial cost savings to the hospital and improvement in patient care. However, the routine use of high-dose antibiotics in cement employed for fixation of

Another basic concern regarding antibiotic-loaded polymethylmethacrylate bone cement include the potential for development of drug-resistant bacteria. Many of the bacterial pathogens involved in bone and soft tissue infections, particularly Staphylococcus epidermidis, produce a biofilm that limits the activity of antibiotics (Gracia et al, 1998). The biofilm, known as the extracellular slime of glycocalyx, is produced by strains of Staphylococcus aureus and Staphylococcus epidermidis, it also provides these strains with the capacity to adhere the foreign materials, such as the acrylic bone cement beads (Bayston & Rogers, 1990). Consequently, despite adequate killing of these micro-organisms by invitro elution of antibiotic in close proximity to the beads, the same micro-organisms survive on their surface (Kendall et al, 1996). This stable adherence might provide a mechanism of recurrence of the infection and of development of resistance, since small colony variants of Staphylococcus aureus resistant to gentamicin have been isolated from the wounds of patients with bone and soft tissue infections treated with gentamicin-impregnated acrylic bone cement beads (vonEiff et al, 1997). In a report from the Ohio State University Medical Center, the overall rate of infection decreased with the introduction and use of antibiotic-loaded acrylic bone cement; however, the prevalence of aminoglycosideresistant bacteria, particularly in Staphylococcus aureus and coagulase-negative staphylococcal infections, increased (Wininger & Fass, 1996). Because of the considerable data suggesting the potential for the development of bacterial antibiotic resistance, antibiotic-loaded polymethylmethacrylate bone cement should not be used routinely for prophylaxis. Rather, it should be used for prophylaxis only when there are clear indications, such as a high-risk primary procedure or a high-risk revision arthroplasty. Vancomycin should not be used as a primary agent for prophylaxis because of the emergence of resistant organisms and the need to reserve this antibiotic for patients who

A variety of bone cement alternatives have been used experimentally and clinically as local antibiotic delivery vehicles and there are many additional products in development. Currently, there are no FDA-approved biodegradable materials available for use to treat

Biodegradable implants could provide high local bacteridical concentrations in tissue for the prolonged time needed to completely eradicate the infection and the possibility to match the rate of implant biodegradability according to the type of infection and the possibility to match the rate of implant biodegradability according to the type of infection treated.

prostheses is not supported by evidence (Jiranek et al, 2006).

require it for treatment (Hanssen & Osmon, 1999).

established musculoskeletal infection (Nelson, 2004).

**4. Biodegradable materials** 

Biodegradation also makes surgical removal of the implant unnecessary. The implant can also be used initially to obliterate the dead space and, eventually, to guide its repair. Furthermore, secondary release of the antibiotic may occur during the degradation phase of the carrier, which could increase antibacterial efficacy compared to non-biodegradable carriers (Nandi et al, 2009).

The biodegradable antibiotic delivery materials have been classified into four broad categories: bone graft and bone substitutes, protein-based materials (natural polymers), synthetic polymers and miscellaneous biodegradable materials (McLaren, 2004). Within these four categories there are several mechanisms of antibiotic release such as the first order kinetics associated with antibiotics attached by surface adsorption and variable antibiotic release rates that are observed with products whereby antibiotics are admixed within the substance of the biomaterial (Hanssen, 2005). In vitro and in vivo elution of antibacterial agents from biodegradable materials are show in tables 4 and 5.


Table 4. Cumulative data from in-vitro studies with antibiotic-loaded in biodegradable materials

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 29

over three weeks. Tobramycin levels exceeded usual bacteridical concentrations for three weeks in the graft material implanted in a rabbit. In another study, the results showed that morselized bone graft can act as a carrier netilmicin, vancomycin, clindamycin and rifampicin in vitro and in vivo. Antibiotics levels exceeded usual bacteridical concentrations

Application of antibiotic impregnated autogenic cancellous bone grafting has already been introduced in clinical practice. Chan et al, in 1998, reported results from 36 patients with infected fractures resulting from traffic accidents. After surgical debridement an iliac cancellous bone graft was taken and mixed by the surgeon with piperacillin and/or vancomycin, depending on the susceptibility of the isolated infective micro-organism. The graft was then implanted at the site of infection inside the osseous defect, which occurred principally in the proximal, middle or distal segment of the left or right tibia. Four to five months were necessary for bone union, and the only complications presented were skin

Impregnation of antimicrobial agents within osteoconductive biomaterials (calcium sulfate, calcium phosphate, hydroxyapatite or tricalcium phosphate) has been proposed for local treatment of osteomyelitis and to aid dead space management (Kawanabe et al, 1998; Makinen et al, 2005; Nelson et al, 2005). As a common feature, these implants show a rapid release of the antibiotic in a more or less controlled manner (McLaren, 2004). One of the benefits of this class of materials is that implantation provides the opportunity to deliver local antibiotics at high concentrations and simultaneously participate in the bone regeneration process during the time period of material degradation. These materials also avoid the risk of transmitting disease pathogens associated with the use of allograft bone. Of these materials, commercial calcium sulfate has probably been used most commonly in the clinical setting of osteomyelitis treatment (Gitelis & Brebach, 2002). The most appropriate antibiotic dosage regimen not clear however, the most common formulation used clinically has been 3.64% vancomycin or 4.25% tobramycin per weight (Gitelis & Brebach, 2002). These percentages equate to 1g of vancomycin or 1.2g for tobramycin per 25g of calcium sulfate. Other antibiotic-loaded biomaterials being investigated in this category include calcium hydroxyapatites (Shirliff et al, 2002), calcium phosphates (Lazarettos et al, 2004), bioactive glasses (Kawanabe et al, 1998) and antibiotic loaded blood

This category includes antibiotic-loaded sponge collagen (Mehta et al, 1996; Ruszcak & Friess, 2003), fibrin (Tredwell et al, 2005; Tsourvakas et al, 1995), thrombin, and other commercially available systems that use clotted blood products. Although there are investigators actively involved in the use of these materials, their use as local antibiotic delivery vehicles is not as common as the use of antibiotic-loaded bone cement, antibiotic-

These materials function as delivery vehicles by providing a physical scaffold around the antibiotic mechanically limiting fluid flow, or by providing a protein to bind the antibiotic. Some data on release properties are published for all of these materials determined by either elution studies or by animal studies. Elution rates, tend to be rapid, leading to release of

loaded bone graft substitutes in the treatment of bone and soft tissue infections.

for seven days in the graft material implanted in a rat (Witso et al, 2000).

coated demineralized bone (Rhyu et al, 2003).

**4.2 Natural polymers (protein-based materials)** 

rashes.


Table 5. Cumulative data from in-vivo studies with antibiotic-loaded in biodegradable materials

#### **4.1 Bone grafts and bone substitutes**

Bone graft, either as autograft or allograft, as a vehicle for local antibiotic delivery, has been used clinically for more than twenty years (McLaren, 2004).

Morselized cancellous bone has been used extensively as bone graft material. There are variations in the material that depend on the method of preparation. The use of morselized cancellous bone as a delivery carrier for antibiotics was developed in 1984 when there was limited choice in bone-grafting material and constraints related to biologic hazards were manageable (McLaren & Miniaci, 1986). Antibiotics can be added as a powered to morselized cancellous bone or by soaking the bone-graft in an antibiotic-loaded solution. The antibiotic is absorbed directly to the bone surfaces and subsequent release of antibiotics is based on first-order kinetics (McLaren, 2004). Although this clinical application protocols with a variety of different antibiotics, there are very little data regarding the actual concentration levels of the local antibiotics and the clinical effects that this practice has an eventual bone graft incorporation.

In vitro elution studies (McLaren & Miniaci, 1986) and in vivo studies in a rabbit model (McLaren, 1988) have shown first-order kinetics for release of tobramycin during a period of

Model

Duration of release (days)

Study Carrier Antibiotic Animal

Witso et al, 2000 Bone-graft Vancomycin Rat 7

Ciprofloxacin 3

Shinto et al, 1992 Hydroxyapatite Gentamicin Rat 90

Table 5. Cumulative data from in-vivo studies with antibiotic-loaded in biodegradable

Bone graft, either as autograft or allograft, as a vehicle for local antibiotic delivery, has been

Morselized cancellous bone has been used extensively as bone graft material. There are variations in the material that depend on the method of preparation. The use of morselized cancellous bone as a delivery carrier for antibiotics was developed in 1984 when there was limited choice in bone-grafting material and constraints related to biologic hazards were manageable (McLaren & Miniaci, 1986). Antibiotics can be added as a powered to morselized cancellous bone or by soaking the bone-graft in an antibiotic-loaded solution. The antibiotic is absorbed directly to the bone surfaces and subsequent release of antibiotics is based on first-order kinetics (McLaren, 2004). Although this clinical application protocols with a variety of different antibiotics, there are very little data regarding the actual concentration levels of the local antibiotics and the clinical effects that this practice has an

In vitro elution studies (McLaren & Miniaci, 1986) and in vivo studies in a rabbit model (McLaren, 1988) have shown first-order kinetics for release of tobramycin during a period of

Collagen Sponge Gentamicin Rabbit 56

Fibrin-clot Ciprofloxacin Rabbit 15

Lactic-acid Pefloxacin Rabbit 33

Gentamicin Canine 42

Ciprofloxacin Rabbit 42

Stemberger et al, 1997

Tsourvakas et al, 1995

Kanellakopoulou et al, 2000

materials

Garvin et al, 1994b Synthetic

Koort et al, 2008 Synthetic

**4.1 Bone grafts and bone substitutes** 

eventual bone graft incorporation.

Polymers

Polymers

used clinically for more than twenty years (McLaren, 2004).

over three weeks. Tobramycin levels exceeded usual bacteridical concentrations for three weeks in the graft material implanted in a rabbit. In another study, the results showed that morselized bone graft can act as a carrier netilmicin, vancomycin, clindamycin and rifampicin in vitro and in vivo. Antibiotics levels exceeded usual bacteridical concentrations for seven days in the graft material implanted in a rat (Witso et al, 2000).

Application of antibiotic impregnated autogenic cancellous bone grafting has already been introduced in clinical practice. Chan et al, in 1998, reported results from 36 patients with infected fractures resulting from traffic accidents. After surgical debridement an iliac cancellous bone graft was taken and mixed by the surgeon with piperacillin and/or vancomycin, depending on the susceptibility of the isolated infective micro-organism. The graft was then implanted at the site of infection inside the osseous defect, which occurred principally in the proximal, middle or distal segment of the left or right tibia. Four to five months were necessary for bone union, and the only complications presented were skin rashes.

Impregnation of antimicrobial agents within osteoconductive biomaterials (calcium sulfate, calcium phosphate, hydroxyapatite or tricalcium phosphate) has been proposed for local treatment of osteomyelitis and to aid dead space management (Kawanabe et al, 1998; Makinen et al, 2005; Nelson et al, 2005). As a common feature, these implants show a rapid release of the antibiotic in a more or less controlled manner (McLaren, 2004). One of the benefits of this class of materials is that implantation provides the opportunity to deliver local antibiotics at high concentrations and simultaneously participate in the bone regeneration process during the time period of material degradation. These materials also avoid the risk of transmitting disease pathogens associated with the use of allograft bone.

Of these materials, commercial calcium sulfate has probably been used most commonly in the clinical setting of osteomyelitis treatment (Gitelis & Brebach, 2002). The most appropriate antibiotic dosage regimen not clear however, the most common formulation used clinically has been 3.64% vancomycin or 4.25% tobramycin per weight (Gitelis & Brebach, 2002). These percentages equate to 1g of vancomycin or 1.2g for tobramycin per 25g of calcium sulfate. Other antibiotic-loaded biomaterials being investigated in this category include calcium hydroxyapatites (Shirliff et al, 2002), calcium phosphates (Lazarettos et al, 2004), bioactive glasses (Kawanabe et al, 1998) and antibiotic loaded blood coated demineralized bone (Rhyu et al, 2003).

#### **4.2 Natural polymers (protein-based materials)**

This category includes antibiotic-loaded sponge collagen (Mehta et al, 1996; Ruszcak & Friess, 2003), fibrin (Tredwell et al, 2005; Tsourvakas et al, 1995), thrombin, and other commercially available systems that use clotted blood products. Although there are investigators actively involved in the use of these materials, their use as local antibiotic delivery vehicles is not as common as the use of antibiotic-loaded bone cement, antibioticloaded bone graft substitutes in the treatment of bone and soft tissue infections.

These materials function as delivery vehicles by providing a physical scaffold around the antibiotic mechanically limiting fluid flow, or by providing a protein to bind the antibiotic. Some data on release properties are published for all of these materials determined by either elution studies or by animal studies. Elution rates, tend to be rapid, leading to release of

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 31

dissolves and diffuses slowly from the fibrin clot. Even more water-soluble antibiotics such as gentamicin and ciprofloxacin have been shown to release in vitro from fibrin over 5-7 days for gentamicin (Kram et al, 1991) and over 60 days for ciprofloxacin (Tsourvakas et al, 1995), although more than 66% was released in the first two days. In an animal model the maximum level of ciprofloxacin in bone and soft tissues, after the implantation of composite in the medullary canal of rabbit tibia, was obtained on the second day after implantation, and the

Zilch and Lambiris (1986) measured the cefotaxime concentrations in both blood and wound drainage from 46 patients with osteomyelitis who were treated with a fibrin clot cefotaxime mixture injected into the bone cavity. These authors reported serum levels that were low within 12 hours after fibrin clot placement, but wound drainage fluid maintained high

Fibrin clot antibiotic mixtures are a promising approach to providing a biocompatible tissue sealant with local antibiotic release that may decrease the incidence of postoperative infections. Further in vitro work is necessary to characterize the effect the addition of antibiotics has on the rate and strength of fibrin clotting. Additional in vivo data are necessary to determine what effect low systemic levels of antibiotics might have on

Although collagen sponge is an established method of managing infection, there is great interest in developing a carrier with longer lasting effects and better penetration. Biodegradable synthetic polymers have been used in surgery since the 1950s as suture material. Advances in processing have generated stronger, more reliable synthetic polymers

The most active area of current research using biodegradable polymers from glycolide and lactide is in the controlled delivery of drugs especially in antibiotics such as ampicillin, gentamicin, polymyxin B and quinolones (Calhoun & Mader, 1997; Kanellakopoulou et al, 1994; Nie et al, 1995). Polylactide/polyglycolide was selected to act as a carrier because it undergoes a gradual degradation in a controlled manner and dissolves at physiological pH and removal is thus not necessary in patients who have bone and soft tissue infections (Nandi et al, 2009). A second advantage is that the kinetics of the release of the antibiotic can be modified by the selection of copolymers of varying monometric composition, polymer crystallinity and molecular weight as well as by alteration of the geometry of the implant. Finally, preliminary studies indicated that these materials is highly compatible with a wide variety of antibiotics and the in vivo release of antibiotics occurs for a definite time period with therapeutic concentrations, which may minimize slow residual release at suboptimal

Polymers are available in different patterns such as polylactides, copolymers of lactide and glycolide, polyanhydride and polycarpolactone. Copolymers of polylactides and polyglycolic acid have been produced with a ratio between the two composites varying between 90:10 and 50:50. It has been observed from in vitro studies that the 90:10 ratio provides better stability, delayed decomposition and superior elution concentrations of

based implants for consideration as carriers (El-Husseiny et al, 2011).

drug was undetectable after ten days (Tsourvakas et al, 1995).

concentrations for more than 3 days.

antibiotic resistance patterns.

concentrations (Makinen et al, 2005).

**4.3 Synthetic polymers** 

essentially all of the contained antibiotic in the range of hours to a few days. Antibiotic release in animal models is slower. Time to release the majority of contained antibiotic ranges from many days to several weeks. The investigations generating these data are limited, using a wide spectrum of methods, making a comparison of performance of these materials invalid. Clinical guidelines for the amount of the material to be used and for the dose of the contained antibiotic are not possible (McLaren, 2004).

Collagen sponge is the material in this group that was the best supporting data. It is a solid mesh of collagen-based spongy material, produced from sterile animal skin or tendo Achillis. Since collagen is a major component of connective tissue and the main structural protein of all organs, it has several desirable biological properties, including both biocompatibility and non-toxicity. Its ability to release drugs can be modified by changing the porosity of the matrix or by treating it with chemicals (Rao, 1995). It can also attract and stimulate the proliferation of osteoblasts, thereby promoting mineralization and the production of collagenous callus tissue, which aids the formation of new bone (Reddi, 1985).

Collagen sheets with impregnated gentamicin have been used to treat chronic osteomyelitis (Ipsen et al, 1991). It has been commercially available in Europe for ten years and is produced from sterilized bovine tendon in which gentamicin is suspended. In vitro studies of antibiotic release from collagen sponges showed four days to complete (Wachol-Drewek et al, 1996). When collagen sponge is combined with liposome encapsulated antibiotics, the duration of time for release of the antibiotics has been reported to be up to three times greater that that of collagen sponge alone (Trafny et al, 1996). Polymyxin-B and amikacin have been shown in other laboratory experiments to have significant sustained release action against Pseudomonas aeruginosa when attached to type I collagen (Trafny et al, 1995). Gentamicin impregnated collagen sponge shows up to 600 times MIC as compared to polymethylmethacrylate beads at 300 times MIC .It has also been observed that due to its release of large amounts of gentamicin the flexible gentamicin-contained collagen sponge proved to be superior to the rigid polymethylmethacrylate beads. Other authors conclude that it is an effective delivery vehicle for up to 28 days in a rabbit model (Humphrey et al, 1998) and that it is effective clinically (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Further characterization and technique refinement are required before it can be recommended as a delivery vehicle for antibiotics. Commercially prepared antibiotic-laden collagen sponge is not available for use in the United States.

Fibrin sealants are topical hemostatic materials derived from plasma coagulation proteins that are being used increasingly in surgical procedures (Jackson, 2001). Fibrin sealants have great potential for the delivery of antibiotics, chemotherapy, and even growth factors at surgical sites (Jackson, 2001). They are biocompatible and degrade by normal fibrinolysis within days or weeks depending on the site. The main use of fibrin sealants has been in cardiovascular, thoracic, dental, plastic and reconstructive surgery. More recently, orthopedic procedures, such as total knee arthroplasty or hip replacement, have also been shown to benefit from the use of fibrin sealants (Jackson, 2001).

Clearly, the compatibility of these materials with surgical wound sites makes fibrin sealant logical candidates for use as controlled-release carriers for local antibiotic delivery. It has been shown that antibiotics with low water solubility, such as tetracycline base, are particularly suited to this system (Woolveron et al, 2001), presumably because the precipitated drug dissolves and diffuses slowly from the fibrin clot. Even more water-soluble antibiotics such as gentamicin and ciprofloxacin have been shown to release in vitro from fibrin over 5-7 days for gentamicin (Kram et al, 1991) and over 60 days for ciprofloxacin (Tsourvakas et al, 1995), although more than 66% was released in the first two days. In an animal model the maximum level of ciprofloxacin in bone and soft tissues, after the implantation of composite in the medullary canal of rabbit tibia, was obtained on the second day after implantation, and the drug was undetectable after ten days (Tsourvakas et al, 1995).

Zilch and Lambiris (1986) measured the cefotaxime concentrations in both blood and wound drainage from 46 patients with osteomyelitis who were treated with a fibrin clot cefotaxime mixture injected into the bone cavity. These authors reported serum levels that were low within 12 hours after fibrin clot placement, but wound drainage fluid maintained high concentrations for more than 3 days.

Fibrin clot antibiotic mixtures are a promising approach to providing a biocompatible tissue sealant with local antibiotic release that may decrease the incidence of postoperative infections. Further in vitro work is necessary to characterize the effect the addition of antibiotics has on the rate and strength of fibrin clotting. Additional in vivo data are necessary to determine what effect low systemic levels of antibiotics might have on antibiotic resistance patterns.

#### **4.3 Synthetic polymers**

30 Selected Topics in Plastic Reconstructive Surgery

essentially all of the contained antibiotic in the range of hours to a few days. Antibiotic release in animal models is slower. Time to release the majority of contained antibiotic ranges from many days to several weeks. The investigations generating these data are limited, using a wide spectrum of methods, making a comparison of performance of these materials invalid. Clinical guidelines for the amount of the material to be used and for the

Collagen sponge is the material in this group that was the best supporting data. It is a solid mesh of collagen-based spongy material, produced from sterile animal skin or tendo Achillis. Since collagen is a major component of connective tissue and the main structural protein of all organs, it has several desirable biological properties, including both biocompatibility and non-toxicity. Its ability to release drugs can be modified by changing the porosity of the matrix or by treating it with chemicals (Rao, 1995). It can also attract and stimulate the proliferation of osteoblasts, thereby promoting mineralization and the production of collagenous callus tissue, which aids the formation of new bone (Reddi, 1985). Collagen sheets with impregnated gentamicin have been used to treat chronic osteomyelitis (Ipsen et al, 1991). It has been commercially available in Europe for ten years and is produced from sterilized bovine tendon in which gentamicin is suspended. In vitro studies of antibiotic release from collagen sponges showed four days to complete (Wachol-Drewek et al, 1996). When collagen sponge is combined with liposome encapsulated antibiotics, the duration of time for release of the antibiotics has been reported to be up to three times greater that that of collagen sponge alone (Trafny et al, 1996). Polymyxin-B and amikacin have been shown in other laboratory experiments to have significant sustained release action against Pseudomonas aeruginosa when attached to type I collagen (Trafny et al, 1995). Gentamicin impregnated collagen sponge shows up to 600 times MIC as compared to polymethylmethacrylate beads at 300 times MIC .It has also been observed that due to its release of large amounts of gentamicin the flexible gentamicin-contained collagen sponge proved to be superior to the rigid polymethylmethacrylate beads. Other authors conclude that it is an effective delivery vehicle for up to 28 days in a rabbit model (Humphrey et al, 1998) and that it is effective clinically (Kanellakopoulou & Giamarellos-Bourboulis, 2000). Further characterization and technique refinement are required before it can be recommended as a delivery vehicle for antibiotics. Commercially prepared antibiotic-laden

Fibrin sealants are topical hemostatic materials derived from plasma coagulation proteins that are being used increasingly in surgical procedures (Jackson, 2001). Fibrin sealants have great potential for the delivery of antibiotics, chemotherapy, and even growth factors at surgical sites (Jackson, 2001). They are biocompatible and degrade by normal fibrinolysis within days or weeks depending on the site. The main use of fibrin sealants has been in cardiovascular, thoracic, dental, plastic and reconstructive surgery. More recently, orthopedic procedures, such as total knee arthroplasty or hip replacement, have also been

Clearly, the compatibility of these materials with surgical wound sites makes fibrin sealant logical candidates for use as controlled-release carriers for local antibiotic delivery. It has been shown that antibiotics with low water solubility, such as tetracycline base, are particularly suited to this system (Woolveron et al, 2001), presumably because the precipitated drug

dose of the contained antibiotic are not possible (McLaren, 2004).

collagen sponge is not available for use in the United States.

shown to benefit from the use of fibrin sealants (Jackson, 2001).

Although collagen sponge is an established method of managing infection, there is great interest in developing a carrier with longer lasting effects and better penetration. Biodegradable synthetic polymers have been used in surgery since the 1950s as suture material. Advances in processing have generated stronger, more reliable synthetic polymers based implants for consideration as carriers (El-Husseiny et al, 2011).

The most active area of current research using biodegradable polymers from glycolide and lactide is in the controlled delivery of drugs especially in antibiotics such as ampicillin, gentamicin, polymyxin B and quinolones (Calhoun & Mader, 1997; Kanellakopoulou et al, 1994; Nie et al, 1995). Polylactide/polyglycolide was selected to act as a carrier because it undergoes a gradual degradation in a controlled manner and dissolves at physiological pH and removal is thus not necessary in patients who have bone and soft tissue infections (Nandi et al, 2009). A second advantage is that the kinetics of the release of the antibiotic can be modified by the selection of copolymers of varying monometric composition, polymer crystallinity and molecular weight as well as by alteration of the geometry of the implant. Finally, preliminary studies indicated that these materials is highly compatible with a wide variety of antibiotics and the in vivo release of antibiotics occurs for a definite time period with therapeutic concentrations, which may minimize slow residual release at suboptimal concentrations (Makinen et al, 2005).

Polymers are available in different patterns such as polylactides, copolymers of lactide and glycolide, polyanhydride and polycarpolactone. Copolymers of polylactides and polyglycolic acid have been produced with a ratio between the two composites varying between 90:10 and 50:50. It has been observed from in vitro studies that the 90:10 ratio provides better stability, delayed decomposition and superior elution concentrations of

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 33

The range of different intended functions of these materials include different rates and timing of antibiotic release, provision of physicochemical characteristics necessary for osteoconduction, and provision of a scaffold that allows osteoconduction, osseous

Antibiotic loaded plaster of Paris pellets is an effective ancillary treatment in the surgery of infected cavities in bone. It is well tolerated and spontaneous absorbed over a period of weeks to months, being replaced by bone if normal architecture (Mackey et al, 1982). Many antibiotics can be added to plaster of Paris, such as gentamicin, fucidic acid, and teicoplanin

Fibres locally releasing tetracycline hydrochloride have been successfully introduced for the therapy of persistent or recurrent periodontitis (Tonetti et al, 1998). Chitosan is an excellent biomaterial with biodegradable and immunologic activity, the gentamicin loaded chitosan bar seems to be a clinically useful method for the treatment of bone and soft tissue infections (Aimin et al, 1999). Different types of gel like hyalouronic acid (Matsuno et al, 2006), fibrin gel with bone marrow derived mesenchymal stem cells (Hou et al, 2008), and monoolein-water gels (Ouedraogo et al, 2008) have been used as an

Some unconventional marine biomaterials like sponge skeleton, coral, snail slime with varied intraglanular porosity are future promising options as bone grafts substitute. Most of the commonly used and under trial bone graft substitutes only have osteoconductive and osteogenic characters. Therefore, it is of paramount necessity to develop an ideal novel smart biomaterials with all three properties which cannot only provide sufficient concentration of antibiotic at the target site but also act as a bone strut to accelerate the goal. This may be achieved by combining conventional and some unconventional growth factors with the carrier materials including the incorporation of stem cells (Nandi et al, 2009).

The necessary data on the efficacy of these new biodegradable materials still are in early stages of development and assessment. Despite the vast potential to develop composite biomaterials that can provide multiple functions, the complexity of the cellular and molecular interactions within the wound environment exposes the potential for unforeseen adverse consequences. In fact, many of the clinical scenarios of treatment of musculoskeletal infection include the need for local antibiotics and stimulation of the process of bone regeneration. One of the most obvious adverse effects of high level of local antibiotics is an osteoblast function and subsequent bone regeneration. The concern is valid for specific clinical situations such as antibiotic bead pouches for treatment of open fractures (Henry et al, 1993b), bone grafting for nonunions, and implantation of devices into bone defects where bone regeneration is an intended outcome of the dead-

The appropriate use of antimicrobial agents has decreased morbidity and mortality from orthopedic-related infections. Although systemic antibiotic use has been used for many years, new methods of local antibiotic delivery may result in increased antibiotic levels, decreased toxicity, and possibly greater efficacy. Antibiotic impregnated polymethylmethacrylate beads

**4.4 Miscellaneous** 

integration, and sufficient structural properties.

alternative treatment for bone and soft tissue infections.

space management strategy (Gitelis & Brebach, 2002).

**5. Conclusion** 

(Dacquet et al, 1992; Mackey et al, 1982).

tobramycin, clindamycin and vancomycin than copolymers produced at other ratios (Bunetel et al, 1990). Copolymers (50:50)-gentamicin implant was significantly more successful than the use of the standard parenteral therapy in experimental osteomyelitis in canine model (Garvin et al, 1994).

The biocompatibility of polylactide/polyglycolide acid has been well established. The tissue reaction to implanted materials is minimum, with the inflammatory response limited to a narrow region, which gradually diminishes as the polymer is desorbed (Brady et al, 1973).

Although lactide/glycolide polymers were suggested as carriers for antibiotics thirty years ago (Thies, 1982), it was ten years before linked lactic acid chains were proposed as a drug delivery system for the treatment of bone and soft tissue infections. Wei et al in 1991 implanted molded rods, made by heating a mixture of lactic acid oligomer and dideoxykanamycin B, into rabbit models. They showed that the MIC of antibiotic for the common causative organisms of osteomyelitis was exceeded for six weeks in the cortex, the cancellous bone, and in the bone marrow. Furthermore, the majority of the implant material has been absorbed, and the bone marrow had returned to a nearly normal state within nine weeks of implantation.

Sampath et al in 1992 demonstrated an alternative method of delivering gentamicin locally using polymers. They prepared microcapsules composed of a polylactic acid shell containing gentamicin which was then compressed into the desired shape. It was noted that more 80% of antibiotic was released in the first three weeks in vitro. The efficacy of microcapsules in osteomyelitis has also been demonstrated in a study by Garvin et al, in 1994.

The polylactate polymers achieve prolonged in vivo quinolones release at higher levels than the other systems and produced their peal drug release after 15 days (Kanellakopoulou et al, 1994). On the basis of the adequacy of elution of quinolones from the polylactate carrier, pefloxacin impregnated of this carrier was used for therapy of an experimental osteomyelitis caused by the local application of MRSA in rabbits (Kanellakopoulou et al, 2000).

One of the primary drawbacks with synthetic polymers has been the difficulties associated with designing implants that also providing structural integrity. For this specific reason, the use of this category of biomaterials, like the other non-cement alternatives, has primarily been for the treatment of osteomyelitis. Although the structural requirements necessary for other applications can be accomplished for these implants initially, the process of polymer degradation often has led to severe loss of structural integrity during the course of treatment (Hanssen, 2005).

Synthetic polymers could function as a delivery vehicle for antibiotics with further evaluation and development. Manipulation of the material properties and combinations of one or more of these material can lead to any clinically desirable release rate. Investigations have been exploring these variables (Ambrose et al, 2003). However, no one material has shown dominance with confirmatory investigations and progression in development towards a usable clinical preparation. There are not available for clinical use as a depot antibiotic delivery vehicle. This may be related in part to the economics of bringing these products to market premixed with antibiotic. Currently, there is no polymer available that can be hand mixed with antibiotics in the operating room.

#### **4.4 Miscellaneous**

32 Selected Topics in Plastic Reconstructive Surgery

tobramycin, clindamycin and vancomycin than copolymers produced at other ratios (Bunetel et al, 1990). Copolymers (50:50)-gentamicin implant was significantly more successful than the use of the standard parenteral therapy in experimental osteomyelitis in

The biocompatibility of polylactide/polyglycolide acid has been well established. The tissue reaction to implanted materials is minimum, with the inflammatory response limited to a narrow region, which gradually diminishes as the polymer is desorbed (Brady et al, 1973). Although lactide/glycolide polymers were suggested as carriers for antibiotics thirty years ago (Thies, 1982), it was ten years before linked lactic acid chains were proposed as a drug delivery system for the treatment of bone and soft tissue infections. Wei et al in 1991 implanted molded rods, made by heating a mixture of lactic acid oligomer and dideoxykanamycin B, into rabbit models. They showed that the MIC of antibiotic for the common causative organisms of osteomyelitis was exceeded for six weeks in the cortex, the cancellous bone, and in the bone marrow. Furthermore, the majority of the implant material has been absorbed, and the bone marrow had returned to a nearly normal state

Sampath et al in 1992 demonstrated an alternative method of delivering gentamicin locally using polymers. They prepared microcapsules composed of a polylactic acid shell containing gentamicin which was then compressed into the desired shape. It was noted that more 80% of antibiotic was released in the first three weeks in vitro. The efficacy of microcapsules in

The polylactate polymers achieve prolonged in vivo quinolones release at higher levels than the other systems and produced their peal drug release after 15 days (Kanellakopoulou et al, 1994). On the basis of the adequacy of elution of quinolones from the polylactate carrier, pefloxacin impregnated of this carrier was used for therapy of an experimental osteomyelitis caused by the local application of MRSA in rabbits

One of the primary drawbacks with synthetic polymers has been the difficulties associated with designing implants that also providing structural integrity. For this specific reason, the use of this category of biomaterials, like the other non-cement alternatives, has primarily been for the treatment of osteomyelitis. Although the structural requirements necessary for other applications can be accomplished for these implants initially, the process of polymer degradation often has led to severe loss of structural integrity during the course of treatment

Synthetic polymers could function as a delivery vehicle for antibiotics with further evaluation and development. Manipulation of the material properties and combinations of one or more of these material can lead to any clinically desirable release rate. Investigations have been exploring these variables (Ambrose et al, 2003). However, no one material has shown dominance with confirmatory investigations and progression in development towards a usable clinical preparation. There are not available for clinical use as a depot antibiotic delivery vehicle. This may be related in part to the economics of bringing these products to market premixed with antibiotic. Currently, there is no polymer available that

can be hand mixed with antibiotics in the operating room.

osteomyelitis has also been demonstrated in a study by Garvin et al, in 1994.

canine model (Garvin et al, 1994).

within nine weeks of implantation.

(Kanellakopoulou et al, 2000).

(Hanssen, 2005).

The range of different intended functions of these materials include different rates and timing of antibiotic release, provision of physicochemical characteristics necessary for osteoconduction, and provision of a scaffold that allows osteoconduction, osseous integration, and sufficient structural properties.

Antibiotic loaded plaster of Paris pellets is an effective ancillary treatment in the surgery of infected cavities in bone. It is well tolerated and spontaneous absorbed over a period of weeks to months, being replaced by bone if normal architecture (Mackey et al, 1982). Many antibiotics can be added to plaster of Paris, such as gentamicin, fucidic acid, and teicoplanin (Dacquet et al, 1992; Mackey et al, 1982).

Fibres locally releasing tetracycline hydrochloride have been successfully introduced for the therapy of persistent or recurrent periodontitis (Tonetti et al, 1998). Chitosan is an excellent biomaterial with biodegradable and immunologic activity, the gentamicin loaded chitosan bar seems to be a clinically useful method for the treatment of bone and soft tissue infections (Aimin et al, 1999). Different types of gel like hyalouronic acid (Matsuno et al, 2006), fibrin gel with bone marrow derived mesenchymal stem cells (Hou et al, 2008), and monoolein-water gels (Ouedraogo et al, 2008) have been used as an alternative treatment for bone and soft tissue infections.

Some unconventional marine biomaterials like sponge skeleton, coral, snail slime with varied intraglanular porosity are future promising options as bone grafts substitute. Most of the commonly used and under trial bone graft substitutes only have osteoconductive and osteogenic characters. Therefore, it is of paramount necessity to develop an ideal novel smart biomaterials with all three properties which cannot only provide sufficient concentration of antibiotic at the target site but also act as a bone strut to accelerate the goal. This may be achieved by combining conventional and some unconventional growth factors with the carrier materials including the incorporation of stem cells (Nandi et al, 2009).

The necessary data on the efficacy of these new biodegradable materials still are in early stages of development and assessment. Despite the vast potential to develop composite biomaterials that can provide multiple functions, the complexity of the cellular and molecular interactions within the wound environment exposes the potential for unforeseen adverse consequences. In fact, many of the clinical scenarios of treatment of musculoskeletal infection include the need for local antibiotics and stimulation of the process of bone regeneration. One of the most obvious adverse effects of high level of local antibiotics is an osteoblast function and subsequent bone regeneration. The concern is valid for specific clinical situations such as antibiotic bead pouches for treatment of open fractures (Henry et al, 1993b), bone grafting for nonunions, and implantation of devices into bone defects where bone regeneration is an intended outcome of the deadspace management strategy (Gitelis & Brebach, 2002).

#### **5. Conclusion**

The appropriate use of antimicrobial agents has decreased morbidity and mortality from orthopedic-related infections. Although systemic antibiotic use has been used for many years, new methods of local antibiotic delivery may result in increased antibiotic levels, decreased toxicity, and possibly greater efficacy. Antibiotic impregnated polymethylmethacrylate beads

Local Antibiotic Therapy in the Treatment of Bone and Soft Tissue Infections 35

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are currently being used in a variety of applications, but this method require a second procedure for removal of the antibiotic delivery system.

There is considerable interest in finding methods of delivering effective doses of antimicrobial drugs locally, not only in orthopedics, but across a range of specialists. While most of the antibacterial agent contained within a biodegradable system may be eluted, only 25% is actually released from polymethylmethacrylate beads. Biodegradable materials could mimic bone substances like calcium phosphate based carriers can be chosen for local drug delivery system in osteomyelitis with potential clinical application in orthopedic surgery. Widespread research is currently being conducted in the area of local drug delivery systems to treat osteomyelitis. Despite this fact, much work is still desired in the areas of biodegradable and biocompatible materials, the kinetics of antibiotic release, and further development of current systems before many of these formulations can be used. The seer diversity of available systems and the lack of suitable trials comparing them in-vivo makes their evaluation difficult. Nonetheless, it is apparent that while collagen fleece is currently the most widely used antimicrobial carrier system, the duration of its antibiotic delivery is the shortest. Other delivery systems have shown greater promise, and these that are able both to stimulate the formation of new bone and provide a scaffold, such as composite antibiotic carriers, are most likely to gain widespread acceptance in the future.

In future, researchers remain optimistic that many of these systems can be developed with ideal zero-order release kinetics profiles, in-vivo, over long periods of time, allowing for widespread use in chronic osteomyelitis patients. By utilizing newer forms of sustainedrelease antibiotic delivery systems, it will be possible to deliver such antibiotics at constant rates over a prolonged period of time and would eliminate the need for multiple dosing. It is hoped that in the future, development of new implantable systems would be helpful to reduce the cost of drug therapy, increase the efficacy of drugs, and could enhance the patient's compliance.

#### **6. References**


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There is considerable interest in finding methods of delivering effective doses of antimicrobial drugs locally, not only in orthopedics, but across a range of specialists. While most of the antibacterial agent contained within a biodegradable system may be eluted, only 25% is actually released from polymethylmethacrylate beads. Biodegradable materials could mimic bone substances like calcium phosphate based carriers can be chosen for local drug delivery system in osteomyelitis with potential clinical application in orthopedic surgery. Widespread research is currently being conducted in the area of local drug delivery systems to treat osteomyelitis. Despite this fact, much work is still desired in the areas of biodegradable and biocompatible materials, the kinetics of antibiotic release, and further development of current systems before many of these formulations can be used. The seer diversity of available systems and the lack of suitable trials comparing them in-vivo makes their evaluation difficult. Nonetheless, it is apparent that while collagen fleece is currently the most widely used antimicrobial carrier system, the duration of its antibiotic delivery is the shortest. Other delivery systems have shown greater promise, and these that are able both to stimulate the formation of new bone and provide a scaffold, such as composite

antibiotic carriers, are most likely to gain widespread acceptance in the future.

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**3** 

*USA* 

Alessandro Bonanno

**The Social Limits of Reconstructive Surgery:** 

**Stigma in Facially Disfigured Cancer Patients** 

The last few decades have been particularly significant in terms of advancements of scientific knowledge and medical knowledge in particular. Within medicine, reconstructive surgical procedures have achieved spectacular results. While the popularity of elective cosmetic procedures has reached unprecedented – and in some instances socially concerning – proportions, the beneficial effects of reconstructive surgery for trauma and/or disease generated cases have been significant. This is also the instance of patients affected by cancer of the head and neck. The multiplicity and frequencies of these forms of cancers now generate a large enough group of patients who face the condition of survivors

This chapter probes the issue of the limits of reconstructive surgery as a form of intervention that while addresses relevant medical problems, it also opens up new social problems. In this case, the issue studied is the social consequences of reconstructive surgery on head and neck cancer patients. In particular, this chapter investigates the manner in which social stigma is generated as cancer survivors re-enter society after reconstructive surgery and

Developments recorded in medicine increasingly generate the long term survival of cancer patients (American Cancer Society, 2009; Mood 1997; Davis, Wingo and Parker 1998). These medical improvements have also had beneficial results for head and neck patients (Davis, Roumanas and Nishimura 1997; Dropkin 1999). In the instance of this particular group of patients, needed surgical intervention signifies the removal of portions of the face that are affected by the malignancy. One of the common consequences of this type of intervention is the alteration of the patient's face and the permanent facial disfigurement that it entails (American Cancer Society, 2009). Surgical procedures to restore the original facial appearance are common. Similarly common is the availability of increasingly sophisticated – albeit often costly and difficult to use – prostheses (Davis, Roumanas and Nishimura 1997). Reconstructive surgery is central in the processes and its success is evident. However, the severity of the alterations caused by the removal of the malignancy, make a restoration of the normal shape of the face virtually impossible. The result is that the survival of the

with an added social problem: The stigma of being facially disfigured.

associated treatments concluded their cancer therapies.

**1. Introduction** 

*Texas State University System Regents Professor of Sociology Department of Sociology, Sam Houston State University* 


### **The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients**

#### Alessandro Bonanno

*Texas State University System Regents Professor of Sociology Department of Sociology, Sam Houston State University USA* 

#### **1. Introduction**

44 Selected Topics in Plastic Reconstructive Surgery

Walenkamp GH. (1997). Chronic osteomyelitis. *Acta Orthopaedica Scandinavica,* Vol. 68, No 5,

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Whiteside LA. (1994). Treatment of infected total knee arthroplasty. *Clinical Orthopaedic Related Research,* Vol. 299, (February 1994), pp. 169-172, ISSN 0009-921X Wilson KJ., Cierny G., Adams KR., & Mader JT. (1988). Comparative evaluation of the

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Witso E., Persen L., Loseth K., Benum P., & Bergh K. (2000). Cancellous bone as an antibiotic

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bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier. *Journal bone joint Surgery,* Vol. 73-B, No 2, (March

diffusion of tobramycin and cefotaxime out of antibiotic-impregnated polymethylmethacrylate beads. *Journal Orthopaedic Research,* Vol. 6, No 2, (March

infections. *Antimicrobial Agents Chemotherapy,* Vol. 40, No 12, (December 1996), pp.

carrier. *Acta Orthopaedica Scandinavica,* Vol. 71, No 1, (February 2000), pp.80-84,

M. (2001). Tetracycline delivery from fibrin controls peritoneal infection without measurable systemic antibiotic. *Journal Antimicrobial Chemotherapy,* Vol. 48, No 6,

segmental bone loss in the proximal part of the femur in two stages with use of an antibiotic loaded interval prosthesis. *Journal Bone Joint Surgery,* Vol. 80-A, No 1,

compound in treatment of osteitis. Pharmacokinetic study and clinical results. *Archives Orthopaedic Trauma Surgery,* Vol. 106, No 1, (January 1986), pp. 36-41, ISSN

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ISSN 0001-6470

0936-8051

The last few decades have been particularly significant in terms of advancements of scientific knowledge and medical knowledge in particular. Within medicine, reconstructive surgical procedures have achieved spectacular results. While the popularity of elective cosmetic procedures has reached unprecedented – and in some instances socially concerning – proportions, the beneficial effects of reconstructive surgery for trauma and/or disease generated cases have been significant. This is also the instance of patients affected by cancer of the head and neck. The multiplicity and frequencies of these forms of cancers now generate a large enough group of patients who face the condition of survivors with an added social problem: The stigma of being facially disfigured.

This chapter probes the issue of the limits of reconstructive surgery as a form of intervention that while addresses relevant medical problems, it also opens up new social problems. In this case, the issue studied is the social consequences of reconstructive surgery on head and neck cancer patients. In particular, this chapter investigates the manner in which social stigma is generated as cancer survivors re-enter society after reconstructive surgery and associated treatments concluded their cancer therapies.

Developments recorded in medicine increasingly generate the long term survival of cancer patients (American Cancer Society, 2009; Mood 1997; Davis, Wingo and Parker 1998). These medical improvements have also had beneficial results for head and neck patients (Davis, Roumanas and Nishimura 1997; Dropkin 1999). In the instance of this particular group of patients, needed surgical intervention signifies the removal of portions of the face that are affected by the malignancy. One of the common consequences of this type of intervention is the alteration of the patient's face and the permanent facial disfigurement that it entails (American Cancer Society, 2009). Surgical procedures to restore the original facial appearance are common. Similarly common is the availability of increasingly sophisticated – albeit often costly and difficult to use – prostheses (Davis, Roumanas and Nishimura 1997). Reconstructive surgery is central in the processes and its success is evident. However, the severity of the alterations caused by the removal of the malignancy, make a restoration of the normal shape of the face virtually impossible. The result is that the survival of the

The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients 47

In the course of the interviews both patients and family members were asked to reconstruct instances of encounters with strangers and acquaintances. The interviews were audio recorded with the participants' and family members' consent and the transcribed texts were analyzed employing the qualitative methodology Grounded Theory (Charmaz 2006). The guiding assumption of the study was to develop analytical categories (variables) that would identify patterns of interaction between facially disfigured cancer patients and members of secondary groups. These categories were created to illustrate the collective action process leading to stigma rather than the manner in which patients felt in the interaction process itself. Analytical categories were constructed through line-by-line coding and constant comparative analysis (Charmaz 2006). Once developed, codes were grouped in relevant categories that were saturated as no new relevant properties of these categories emerged. Along with saturation, the negative cases technique was employed to validate categories and their properties (Charmaz 2006; Holton 2007). In this case, there was a deliberate search for situations that would contradict the analysis. Their absence was employed to validate

Photo 1

the conclusions (Charmaz 2006).

patient and the success of the surgical interventions and medical treatments translate into a social problem: patients remain facially disfigured. Survivors typically live the rest of their lives with facial disfigurement.

Because of the importance of the face in social relations –a central element of communication (Kish and Lansdown, 2000; Macgregor, 1990), and an item employed to attribute both "normality" and ownership of socially desirable characteristics (Furness, Garrud, Faulder, Swift 2006; Goffman, 1963; Hawkesworth, 2001; Hughes, 1998; Ishii, Carey, Byrne, Zee and Ishii. 2009; Macgregor, 1974) –individuals with the abnormal face experience stigma and are treated differently than the rest of the members of society. They are labeled as different and treated as such (Bull and Stevens 1981; Callahan 2004:75; Furness et al. 2006; Hawkesworth 2001; Hughes 1998; Kent 2000; Macgregor 1951; 1974; 1990; Millstone 2008). According to available literature, facially disfigured patients' interaction with acquaintances and strangers – these are members of secondary social groups – is viewed as a constant source of stigma. Acquaintances and strangers are seen as exercising prejudice (negative feelings and/or beliefs) and/or discrimination (actual differential treatment) against patients. However, the characteristics of the interaction process have not been clearly mapped out leaving a gap in the available knowledge on the manner in which stigma is actually created (Hughes, 1998; Macgregor 1990; van Doorne, van Waas and Bergsma 1994). The knowledge obtained from this study contributes to the reduction of this gap and can be employed to inform caregivers as they deal with disfigured patients and their families.

#### **2. Methods**

This is a qualitative research based on in-depth interviews with a purposive sample fifteen cancer patients who underwent surgery to treat head and neck malignancies that affected their facial appearance. Patients were selected through the review of records at a major cancer center located in the Southwest of the United States of America. Eligibility criteria excluded persons under the age of 18, those who had surgery six month prior to the interview, those who were receiving active cancer therapy at the time of the interview, and those who could not express themselves in English. In-depth individual interviews were conducted between January 2008 and February 2010. Twenty potential participants were contacted. Two of them could not participate for scheduling problems and three refused to be part of the project. Finally, a total of eight men and seven women were interviewed. The median age of these patients was 66 years and the youngest patient was 31 and the oldest 81. The patients included in the study all underwent orbital exenteration. At the time of the interview, the post-surgical period ranged from ten months to thirty five years and the median was five years. Some patients underwent additional reconstructive and plastic surgical procedures. While the extent of disfigurement varied, all of the patients were left with significant alterations in their facial appearance. An illustration of the degree of disfigurement can be seen through the photos accompanying this chapter. Photos 1 and 2 are illustration of severe cases of disfigurement after ablative surgery. Photo 3 illustrates a case in which surgery allowed the use of a prosthesis that adequately concealed the disfigurement (Photo 4). One family member for each of the participating patients was also interviewed.

#### Photo 1

46 Selected Topics in Plastic Reconstructive Surgery

patient and the success of the surgical interventions and medical treatments translate into a social problem: patients remain facially disfigured. Survivors typically live the rest of their

Because of the importance of the face in social relations –a central element of communication (Kish and Lansdown, 2000; Macgregor, 1990), and an item employed to attribute both "normality" and ownership of socially desirable characteristics (Furness, Garrud, Faulder, Swift 2006; Goffman, 1963; Hawkesworth, 2001; Hughes, 1998; Ishii, Carey, Byrne, Zee and Ishii. 2009; Macgregor, 1974) –individuals with the abnormal face experience stigma and are treated differently than the rest of the members of society. They are labeled as different and treated as such (Bull and Stevens 1981; Callahan 2004:75; Furness et al. 2006; Hawkesworth 2001; Hughes 1998; Kent 2000; Macgregor 1951; 1974; 1990; Millstone 2008). According to available literature, facially disfigured patients' interaction with acquaintances and strangers – these are members of secondary social groups – is viewed as a constant source of stigma. Acquaintances and strangers are seen as exercising prejudice (negative feelings and/or beliefs) and/or discrimination (actual differential treatment) against patients. However, the characteristics of the interaction process have not been clearly mapped out leaving a gap in the available knowledge on the manner in which stigma is actually created (Hughes, 1998; Macgregor 1990; van Doorne, van Waas and Bergsma 1994). The knowledge obtained from this study contributes to the reduction of this gap and can be employed to inform caregivers as they deal with

This is a qualitative research based on in-depth interviews with a purposive sample fifteen cancer patients who underwent surgery to treat head and neck malignancies that affected their facial appearance. Patients were selected through the review of records at a major cancer center located in the Southwest of the United States of America. Eligibility criteria excluded persons under the age of 18, those who had surgery six month prior to the interview, those who were receiving active cancer therapy at the time of the interview, and those who could not express themselves in English. In-depth individual interviews were conducted between January 2008 and February 2010. Twenty potential participants were contacted. Two of them could not participate for scheduling problems and three refused to be part of the project. Finally, a total of eight men and seven women were interviewed. The median age of these patients was 66 years and the youngest patient was 31 and the oldest 81. The patients included in the study all underwent orbital exenteration. At the time of the interview, the post-surgical period ranged from ten months to thirty five years and the median was five years. Some patients underwent additional reconstructive and plastic surgical procedures. While the extent of disfigurement varied, all of the patients were left with significant alterations in their facial appearance. An illustration of the degree of disfigurement can be seen through the photos accompanying this chapter. Photos 1 and 2 are illustration of severe cases of disfigurement after ablative surgery. Photo 3 illustrates a case in which surgery allowed the use of a prosthesis that adequately concealed the disfigurement (Photo 4). One family member for each of the participating patients was also

lives with facial disfigurement.

disfigured patients and their families.

**2. Methods** 

interviewed.

In the course of the interviews both patients and family members were asked to reconstruct instances of encounters with strangers and acquaintances. The interviews were audio recorded with the participants' and family members' consent and the transcribed texts were analyzed employing the qualitative methodology Grounded Theory (Charmaz 2006). The guiding assumption of the study was to develop analytical categories (variables) that would identify patterns of interaction between facially disfigured cancer patients and members of secondary groups. These categories were created to illustrate the collective action process leading to stigma rather than the manner in which patients felt in the interaction process itself. Analytical categories were constructed through line-by-line coding and constant comparative analysis (Charmaz 2006). Once developed, codes were grouped in relevant categories that were saturated as no new relevant properties of these categories emerged. Along with saturation, the negative cases technique was employed to validate categories and their properties (Charmaz 2006; Holton 2007). In this case, there was a deliberate search for situations that would contradict the analysis. Their absence was employed to validate the conclusions (Charmaz 2006).

The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients 49

Three primary analytical categories were generated to illustrate patients' interaction with secondary groups leading to stigmatization: Intrusion, sympathy and benign neglect. Intrusion indicates interaction based on unsolicited attention paid to patients. Strangers and acquaintances ask unwanted questions, make unwelcome remarks, stare and/or make their unspoken curiosity felt. Sympathy refers to unsolicited comments and/or actions showing support to patients and the desire to be of assistance, while benign neglect denotes a situation in which interaction is characterized by people not paying particular attention to patients. Additionally, small and large groups also emerged as relevant categories as differences exist in interaction within these groups. Intrusion, sympathy and benign neglect describe conditions that are decreasingly favorable to the creation of stigma. As intrusion fosters stigma, benign neglect defines patterns on interaction in which patients are granted that kind indifference that is "normally" given to strangers and/or distant attention granted

Photo 4.

to acquaintances.

Photo 2

Photo 3.

#### Photo 4.

48 Selected Topics in Plastic Reconstructive Surgery

Photo 2

Photo 3.

Three primary analytical categories were generated to illustrate patients' interaction with secondary groups leading to stigmatization: Intrusion, sympathy and benign neglect. Intrusion indicates interaction based on unsolicited attention paid to patients. Strangers and acquaintances ask unwanted questions, make unwelcome remarks, stare and/or make their unspoken curiosity felt. Sympathy refers to unsolicited comments and/or actions showing support to patients and the desire to be of assistance, while benign neglect denotes a situation in which interaction is characterized by people not paying particular attention to patients. Additionally, small and large groups also emerged as relevant categories as differences exist in interaction within these groups. Intrusion, sympathy and benign neglect describe conditions that are decreasingly favorable to the creation of stigma. As intrusion fosters stigma, benign neglect defines patterns on interaction in which patients are granted that kind indifference that is "normally" given to strangers and/or distant attention granted to acquaintances.

The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients 51

Among the limits of this otherwise important literature, is the lack of attention paid to the social process that generates stigma (Kent 2000:199; Clarke 1999; Furness et al., 2006; Thompson and Kent 2001). In particular, limited attention has been paid to the fact that disfigurement and stigma are socially constructed and generated through processes of interaction that involve multiple actors and take different forms according to the settings in which they unfold (Kent 2000). Accordingly, it is important to recognize that attention paid to the adaptation of patients to their condition of facially disfigured is only one component of an otherwise much more complex process in which "others" are often the source of stigma. In this respect, and while evidence indicates that society as a whole is the primary source of stigma (Callahan, 2004; Hagedoorm and Molleman, 2006; Kish and Lansdown 2000; Pruzinsky et al. 2006; van Doorne et al. 1994:325), the manners through which stigma emerges in interaction between the patients and "others" requires further investigation (Bonanno, Choi and Esmaeli 2008). More specifically, because stigma does not occur homogeneously, it is important to identify the circumstances in which it appears in interaction and the ways in which interaction can be directed to avoid the occurrence of stigma. Van Doorne et al. (1994), for instance, indicate that interaction with strangers almost certainly leads to the creation of stigma. They, however, stress that interaction with acquaintances requires additional investigation. The present study addresses this

A model of interaction patterns between facially disfigured cancer patients and members of secondary groups was generated through the application of Grounded theory (Charmaz

In the case of the interaction of patients with members of secondary groups, three fundamental analytical categories were developed. *Intrusion* indicates interaction based on unsolicited attention paid to patients by strangers and acquaintances. People ask unwanted questions, make unwelcome remarks, stare and make their unspoken curiosity felt. *Sympathy* refers to unsolicited comments and/or actions showing support to patients and the desire to be of assistance. Finally, *benign neglect* denotes a situation in which interaction is characterized by people not paying particular attention to patients and giving them that "civil inattention" and/or distant attention that characterizes everyday interaction among strangers. Benign neglect is the desired form of interaction as it does not generate stigma.

Interaction patterns change in regard to the size of interacting groups. Interaction characterized by intrusion in large and small groups generates stigma. These are *felt* and *enacted* forms of stigma. Sympathy produces enacted stigma in interaction in small groups and enacted and felt stigma in interaction within large groups. As by definition, benign neglect does not produce stigma in interaction within all groups. Following are more

*Intrusion* – This is a situation that engenders stigma in interaction within small and large groups alike. Members of interacting groups grant disfigured individuals the particular status of "different" through the construction of actions based on unwanted attention. Strangers and acquaintances' questions, stares, remarks constitute elements that transform disfigurement into stigma. Of particular importance are situations in which patients remain for relatively long periods of time in a relatively still position in full view of others. Because of this

2006; Holton 2007). Figure 1 graphically synthesizes this model.

gap in current knowledge.

detailed illustrations of these patterns.

**4. Results** 

#### **3. Brief review of salient literature on cancer generated facial disfigurement**

Stigma is defined as the "social disgrace" associated with people who are considered different (Goffman 1963). Difference is socially constructed and is the outcome of discrepancies between an individual virtual social identity (expectations about what that individual ought to be) and his/her actual social identity (the attributes he/she actually posses) (Goffman 1963:2). When the actual social identity is perceived as departing from normality, the individual is stigmatized. Stigma is attached to an individual's feature "that is deeply discrediting" and that separates that person from the group of the "normals." However, its actual genesis is relational as he/she is constantly compared to other members of society. Therefore, some specific individual characteristics generate stigma in some instances but not in others (de-stigmatization). Stigma is generated by the existence of a number of blemishes. There are those of individual character such as homosexuality, dishonesty, imprisonment, radical political behavior, and addiction. There are those of tribal stigma that are related to a person's group of reference such as religion, ethnicity or race. And there are those of "abominations of the body" that refer to physical abnormalities. Facial disfigurement pertains to this last category.

Stigma has been widely studied and this production includes works such as those on stigma generated from diseases (i.e., cancer and AIDS) (Fife and Wright, 2000), physical disabilities (Cahill and Eggleston, 1995; Susman 1994 Link and Phelan 2001:365-66; Jacobi 1994), and mental health (Angermeyer and Matschinger 1994; Corrigan and Penn 1999; Cahill and Eggleston, 1995). Despite this wealth of contributions, stigma caused by facial disfigurement has been the subject of only a relatively small number of works (Clarke 1999; Clarke et al. 2003; Kent, 2000; Kish and Lansdown 2000; Hughes, 1998; Pruizinsky et al. 2006). These analyses stress the social importance of the face, the problems that affect those who display visible facial blemishes and indicate that the face represents one of the most notable physical attributes and a significant source of social information prior to, and during, social interaction (Anderson and Franke 2002; Cole 1998; Furness et al. 2006; Goffman 1963; Hawkesworth 2001; Hughes, 1998; Macgregor 1974) Accordingly, people possessing an attractive face are not only considered physically pleasing, but they are often viewed as endowed with intellectual and emotional characteristics such as intelligence, kindness, and high morality and better treated by others than less attractive individuals (Bull and Rumsey 1998; Cash and Pruzinsky 2002; Feingold 1992; Kish and Lansdown 2000; Macgregor 1990). Facially disfigured individuals commonly engender negative responses by other members of society (Callahan, 2004; Hagedoorm and Molleman, 2006: Kish and Lansdown 2000). Stigma is further divided into felt stigma and enacted stigma (Jacobi 1994). Felt stigma refers to situations in which the individual perceive that he/she is viewed as different. Enacted stigma refers to explicit actions that result in stigma. In both instances, stigma is a relational process as it involves at least two interacting parties.

Facially disfigured cancer patients are primarily concerned with surviving cancer. Yet, as their survival becomes apparent, they become concerned with disfigurement: a situation that affects both patients and their family members (Bonanno 2009; van Doorne, van Waas and Bergsma 1994). The association of cancer and disfigurement is persistent. Therapy almost inevitably mandates surgical removal of cancer-affected parts of the face making it an undesirable consequence of successful medical intervention (Callahan 2004; Millsopp, Brandom, Humphris, and Lowe 2006; Valente 2004).

Among the limits of this otherwise important literature, is the lack of attention paid to the social process that generates stigma (Kent 2000:199; Clarke 1999; Furness et al., 2006; Thompson and Kent 2001). In particular, limited attention has been paid to the fact that disfigurement and stigma are socially constructed and generated through processes of interaction that involve multiple actors and take different forms according to the settings in which they unfold (Kent 2000). Accordingly, it is important to recognize that attention paid to the adaptation of patients to their condition of facially disfigured is only one component of an otherwise much more complex process in which "others" are often the source of stigma. In this respect, and while evidence indicates that society as a whole is the primary source of stigma (Callahan, 2004; Hagedoorm and Molleman, 2006; Kish and Lansdown 2000; Pruzinsky et al. 2006; van Doorne et al. 1994:325), the manners through which stigma emerges in interaction between the patients and "others" requires further investigation (Bonanno, Choi and Esmaeli 2008). More specifically, because stigma does not occur homogeneously, it is important to identify the circumstances in which it appears in interaction and the ways in which interaction can be directed to avoid the occurrence of stigma. Van Doorne et al. (1994), for instance, indicate that interaction with strangers almost certainly leads to the creation of stigma. They, however, stress that interaction with acquaintances requires additional investigation. The present study addresses this gap in current knowledge.

#### **4. Results**

50 Selected Topics in Plastic Reconstructive Surgery

**3. Brief review of salient literature on cancer generated facial disfigurement**  Stigma is defined as the "social disgrace" associated with people who are considered different (Goffman 1963). Difference is socially constructed and is the outcome of discrepancies between an individual virtual social identity (expectations about what that individual ought to be) and his/her actual social identity (the attributes he/she actually posses) (Goffman 1963:2). When the actual social identity is perceived as departing from normality, the individual is stigmatized. Stigma is attached to an individual's feature "that is deeply discrediting" and that separates that person from the group of the "normals." However, its actual genesis is relational as he/she is constantly compared to other members of society. Therefore, some specific individual characteristics generate stigma in some instances but not in others (de-stigmatization). Stigma is generated by the existence of a number of blemishes. There are those of individual character such as homosexuality, dishonesty, imprisonment, radical political behavior, and addiction. There are those of tribal stigma that are related to a person's group of reference such as religion, ethnicity or race. And there are those of "abominations of the body" that refer to physical abnormalities.

Stigma has been widely studied and this production includes works such as those on stigma generated from diseases (i.e., cancer and AIDS) (Fife and Wright, 2000), physical disabilities (Cahill and Eggleston, 1995; Susman 1994 Link and Phelan 2001:365-66; Jacobi 1994), and mental health (Angermeyer and Matschinger 1994; Corrigan and Penn 1999; Cahill and Eggleston, 1995). Despite this wealth of contributions, stigma caused by facial disfigurement has been the subject of only a relatively small number of works (Clarke 1999; Clarke et al. 2003; Kent, 2000; Kish and Lansdown 2000; Hughes, 1998; Pruizinsky et al. 2006). These analyses stress the social importance of the face, the problems that affect those who display visible facial blemishes and indicate that the face represents one of the most notable physical attributes and a significant source of social information prior to, and during, social interaction (Anderson and Franke 2002; Cole 1998; Furness et al. 2006; Goffman 1963; Hawkesworth 2001; Hughes, 1998; Macgregor 1974) Accordingly, people possessing an attractive face are not only considered physically pleasing, but they are often viewed as endowed with intellectual and emotional characteristics such as intelligence, kindness, and high morality and better treated by others than less attractive individuals (Bull and Rumsey 1998; Cash and Pruzinsky 2002; Feingold 1992; Kish and Lansdown 2000; Macgregor 1990). Facially disfigured individuals commonly engender negative responses by other members of society (Callahan, 2004; Hagedoorm and Molleman, 2006: Kish and Lansdown 2000). Stigma is further divided into felt stigma and enacted stigma (Jacobi 1994). Felt stigma refers to situations in which the individual perceive that he/she is viewed as different. Enacted stigma refers to explicit actions that result in stigma. In both instances, stigma is a relational

Facially disfigured cancer patients are primarily concerned with surviving cancer. Yet, as their survival becomes apparent, they become concerned with disfigurement: a situation that affects both patients and their family members (Bonanno 2009; van Doorne, van Waas and Bergsma 1994). The association of cancer and disfigurement is persistent. Therapy almost inevitably mandates surgical removal of cancer-affected parts of the face making it an undesirable consequence of successful medical intervention (Callahan 2004; Millsopp,

Facial disfigurement pertains to this last category.

process as it involves at least two interacting parties.

Brandom, Humphris, and Lowe 2006; Valente 2004).

A model of interaction patterns between facially disfigured cancer patients and members of secondary groups was generated through the application of Grounded theory (Charmaz 2006; Holton 2007). Figure 1 graphically synthesizes this model.

In the case of the interaction of patients with members of secondary groups, three fundamental analytical categories were developed. *Intrusion* indicates interaction based on unsolicited attention paid to patients by strangers and acquaintances. People ask unwanted questions, make unwelcome remarks, stare and make their unspoken curiosity felt. *Sympathy* refers to unsolicited comments and/or actions showing support to patients and the desire to be of assistance. Finally, *benign neglect* denotes a situation in which interaction is characterized by people not paying particular attention to patients and giving them that "civil inattention" and/or distant attention that characterizes everyday interaction among strangers. Benign neglect is the desired form of interaction as it does not generate stigma.

Interaction patterns change in regard to the size of interacting groups. Interaction characterized by intrusion in large and small groups generates stigma. These are *felt* and *enacted* forms of stigma. Sympathy produces enacted stigma in interaction in small groups and enacted and felt stigma in interaction within large groups. As by definition, benign neglect does not produce stigma in interaction within all groups. Following are more detailed illustrations of these patterns.

*Intrusion* – This is a situation that engenders stigma in interaction within small and large groups alike. Members of interacting groups grant disfigured individuals the particular status of "different" through the construction of actions based on unwanted attention. Strangers and acquaintances' questions, stares, remarks constitute elements that transform disfigurement into stigma. Of particular importance are situations in which patients remain for relatively long periods of time in a relatively still position in full view of others. Because of this

The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients 53

*Sympathy* – It refers to intrusive patterns of interaction in which individuals provide and/or manifest support to facially disfigured patients. It creates enacted stigma in small group interaction and felt and enacted stigma in large group interaction. In the case of small group interaction, *supportive curiosity* occurs. It refers to questions that people ask about patients' appearance that are accompanied by actions and expressions that are supportive of patients. It is a form of enacted stigma. The expression "everybody is nice," frequently reported by patients, captures this pattern of interaction. Patients do not experience felt stigma as they feel comfortable with the support that strangers and acquaintances offer. In large group interaction, patients may use this offered support to their advantage even when it is not necessary. This *instrumentality* is not exercised in small groups. Interaction in large groups, however, leads to stigma when offered assistance is viewed as unnecessary and/or exaggerated in relation to the actual physical conditions of patients. Simultaneously, when sympathy guided action transcends established expectations and creates *unfounded attention* enacted stigma occurs in small and large groups. Because of their status of cancer survivors and facially disfigured individuals, patients are granted what they perceive as undeserved respect. These actions

*Benign Neglect* – refers to interaction in which strangers and acquaintances do not pay particular attention to disfigured individuals. It is that common pattern that characterizes interaction among people who are not familiar with each other. While people are aware of the presence of others, they do not focus on, nor pay particular attention to, their actions. As Macgregor (1974: 60) put it, "it is that civil inattention normally granted to others in society." Because of its "normality," interaction characterized by benign neglect becomes particularly important in situations in which difference is present. Facially disfigured individuals not only feel comfortable during these interactions, but also acknowledge the fact that they are treated normally without any particular emphasis placed on their

This study demonstrates the ways in which interaction between facially disfigure cancer patients and secondary groups creates stigma. Because only limited knowledge is available on this topic, caregivers should use these results to assist patients and provide needed information and assistance to patients' family members. Through a grounded theory analysis, the study identifies key types of interaction patterns related to social stigma. These findings add to existing knowledge in a variety of ways. First, they point out that interaction between facially disfigure cancer patients and secondary groups is not a uniform process but it varies according to different settings and groups. It follows that current knowledge that indicates that "the reaction of people on the streets or in the neighborhood is …. consistent: they stare at most patient with facial defect" (van Doorne at al 1994:325; see also Hughes 1998; Macgregor 1990), while overall accurate, requires to be specified. This research demonstrates that the behavior of members of secondary groups consists of three

Benign neglect is the only type of interaction that does not create stigma. It refers to "normal" interaction as individuals are aware of the presence of others but do not pay particular attention to them. Accordingly, patients and their family members should be informed on the importance of creating conditions that lead to this type of interaction. In

**5. Relevance of these findings for surgeons and other caregivers** 

create felt stigma.

physical appearance.

distinct interaction patterns.

*immobility*, patients tend to feel uncomfortable. This felt stigma, however, can translate into enacted stigma as stares, comments, or questions characterized the behavior of others. The unusual shape of patient's face makes strangers and acquaintances curious. As this *curiosity* is made explicit, stigma occurs. This is the case even when interacting individuals attempt to conceal their intrusive behavior. This *concealed enacted stigma* refers to actions of intrusions accompanied by attempts to hide them from patients. Patients tend to feel *resentment* to intrusive actions. They resent the unwanted attention of others and often express this resentment by defining these actions as "rude" and "inconsiderate." Simultaneously, patients display *unconcerned awareness*. This is a pattern in which patients remain aware of stigmatizing actions but simultaneously indicate that are not affected by them.

Fig. 1.

*immobility*, patients tend to feel uncomfortable. This felt stigma, however, can translate into enacted stigma as stares, comments, or questions characterized the behavior of others. The unusual shape of patient's face makes strangers and acquaintances curious. As this *curiosity* is made explicit, stigma occurs. This is the case even when interacting individuals attempt to conceal their intrusive behavior. This *concealed enacted stigma* refers to actions of intrusions accompanied by attempts to hide them from patients. Patients tend to feel *resentment* to intrusive actions. They resent the unwanted attention of others and often express this resentment by defining these actions as "rude" and "inconsiderate." Simultaneously, patients display *unconcerned awareness*. This is a pattern in which patients remain aware of stigmatizing

actions but simultaneously indicate that are not affected by them.

Small

Large Groups

Small Groups

Large Groups

Small Groups

Large Groups

Groups Stigma

No Stigma

No Stigma

Stigma

Felt

Enacted

Felt

Enacted

Enacted

Felt

Enacted

Stigma

Stigma

Fig. 1.

**Sympathy** 

Enacted and Felt Stigma: Supportive

Curiosity; Instrumentality; Unfounded respect; Unconcerned

**Intrusion** 

Curiosity; Immobility: Concealed Enacted S; Enacted and Felt Stigma; Unconcerned

Awareness; Resentment

**Benign Neglect** 

*Sympathy* – It refers to intrusive patterns of interaction in which individuals provide and/or manifest support to facially disfigured patients. It creates enacted stigma in small group interaction and felt and enacted stigma in large group interaction. In the case of small group interaction, *supportive curiosity* occurs. It refers to questions that people ask about patients' appearance that are accompanied by actions and expressions that are supportive of patients. It is a form of enacted stigma. The expression "everybody is nice," frequently reported by patients, captures this pattern of interaction. Patients do not experience felt stigma as they feel comfortable with the support that strangers and acquaintances offer. In large group interaction, patients may use this offered support to their advantage even when it is not necessary. This *instrumentality* is not exercised in small groups. Interaction in large groups, however, leads to stigma when offered assistance is viewed as unnecessary and/or exaggerated in relation to the actual physical conditions of patients. Simultaneously, when sympathy guided action transcends established expectations and creates *unfounded attention* enacted stigma occurs in small and large groups. Because of their status of cancer survivors and facially disfigured individuals, patients are granted what they perceive as undeserved respect. These actions create felt stigma.

*Benign Neglect* – refers to interaction in which strangers and acquaintances do not pay particular attention to disfigured individuals. It is that common pattern that characterizes interaction among people who are not familiar with each other. While people are aware of the presence of others, they do not focus on, nor pay particular attention to, their actions. As Macgregor (1974: 60) put it, "it is that civil inattention normally granted to others in society." Because of its "normality," interaction characterized by benign neglect becomes particularly important in situations in which difference is present. Facially disfigured individuals not only feel comfortable during these interactions, but also acknowledge the fact that they are treated normally without any particular emphasis placed on their physical appearance.

#### **5. Relevance of these findings for surgeons and other caregivers**

This study demonstrates the ways in which interaction between facially disfigure cancer patients and secondary groups creates stigma. Because only limited knowledge is available on this topic, caregivers should use these results to assist patients and provide needed information and assistance to patients' family members. Through a grounded theory analysis, the study identifies key types of interaction patterns related to social stigma. These findings add to existing knowledge in a variety of ways. First, they point out that interaction between facially disfigure cancer patients and secondary groups is not a uniform process but it varies according to different settings and groups. It follows that current knowledge that indicates that "the reaction of people on the streets or in the neighborhood is …. consistent: they stare at most patient with facial defect" (van Doorne at al 1994:325; see also Hughes 1998; Macgregor 1990), while overall accurate, requires to be specified. This research demonstrates that the behavior of members of secondary groups consists of three distinct interaction patterns.

Benign neglect is the only type of interaction that does not create stigma. It refers to "normal" interaction as individuals are aware of the presence of others but do not pay particular attention to them. Accordingly, patients and their family members should be informed on the importance of creating conditions that lead to this type of interaction. In

The Social Limits of Reconstructive Surgery: Stigma in Facially Disfigured Cancer Patients 55

presentation of stigma as an issue that pertains exclusively to the patients' individual

Finally, the issue of stigma associated to cancer generated facial disfigurement is the byproduct of advancements in medicine and surgical techniques. It is a situation that is the outcome of the success of scientific advancements. However, it is a state of affairs that cannot be address exclusively by medicine in general and surgical actions in particular. It requires a multidisciplinary effort and the cooperation of multiple actors in the medical sciences as well as the social and behavioral sciences. Accordingly, it is important that surgeons become aware of this and similar conditions and that these situations become integrated into training protocols. Surgeons as well as other caregivers should be exposed to knowledge about the creation of pertinent social problems and to the boundaries that

Angermeyer M. & Matschinger H. (1994). Lay beliefs about schizophrenic disorder: the results of a population study in Germany.*Acta Psychiatrica Scandinavica*. 89, 39-45. American Cancer Society. (2009). Detailed guide: Eye cancer. Retrieved July 5, 2009 from

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particular, patients and family members should be instructed on the tendency of people to pay unwanted attention to patients. This is a situation that should be addressed through action planning and education whereby patients ought to plan their social activities carefully. Similarly, the general public should receive education on the conditions of these patients1.

Interaction characterized by intrusion consistently generates felt and enacted stigma. Episodes of felt and enacted stigma occur in small and large group settings, making it the most difficult type of interaction for patients and family members. Patients and their families should be advised of the difficulties that episodes of intrusion generate. Strangers and acquaintances alike will ask questions, make comments, stare and make other intrusive actions. A number of additional elements characterize this type of interaction. The categories of curiosity; immobility; unconcerned awareness and resentment discussed above frequently accompany intrusion. As indicated above, educational efforts should be made to sensitize the general public on episodes of intrusion. It is also important to inform patients and their family members that these conditions may or may not be alleviated by reconstructive surgery.

In the case of interaction characterized by sympathy, stigma develops in different ways in small groups than in large groups. In small groups stigma takes the form of enacted stigma. In large groups it takes the forms of both enacted and felt stigma. While sympathy indicates that interacting individuals either provide or manifest support to facially disfigured patients, it also refers to the fact that this interaction ultimately creates stigma. The categories of supportive curiosity, instrumentality and unfounded respect characterize this type of interaction. Caregivers should make clear to patients and family members that the desire of strangers and acquaintances to assist patients does not necessarily translate into a non-stigmatized interaction. Accordingly, efforts to educate interested parties on this contradictory situation can be beneficial.

Second, this study indicates that acquaintances' interaction with patients does not differ significantly from that recorded for strangers. Both strangers and acquaintances contribute to the creation of stigma when intrusion and sympathy occur. Both groups are capable, however, to establish interaction based on benign neglect. These findings add to existing knowledge by clarifying patterns of interaction between patients and acquaintances.

Third, this research underscores the importance of approaching the creation of stigma for facially disfigured cancer patients in relational terms. Stigma emerges as the product of interaction. As such, it involves facially disfigured patients and other segments of society as they interact in varying ways and with varying results. While the study of the manner through which individuals respond to disfigurement remains important, an enhanced understanding of the construction of stigma is achieved by considering the collective dimension of this process. Caregivers should be aware of this aspect and avoid the

<sup>1</sup> The patterns of actions needed to address stigma are not the topic of this chapter. However, it is important to note that both education of the public and action planning are to be considered two of the most important strategies to address this problem.

presentation of stigma as an issue that pertains exclusively to the patients' individual sphere. Stigma is a collective process that involves a multiplicity of actors.

Finally, the issue of stigma associated to cancer generated facial disfigurement is the byproduct of advancements in medicine and surgical techniques. It is a situation that is the outcome of the success of scientific advancements. However, it is a state of affairs that cannot be address exclusively by medicine in general and surgical actions in particular. It requires a multidisciplinary effort and the cooperation of multiple actors in the medical sciences as well as the social and behavioral sciences. Accordingly, it is important that surgeons become aware of this and similar conditions and that these situations become integrated into training protocols. Surgeons as well as other caregivers should be exposed to knowledge about the creation of pertinent social problems and to the boundaries that surgical intervention entails for the overall quality of life of patients.

#### **6. References**

54 Selected Topics in Plastic Reconstructive Surgery

particular, patients and family members should be instructed on the tendency of people to pay unwanted attention to patients. This is a situation that should be addressed through action planning and education whereby patients ought to plan their social activities carefully. Similarly, the general public should receive education on the conditions of these

Interaction characterized by intrusion consistently generates felt and enacted stigma. Episodes of felt and enacted stigma occur in small and large group settings, making it the most difficult type of interaction for patients and family members. Patients and their families should be advised of the difficulties that episodes of intrusion generate. Strangers and acquaintances alike will ask questions, make comments, stare and make other intrusive actions. A number of additional elements characterize this type of interaction. The categories of curiosity; immobility; unconcerned awareness and resentment discussed above frequently accompany intrusion. As indicated above, educational efforts should be made to sensitize the general public on episodes of intrusion. It is also important to inform patients and their family members that these conditions may or may not be alleviated by

In the case of interaction characterized by sympathy, stigma develops in different ways in small groups than in large groups. In small groups stigma takes the form of enacted stigma. In large groups it takes the forms of both enacted and felt stigma. While sympathy indicates that interacting individuals either provide or manifest support to facially disfigured patients, it also refers to the fact that this interaction ultimately creates stigma. The categories of supportive curiosity, instrumentality and unfounded respect characterize this type of interaction. Caregivers should make clear to patients and family members that the desire of strangers and acquaintances to assist patients does not necessarily translate into a non-stigmatized interaction. Accordingly, efforts to educate interested parties on this

Second, this study indicates that acquaintances' interaction with patients does not differ significantly from that recorded for strangers. Both strangers and acquaintances contribute to the creation of stigma when intrusion and sympathy occur. Both groups are capable, however, to establish interaction based on benign neglect. These findings add to existing knowledge by clarifying patterns of interaction between patients and

Third, this research underscores the importance of approaching the creation of stigma for facially disfigured cancer patients in relational terms. Stigma emerges as the product of interaction. As such, it involves facially disfigured patients and other segments of society as they interact in varying ways and with varying results. While the study of the manner through which individuals respond to disfigurement remains important, an enhanced understanding of the construction of stigma is achieved by considering the collective dimension of this process. Caregivers should be aware of this aspect and avoid the

1 The patterns of actions needed to address stigma are not the topic of this chapter. However, it is important to note that both education of the public and action planning are to be considered two of the

patients1.

reconstructive surgery.

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