**12. The evolving burn scar paradigm**

Irreversible scarring has long been thought to be the unavoidable, aggregated response to gross tissue injury after a severe burn. From the historical "tooth and claw" injury perspective, such a clinical endpoint made perfect sense: the inflammatory cascade would effectively help plug hemorrhage, prevent infection, and patch up the wounded enough so that they could get back into action. In the context of modern medicine, however, scarring is no longer necessarily ideal. When one considers the phenomenon of the burn survivor's paradox—in which severely burned patients are living longer through more extreme injuries but are consequently forced to deal with the physical, psychosocial, and financial implications associated with their survival—it is clear that a disfiguring or function-limiting scar no longer confers the same advantages it did in pre-historic times. Consequently, a relatively new field of dermato-surgical medicine is evolving to address this new perspective with a focus on scar prevention, mitigation, rehabilitation, and an overall goal to reintegrate the burn survivor to "normalcy."

Many animals (e.g., starfish, salamanders, lizards, etc.) have long been known to be able to regenerate tissue; however, it was not until relatively recently, in 2012, that researchers demonstrated the phenomenon of skin shedding and tissue regeneration in an adult mammal population, using the African spiny mouse as a model [224]. Coupling this discovery with the fact that fetal wounds heal without a scar early in human gestation and that adult humans retain the capacity to heal micro-wounds (e.g., bee stings, venipuncture, or facial rejuvenation with a fractional carbon dioxide laser, etc.) without scarring, we can now start to imagine that the door to scarless burn wound healing may not be as permanently closed to us as we once believed.

#### **12.1 Skin copying and epidermal micrografting**

Prevention of scarring might be as simple as ensuring that normal skin replaces the major wound defect [225, 226]. In essence, that is what full-thickness skin grafting seeks to accomplish, allowing the surgeon to bring in hair follicles, sweat glands, reticular dermis, subcutaneous fat, and other deep structures and relocating them to the wound bed. Unfortunately, it does so by creating another full-thickness skin wound at the donor site, a fact that limits this strategy to small wounds. Additionally, for a full-thickness graft to properly "take," it must connect successfully to the wound bed's underlying blood supply or the grafted tissue may die. Recently, an autologous micrografting device came to market offering to

**159**

*Burn Shock and Resuscitation: Many Priorities, One Goal*

deliver the benefits of a full-thickness skin graft without the limitations. In this technique, the proprietary device (CelluTome™ Epidermal Harvesting System, KCI, an Acelity Company, San Antonio, TX) uses suction and heat to homogenously harvest hundreds of exceedingly small columns (700 μm diameter) of full-thickness skin without the need for anesthesia [227, 228]. The micrografts are then manually transferred directly to the recipient area. Donor sites reepithelialize within days and with little to no evidence of scarring. The recipient sites appear to demonstrate accelerated reepithelialization and seem to heal without the "fish-net" patterning associated with split-thickness skin grafts. While this novel technology is promising, long-term, prospective studies are needed to evaluate the true efficacy and clinical

The "holy grail" of employing stem cell therapy to improve—or even perfect! desired wound healing after burn injury has long attracted the attention of burn surgeons. Combined gene delivery with stem cell therapy remains particularly promising. This process involves inserting a gene into recipient cells with the goal of delivering a concoction of growth factor genes at critical time points in the wound healing process [231]. This could be accomplished through any number of techniques including viral transfection, high pressure injection, liposomal vectors, naked DNA application, and it even introduces a new potential role for laser-assisted drug delivery (see below) [232]. Optimized culture conditions, preconditioning cell treatments, and the development of ideal scaffolds or matrices to optimize cell mobilization, homing, adhesion, and differentiation remain elusive

In burn patients where the injuries are so extensive that donor site availability is limited or not practical, the notion of culturing human keratinocytes remains a still hopeful approach. From a general perspective, this technique is accomplished by, first, taking a small sample of the patient's own healthy skin [233]. Next, the cells within the epidermis are separated, and the keratinocytes are grown, a process that involves providing the cells with specific nutrients. The resulting cultured skin is then applied to cover the burn wound, thus reducing the amount of healthy skin that must be removed for traditional burn wound grafting. Several companies are developing competing technologies to accomplish this goal, with one company receiving FDA approval, in 2018, for its proprietary "spray-on skin" system [234].

Multiple laser and energy-based devices are now employed within the burn scar management algorithm in an effort to better "rehabilitate" the injured skin. This armamentarium includes, primarily, the vascular-specific pulsed dye laser (PDL), which helps to reduce erythema and hypertrophic scar formation, and the technique of ablative or non-ablative fractional laser resurfacing, which helps to

The pulsed dye laser (PDL) was the first laser to be specifically developed to treat port wine birthmarks with the principle of "selective photothermolysis" in mind [235]. First-generation PDL devices utilized a yellow light emitting at wavelength 577 nm to target oxyhemoglobin, a chromophore with absorption peaks located around 418, 542, and 577 nm. Through diffusion of heat, this laser caused selective

normalize scar texture, thickness, and stiffness of the scars.

*DOI: http://dx.doi.org/10.5772/intechopen.85646*

outcomes of this approach [227–230].

but may be just over the horizon.

**12.3 Cell culture autografting**

**12.4 Laser surgery**

**12.2 Stem cell therapy**

*Burn Shock and Resuscitation: Many Priorities, One Goal DOI: http://dx.doi.org/10.5772/intechopen.85646*

deliver the benefits of a full-thickness skin graft without the limitations. In this technique, the proprietary device (CelluTome™ Epidermal Harvesting System, KCI, an Acelity Company, San Antonio, TX) uses suction and heat to homogenously harvest hundreds of exceedingly small columns (700 μm diameter) of full-thickness skin without the need for anesthesia [227, 228]. The micrografts are then manually transferred directly to the recipient area. Donor sites reepithelialize within days and with little to no evidence of scarring. The recipient sites appear to demonstrate accelerated reepithelialization and seem to heal without the "fish-net" patterning associated with split-thickness skin grafts. While this novel technology is promising, long-term, prospective studies are needed to evaluate the true efficacy and clinical outcomes of this approach [227–230].

#### **12.2 Stem cell therapy**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

**12. The evolving burn scar paradigm**

overall goal to reintegrate the burn survivor to "normalcy."

**12.1 Skin copying and epidermal micrografting**

community-based methicillin-resistant *Staphylococcus aureus*, Gram-negative bacteria, mixed infection, etc.) [220, 221]. It is characterized by widespread dermal necrosis, vessel thrombosis, and a massive, destructive inflammatory reaction. Mortality rate without surgical involvement may approach 100%. Similar to burn wounds, surgical management of this condition may include extensive debridement and management of the associated compartment syndrome. Also similar to burns, successful treatment depends on careful fluid replacement, broad-spectrum antibiotic coverage (including for Gram-negative organisms), specialized surgical dressings, and vigilant monitoring for signs of shock [222, 223]. Eventual skin grafting and/or tissue flaps may be required to cover large soft tissue defects. Directly relevant to the theme of the current chapter, all three of the above dermatological conditions (and many others) are subject to the same general complications and considerations, and their final prognosis is directly proportional to the extent of their skin injuries and the level of expert care they urgently receive.

Irreversible scarring has long been thought to be the unavoidable, aggregated response to gross tissue injury after a severe burn. From the historical "tooth and claw" injury perspective, such a clinical endpoint made perfect sense: the inflammatory cascade would effectively help plug hemorrhage, prevent infection, and patch up the wounded enough so that they could get back into action. In the context of modern medicine, however, scarring is no longer necessarily ideal. When one considers the phenomenon of the burn survivor's paradox—in which severely burned patients are living longer through more extreme injuries but are consequently forced to deal with the physical, psychosocial, and financial implications associated with their survival—it is clear that a disfiguring or function-limiting scar no longer confers the same advantages it did in pre-historic times. Consequently, a relatively new field of dermato-surgical medicine is evolving to address this new perspective with a focus on scar prevention, mitigation, rehabilitation, and an

Many animals (e.g., starfish, salamanders, lizards, etc.) have long been known to be able to regenerate tissue; however, it was not until relatively recently, in 2012, that researchers demonstrated the phenomenon of skin shedding and tissue regeneration in an adult mammal population, using the African spiny mouse as a model [224]. Coupling this discovery with the fact that fetal wounds heal without a scar early in human gestation and that adult humans retain the capacity to heal micro-wounds (e.g., bee stings, venipuncture, or facial rejuvenation with a fractional carbon dioxide laser, etc.) without scarring, we can now start to imagine that the door to scarless burn wound healing may not be as permanently closed to us as we once believed.

Prevention of scarring might be as simple as ensuring that normal skin replaces

the major wound defect [225, 226]. In essence, that is what full-thickness skin grafting seeks to accomplish, allowing the surgeon to bring in hair follicles, sweat glands, reticular dermis, subcutaneous fat, and other deep structures and relocating them to the wound bed. Unfortunately, it does so by creating another full-thickness skin wound at the donor site, a fact that limits this strategy to small wounds. Additionally, for a full-thickness graft to properly "take," it must connect successfully to the wound bed's underlying blood supply or the grafted tissue may die. Recently, an autologous micrografting device came to market offering to

**158**

The "holy grail" of employing stem cell therapy to improve—or even perfect! desired wound healing after burn injury has long attracted the attention of burn surgeons. Combined gene delivery with stem cell therapy remains particularly promising. This process involves inserting a gene into recipient cells with the goal of delivering a concoction of growth factor genes at critical time points in the wound healing process [231]. This could be accomplished through any number of techniques including viral transfection, high pressure injection, liposomal vectors, naked DNA application, and it even introduces a new potential role for laser-assisted drug delivery (see below) [232]. Optimized culture conditions, preconditioning cell treatments, and the development of ideal scaffolds or matrices to optimize cell mobilization, homing, adhesion, and differentiation remain elusive but may be just over the horizon.

#### **12.3 Cell culture autografting**

In burn patients where the injuries are so extensive that donor site availability is limited or not practical, the notion of culturing human keratinocytes remains a still hopeful approach. From a general perspective, this technique is accomplished by, first, taking a small sample of the patient's own healthy skin [233]. Next, the cells within the epidermis are separated, and the keratinocytes are grown, a process that involves providing the cells with specific nutrients. The resulting cultured skin is then applied to cover the burn wound, thus reducing the amount of healthy skin that must be removed for traditional burn wound grafting. Several companies are developing competing technologies to accomplish this goal, with one company receiving FDA approval, in 2018, for its proprietary "spray-on skin" system [234].

#### **12.4 Laser surgery**

Multiple laser and energy-based devices are now employed within the burn scar management algorithm in an effort to better "rehabilitate" the injured skin. This armamentarium includes, primarily, the vascular-specific pulsed dye laser (PDL), which helps to reduce erythema and hypertrophic scar formation, and the technique of ablative or non-ablative fractional laser resurfacing, which helps to normalize scar texture, thickness, and stiffness of the scars.

The pulsed dye laser (PDL) was the first laser to be specifically developed to treat port wine birthmarks with the principle of "selective photothermolysis" in mind [235]. First-generation PDL devices utilized a yellow light emitting at wavelength 577 nm to target oxyhemoglobin, a chromophore with absorption peaks located around 418, 542, and 577 nm. Through diffusion of heat, this laser caused selective

thermal damage of the abnormally dilated blood vessels with minimal to no collateral damage of surrounding cutaneous structures. Eventually, 585 and 595 nm wavelength PDL devices were developed to allow slightly deeper penetration through the skin (to a depth of around 1.2 mm) while still maintaining precise absorption. The development of surface cooling devices has, subsequently, afforded the use of higher energy fluences with larger spot sizes and improved treatment in darker skin surfaces. When applied to hypertrophic burn scars, PDL causes selective photothermolysis that induces coagulation necrosis of capillaries within the scar itself [236]. Because hypertrophic burn scars are characterized by pathologic neovascularization, PDL devices help to mitigate inflammation and collagen production and reduce the overall hypervascular response. From a patient perspective, PDL is also useful for helping to improve overall burn scar texture, pruritus, pain, and pliability [237].

Laser resurfacing has long been used for cosmetic indications such as treatment of fine rhytids of the eyelids and mouth, treatment of photoaging, and management of dyspigmentation. Original "fully ablative" devices, such as the carbon dioxide laser, target intracellular water as the main chromophore. Because of the abundance of water in human tissue, this process leads to non-selective and near-immediate vaporization of treated skin and a denaturation of surrounding extracellular proteins. In contrast to ablative devices, nonablative approaches induce coagulation as their primary mechanism of action without directly destroying tissue or exposing dermis to the external environment. The concept of "fractional photothermolysis" was fairly recently introduced and describes treatment of the target tissue with the generation of a precise array of evenly spaced areas of injury known as microscopic treatment zones (MTZ) [238]. Clinically, this technique results in untreated areas between the MTZs, containing significant amounts of intact epidermis and dermis available as a reservoir for a more rapid micro-healing response. With ablative fractional resurfacing (AFR) technologies, such as the fractional carbon dioxide (CO2) and Erbium-YAG lasers, the operating surgeon may change device parameters to adjust for desired depth of treatment (to a maximum of about 3.5–4.0 mm with current devices) and accurately control the total ablated surface area within a treated area. The general rule for AFR is to decrease density (i.e., total ablated surface area) while increasing fluence (i.e., energy). How repeated pixelated thermal injuries to a burn scar could result in subjective and objective improvements is not entirely understood; however, the technique has consistently demonstrated the ability to facilitate rapid reepithelialization and a vigorous scar remodeling process while maintaining excellent safety margins [239–243]. Perhaps most notably, long-term, persistent gains in pliability, resulting in improved function and quality of life, most likely occur from a gradual process of diffuse dermal remodeling and a relative rehabilitation of dysfunctional scar tissue [244].

The varied nature of individual burn scars, the heterogeneity of burn patients, small sample sizes, a lack of treatment controls, and the cost of the devices themselves have been major limitations to research surrounding the use of lasers in the treatment of burn scars. Thankfully, several large, prospective studies are currently underway to investigate the utility of these devices, including in the pediatric population.

#### **12.5 Laser-assisted drug delivery**

The notion that certain medications or agents could be delivered topically through burn scar tissue has three potential advantages over oral administration of the same agent: directed therapy to the targeted tissue, limited systemic toxicity and side effects, and avoidance of first-pass metabolism. To this end, various chemical, biochemical, and physical strategies have attempted to enhance topical drug delivery into burn scar tissue. It is only relatively recently that AFR devices

**161**

**Table 4.**

*Burn Shock and Resuscitation: Many Priorities, One Goal*

have been utilized for this purpose [245]. In a process referred to as "laser-assisted drug delivery," AFR devices create vertical columns of ablated tissue in the MTZs that then serve as conduits or channels for delivery of specific topical medications or agents. Pairing the delivery of topical agents temporally with AFR therapy is believed to allow for increased penetration and absorption of the applied agents, an approach that is particularly helpful in the treatment of burn scar tissue given its variable and fibrotic nature. Corticosteroids, 5-fluorouracil (5-FU), imiquimod, methotrexate, and other immunomodulators have all been used for this purpose with varying degrees of success. Overall, laser-assisted drug delivery is a promising intervention for burn scar treatment. Investigation of the optimal channel depth and channel density continues and will likely depend on each individual drug or agent's chemical structure and the desired clinical target. Likewise, many drugs and agents have not been designed to be delivered to their target tissues in this manner, so larger prospective studies to determine safety and efficacy of this procedure will

The primary goal of clinical management of burns is to prevent the development of "burn shock." Early classification of burns by depth and size is critical to goal-directed treatment strategies, with subsequent approaches guided by the post-injury physiological and metabolic demands. Appropriate anticipation and proactive, multimodality support of the patient, through fluid resuscitation, nutritional supplementation, and pharmacologic therapy is required for optimizing patient outcomes. Additionally, clinicians should closely monitor the patient for the development of secondary adverse events, such as infections and under- or over-resuscitation. Management of burns is complex and requires specialized facilities, teams of experienced burn surgeons, dedicated burn nurses, social workers, nutritionists, physical therapists, occupational therapists, pharmacists, respiratory interventionists, pain specialists, dermatologists, and psychologists [246, 247].

*DOI: http://dx.doi.org/10.5772/intechopen.85646*

be critical.

**13. Conclusion**

**Burn center referral criteria**

5 Chemical burns 6 Inhalation injury

1 Partial thickness burns >10% TBSA

3 Third degree burns in any age group 4 Electrical burns, lightning injury

prolong recovery, or affect mortality

trauma center may be necessary prior to transport

*Summary of burn center referral criteria; Legend: TBSA = Total body surface area.*

*Patient 2006, Committee on Trauma, American College of Surgeons.*

2 Burns involving the face, hands, feet, genitalia, perineum, or major joints

7 Burn injury in patients with preexisting medical disorders that could complicate management,

8 Any patient with burns and traumatic injury wherein the burn poses the greatest risk of morbidity/ mortality. When a traumatic injury poses the greatest risk, adequate stabilization of the patient at a

9 Burned children in hospitals lacking the qualified personnel/equipment necessary to care for children

10 Burn injury to patients who require special social, emotional, or rehabilitative intervention *Excerpted from Guidelines for the Operation of Burn Centers (pp. 79–86), Resources for Optimal Care of the Injured*  *Burn Shock and Resuscitation: Many Priorities, One Goal DOI: http://dx.doi.org/10.5772/intechopen.85646*

have been utilized for this purpose [245]. In a process referred to as "laser-assisted drug delivery," AFR devices create vertical columns of ablated tissue in the MTZs that then serve as conduits or channels for delivery of specific topical medications or agents. Pairing the delivery of topical agents temporally with AFR therapy is believed to allow for increased penetration and absorption of the applied agents, an approach that is particularly helpful in the treatment of burn scar tissue given its variable and fibrotic nature. Corticosteroids, 5-fluorouracil (5-FU), imiquimod, methotrexate, and other immunomodulators have all been used for this purpose with varying degrees of success. Overall, laser-assisted drug delivery is a promising intervention for burn scar treatment. Investigation of the optimal channel depth and channel density continues and will likely depend on each individual drug or agent's chemical structure and the desired clinical target. Likewise, many drugs and agents have not been designed to be delivered to their target tissues in this manner, so larger prospective studies to determine safety and efficacy of this procedure will be critical.
