Acellular dermal matrices in reconstructive surgery; history, current implications and future perspectives for surgeons

Abstract

Large-scale defects of body in the reconstructive surgical practice, and the helplessness of their repair with autologous tissues, have been an important factor in the development of artificial biological products for the temporary, definitive, or staged repair of these defects. A major advance in the field of plastic and other reconstructive surgery in this regard has been the introduction and successful use of acellular dermal matrices (ADMs). In recent years, not only the type of tissue from which ADMs are produced, product range, diversity and areas of use have increased, but their use in reconstructive fields, especially in post oncologic breast surgery, has become highly regarded and this has favored ADMs to be a potential cornerstone in specific and well-defined surgical fields in future. It is essential that reconstructive surgeons become familiar with some of the ADM’s as well as the advantages and limitations to their use. This review not only provides basic science and clinical evidence of the current use of ADMs in wide range of surgical fields but also targets to keep them as an important backdrop in the armamentarium of reconstructive surgeons. Brief considerations of possible future directions for ADMs are also conducted in the end.

Key Words: Acellular dermal matrices; Breast; Decellularization; Reconstruction; Surgery; Tissue defect

Core Tip: The use of acellular dermal matrix in parotid tumor surgery can reduce the incidence of Frey syndrome, especially when the diameter of the surgically removed parotid tissue is greater than 4 cm. This review not only provides basic science and clinical evidence of the current use of acellular dermal matrices in wide range of surgical fields but also targets to keep them as an important backdrop in the armamentarium of reconstructive surgeons.

INTRODUCTION

Normal wound healing is a dynamic process that involves the restoration of the skin's barrier function and mechanical and functional integrity. This process involves interactions of the cells with their non-cellular microenvironment called extracellular matrix (ECM) via complex protein-mediated signaling pathways. ECM interactions of the cellular fraction of the wound bed direct them to differentiate or dedifferentiate, proliferate, or remain quiescent, and assume the architecture and function of the skin or other organ tissues[1]. Although, fundamentally, the ECM is composed of water, proteins, proteoglycans, hyaluronic acid, collagen, and elastin, each tissue has an ECM with a unique composition and topology that is generated during tissue regeneration through a dynamic and reciprocal dialogue with the cellular fractions. Through these topologies and unique characteristics, the ECM generates the biochemical and mechanical properties of each organ, such as its tensile and compressive strength and elasticity, and also mediates protection by a buffering action that maintains extracellular homeostasis and water retention[1].

In chronic wounds, the ECM is often damaged or depleted to the extent that it can no longer adequately support healing through cellular interactions[2]. This usually results from inflammatory and proteolytic environment of chronic wounds. A high ratio of protease-to-protease inhibitors indeed, has been a well-shown mechanism for degradation of ECM, growth factors and growth factor receptors in chronic wounds[2].

Large-scale traumatic wounds of the body on the other hand, despite the numerous improvements of the flap number and choices, still remain as a major challenge for the reconstructive surgeons. Additionally, each of these reconstructive options has disadvantages such as donor site morbidity, risk of flap/graft complications or even failure. In some cases, such as excessive wound depth or specialized function of tissue needing repair, patient and/or wound characteristics may preclude the use of traditional techniques for soft-tissue coverage as well[3].

The inability of the repair of various wounds with autologous tissues, have been an important factor in the development of artificial biomaterials for the temporary, definitive, or staged repair of the large defects and the defects that lack appropriate well-vascularized soft tissue elements for grafting, such as wounds with exposed bone, cartilage, and tendon. The terms biomaterials, biologic scaffolds, bioprosthetic, and biologic matrices are used interchangeably and represent a diverse continuum of engineered products that serve as scaffolds which interact with native tissue, promoting vascular and cytologic ingrowth[4,5], cell propagation, migration, and differentiation[6]. A major advance in the field of plastic and other reconstructive surgery in this regard has been the introduction and successful use of acellular dermal matrices (ADMs).

MECHANISM OF ADM

In simple terms, ADMs are biological membranes that are free of cellular components and other antigenic structures, where immunogenicity is no longer an issue. When ADMs are placed in the wound, host cells are incorporated into the matrix and directed by preserved growth factors and mechanical signals in the matrix structure[6,7]. A variety of host cells invade the ADM[4,5], including fibroblasts, myofibroblasts, lymphocytes, macrophages, granulocytes, mast cells and others[7]. After inflammatory cell infiltration, the matrix undergoes remodeling[7], collagen and elastin levels increase, and revascularization is initiated[4,5-8]. Essentially, the ADM acts as a scaffold to promote host tissue growth[3]. These processes not only make ADM a well vascularized graft bed, but also render a durable, relatively thicker barrier, paving the way for its use where anatomical layers need to be kept apart, or soft tissues need to be reinforced.

ADMs can be derived either from donated skin and other organs (allograft or from animals such as swine or cattle xenograft). The process of removing cells from tissues and organs is known as decellularization that has been described extensively in the literature[9,10]. More briefly, decellularization has been performed through chemical, physical, enzymatic, or combinative methods. As the most important step, it strictly aims minimal disruption of the 3-D structure of the ECM of tissues so that the method must be individualized for each tissue characteristics[11]. However, complete removal of all cell remnants may not always be completely possible, and decellularization processes inevitably and invariably cause some degree of disruption of matrix architecture which leads the seek for more perfection of these steps by the researchers and industry[10]. Next steps include decontamination of the chemicals, optional cross-linking, quality analysis of the remaining ECM scaffold, sterilization, packaging, and preservation for marketing[12,13] (Figure 1).

Figure 1 The flowchart summarizes the techniques commonly used in the process of obtaining acellular dermal matrix from a variety of tissues. ECM: Extracellular matrix.

Tissue from which the antigenic content has been removed has now become a cell-free scaffold containing ECM elements[4,5] such as collagen, fibronectin, elastin, laminin, glycosaminoglycans and hyaluronic acid as well as some growth factors. This 3-D acellular collagenous mesh scaffold without immunogenicity can be now gradually de novo revitalized by autologous cells after implantation. Indeed, many studies have shown that cell-free ECM scaffolds are capable of promoting proliferation[6,7], growth[6], and differentiation[6,7] of many kinds of cell populations in vitro[4,5,7,8], as well as inducing structural tissue remodeling processes after transplantation in humans[6,14-17]. Therefore, the use of 3-D ADM meshes derived from tissues is an increasingly used method in reconstructive surgery, regenerative medicine, and bioengineering.

It is not always possible for surgeons to accurately estimate the amount of tissue to be mobilized or to accurately predict the laxity, vascularity, access limits or arc of rotation of these tissues before surgery. In addition, sometimes the size of the defect may be larger, or the tension of the repaired anatomical layers may be higher than predicted. Undoubtedly, every surgeon will appreciate the availability of ADMs as reliable members of the bench, which always have the potential to offer a quick, staged, temporary or permanent solution alternatives to such, unexpected problems. Furthermore, although such the advantages of ADMs for each clinical area of use may vary, it is clear that another great advantage is the elimination of donor site morbidity and related operative efforts, such as pursuit for neighboring soft tissue, which should be loose, well vascularized, and abundant or preparation for another operative field for graft harvest.

CHALLENGES AND LIMITATIONS

ADM’s are still foreign and possess the risk of rejection[13,17] and disease transmission[13,14]. Furthermore, the classic risks of complications associated with autologous reconstructions, such as infection, necrosis, seroma, and failed engraftment still apply to ADMs. Moreover, patients belonging to certain ethnic and/or religious groups may hold beliefs that preclude the use of products with certain tissue origins. For example, although there are views that the use of pig-derived biologics is permitted in Islam[18], Christianity[19] and Judaism[20] under certain conditions, these have not become consensuses that are readily accepted by all sub-fractions. Also, the vegan perspective[21] strongly opposes the use of animals as organ donors and emphasizes the need to develop animal-free alternatives. On the other hand, the perception that ADM is expensive is often ingrained in surgeons and indeed, ADM can be a reasonable choice for only some patients among various healthcare systems when it comes to the standard product costs ranging from several hundred to thousands of dollars. Nevertheless, given the overall clinical context, risks, complications and outcomes compared to alternative conventional treatments, some authors have advocated[22-25] evidence of cost-effectiveness, while other studies have found ADMs not to be cost-effective[26-28]. Some authors also probed the associations between ADM-related publication, industry funding, funding disclosure, and public interest and criticized the objectivity of the reports in regard with the strong correlation between them[29].

Table 1 provides some examples of ADMs on the market. However, the options are more numerous, and their advantages or differences are often subtle. Things to consider when making a choice include the source, cross-linking, how it is stored, whether it requires a rehydration period before implantation, the method of sterilization, how it can be stretched in vitro and so on. The following sections provide examples of the wide range of uses of ADMs in plastic and reconstructive surgery, from head to toe, from visible to visceral, and list the main exemplary articles for each region. Indications and techniques are not absolute and are intended to give the surgeon discretion from a broader perspective.

Table 1 Some of the commonly available acellular dermal matrices.

ADM	Source	Processor
Alloderm®	Human	LifeCell Corp., Bridgewater, NJ, United States
Allomax®	Human	CR Bard/Davol Inc., Cranston, RI, United States
DermACELL®	Human	LifeNet Health Inc., Virginia Beach, VA, United States
NeoForm®	Human	Mentor, United States
Ethicon®	Human	Ethicon Inc., Somerville, NJ, United States
MatriDerm®	Bovine	Dr Suwelack AG, Billerbeck, Germany
IntegraTM	Bovine	Life Sciences, Princeton, NJ, United States
Renoskin®	Bovine	Perouse Plastie, France
PermacolTM	Porcine	Medtronic, Minneapolis, MN, United States
Strattice®	Porcine	Allergan, Madison, NJ, United States
CollaMendTM	Porcine	CR Bard/Davol Inc., Cranston, RI, United States

CLINICAL APPLICATIONS

Burns

Reconstruction of skin continuity after a severe burn is crucial for healing. Reconstruction after a severe burn injury also involves healing of the skin’s natural elasticity, texture, and contour. Complete destruction of the skin requires the use of a skin substitute. The method of choice is a graft consisting of the epidermis and a super thin layer of dermis. It is important to rebuild and replace this tissue to achieve good epithelial coverage. The optimal method of treating extensive full-thickness or deep dermal skin burns is split-thickness skin grafts. However, in extensive burn conditions autologous donor skin sources are often scarce and skin grafts can fall short in providing stable coverage to restore the structure and function of skin. Moreover, the debrided defective area may not yet be ready to form a good bed for grafting and grafts taken limited harvest sites may not contain sufficient dermal thickness. In the face of these difficulties in burn conditions, ADMs were initially used successfully in combination with a thin partial thickness skin graft to cover full thickness burn defects[30], and then expanded their use as a useful adjunct to promote secondary healing or provide temporary wound coverage in deep dermal burns[31-35]. Later, the already widespread use of ADMs and the accumulating clinical evidence in the field of burns (Table 2) make them an important tool not only for extensive burns where surgeons are helpless, but also in situations where it is desirable to reduce or prevent contracture, scarring and poor wound healing[36-40]. Until recently, a few long-term high-quality studies evaluated the use of ADMs in burns and supported the positive results obtained up to that time, showing that the use of ADMs improves scar quality[41-43] and that their use around the joint[44] may be advantageous. Randomized controlled trials also advocated that ADM used in acute extensive burns are associated with rapid healing[45,47], better function[45,46] and higher quality of life[46,47]. However, more recently, a growing number of randomized controlled trials have revealed some conflicting data with these frequently reported positive results. Almeida et al[48] reported no significant difference in scar quality, clinical and biomechanical characteristics between 3 different ADM products and split thickness skin grafts at the end of 1 year. Another similar structured study[49] reported that burn contractures reconstructed using ADM had a significantly higher rate of recurrence at 12 months. In both two studies, however, the sample groups consisted of contracture patients rather than acute burn patients. Gardien et al[50] also reported no significant difference in scar quality between the ADM and non-ADM groups at 6 years in a population of 24 patients. As more well-planned and larger sample randomized controlled trials are conducted, we will be able to better understand the limitations and benefits of ADMs in burns. However, the data on the safety of ADMs in burns is uncontroversial and their role in reducing the need for donor sites, especially in extensive burns, will probably ensure that they will remain irreplaceable for longer periods.

Table 2 Clinical evidence examples of the utilization of acellular dermal matrix in burn.

Ref.	Year	Title	Note
Li et al[45]	2015	Human acellular dermal matrix allograft: A randomized, controlled human trial for the long-term evaluation of patients with extensive burns	This randomized controlled clinical trial of human acellular dermal matrix (ADM) showed that the composite graft of human ADM with thinner split-thickness skin graft could provide acceptable esthetic outcomes, good functional recovery, and less scar formation at the donor site
Heimbach et al[33]	2003	Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment	Integra® has been found useful in postburn reconstructive procedures both for pediatric and adult patients, affording improved cosmetic results. It clearly provides a valuable, effective and safe clinical treatment modality for dealing with the difficult clinical management challenge posed by the extensively burned patient
Nguyen et al[32]	2010	An objective long-term evaluation of Integra (a dermal skin substitute) and split thickness skin grafts, in acute burns and reconstructive surgery	Authors conclude that when objectively measured ADM treated sites correlate well with subject’s normal skin elasticity whilst no correlation was seen with the subject’s skin grafted sites
Guo et al[35]	2016	Use of porcine acellular dermal matrix following early dermabrasion reduces length of stay in extensive deep dermal burns	In this retrospective study authors conclude that early dermabrasion combined with porcine ADM coverage facilitates wound healing, decreases the length of hospital stay, and improves esthetic and functional results in extensive deep dermal burns of adult patients
Wang et al[51]	2020	Clinical Applications of Allograft Skin in Burn Care	This compact review summarizes the current use of ADMs and skin allografts in burns in the light of clear evidence
Chen et al[47]	2024	Multicenter effect analysis of one-step acellular dermis combined with autologous ultra-thin split thickness skin composite transplantation in treating burn and traumatic wounds	In this open, randomized, controlled, multicenter study, the authors suggest that ADMs can be successfully combined with partial-thickness skin grafts in many other acute traumatic and chronic non-burn wounds

Chronic wounds

Wounds that are difficult to heal, contain exposed bone, tendons or are infected are frequently encountered by plastic surgeons and other related sub-disciplines. Replacing the defective dermis using ADMs instead of performing reconstructions with long operative time, several steps, long hospitalization or large donor site morbidities has made ADMs, which have proven their efficacy in burns, an important backup tool for surgeons, especially in the elderly and comorbid population or patients undergone repeated failed reconstructive attempts. Despite the paucity of high-quality data, the overwhelming body of literature, consisting of numerous case reports or case series, should be kept in mind by reconstructive surgeons and ADMs should be considered as an option as a lifeboat in well-considered, well-planned and well-selected cases. Table 3 provides examples of the use of ADMs in the management of a wide range of difficult wounds.

Table 3 Clinical evidence examples of the utilization of acellular dermal matrix in various chronic wounds.

Ref.	Year	Title	Note
Luthringer et al[56]	2020	Human-derived Acellular Dermal Matrix Grafts for Treatment of Diabetic Foot Ulcers: A Systematic Review and Meta-analysis	Authors conclude that Human-derived acellular dermal matrices (ADMs) are associated with a higher likelihood of complete healing and fewer days to complete healing within a 12-week and 16-week periods when compared with standard of care
Gormley et al[52]	2024	The use of fetal bovine acellular dermal matrix in severe diabetic foot ulceration and threatened limbs with tissue loss the use of FBADM as an adjunct for complex wounds	Authors conclude that ADM may be a useful adjunct in the acute setting of complex diabetic foot disease and critical limb-threating ischemia ulceration to assist with wound healing
Climov et al[53]	2016	The Role of Dermal Matrices in Treating Inflammatory and Diabetic Wounds	Authors review wide range of inflammatory wounds such as pyoderma gangrenosum, sickle cell ulcer, sarcoid ulcer as well as diabetic foot ulcer where ADMs may enhance the regenerative potential
Zelen et al[55]	2018	An aseptically processed, acellular, reticular, allogenic human dermis improves healing in diabetic foot ulcers: A prospective, randomised, controlled, multicentre follow-up trial	This randomized controlled trial demonstrates the effectiveness of the human derived ADM in facilitating the closure of nonhealing diabetic foot ulcers refractory to standard of care
Cazzell[58]	2019	A Randomized Controlled Trial Comparing a Human Acellular Dermal Matrix Versus Conventional Care for the Treatment of Venous Leg Ulcers	According to this multicenter, randomized, controlled, open-label trial, authors conclude that successful increase in healing rates and rate of percent wound closure in ADM application as compared with conventional care options
Strauss and Brietstein[59]	2012	Fetal Bovine Dermal Repair Scaffold Used for the Treatment of Difficult-to- Heal Complex Wounds	Authors conclude that ADMs can be used as part of an effective treatment regimen to heal complex wounds with exposed tendon/bone caused by varying etiologies

Besides good quality clinical evidence indicating the efficacy[52,53] of ADM in diabetic foot ulcer (DFU), it bears highest number of randomized controlled trials among chronic wounds[54-56]. Hu et al[54] found 46.2%, 69.2%, and 88.5% rates of complete wound closure in the ADM + skin grafting group at 2, 4- and 8-weeks post-grafting, respectively. These were not significantly different from those of the control (only skin grafting) group (61.5%, 76.9%, and 84.6%) at each timepoint. However, the recurrence rate during the follow-up period (12 months) was significantly lower in the experimental group compared with the control group. Authors concluded that combining skin graft on top of an ADM is a safe, effective and favorable option for treating DFUs and it may improve the quality of life of patients with DFUs by reducing the risk of amputation and recurrence. Zelen et al[55] in their prospective, randomized, controlled, multicenter follow-up trial, found significantly higher healing ratio in ADM + standard of care (SOC) group compared to SOC alone group at 12 weeks. They also associated rapid healing time with low costs when compared to other treatment modalities. Current data revealed that compared with SOC, acellular dermal matrix may accelerate the healing velocity of uninfected, non-ischemic, full-thickness DFU[57]. It also seems to have superiority in generating no more complications, such as recurrence[57]. ADMs represent a promising option for managing DFUs, offering several benefits that can enhance healing and improve patient outcomes. However, careful consideration of the patient's specific circumstances and potential challenges is essential for optimal use.

ADMs have also shown efficacy as an adjunct in lower limb venous ulcers treatment. In one of the randomized controlled trial[58], ADM resulted in greater reduction in wound size at 24 weeks (59.6% ADM vs 8.1% control). Additionally, all of the ADM-treated wounds remained healed at four weeks postoperatively and 75% remained healed at 12 weeks compared to 66.7% at four weeks and 33.3% at 12 weeks in the control group.

Although their lower quality, there are some studies[59-61] indicating that the ADM can be particularly useful when treating exposed tendons and bones that may be unsuitable for skin graft coverage. Despite their low quality, there are some studies[59-61] showing that ADM may be particularly useful in the treatment of exposed tendons and bones that may not be suitable for skin grafting. According to these studies, ADMs applied after appropriate debridement of exposed bone and tendon segments accelerate granulation in these areas and make the wound bed favorable for grafting.

ADMs have also been associated with complications in chronic wound management, such as hypopigmentation; failure of vascularization, absence of hair follicles, sweat and sebaceous glands; and incomplete innervation[62].

Breast

To date, the increasing rates of breast reconstruction with the effort to achieve the best aesthetic result in less step with minimal complications have made breast surgery the most studied and clinically evidenced area for ADMs. The first ADM-related report in breast surgery was reported by Duncan[63] in 2001 in aesthetic implant surgery. This series, which reported the prevention of implant rippling by thickening the tissue envelope, was followed by the successful use of ADMs in aesthetic revisional implant surgeries[64]. Not surprisingly, the use of ADMs then expanded to reconstructive breast surgery[65] and the development of technical properties of ADMs and their clinical utility has accelerated. Presently, ADMs are used routinely in many centers in both primary and revisional alloplastic breast reconstructive and aesthetic surgery. ADMs are generally preferred in one-stage, direct-to-implant surgeries to strengthen the soft tissue envelope in the inferior and lateral breast pole by being sutured between the lower edge of the pectoral muscle and the inframammary fold to reinforce the implant pocket as a sling (Figure 2), while in two-stage breast reconstructions, they are used to strengthen the soft tissue envelope in the inferior and lateral pole of the breast to be expanded and projected. Thus, the surgeon can have greater control and handling over breast projection, lower pole fullness and inframammary fold position. A systematic review of 1039 one-stage immediate breast reconstructions with either ADM showed low overall rates of skin and nipple necrosis (11% and 5%, respectively), infection (12%), hematoma (1%) and seroma (5%), with only 9% of patients requiring reoperation[66]. Also, Nahabedian and Jacobson[67] reported low infection and seroma rates in their multiple series with two-stage reconstruction combined with ADM. In these patients, while the range of surgical site infection was 2.4%-8.1% in prepectoral and 4.8%-11.5% in partial subpectoral reconstructions, seroma was seen in a range of 3.6%-15% in prepectoral and 2.4%-6.5% in partial subpectoral reconstructions. The reconstructive failure rates were also favorable in these patients (subpectoral range 4.3%-15.4%, prepectoral range 1.2%-8.5%). The benefits of ADM in reducing capsular contracture with implants placed in the subpectoral position have been also well documented[68]. Indeed, studies of prepectoral placement of devices without ADM have demonstrated higher rates of capsular contracture[69] compared to when ADM is used. Besides reconstructive era, by inserting ADM prophylactically in primary breast augmentation patients, Hester et al[70] reported zero capsular contracture in 49 women.

Figure 2 Two case examples for acellular dermal matrix-assisted breast surgery. Left represents breast one stage reconstruction after nipple sparing mastectomy. Right is for a revisional implant exchange and mastopexy. Fenestrated acellular dermal matrix is preferred for both cases.

Placement of implants in the prepectoral plane by wrapping partially or completely with ADM sheets is also a promising and more popular option, and this technique promises greater patient comfort along with better aesthetic results, while reducing pectoral muscle-related morbidities, such as pain, animation deformity and displacement[71-73]. However, although early reports showed that this plane was associated with more complications, more recent reports[74,75] and a meta-analysis[76] indicate similar complication rates when compared to subpectoral plane.

In revision cosmetic surgery, ADMs are used to provide soft tissue reinforcement that is often lacking in augmentation patients, to reinforce breast pockets to correct implant malposition, and to reinforce thinned soft tissue to correct rippling. Furthermore, matrices have also been used in primary mastopexy or reduction mastopexy to provide dermal support to improve breast shape and projection and to prevent "bottoming out"[63,64,70,78]. In addition, ADMs are increasingly securing their position as an important backup player in surgeon’s armamentarium in the correction of complications and deformities such as symmastia, capsular contracture and rippling, that may develop after both aesthetic and reconstructive surgeries[78,79]. Table 4 provides examples of current clinical evidence for the use of ADMs in breast surgery.

Table 4 Clinical evidence examples of the utilization of acellular dermal matrix in breast surgery.

Ref.	Year	Title	Note
Sigalove et al[71]	2017	Prepectoral implant-based breast reconstruction: Rationale, indications, and preliminary results	In this report, the authors discuss the rationale for prepectoral implant reconstruction, its indications/contraindications, and preliminary results from over 350 reconstructions
Chopra et al[72]	2021	The Journey of Prepectoral Breast Reconstruction through Time	Authors review the breast reconstruction history and favor prepectoral implant placement. They also encourage the use of acellular dermal matrix (ADM)/Synthetic Mesh with prepectoral breast reconstruction as they are an efficient and effective mode of breast reconstruction, causing minimal morbidity whilst providing good cosmesis
Haddock et al[73]	2021	Prepectoral versus Subpectoral Tissue Expander Breast Reconstruction: A Historically Controlled, Propensity Score-Matched Comparison of Perioperative Outcomes	When compared two groups, authors found similar rates of overall perioperative complications. However, prepectoral placement might reduce unnecessary clinic visits; shorten the delay before adjuvant therapy, and minimize patient apprehension, pain, and discomfort related to clinic-based expansion
Nahabedian and Jacobson[67]	2019	Two-stage prepectoral breast reconstruction	Authors suggest that the prepectoral two-stage approach is indicated in the majority of patients and can be performed with fewer complications using ADM, especially in patients who will receive radiotherapy
Asaad et al[74]	2023	Surgical and Patient-Reported Outcomes of 694 Two-Stage Prepectoral versus Subpectoral Breast Reconstructions	A large population reconstructed with ADM. Analysis demonstrated overall similar complication rates between the two-implant plane
Sbitany et al[75]	2017	A Safe Alternative to Submuscular Prosthetic Reconstruction following Nipple-Sparing Mastectomy	After two-staged implant reconstructions with ADM, analysis revealed no difference in total complication rate between the two groups and no differences in any of the individual complications measured that included infection, seroma and explantation
Nahabedian and Spear[79]	2011	Acellular dermal matrix for secondary procedures following prosthetic breast reconstruction	Authors defines novel ADM involving techniques for correcting deformities and complications, such as rippling, displacement, capsular contracture etc.
Kaufman[78]	2012	Pocket reinforcement using acellular dermal matrices in revisionary breast augmentation	Author describes techniques for correcting deformities with ADM after primary breast augmentation

Despite promising reports, ADM is not without its drawbacks in the breast. Many reports have also shown ADM to result in significantly increased risk of certain complications[80-82] such as seroma, infection, skin necrosis and reconstructive failure. Much of the expertise along with the promising results are usually derived from case series of certain number of surgeons who steadily use ADM. While many results are promising, as in other application fields, the absence or paucity of high-quality, randomized controlled data in regard to ADM use in breast-related surgeries prevents clearly define indications as well as creating algorithms and limits[83] their generalizability and reproducibility.

Although the one of the most studied in the body fields, ADM costs are still another issue of concern in breast. Despite the baseline cost increases some authors found this cost-effective technology in single[24] and two-stage reconstructions[23,24]. In the contrary, in their retrospective comparative study, Viezel-Mathieu et al[28] reported 25% less costs in one-stage ADM-sparing technique compared to their traditional two-stage technique using ADM. A randomized controlled trial[26] also showed, despite the similar health status at the end, one-stage reconstruction using ADM is associated with higher costs compared with the traditional two-stage reconstruction. As can be appreciated, the literature does not seem to have reached a consensus on costs. To determine the impact and effectivity of ADMs on the costs of aesthetic breast surgery, large prospective observational studies with more standardized techniques are needed to evaluate outcomes in the long term.

Many questions are yet to be answered regarding ADM in breast surgery, and hopefully the design of high-quality studies will begin to define a clearer data about their use. In this way, the contribution, or advantages of ADMs over conventional methods can be offered as a more predictable option and the economic cost of the procedure can be undertaken with less risk.

Chest

Most chest wall defects result from oncologic resections and require meticulous reconstructive planning depending on the size and/or location of the defect, the patient's comorbidities and the condition of local tissues. It is also necessary to create a tissue composition that will protect the internal organs and support the upper extremities whilst not complicating the ventilation. Furthermore, a The use of ADMs for chest wall reconstruction was first reported by Cothren et al[84] in 2004 and since then, the defined utilities of the ADMs for chest wall reconstruction can be summarized as follows: To support local soft tissue coverage for small thoracic defects, to stabilize the chest wall in large musculoskeletal defects, to correct congenital and acquired contour deformities, and to support the barrier function of autologous flaps in covering the thoracic cavity. In addition, another reason to prefer ADMs for chest wall reconstruction over synthetic materials is that there is a large body of basic science evidence showing that ADMs have increased resistance to infection, and, even in case of infection, treatment can be performed without removal of the material[85]. Although there are no evidence-based guidelines or standardized approaches in terms of the need for ADM use and surgical technique, the literature provides examples of highly successful reconstructions[84-88] (Table 5).

Table 5 Clinical evidence examples of the utilization of acellular dermal matrix in chest wall reconstruction.

Ref.	Year	Title	Note
Sodha et al[85]	2012	The use of acellular dermal matrices in chest wall reconstruction	First review of acellular dermal matrix (ADM) utilization in chest wall defects. Authors share their experiences and conclude that they favor acellular dermal matrices when there is concern for possible field contamination, active infection, or concern over wound healing
Cothren et al[84]	2004	Chest wall reconstruction with acellular dermal matrix (AlloDerm) and a latissimus muscle flap	First case report utilizing ADM in a chest wall defect
Khalil et al[86]	2018	Chest Wall Reconstruction with Porcine Acellular Dermal Matrix (Strattice) and Autologous Tissue Transfer for High Risk Patients with Chest Wall Tumors	Reconstruction 7 sarcoma and 1 breast cancer resection involving chest wall. Authors encourage ADM use in chest wall reconstruction to resist infection in high-risk patients with extensive defects
Alshehri[87]	2023	Chest wall osteochondroma resection with biologic acellular bovine dermal mesh reconstruction in pediatric hereditary multiple exostoses: A case report and review of literature	Resection and ADM involving reconstruction of a 5-year-old
Delgado-Miguel et al[88]	2022	The Use of Acellular Dermal Matrix (Integra Single Layer) for the Correction of Malformative Chest Wall Deformities: First Case Series Reported	Four cases of congenital chest malformation

Abdominal wall

Abdominal wall reconstruction remains a complex problem for both plastic and general surgeons. The use of traditional synthetic materials such as polypropylene, polyethylene terephthalate and polytetrafluoroethylene has lost favor to mildly absorbable or partially absorbable materials such as polyglactin or poliglecaprone[89,90]. However, the indications for use or preference for any of these materials are not clear, and none of them is an appropriate choice, especially in contaminated areas. In such defects, where complications such as visceral adhesion, fistula formation, infection, seroma and wound dehiscence are also on the rise, the rate of removal of the meshes can reach 50%-90%[91]. With synthetic meshes failing to meet the needs of the patient in certain circumstances, ADM has become an important consideration in abdominal wall reconstruction of the selected cases. Perhaps the most significant advantage is the opportunity for use in contaminated fields where synthetic meshes are contraindicated (typically, these are Ventral Hernia Working Group class 3 and 4 hernias). Baumann and Butler[89] advocated the first report including such scenarios (grossly contaminated fields, patients have high risk factors for wound healing complications, where increased resistance to infection is desired, direct coverage of viscera and predicted reoperation because of the use of synthetic mesh) which all have been further investigated[92-95] and commonly adopted[96,97] later on. However, well-known risk factors of abdominal wall surgery such as obesity, recurrent hernias, concomitant digestive surgery, smoking and ongoing infection are associated with increased hernia recurrence, and this rate may still remain high in the use of ADM[98,99]. Among complications, reconstructive failure leading recurrence is the most interested and ranges from 6% to as high as 100%[100,101]. The wide range of complications reported in this way has intensified the investigation of the types of ADMs used. Among the ADMs of human, bovine and porcine origin, all of which bear different nuances of use, the high recurrence rates reported in human-derived ADMs[96,97,100,102-105] have greatly increased the interest in animal-derived ADMs. More recently, Lightfoot et al[106] performed a well-designed retrospective cohort study comparing 40 consecutive patients who underwent open component separation with porcine ADM reinforcement to 39 consecutive patients who underwent open component separation with bovine ADM. They reported that bovine ADM was statistically significantly superior in terms of wound complications, while recurrence and reasons requiring reoperation were less common but not statistically significant. This indicates that even with the diverse array of xenogeneic meshes on the market, the ideal mesh is yet to be identified. While the chosen ADM product certainly contributes to the failure, there is ample data to suggest that this extremely wide failure range is not solely due to the chosen product. For example, Garvey et al[104] in their high-volume single center study not only reported remarkable recurrence rates of 11.5% and 14.6% detected by CT at 3 and 5 years, respectively, but also demonstrated that bridged repair technique was highly unsuccessful in preventing recurrence compared to primary fascial repair technique and reinforcement with ADM. Indeed, in addition to superiority of xenogeneic ADM, there are two more points that literature agrees upon. First, primary fascial repair with the use of ADM as reinforcement has repeatedly been shown to be superior to bridged repair technique in preventing recurrence[101-105] and second, component separation technique facilitates fascial closure and reduces overall complications when used in conjunction with ADM[105-108]. Even though there are descriptions for different surgical variables commonly used, such as suture choice, fascial overlap amount and suture technique for ADM, lack of standardization in these data warrants further studies. As with other ADM applications, paucity of randomized controlled studies with long-term outcomes limits the opportunity to draw more specific therapeutic conclusions about ADM in abdominal wall repair. Table 6 summarizes the some of the clinical evidence for ADM use in abdominal wall repair.

Table 6 Clinical evidence examples of the utilization of acellular dermal matrix in abdominal wall reconstruction.

Ref.	Year	Title	Note
Zhong et al[96]	2011	Outcomes after abdominal wall reconstruction using acellular dermal matrix: a systematic review	Authors conclude the need for high-level evidence when comparing acellular dermal matrix (ADM) use with other methods to make data-driven recommendations on clinical indications, surgical techniques and outcomes following ADM-assisted abdominal wall reconstruction
Sbitany et al[98]	2015	Outcomes Analysis of Biologic Mesh Use for Abdominal Wall Reconstruction in Clean-Contaminated and Contaminated Ventral Hernia Repair	Authors conclude that single-stage repair of grade 3 hernias performed with component separation and biologic mesh reinforcement is effective and offers a low recurrence rate. The use of biologic mesh allows for avoidance of mesh explantation in instances of wound breakdown or infection. Bridging repairs are associated with a high recurrence rate, as is single-stage repair of grade 4 hernias
Atema et al[99]	2017	Major Complex Abdominal Wall Repair in Contaminated Fields with Use of a Non-cross-linked Biologic Mesh: A Dual-Institutional Experience	Author proposes that the repair of the most challenging abdominal wall defect can be done effectively with combination of a non-cross-linked biologic mesh and component separation technique without the need for mesh removal despite wound infections
Hassan et al[107]	2023	Outcomes of Complex Abdominal Wall Reconstruction After Oncologic Resection: 14-Year Experience at an NCI-Designated Cancer Center	Authors conclude that ADM-assisted abdominal wall repair after extirpative wall resections demonstrated comparable outcomes with primary herniorrhaphy
Giordano et al[108]	2024	Component Separation Decreases Hernia Recurrence Rates in Abdominal Wall Reconstruction with Biologic Mesh	Authors concluded that the component separation technique combined with ADM was associated with fewer hernia recurrences, while surgical site occurrence was similar in long-term follow-up despite additional surgery

Head and neck

Besides the oral-maxillofacial, head and neck and craniofacial reconstructive procedures, there is an increasing number of evidence that ADMs can be used for aesthetic purposes. In 2012, Shridharani and Tufaro[109] compiled a systematic review of nearly 3 dozen studies with objective and measurable results, including surgeries such as nasal soft tissue and skeletal repair[110,111], tympanoplasty[112], parotidectomy sequelae[113,114], oral-mucosal[115], palatal[116] and pharyngeal defects[117] and fistulas as well as periorbital soft tissue[118] and dura mater[119] reconstructions. Today, however this number has probably reached several hundred, making the head and neck as a whole the most comprehensive area for the use of ADM. There was an inspiring earlier report of Clark et al[120], which consisted of 7 consecutive patients with clefts of the hard and soft palate wider than 15 mm. Palates were repaired in the standard 2-flap approach with intravelar veloplasty and placement of ADM immediately deep to the oral mucosal closure. There were no fistulas even though the wound dehiscence and ADM exposure occurred in two patients in early period. Since then, a growing body of evidence suggests that ADM is an effective adjunct in the repair of cleft[121,122]. More recently, some authors, based on their prospective studies, also recommend the routine use of ADM in primary palate repair due to reduced fistula rates[116]. Some meta-analyses advocate the routine use of ADM after parotidectomy[114], citing the lower incidence of Frey syndrome since its constitution as an extra durable anatomic layer between remaining parotid and dermis. One meta-analysis also validate that ADM might be an effective alternative to autologous grafts for tympanoplasty[112]. ADMs can be used internally to repair nasal septal perforations by placing as a graft between mucoperichondrial flaps and therefore it can increase the durability of the repair where watertight closure is essential[123,124]. ADMs are also still a particularly valuable tool in the treatment for patients with mucosal defects of the oral cavity (tongue, floor of mouth, palate, lip, and tonsil) following resection of primary intraoral tumors and they can provide an alternative to split-thickness skin grafting for mucosal resurfacing[115]. In addition to reconstructive procedures, it worths to mention that the use of ADMs in aesthetic-related procedures has become more widespread. ADM, for instance, has established itself as an important tool in blepharoplasty-related procedures such as correction of lower eyelid retraction[125,126] and restoring orbital septal tone[118]. In primary and revisional secondary rhinoplasty surgeries, ADM can be useful when correcting dorsal nasal irregularities[110,111] and osseocartilaginous frame[127] by on lay grafting ADM at the expense of prolonged edema. These examples may be interpreted as the utility of ADM in the head and neck region have started to consolidate with higher quality clinical evidence although more high-quality studies in all examples are still warranted to make evidence-based recommendations. Table 7 lists some of the important clinical evidence examples of ADM utility in head and neck region.

Table 7 Clinical evidence examples of the utilization of acellular dermal matrix in head and neck.

Ref.	Year	Title	Note
Shridharani and Tufaro[109]	2012	A systematic review of acelluar dermal matrices in head and neck reconstruction	First systematic review for the head and neck region
Gilardino et al[116]	2018	A Prospective Study Investigating Fistula Rate Following Primary Palatoplasty Using Acellular Dermal Matrix	This prospective study proposes the routine use of ADM in Veau II-IV clefts since it significantly reduce the fistula rate when compared their retrospective cohort
Linn et al[114]	2022	Comparison of the use of allogenic acellular dermal matrix on rates of Frey syndrome post parotidectomy: A systematic review and meta-analysis	Authors conclude that the use of ADM was associated with lower Frey syndrome rates compared to no ADM and should be considered in routine use to prevent this condition
Xu et al[112]	2021	Human-derived acellular dermal matrix may be an alternative to autologous grafts in tympanic membrane reconstruction: systematic review and meta-analysis	Authors conclude that human-derived ADM might be an effective alternative to autologous grafts for tympanoplasty
Girod et al[115]	2009	Acellular dermis compared to skin grafts in oral cavity reconstruction	Authors conclude that acellular dermis grafting for reconstruction of the oral cavity offers several advantages over split-thickness skin graft, including the lack of donor site morbidity, lower cost, a natural appearing mucosal surface, and comparable if not superior functional status
Warren et al[119]	2000	Dural repair using acellular human dermis: experience with 200 cases: technique assessment	Authors conclude that acellular human dermis is a reasonable alternative to the available dural graft materials. Its handling characteristics are similar to those of dura, it is biologically inert, and it does not produce adhesion formation
Zang et al[117]	2020	Comparison of xenogeneic acellular dermal matrix and skin grafts in reconstruction of postoperative defects of hypopharyngeal cancer: A retrospective cohort study	Authors conclude that both ADM and abdominal skin grafts demonstrated good effects in the reconstruction of hypopharynx, but the recovery time of eating function in patients with ADM was faster, which may be due to rapid epithelialization
Conrad et al[124]	2018	Acellular Human Dermal Allograft as a Graft for Nasal Septal Perforation Reconstruction	Authors conclude that as the first study to use objective and subjective measurements to confirm success with acellular dermis allograft as an adjunct for septal perforation repair it demonstrated a statistically significant reduction in patient nasal symptoms following repair
Grumbine et al[126]	2019	Correction of Lower Eyelid Retraction with En Glove Placement of Porcine Dermal Collagen Matrix Implant	Authors describe the technique for mild to moderate retractions. The operative time is brief (< 30 minutes), with limited dissection and resultant minimal to no clinically significant ocular surface inflammation postoperatively
Kook et al[110]	2023	Prevention and Resolution of Silicone Implant-Related Problems in Secondary Rhinoplasty Using a Cross-Linked Human Acellular Dermal Matrix	Authors conclude that dorsal augmentation using the cross-linked human ADM along with various nasal tip work using autogenous cartilage. Surgical outcome showed favorable resolution of contracture deformities, a low infection rate, firm fixation of the implant, good skin texture/thickness of the skin/soft tissue envelope and gain of desired height and dorsal line
Fisher et al[111]	2023	Current Practices in Dorsal Augmentation Rhinoplasty	Authors describe acellular dermal matrices are alternatives to autologous graft with many similar advantages and no need for an additional surgical site

Extremity

The use of ADMs in the extremities is widespread and varied, with burns, contractures and scars constituting the majority. The frequency of injuries, especially in the distal upper extremity, the scarcity of local soft tissues and the abundance of superficial nerves and vessels make this region the center of many up-to-date applications. However, the majority of the clinical evidence in this region are mostly either limited studies or small case series. However, some of the important, noteworthy uses in some fields are also listed in Table 8.

Table 8 Clinical evidence examples of the utilization of acellular dermal matrix in extremity.

Ref.	Year	Title	Note
Acevedo et al[128]	2015	Orthopedic applications of acellular human dermal allograft for shoulder and elbow surgery	Authors review a wide variety of orthopedical applications of acellular dermal matrices (ADMs) such as, rotator cuff tears, latissimus dorsi transfers, pectoralis major and biceps tendon repairs, glenoid resurfacing and acromioclavicular reconstruction
Cole et al[131]	2018	Achilles Tendon Augmented Repair Using Human Acellular Dermal Matrix: A Case Series	Authors report no cases of rerupture or complications that require additional treatment over average of 14.4 months of nine patient
Rabinovich and Lee[134]	2018	Proximal Row Carpectomy Using Decellularized Dermal Allograft	Authors describe their ADM-assisted resurfacing technique with illustration and figures
Hoang et al[135]	2019	Use of Acellular Dermal Matrix Following Fasciectomy for the Treatment of Dupuytren's Disease	Authors conclude that the adjunct placement of acellular dermal matrix into the wound bed following fasciectomy may be an important surgical strategy to reduce recurrence rates as well as augment coverage of exposed vital structures in cases of severe flexion contracture
Ellis and Kulber[37]	2012	Acellular dermal matrices in hand reconstruction	A comprehensive review for ADM-assisted reconstruction of difficult skin and soft tissue defects resulted from various etiologies such as, ischemia, infection, advanced Dupuytren disease and burn contractures
Shim et al[132]	2021	Preventing postoperative adhesions after hand tendon repair using acellular dermal matrix	Authors conclude that he use of ADM after tendon repair has the potential to significantly improve the outcome of tendon surgery in terms of range of motion

In both primary and revision rotator cuff repairs, some studies reported incorporation of ADMs has led to improvements in pain, ROM and muscle strength in long-term follow-ups[128,129]. Furthermore, in irreparable rotator cuff tears, ADMs have been used to cover the exposed bone, leading to decreased pain and better functional scores[130]. Efforts to reinforce or augment the deficient long tendon repairs have led combining them with ADMs. Cole et al[131] successfully repaired 9 Achilles tendon with ADM augmentation without any complications requiring re-operation. Postoperative flexor tendon adhesion in hand is annoying and it can contribute to functional disability and reconstructive failure. In their prospective study Shim et al[132] found improved ROM and function in ADM-treated group at six months. Arthritic hands have also long been difficult cases. Reconstruction of ligaments or resurfacing damaged joints usually requires donor tendon, but this might often associate with scarring, chronic pain, tendonitis, and rupture. Using ADM rather own tissue may significantly reduce the donor site related morbidity[133,134]. While there are some studies investigating and showing benefit of the use of ADM for other upper extremity applications, such as Dupuytren disease[135], congenital malformations, and traumatic reconstructions[37] these are limited studies or small case series. As in the other uses in extremities further investigation into these proposed uses is also warranted.

CONCLUSION

After the processing journey of ADMs, which starts as allo- or xeno-product, the market generously offers them to us in a package like synthetic merchandise, and after the appropriate implantation technique, they adapt the body as if they were already part of it, without any alienation. This review demonstrated that as manufacturing technology improved and their popularity grew, ADMs found their way into the surgeon's armamentarium for a wide range of conditions. The compelling clinical examples showcased in this study affirm that the applications of human ADM extend significantly beyond its initial use for skin defect treatments. Although the literature is encouraging in almost all areas, more rigorous and higher-quality prospective studies are needed for more widespread use. It is clear that these products, which tissue engineering and bioengineering have already made practical and widely available, will be further developed in the future.

Experimental studies are ongoing with the aim of evolving ADM-based scaffolds into the desired 3D shape[136], combining them with stem cells[137] and growth factors[138]. Although many of these ideas are still in the proof-of-concept phase, there are also exciting clinical applications with some early promising results in patient trials[53,139-140].

Another development that has become very important in the recent past is synthetic substitutes or templates. Known as, biodegradable temporizing matrix (BTM), this completely synthetic bilayer skin substitute is made of a biodegradable polyurethane matrix foam covered with a nonbiodegradable polyurethane sealing membrane to mimic the dermis and epidermis, respectively[141]. When placed over a wound, it promotes vascularization and dermal regeneration[142]. Polyurethane was selected for its low manufacturing cost and ability to withstand infection, combating two important limitations of biological dermal scaffolds[143]. Although BTM has shown promising results as a lower-cost skin substitute in preliminary reports, it is also carrying out very exciting and successful missions in the use of skin as a highly vascularized bed for transplantation of islet cells[144] or as a scaffold for adrenal organoid formation in adrenocortical cell transplantations[145]. Indeed, it would not be surprising to see an increase in successful cell transplantations using BTM in the next decade. Until all the rapidly developing processes of whole organ decellularization and recellularization have been perfected, ADM and BTM will likely maintain their potential as a reliable scaffold for many cells to adapt and proliferate.