Treatment of Deep Full-thickness Wounds Containing Exposed Muscle, Tendon, and/or Bone Using a Bioactive Human Skin Allograft: A Large Cohort Case Series

Background. Deep wounds with exposed muscle, tendon, and/or bone structures are especially difficult to treat, often requiring a multifaceted approach. Bioactive human skin allograft (BSA) has been proven to be effective in the treatment of deep wounds, but the mechanism of action and clinical use in the real-world setting is not as well known. Objective. The aim of this case series is to study deep wounds treated with BSA to better understand how it is used in real-world patients and discuss its mechanism of action. Materials and Methods. A total of 51 deep wounds of various etiologies and locations were included from 10 sites across the United States. To be included, patients must have failed wound care without BSA for at least 30 days, with more than 50% reduction in size prior to BSA application. Results. The mean wound area was 50.37 cm² and average wound duration was 3.67 months. The mean time to closure was 15.33 weeks, achieved with an average of 4.24 BSA applications. Many patients received adjunctive therapies either prior to or in combination with BSA. Conclusions. This study demonstrates the effectiveness of BSA in the treatment of deep wounds of various etiologies. The authors provide clinical information on using BSA either alone or in conjunction with other advanced modalities and offer insight into the hypothesized mechanism of action in which these grafts become incorporated. Ultimately, this information can guide best practices in the treatment of full-thickness wounds to improve outcomes.

A full-thickness wound, or deep wound, is defined as a loss of continuity of the skin and is associated with tissue loss of the epidermis and dermis.¹ When full-thickness wounds extend past the subdermal layers of the skin and involve exposed underlying structures such as tendons, muscle, and bone, they are sometimes referred to as cavity wounds.¹ The challenge with these full-thickness wounds is that the exposed structures are frequently dysvascular and a great number of obstacles must be overcome in order to achieve wound closure. Wound closure must occur in layers, with deep tissue reconstruction mimicking the normal morphology found beneath the dermis.² Healing in these wounds can be further obstructed by deep infections, an abundance of synovial fluid exudate, tissue maceration, and disruption of delicate neodermis from muscle, tendon, joint, and bone motion compounding this process. Diminished vascular supply in the wound bed and adjacent tissues certainly complicates matters further. Deep cavity wounds in patients with diabetes are of particular importance because they are associated with higher amputation risk.³

Closure of deep wounds is achieved with a multifaceted approach that includes moist (but not macerated) wound care, debridement, edema control, offloading, immobilization, optimization of blood flow, reduction of bioburden, and appropriate medical management.⁴ Simply providing the raw materials to facilitate healing of these complex wounds is often insufficient, and many patients will require primary closure through flap reconstruction and potentially lengthy microsurgery. Unfortunately, flap reconstruction and microsurgery are typically implausible in this patient population that is highly complex and typically has innumerable comorbidities.⁵ Given the morbidity, mortality, and costs associated with these wounds, it is critical to find alternative advanced modalities that encourage rapid granulation over the exposed structures and achieve wound closure when good wound care alone is not enough.

A commonly used advanced treatment modality for deep cavity wounds is negative pressure wound therapy (NPWT) in which a reticulated foam dressing is applied to the wound bed and connected to a vacuum pump. Often, NPWT alone is not enough to stimulate granulation over exposed deep structures, and a tissue scaffold that can support the migration of tissues over the deep, poorly vascularized, and otherwise hostile environment of exposed tendon or bone is needed.⁶ Clinically, these wounds appear to have excellent granulation tissue to either side of the exposed tissue, but with no bridging over the exposed structure (Figure 1).⁶ 

Options for the treatment of these complex wounds using biologics, xenografts, synthetics, or bioengineered tissues are limited, because the majority of these materials and medical devices have never been studied under these conditions or are not cleared by the United States Food and Drug Administration for use over exposed structures.⁷ In addition, many of the aforementioned tissues have differing properties (eg, variations in scaffold thickness or absence of a scaffold altogether) that limit their ability to rapidly vascularize and granulate over the exposed structure.⁷ 

This study focused on a bioactive human split-thickness skin allograft (BSA; TheraSkin; Misonix), which is cleared for the treatment of deep, full-thickness, and cavity wounds, and has been shown to be effective in previous studies for these types of wounds.^7-10 A BSA is a minimally manipulated human skin allograft that has been uniquely cryopreserved to maintain cellular viability.¹¹ The BSA is a donated human tissue, which meets similar strict criteria to any other donated human organ.⁷ Following a careful screening of the donors to determine they meet the quality and safety criteria, the skin is procured from organ donors in less than 24 hours postmortem.⁷ After cleansing and cryopreservation, it is ready for implantation on a recipient wound. Previously, it has been shown¹¹ that about 70% of the living cells are viable at the time of implantation, and produce cytokines, growth factors, and collagen typically found in healing skin. Thus, BSA is considered bioactive because it contains the elements necessary for stimulating the healing process, and it preserves the architectural structure of the human extracellular matrix (ECM).¹¹ This is an important distinction to make when comparing the science of various skin substitutes whose purpose it is to replicate the properties of native human skin. The common commercially available skin substitutes can be described as striving to provide the wound with some, or many of the components found in human skin, without achieving actual parity.¹¹ 

In 3 real-world studies,^7,8,10 BSA was shown to be clinically effective in healing wounds involving exposed deep structures, especially in large wounds of long duration in a medically complex patient population. Of the 3 studies, 2 were large, well-conducted matched cohort studies.^7,8 The studies^7,8 included thousands of patients who reported higher healing rates with BSA in full-thickness wounds when compared with the standard of care (SOC) group, but they also found that wound recidivism rates were significantly reduced compared with SOC alone. Both matched cohort studies^7,8 used rigorous methodologies to create identically matched groups from data drawn from several hundred sites that used the same evidence-based clinical practice. One study⁸ involving close to 4000 patients with wounds below the knee, reported fewer lower extremity amputations in BSA-treated patients as compared with SOC alone, including a large number of wounds with exposed structures. Similarly, in the other propensity matched cohort study⁷ looking at nearly 1600 diabetic wounds, the authors observed significant improvement in healing rates and less recidivism in cavity wounds treated with BSA versus SOC alone. Both matched cohort studies^7,8 accounted for the concomitant use of hyperbaric oxygen therapy (HBOT) and NPWT and found no impact on the outcomes reported, based, in part, on the small number of patients who received both therapies. A third study by Wilson et al¹⁰ consisted of a case series of 15 diabetic foot ulcers treated with BSA. In their study,¹⁰ they reported an average of 5 weeks to achieve granulation over exposed bone or tendon and a total of 2 graft applications to achieve wound closure. 

All wounds, especially complex full-thickness wounds, must first heal vertically (ie, granulate to fill in the defect) before they can heal horizontally (ie, close through epithelialization). Deep wounds treated with BSA heal vertically though granulation and angiogenesis (via vascularization of the ECM scaffold which occurs within 72 hours after application) followed by epithelialization aided by the presence of living cells, relevant growth factors, and an intact basement membrane.¹² The process of BSA incorporation is very similar to split-thickness skin autografts; and so, in order to appreciate the benefit of BSA, one must first explore the similarities of BSA to autologous split-thickness skin grafts (STSGs). 

Graft incorporation
When an autologous STSG is placed on a properly prepared wound bed, imbibition takes place during the first 24 hours.¹³ During this phase, the STSG “imbibes” plasmatic fluid carrying oxygen and nutrients into the graft and onto the wound surface through an osmotic gradient.¹³ A fibrin seal is formed between the graft and wound surface to ensure good contact and prevent shearing.¹³ During the next 24 hours (ie, 48 hours after application of the graft), inosculation occurs, whereby the capillary network from the wound bed and the capillary network from the graft “kiss” and share nutrients in preparation for the final phase of graft incorporation, known as revascularization. Revascularization occurs about 72 hours after initial application of the graft when blood flows through the implanted capillary network. Once revascularization has occurred, the graft will eventually become fully incorporated.

This entire process of autograft incorporation is not only dependent on the existence of living cells that produce the various growth factors that stimulate the process, but also a considerable supply of type 1 and type 3 collagen that encompass the established capillary network of the ECM.¹⁴ This collection of materials will support the exchange of fluids, cytokines, and growth factors between the recipient site and the applied graft.¹⁴ Ideally, the skin autograft will become fully incorporated and integrated into the wound site. When applied to a properly prepared wound bed, BSA and an autologous STSG will vascularize in the same way due to the existence of a fully developed capillary network.¹⁵ 

Tendon and bone. Historically, it has been very difficult to get split-thickness skin autografts to adhere and grow over exposed tendon and bone because the tendon and bone are significantly less vascularized than soft tissues, such as skin or muscle.⁶ In fact, in many cases, as tendons tend to dry out, they are often removed to facilitate wound coverage, leading to loss of function. Tendons easily glide within their sheaths and are coated with slippery synovial fluid that collectively disrupts the attachment process, even with small amounts of movement. The sheaths that surround the tendons are also relatively dysvascular. 

Similarly, exposed bone is also a poor support structure for overlying soft tissues because bone takes about a third of its nutrition from the periosteum. This tough, membranous material is poorly vascularized compared with adjacent soft tissues and can act as a barrier to soft tissue attachment to the bone. During clinical treatment, the periosteum does not exist or is in poor condition, and the surface of the bone is often debrided just prior to application of the graft, to stimulate bleeding and facilitate the vascularization (imbibition, inosculation, and revascularization) process and secure the graft.¹⁶ 

Muscle. Muscle is a well-vascularized tissue that can often be surgically manipulated to cover a site of exposed bone. Once positioned, it can be grafted over, or the tissues may be allowed to granulate in over its surface. The movement of muscle tissue may be disruptive to the graft application process,¹⁷ so immobilization is often necessary, in order to improve the chances of graft attachment.  

Bioburden and necrosis. Bioburden, including bacteria and biofilms, and necrosis result in enzymatic digestion of tissues on the wound bed. Matrix metalloproteases (MMPs) are desirable in small quantities as they can help to stimulate angiogenesis within the graft and at the graft interface.¹⁸ However, in chronic wounds, MMP levels can become high enough that they actually digest the wound bed, which prevents healing and increases the size of the wound.¹⁸ They also are elevated in the presence of inflammation.¹⁸ Similarly, necrotic tissue within the wound bed attracts bacteria and increases drainage as the grafted tissue is broken down, additionally causing local tissue hypoxia.¹⁹ Skin autografts can be very helpful in the presence of MMPs because the human collagen matrix is a competitive inhibitor of MMPs and can help to reduce inflammation and wound bed digestion; unfortunately, the autograft is often destroyed in the process.¹⁸ 

Autografts versus BSA
There are clearly benefits to autografts, which can be summed up in the availability of living cells along with collagen, cytokines, growth factors, and a fully developed capillary network within the ECM.²⁰ Not only do these materials facilitate the growth of skin to achieve wound closure, but with an autograft, the expectation is for the graft to take permanently by incorporating native cells into the wound bed. In the case of deeper wounds, however, autografts are less effective because vertical healing and granulation over the exposed structure are needed first. The additional disadvantages of a skin autograft are typically focused on donor site morbidity, limited donor sites, and the questionable value of harvesting skin from patients who are elderly or diseased to treat themselves with their own skin.²⁰ 

A cryopreserved living skin allograft (eg, BSA) provides the next-best alternative to autografts, because it contains all of the components of human skin, including large quantities of signaling molecules (cytokines and growth factors), living cells, and the fully developed capillary network within the ECM.¹³ Although implanted living cells are allogenic and do not incorporate into the wound bed, the other materials delivered to the wound site (ie, cytokines, growth factors, collagen) are not immunogenic and function in an identical fashion to those delivered by an autograft.¹⁵ Furthermore, the implanted living cells are not recognized by the recipient upon contact but rather take 7 to 10 days before sloughing, leaving behind all of the materials they manufactured from the time of application.¹⁵

When comparing autologous STSG to BSA for deep full-thickness wounds, the greatest asset of BSA is that there is no donor site morbidity, and BSA can be a readily available and recurrent source for the necessary collagen, cells, and growth factors. For deep wounds where vertical healing and timely granulation over the exposed structure are imperative, allografts are readily available if they do not incorporate on first application. On the contrary, there are significant benefits in using the collagen portion of the allograft as a competitive inhibitor of enzymatic degradation from MMPs, which thereby reduces inflammation and digestion of the wound bed while acting as a scaffold for new vascular in-growth.¹⁸ In many cases, the BSA is used to prepare the wound bed and serve as a bridge to an STSG autograft, especially in cases in which there are profound tissue defects that must be filled in prior to autografting.²¹

The objective of this research was to study a series of 51 unique cases of deep full-thickness wounds with exposed muscle, tendon, and/or bone that were treated with BSA in order to understand the role of BSA to achieve healing where good wound care alone failed. The authors propose a mechanism of action to help understand why BSA is effective in healing these wounds and hope the findings of this large case series will be informative for clinicians caring for complex wounds in which the speed to granulation over the exposed structure and healing is critical. Lastly, the authors hope this case series will stimulate some interest in using BSA as a cost-effective alternative to autografts and other biologically active materials in the treatment of deep wounds in a complex environment.

In this series, patients with difficult wounds containing exposed muscle, tendon, and/or bone were treated with a BSA and followed until closure was achieved. A total of 51 cases were drawn from 10 clinical sites and included a variety of wounds, from head to toe; the patients were seen between January 2017 and August 2019 (Table 1). In all of the cases, BSA was used either exclusively, or in conjunction with a complimentary treatment such as NPWT, HBOT, or some form of vascular intervention, in order to achieve closure.

Data were collected retrospectively by reviewing medical records from patients meeting the inclusion and exclusion criteria (Table 2). Abstracted data included the location and etiology of the wounds, as well as the initial wound size, duration prior to initiation of treatment, time to closure, and number of grafts required (Table 1, Table 3). Wound length and width measurements were used to calculate surface area at the start of wound treatment. In some cases, wound depth also was reported, but it was considered less relevant since most deep cavity wounds have depths that vary significantly throughout the entire wound surface. Significant comorbidities, adverse events, and a brief patient summary also were reported. Adjunctive advanced therapies such as NPWT, HBOT, or vascular intervention also were tracked. In a small percentage of cases (15.7%), BSA was used following failed treatment with another skin substitute. Complications that occurred during the treatment period also were recorded.

Each patient was observed throughout the healing process, and representative photographs of the initial wound, a subsequent image during treatment, and final wound closure were collected. Healing was defined as complete epithelialization with no drainage, and it was confirmed by the panel of authors. The outcomes were reviewed by a panel consisting of representatives from the 10 clinical sites and included a discussion of the trends and observations reported herein. Based on the authors’ assessment of healing, they propose a mechanism to describe how BSA is incorporated into the wound bed to facilitate coverage of deep structures and wound closure.  

Due to the insignificant risk of this retrospective study, and absence of personal identifying information, the study was deemed exempt from institutional review board approval.

Wound and patient characteristics
The average wound area was 51.37cm² (SD = 90.59). The mean wound duration at the initiation of treatment with the BSA was 3.67 months (SD = 3.80). The etiology of the wounds was extremely variable and included surgical wound dehiscence, infection, trauma, diabetic ulcers, and wounds following chemotherapy. A list of the various etiologies and patient comorbidities can be found in Table 1. In general, the patient population was of high medical complexity.

Clinical outcomes
Detailed clinical results are reported in Table 3. The mean time to heal for all wounds in the case series was 15.38 weeks (SD = 9.54), and an average of 4.24 BSA grafts (SD = 2.80) were required to achieve closure. In cases in which multiple applications were necessary, the time between applications of BSA was variable, from once weekly to as much as 6 weeks between applications. The time between applications was largely driven by the clinician’s assessment of wound progression, and the clinical appearance of graft incorporation. When wounds were steadily progressing, application was typically delayed. Conversely, when wounds appeared to be stalled, reapplication was usually performed. Complications among this patient population were fairly rare considering the severity of these wounds; complications that did occur included 1 case of type 1 complex regional pain syndrome, 6 cases of infection requiring IV antibiotics, and 1 case of deep venous thrombosis (DVT). None of the reported complications were attributed to pathogens acquired from the BSA treatment.

Use of adjunctive modalities
A large percentage of the cases utilized adjunctive therapies, which included total contact casts (TCCs), vascular intervention, NPWT, HBOT, and a host of therapies as part of a good wound care protocol. A list of these added measures can be found in Table 3. In most cases, adjunctive therapies were performed prior to initiation of treatment with BSA (ie, vascular surgery, use of other types of biologically active materials). Patients evaluated in this study did not heal with those modalities alone and were subsequently treated with BSA. When used, NPWT, TCC, and HBOT were normally performed simultaneously with BSA treatment. In 2 of the cases, BSA was used as a bridge to eventual treatment with an autologous STSG (Figure 2). In addition, NPWT was used to help assist graft incorporation by serving as a bolster to prevent the graft from shearing and manage wound drainage. When HBOT was prescribed during the course of BSA application, the goal was to increase local blood flow through increased microcirculatory perfusion. Vascular intervention to restore circulation prior to application of BSA is a critical aspect of good wound care and is considered more closely in the discussion. 

Healing patterns
Observations of photographs of the healing wounds showed a consistent pattern as the wounds progressed (Figure 3, Figure 4). Initially, the graft began to turn pink in several locations, and gradually progressee as multiple whitish areas eventually became pink while the graft incorporated. Areas that did not turn pink may have been nonadherent and were sometimes removed prior to subsequent applications. The authors hypothesized that this was the result of vascular migration into the existing network of capillaries, which already existed within the BSA allograft. The ability of BSA to provide coverage in deep wounds relies on revascularization from the adjacent wound bed. In cases in which there are sizeable areas of exposed poorly vascularized tendon, coverage was made possible with lateral neovascularization into the human dermal ECM (Figure 1).

In cases of exposed muscle (where there was adequate vascular supply) or bone (where surgical debridement down to bleeding cancellous bone may have been performed), granulation over the exposed structure was rapid because a native vasculature that can “grow” into the BSA matrix was present throughout (Figure 4). In these cases, the incorporation of the graft included a vertical action in addition to lateral migration of vasculature. 

Images taken using near-infrared spectroscopy (NIRS; Snapshot_NIR; Kent Imaging) clearly demonstrated the phenomenon (Figure 5) in which the allograft became perfused. Near-infrared spectroscopy is a technology that utilizes reflected light to calculate the ratio of oxygenated to deoxygenated hemoglobin as a measure of vascular perfusion. These diagrams demonstrate the seamless oxygen perfusion of the BSA as early as 1 week after application.

Although the authors have not presented any histologic evidence of this proposed mechanism, the existence of a capillary network present within the BSA is likely to contribute to the rapid reperfusion and thus integration of the ECM found in the BSA. Rademakers et al²² described the importance of prevascularization (ie, creation of capillary networks within a bioengineered tissue product) prior to application to enhance rapid perfusion and avoid the much slower process of neovascularization where the capillary network must be slowly created. Prevascularized grafts reduce the duration of hypoxia,²³ which facilitates migration of native endothelial cells into the graft. This process is further enhanced by the presence of growth factors such as vascular endothelial growth factor (VEGF),²⁴ which further enhances angiogenesis into the graft. The VEGF found in the BSA fibroblasts and within the ECM is a heparin-binding growth factor that targets the recipient’s endothelial cells and is a major contributor to this angiogenic response.²⁵

Deep wounds with exposed muscle, tendon, and/or bone, are an especially complex subset of difficult wounds. These wounds are more susceptible to infection and desiccation of the exposed structures (requiring surgical removal resulting in subsequent loss of function), and are associated with increased amputations, morbidity, and mortality.³ When not treated effectively, these wounds also result in escalating health care costs incurred after months of failed wound care attempts. The speed to granulation over the exposed structure and subsequent expedient healing are critical in improving both clinical and economic outcomes for both patients and payers.²⁶ Furthermore, when coverage of deep structures fails, complications are inevitable. 

Although BSA is a proven therapy for complex wounds, there is a poor understanding of its mechanism of action in these wounds and how best to utilize BSA as part of a multifaceted approach. In this case series of 51 full-thickness wounds treated with BSA across 10 sites in the United States, the mean wound size in the study was very large (51.37 cm²), and the mean wound duration prior to BSA treatment was 3.67 months. All wounds in the study received good wound care (ie, wound bed preparation, moist wound dressing, offloading, edema control, and in some cases, other advanced modalities) prior to treatment with BSA, and failed to show significant progression toward healing. Once BSA was added to the treatment protocol, these wounds went on to heal.

This large case series provides insight into a unique wound population that, to the authors’ knowledge, has not been extensively studied in either controlled trials or real-world studies for skin substitutes. Despite the large wound size and presence of exposed structures, the mean time to closure was 15.33 weeks and achieved with an average of 4.24 applications of BSA. The number of grafts required for closure in this study was higher than those reported in previous BSA studies^7-10; however, the mean wound size in this study was substantially larger and only included wounds with exposed structures. Interestingly, the mean time to closure was similar to those reported in other real-world studies of BSA.^7-10  The results of this study further support the use of BSA for the treatment of deep cavity wounds in complex patients with extremely large wounds of long duration. 

It is important to discuss the concomitant use of other treatments because many clinicians who do not specialize in chronic wound management as well as payers who make coverage determinations, are often confused about the role of other advanced modalities in complex wound healing. In the present case series, 29 wounds (57%) received NPWT along with BSA application. In fact, NPWT was used in conjunction with wounds from nearly all locations. The BSA is robust enough to be used in conjunction with this therapy, and NPWT also serves as a dressing to bolster the BSA in place. This technique has been previously documented in the clinical literature as a way to prevent autologous graft shearing and improve graft contact with the wound bed for vascularization to occur.^26-29 Given that the mechanism of BSA and autologous STSG vascularization are similar, it is logical to presume that the use of NPWT in addition to BSA in certain situations offers additional clinical benefit. Only 8 patients (all with wounds localized to the foot) received HBOT in addition to BSA treatment. In those cases, vascular intervention was either not an option or HBOT was used in conjunction with vascular intervention in an attempt to improve oxygenation of the tissues and mitigate post-intervention ischemia/reperfusion injury. Both vascular intervention and TCC were considered as adjunctive modalities for completeness of reporting; in clinical practice, the authors consider these interventions to be an important component of good wound care.  

In the presence of other adjunctive modalities, how does one know BSA was the key to wound closure? To answer this question, one can look concept of causality. Causality requires action — the wound did not close until application of BSA. It requires timing — the wound did not close prior to application of BSA, and immediately progressed towards closure after application of BSA. Causality is the first step towards rigorous scientific proof; in this case, causality strongly supports the authors’ contention that BSA was a critical ingredient in the wound closure process. Future studies may help to more clearly define the role of each modality.

One important outcome of this study was the opportunity to observe the progression of healing in these complex wounds. In wounds that were smaller (ie, <5cm²) and more superficial, there appeared to be a progression of healing primarily in the horizontal plane, as demonstrated by circumferential contracture of the wounds. In other words, historically, the authors have observed that the wound heals from the perimeter inward. In the case of deep wounds with exposed muscle, tendon, and/or bone, the healing process appears to stall as the wound margins move towards the exposed deep structures. 

In more superficial wounds, collagen forms a scaffold across the surface of the wound bed, and keratinocytes essentially coat the collagen matrix to attract and facilitate the migration of epithelial cells across the matrix.³⁰ However, the pattern of healing appears to be altered when large areas of deep structures are exposed. By adding the BSA, the authors believe a bridge is created to carry the migration of well-vascularized tissue over these deep structures. Without this bridge, the epithelial cells will never move beyond the edges of these exposed structures. The NIRS images demonstrated that with the passage of time, the BSA scaffold became vascularized directly over the exposed deep structures (Figure 4). Vascularization within central islands of the wound also were observed, in contradistinction to the standard thought process in which vascularization only occurs from the periphery. In many of the present cases, the authors noted centralized vascularization, apart from the wound perimeter.

In a recent study by Henn et al,³¹ the authors demonstrated angiogenesis and dermal regeneration at the cellular level using a murine model.  They found that wounds treated with BSA resulted in a more natural alignment of collagen fibers, as well as enhanced vascularization of the graft itself.

The treated wounds in this study were not limited to the most commonly studied wounds (ie, venous and diabetic ulcers) but rather, included wounds of all etiologies and locations. This is very important for clinicians treating complex wounds, because often times, these wounds are of mixed etiologies that result from numerous patient comorbidities.⁵ For clinicians treating these complicated cases, it is important to understand that because BSA is minimally manipulated human skin that provides the critical components necessary for wound healing (living cells, signaling molecules, and an ECM scaffold that vascularizes), the etiology of the wound or location is less relevant. The purpose of BSA is to provide the same components intrinsic to an autograft but without donor site morbidity and the other limitations of autografts associated with full-thickness wounds discussed earlier. The authors maintain that BSA should be effective in a variety of settings so long as good wound care practices (ie, debridement, control of inflammation/infection, offloading, moist wound environment, adequate blood flow, edema control, and thoughtful management of medical issues) are followed. Further, the authors stress that proper wound bed preparation to remove any devitalized tissue and bioburden is critical for the vascularization of the BSA matrix from the surrounding granulation tissue to occur. All patients in this case series received medical management along with good wound bed preparation prior to BSA application.

There are some limitations to the current study. Due to the retrospective nature of this study, measurement techniques and application protocols were not normalized. The role of adjunctive therapies was indeterminate due to the large variety of therapies utilized in proportion to the number of wounds studied. Because the focus of the study was to learn the characteristics of the large variety of wounds that were successfully closed with BSA, cases that failed to close were not analyzed. This case series does not offer insight into the efficacy of BSA and so clinicians should reference prospective randomized controlled trials studying BSA when looking at the clinical outcomes of BSA in optimal and controlled settings.^32,33 Alternatively, though the case series provides valuable insight for clinicians treating cavity wounds in the real-world setting, the intent of this study was not to provide effectiveness data; clinicians should rely on recent matched cohort studies to determine effectiveness in the real-world setting.^7-9

This large case series validates the results from previous studies that have demonstrated effectiveness of BSA for the treatment of extremely large deep wounds of various etiologies.^7,9,10 More importantly, the authors propose a mechanism of action of BSA that has thus far been poorly understood and offer insights into the science of skin substitutes in the hopes that it can help decrease the confusion caused by the rising number of commercially available products on the market. This study can also help clinicians identify best practices when utilizing BSA, either alone or in conjunction with other advanced modalities, and provide those who treat deep cavity wounds with valuable insight for achieving exposed structure coverage and expedient wound healing in a cost-effective manner. 

Authors: Michael S. Flood, MD, FACS¹; Blake Weeks, DPM²; Kenneth O. Anaeme, MD³; Heather Aguirre, DO, MS⁴; Kimberlee B. Hobizal, DPM, MHA⁵; Sandi E. Jiongco, MSN⁶; Robert J. Klein, DPM⁷; Andrew Lemoi, DPM⁸; Rafael Rafols, MD⁹; and Adam S. Landsman, DPM, PhD¹⁰

Affiliations: ¹Lancaster General Hospital, Lancaster, PA; ²LifePoint Health Inc, Brentwood, TN; ³The Wound Care Clinics of Arizona, Tempe, AZ; ⁴Rollins Brook Center for Wound Care, Lampasas, TX; ⁵Heritage Valley Health System, Beaver, PA; ⁶Edward Hospital Wound and Hyperbaric Center, Naperville, IL; ⁷University of South Carolina School of Medicine, Columbia, SC; ⁸Our Lady of Fatima Wound Care Center, North Providence, RI; ⁹Wound Management at Mission, Mission, TX; and ¹⁰Harvard Medical School, Boston, MA

Correspondence: Adam S. Landsman, DPM, PhD, Assistant Professor, Surgery, Harvard Medical School, Department of Orthopaedics, Massachusetts General Hospital, 55 Fruit Street, Yawkey Building, Suite 3F, Boston, MA 02114; alandsman@mgh.harvard.edu

Disclosure: Dr. Landsman is a paid speaker for Misonix, the distributor of TheraSkin (BSA product). The authors disclose no financial support in relation to this study.