**2. Acellular dermal matrices**

Acellular dermal matrices (ADMs) are biological materials derived from human or animal tissue through complicated and expensive decellularisation processes, leading to acellular material that can be used to aid tissue healing. ADMs were first introduced for the treatment of burn injuries, but are now widely used in a variety of surgical fields, including abdominal wall and breast reconstruction. A wide range of materials can be used to produce ADMs, but usually include bovine, porcine or human tissues (e.g., dermis, pericardium). ADMs act as scaffolds onto which human tissue can incorporate, allowing for an innovative, yet a very effective way to aid tissue regeneration (see **Figure 1**).

First introduced in 1994, a specific acellular dermal matrix (AlloDerm) was used as a dermal substitute in a full thickness burn injury [2]. This overcame the troubling consequences of significant scarring and contracture after the use of split-thickness autografts used for full thickness injuries. A high percentage of 'take' was seen and was assessed using histology and electron microscopy [2]. No specific immune response was seen and this is owing to the processes in which the actual acellular dermal matrices are produced. In addition to the benefits of reduced scarring, contracture and avoidance of immune response, acellular dermal matrices also ensured that any wound of the donor site was avoided—purely due to the fact that the donor site was not necessary! This was particularly important and useful in patients with extensive burns where the donor site availability was limited. All of this led to the increasing popularity of the use of acellular dermal matrices in the treatment of burns and, later on, the introduction of acellular dermal matrices into other surgical fields.

Complex engineering procedures are involved in producing acellular dermal matrices and will also depend on the original type of tissue used. Decellularisation is an essential process and ensures there is no immune reaction once the acellular dermal matrix is introduced into

**Figure 1.** Comparison of DermaMatrix to normal human skin (courtesy of Synthes® [1]).

Scaffold Biomaterials in Tissue Regeneration in Surgery http://dx.doi.org/10.5772/intechopen.73657 49

**Keywords:** tissue regeneration, reconstruction, acellular dermal matrix, adipose tissue-derived stem cells, stem cells, gene regulation, 3D printing, bovine pericardium,

Tissue regeneration is a vast subject, with many different important aspects to consider. From groundbreaking advances in the use of acellular dermal matrices, to the still-evolving stem cell treatments, this chapter provides an overview of the essentials in tissue regeneration science. We will explore the use of acellular dermal matrices, stem cell-based therapies, gene regulation, emerging 3D printing techniques and their potential applications in surgery and

Acellular dermal matrices (ADMs) are biological materials derived from human or animal tissue through complicated and expensive decellularisation processes, leading to acellular material that can be used to aid tissue healing. ADMs were first introduced for the treatment of burn injuries, but are now widely used in a variety of surgical fields, including abdominal wall and breast reconstruction. A wide range of materials can be used to produce ADMs, but usually include bovine, porcine or human tissues (e.g., dermis, pericardium). ADMs act as scaffolds onto which human tissue can incorporate, allowing for an innovative, yet a very

First introduced in 1994, a specific acellular dermal matrix (AlloDerm) was used as a dermal substitute in a full thickness burn injury [2]. This overcame the troubling consequences of significant scarring and contracture after the use of split-thickness autografts used for full thickness injuries. A high percentage of 'take' was seen and was assessed using histology and electron microscopy [2]. No specific immune response was seen and this is owing to the processes in which the actual acellular dermal matrices are produced. In addition to the benefits of reduced scarring, contracture and avoidance of immune response, acellular dermal matrices also ensured that any wound of the donor site was avoided—purely due to the fact that the donor site was not necessary! This was particularly important and useful in patients with extensive burns where the donor site availability was limited. All of this led to the increasing popularity of the use of acellular dermal matrices in the treatment of burns and, later on, the

Complex engineering procedures are involved in producing acellular dermal matrices and will also depend on the original type of tissue used. Decellularisation is an essential process and ensures there is no immune reaction once the acellular dermal matrix is introduced into

xenograft, porcine dermal matrix, Veritas, Strattice

provide an overview of wound and tissue healing in general.

effective way to aid tissue regeneration (see **Figure 1**).

introduction of acellular dermal matrices into other surgical fields.

**1. Introduction**

48 Tissue Regeneration

**2. Acellular dermal matrices**

**Figure 1.** Comparison of DermaMatrix to normal human skin (courtesy of Synthes® [1]).

the recipient's body. All donor cells and antigenic epitopes that have a potential to induce an immune response are removed using a variety of detergents (dependent on a particular type of acellular dermal matrix)—this essentially leaves a scaffold, consisting of collagen, growth factor receptors and vascular channels [3]. Dehydration of the matrix also allows for easier tissue handling and prolonged shelf life [4]. Certain acellular dermal matrices are also terminally sterilised; however, there is no clear evidence whether this provides an advantage [5].

As mentioned above, a variety of different donor tissues can be used in the production of acellular dermal matrices. Commonly, bovine, porcine or human tissues are used, with dermis and pericardium being the most usual types of tissue utilised. A variety of acellular dermal matrices exist at present, some more commonly used examples are listed in **Table 1** [6]:

One of the authors (Chaturvedi) of this chapter has long experience of using the Veritas® acellular dermal matrix, made from bovine pericardium, and has presented this experience in one of the largest series for breast reconstruction [12]. They have found that the advantages of Veritas® included the easy handling and reduction in the incidence of red breast syndrome, as compared to porcine allografts [12].

have been used in breast surgery since 2001, with many benefits gleaned from their use [5]. Acellular dermal matrices have allowed for immediate breast reconstruction with implants by avoiding the stage of tissue expanders. Mastectomy can be performed with immediate implant based, acellular dermal matrix reconstruction, allowing for immediate results and avoiding a second operation at a later date. Not only do acellular dermal matrices act as scaffolds for tissue regeneration in this case, but also add an additional layer of tissue protection for the foreign body, that is, the implant (see **Figure 3**) [13]. Other examples of applications of acellular dermal matrices in breast surgery include correction of symmastia, incorporation into the upper pole (to decrease surface rippling) and correction of inframammary fold malposition [5]. In addition, acellular dermal matrices are also used in two-stage breast reconstruction procedures with tissue expanders; however, despite advantages, such as faster expansion, improved lower pole projection and better aesthetic shape, the costs are high and

**Figure 2.** Patient X—Robust recellularisation and remnants of Strattice™ tissue matrix, 31 months post-implantation

Scaffold Biomaterials in Tissue Regeneration in Surgery http://dx.doi.org/10.5772/intechopen.73657 51

New ways of utilising acellular dermal matrices in breast surgery have also been trialled and include use of meshed and fenestrated acellular dermal matrices [14]. This allows for

**Figure 3.** Tissue expander placement into the Pectoralis major and acellular dermal matrix pocket (courtesy of Weichman

need considered prior to individual patient use [5].

(courtesy of LifeCell [11]).

et al. [12]).

Acellular dermal matrices act as scaffolds for the recipients' tissues to grow and revascularise upon [2]. Whilst providing nutritional and structural support, acellular dermal matrix integrates into the surrounding tissues and is eventually replaced by functional autologous tissue (see **Figure 2**) [2].

Acellular dermal matrices are used widely in abdominal wall, burn and breast reconstruction. The management of burns with acellular dermal matrices has already been mentioned, with significant benefits of ADM over split thickness skin grafts in terms of donor site sparing, less contracture, scarring and avoidance of immune response. In addition to burns management, acellular dermal matrices were also initially used for tympanic membrane replacement, dural repairs, gingival grafting and, as already mentioned, abdominal wall repair. The use of acellular dermal matrices in these areas gave a start to what is now an increasingly important and prevalent component of both reconstructive and aesthetic surgery.

Breast and plastic surgeons currently actively utilise acellular dermal matrices in a variety of procedures, in particular, implant-based breast reconstruction [5]. Acellular dermal matrices


**Table 1.** Examples of currently available acellular dermal matrices.

the recipient's body. All donor cells and antigenic epitopes that have a potential to induce an immune response are removed using a variety of detergents (dependent on a particular type of acellular dermal matrix)—this essentially leaves a scaffold, consisting of collagen, growth factor receptors and vascular channels [3]. Dehydration of the matrix also allows for easier tissue handling and prolonged shelf life [4]. Certain acellular dermal matrices are also terminally sterilised; however, there is no clear evidence whether this provides an advantage [5]. As mentioned above, a variety of different donor tissues can be used in the production of acellular dermal matrices. Commonly, bovine, porcine or human tissues are used, with dermis and pericardium being the most usual types of tissue utilised. A variety of acellular dermal matrices exist at present, some more commonly used examples are listed in **Table 1** [6]:

One of the authors (Chaturvedi) of this chapter has long experience of using the Veritas® acellular dermal matrix, made from bovine pericardium, and has presented this experience in one of the largest series for breast reconstruction [12]. They have found that the advantages of Veritas® included the easy handling and reduction in the incidence of red breast syndrome, as

Acellular dermal matrices act as scaffolds for the recipients' tissues to grow and revascularise upon [2]. Whilst providing nutritional and structural support, acellular dermal matrix integrates into the surrounding tissues and is eventually replaced by functional autologous tissue

Acellular dermal matrices are used widely in abdominal wall, burn and breast reconstruction. The management of burns with acellular dermal matrices has already been mentioned, with significant benefits of ADM over split thickness skin grafts in terms of donor site sparing, less contracture, scarring and avoidance of immune response. In addition to burns management, acellular dermal matrices were also initially used for tympanic membrane replacement, dural repairs, gingival grafting and, as already mentioned, abdominal wall repair. The use of acellular dermal matrices in these areas gave a start to what is now an increasingly important and

Breast and plastic surgeons currently actively utilise acellular dermal matrices in a variety of procedures, in particular, implant-based breast reconstruction [5]. Acellular dermal matrices

**Name of acellular dermal matrix Type of acellular dermal matrix** FlexHD® (Ethicon, Somerville, NJ) [7] Donated human allograft skin AlloDerm® (LifeCell, Branchburg, NJ) [8] Donated human allograft skin Neoform™ (Mentor, Santa Barbara, CA) [9] Donated human allograft skin DermaMatrix™ (Synthes, West Chester, PA) [1] Donated human allograft skin Permacol™ (Covidien, Boulder, CO) [10] Porcine dermal implant Strattice® (LifeCell, Branchburg, NJ) [11] Porcine dermal implant Veritas (Baxter, Deerfield, IL) [12] Bovine pericardium

prevalent component of both reconstructive and aesthetic surgery.

**Table 1.** Examples of currently available acellular dermal matrices.

compared to porcine allografts [12].

(see **Figure 2**) [2].

50 Tissue Regeneration

have been used in breast surgery since 2001, with many benefits gleaned from their use [5]. Acellular dermal matrices have allowed for immediate breast reconstruction with implants by avoiding the stage of tissue expanders. Mastectomy can be performed with immediate implant based, acellular dermal matrix reconstruction, allowing for immediate results and avoiding a second operation at a later date. Not only do acellular dermal matrices act as scaffolds for tissue regeneration in this case, but also add an additional layer of tissue protection for the foreign body, that is, the implant (see **Figure 3**) [13]. Other examples of applications of acellular dermal matrices in breast surgery include correction of symmastia, incorporation into the upper pole (to decrease surface rippling) and correction of inframammary fold malposition [5]. In addition, acellular dermal matrices are also used in two-stage breast reconstruction procedures with tissue expanders; however, despite advantages, such as faster expansion, improved lower pole projection and better aesthetic shape, the costs are high and need considered prior to individual patient use [5].

New ways of utilising acellular dermal matrices in breast surgery have also been trialled and include use of meshed and fenestrated acellular dermal matrices [14]. This allows for

**Figure 3.** Tissue expander placement into the Pectoralis major and acellular dermal matrix pocket (courtesy of Weichman et al. [12]).

the reduction of costs, with evidence also showing that with fenestrated acellular dermal matrices, the incidence of capsular contractures, infections and seroma formation can be decreased [5].

**3. Mesenchymal stem cells**

The exciting field of stem cell therapies has rapidly evolved in order to provide a potential alternative treatment for tissue repair and to enable the regeneration of injured organs. New

Scaffold Biomaterials in Tissue Regeneration in Surgery http://dx.doi.org/10.5772/intechopen.73657 53

Stem cells are unique in that they are undifferentiated cells that can renew themselves throughout the entire lifespan of an organism. They develop from one common precursor and have the ability to differentiate into multiple cell types with specific functions (see **Figure 4**). Stem cells are characterised by their ability to self-renew over prolonged periods of time [23]. Stem cells that have the potential to repair surgical wounds include mesenchymal stem cells (MSC),

The most commonly utilised stem cells are MSCs, which are derived from adult patients. Autologous mesenchymal stem cells are present in almost all adult tissues including the dermis, periosteum and adipose tissue, solid organs, such as the liver, lungs and spleen and within bone marrow and blood, including from the peripheries, menstruation and the umbilical cord [25].

There has been great enthusiasm within the literature regarding the potential use of stem cells in tissue regeneration over the last decade. The initial focus of research surrounded the clinical applications of embryonic stem cells. However, over the past decade, there has been a move within the scientific community to research the potential applications of mesenchymal

**Figure 4.** Skeletal regeneration by mesenchymal stem cells: what else (courtesy of Andrades et al. [26]).

developments are continually arising from this promising topic of research.

embryonic stem cells (ESC) and induced pluripotent stem cells (iPS) [24].

Complications associated with acellular dermal matrices depend on the type of the acellular dermal matrix used and also the particular procedure it is used for. Breast reconstruction with acellular dermal matrix can cause increased risk of post-operative infection, skin necrosis and post-operative seroma [15]. The correct patient should be identified in order to ensure the risks that are acceptable. Caution needs to be used with obese patients (BMI > 30), simultaneous axillary clearance and smoking history. Radiation will affect any reconstructed breast; however, acellular dermal matrices have, in fact, been shown to reducing the severity of capsular contracture [15].

The use of acellular dermal matrices in abdominal wall reconstruction offers an alternative to a permanent prosthetic mesh and has been in use since mid 2000s [16]. Although some surgeons prefer acellular dermal matrices for abdominal wall reconstructions, concerns have previously been raised regarding the long-term outcomes of acellular dermal matrices as compared to synthetic meshes, with the main worry being the durability. A recent study, however, showed that hernia recurrence rates with acellular dermal matrices were comparable to those done with synthetic mesh—in particular, it was also seen that xenograft acellular dermal matrices led to even lower recurrence rates than human allografts [17]. The question of cost, however, arises again, and synthetic meshes are in fact cheaper than acellular dermal matrices [17].

Outcomes with acellular dermal matrices in breast surgery have already been mentioned (and there is extensive literature for this subject, including a systematic review), but favourable reports have been published on outcomes in pelvic, abdominal, chest wall reconstruction, dural repair, hand surgery, urethral reconstruction and gingival graft procedures, too [6]. Butler et al. successfully used AlloDerm in the reconstruction of large and complex pelvic, chest and abdominal wall defects [18]; however, further studies would be needed in the use of acellular dermal matrices for dural repair (Chaplin et al. successfully used XenoDerm in a porcine model and called it "a nearly ideal dural replacement") [19]. Kim et al. also successfully used acellular dermal matrix for a recurrent first dorsal web space defect, showing excellent cosmetic and functional results [20]. Aichelmann-Reidy et al. showed that acellular dermal matrix could also be a useful substitute in root coverage procedures [21]. Controversies, however, still exist and some studies have shown increased infection rates with ADM-based reconstruction as compared to non-ADM-based reconstruction [22].

Significant costs are also involved when using acellular dermal matrices and remain a topical issue in all fields of surgery. Some situations where costs may be unacceptable have already been considered, for example, with some general surgeons preferencing synthetic meshes in abdominal wall reconstruction due to decreased costs [17]. However, in cases where acellular dermal matrix allows for a two-stage procedure (e.g., implant-based reconstruction with tissue expanders placed during the primary procedure) to be converted into a single-stage procedure (i.e., implant-based ADM reconstruction without the need of tissue expanders), significant savings will be made and this needs to be considered on an individual patient basis.
