Clinical Efficacy of Human Split-thickness Skin Allograft in Patients With Pyoderma Gangrenosum: A Case Series

Pyoderma gangrenosum (PG) is a rare, painful ulcerative dermatosis that is difficult to diagnose and manage because of its variable, nonspecific histopathologic and laboratory findings. Although up to 50% of PG cases are associated with systemic disease, many cases are idiopathic and are not associated with systemic disease.^1,2 No clear pathogenesis has been identified in the development of PG. Initially, it was thought that PG was caused primarily by neutrophilic abnormalities; however, more recent research suggests the dysfunction related to neutrophilic chemotaxis is thought to involve abnormalities in the inflammatory cascade that lead to defective neutrophil presentation.³ Leading theories suggest the pathogenesis is multifactorial and involves a combination of inflammatory cytokine dysfunction, with neutrophilic and T-cell abnormalities contributing to immune system malfunction.^2,3 The elevation in proinflammatory cytokines such as interleukin (IL)-1, IL-1β, IL-8, and IL-17 as well as matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor, and tumor necrosis factor alpha have been shown to affect the development of PG.^3,4

Traditionally, PG manifests as a painful ulceration, most commonly in the lower extremities and especially in the pretibial area. Adults are the primary age group affected by PG, with most patients between 20 and 50 years of age.^1,5-7 The 4 clinical variants of PG are ulcerative, pustular, bullous, and superficial/granulomatous/vegetative.² These 4 variants manifest differently clinically in both presentation and progression, as well as in terms of histologic manifestations and associated systemic diseases.

Typically, PG begins as a small papule, pustule, nodule, or vesicle with an erythematous or violaceous base. Within a few days, the lesion quickly transforms into a rapidly enlarging area of central necrosis. Fully developed lesions present as a painful ulceration with a purulent, necrotic base with an undermined, irregular edematous and erythematous border; these are the classic features associated with PG. Typically, the bordering periwound tissue is surrounded by a combination of acneiform and serpiginous morphology with a violaceous/lilac or erythematous ring of color. These ulcerations can be deep or shallow, with deeper lesions sometimes resulting in exposed tendon, muscle, and bone in severe cases. Acute lesions tend to progress quickly, with associated pain that is severe but responsive to the administration of systemic steroids. Chronic lesions that heal with cribriform scar support a diagnosis of PG.⁸

Pyoderma gangrenosum has a distinctive clinical morphology; however, it is important to rule out other more likely diagnoses, including follicular and soft tissue infections, parasitic infections, vasculitic conditions, vascular diseases, lymphomas, drug reactions, other neutrophilic dermatoses, malignancies, myriad inflammatory conditions, and even insect bites.^1,9 The histopathologic findings of PG are relatively nonspecific. However, early lesions tend to exhibit a dense neutrophilic or lymphocytic perivascular infiltrate, whereas older lesions exhibit a more mixed inflammatory infiltrate with evidence of epidermal necrosis and ulceration or infarction.^10,11 These features may aid in the diagnosis of PG, and they are the only major criteria used in diagnosing ulcerative PG.⁸ There are 9 diagnostic criteria of ulcerative PG, with 1 major criterion (biopsy revealing neutrophilic infiltrate) and 8 minor criteria (exclusion of infection on histology; evidence of pathergy; a history of inflammatory bowel disease or inflammatory arthritis; a papule/pustule/vesicle that rapidly ulcerates; periwound peripheral erythema, undermining border, and tenderness; multiple lesions with at least 1 on the anterior lower leg; a cribriform scar at healed lesion sites; and a decrease in ulcer size with immunosuppressive treatment).⁸ The major criterion, in addition to 4 of the 8 criteria, must be met to diagnose ulcerative PG. No specific immunologic dysfunction has been universally identified among all patients with PG, although in 1986 Su et al reported a possible immunopathologic correlation to PG.¹⁰ Findings revealed direct immunofluorescence positivity in the blood vessels of 55% of specimens from patients with PG, in addition to immunoglobulin M, complement 3, and fibrin in dermal vessels, although these latter 3 findings are not specific to PG.¹⁰

Pyoderma gangrenosum is relatively rare, and the incidence has not been well established because of a lack of controlled clinical trials. The estimated incidence of PG varies from approximately 3 to 10 cases per million per year in Italy^2,12 to an incidence possibly closer to 1 in every 100 000 persons per year in the United Kingdom.^13,14 As a result of a combination of all the aforementioned factors, management options for PG have been limited and not particularly effective.

There is no universally effective treatment for PG. Typically, treatment options are either local or systemic.¹⁵ Local treatments aim to provide pain relief, manage secondary bacterial infections, and provide a stable environment for wound healing. Wet compresses, sterile saline, antiseptic solutions, and absorbent dressings are a few examples of local treatment methods used to improve wound healing. The management of PG can be optimized depending on whether the lesion or lesions are in the inflammatory or the noninflammatory phase.¹⁶ During the inflammatory phase, the objective of local management is to reduce the inflammation to the area using medium- to high-potency topical corticosteroids, tacrolimus, or pimecrolimus, in the wound bed and the periwound skin. In this phase, surgical or mechanical debridement of the wound bed is avoided, and the ulcer is typically managed with a combination of autolytic or enzymatic debridement, antiseptics, and steroids followed by coverage with an occlusive dressing.¹⁶ During the noninflammatory phase, periwound treatment is unnecessary unless secondary skin dermatoses are present. In the noninflammatory healing phase, the wound bed is amenable to surgical debridement and the use of skin substitutes.¹⁶ Localized therapy can be used alone in the setting of mild disease.

In contrast, systemic treatments target the underlying clinical pathology, thus promoting healing at the PG wound sites. Forms of systemic therapy include intravenous high-dose pulse steroid therapy, diaminodiphenylsulfone (dapsone), clofazimine, and immunosuppressive therapy.¹⁵ Immunosuppressive therapy is more commonly used in multilesional or widespread disease. These medications include first-line agents such as cyclosporine A or infliximab, or second-line immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and methotrexate.^17-19 A combination of local and systemic treatment often yields the best results.

This case series presents information on the efficacy of TheraSkin (Bioventus), a human bioactive skin allograft (BSA), in the management of PG ulcers. Limited information exists about the use of allografts in patients with PG, and a thorough demonstration of the BSA studied herein on PG ulcers is incomplete. Although skin allografts have been acknowledged as a viable treatment option for patients with PG, notable controversy persists concerning their merit because of the potential for inducing periwound skin complications. In a case report, Araújo et al²⁰ stated that the use of skin allografts in the management of PG wounds “remains . . . a topic of discussion” despite being “well documented in the literature as an option in selected cases.”

Case 1

A female patient with a past medical history of hypothyroidism, prothrombin mutation, and prior deep vein thrombosis presented for evaluation of a nonhealing ulcer of the left posterolateral ankle of several months’ duration (Figure 1). The patient reported persistent ankle issues following ankle surgery performed 3 years previously. The patient initially presented for wound care a few months after undergoing a sural nerve resection to address nerve pain, after which the ulceration began forming in the incision. The ulceration continued to erode and expand without improvement despite various treatments, including cyclosporine, prednisone, and topical clobetasol propionate and betamethasone. The patient never underwent biopsy and was treated clinically for PG during this time. Subsequently, the patient consulted a rheumatologist and underwent a full autoimmune workup, including antinuclear antibody (ANA) titer, rheumatoid factor (RF), antineutrophil cytoplasmic antibody (ANCA), and complement levels in addition to serum protein electrophoresis; all results were normal. Initial biopsy showed mild superficial perivascular lymphocytic inflammation that lacked specific features suggestive of vasculopathy or PG. However, a repeat biopsy at the site of the initial wound showed significant gangrenous necrosis. Extensive workup revealed no underlying immunologic or vasculitic condition. The patient had not responded to multiple interventions, including high-dose steroid taper and ongoing treatment with chronic oral prednisone therapy, dapsone, and adalimumab.

Initial treatment dressings consisted of hypochlorous acid gel mixed with lidocaine gel and crushed prednisone powder that was covered first with nonadherent gauze and then with rolled gauze that was secured with a stockinette. Dressings were changed daily. Debridement of the necrotic tissue in the wound bed was performed in the few weeks leading up to application of BSA to remove necrotic bioburden of the wound bed for maximal allograft adherence and efficacy. Initial application of BSA was accompanied by a secondary dressing of fenestrated silver mesh dressing, methylene blue composite dressing, and a gauze bolster that was applied and secured with a multilayer compression wrap. The dressing was changed 5 days later. Intermittent dressings between applications of BSA included collagen powder with antimicrobial mesh applied to the wound bed and covered with gauze and a conforming bandage. Dressings were changed 3 times weekly. Additionally, hydrocolloid was applied intermittently to the periwound skin. The patient underwent 6 BSA applications between November 2020 and March 2021. The fourth and fifth applications included negative pressure wound therapy with black foam at 125 mm Hg to achieve graft fixation to the wound bed.

Oral prednisone was continued per the recommendation of the dermatologist, with intermittent use of biologic agents such as adalimumab, infliximab, and mycophenolate mofetil during the treatment course. During this time, the patient underwent a second workup by a rheumatologist for repeat evaluation of a potential immunologic or vasculitic disease. The patient’s C-reactive protein, ANCA, ANA titer, RF, and complement levels were all negative. She received a diagnosis of a seronegative autoimmune condition.

As of the time of this writing, wound care for this patient was ongoing, but the wound had improved considerably and was almost completely closed.

Case 2

A female patient with a past medical history of morbid obesity, associated hypertension, and chronic venous insufficiency presented with a nonhealing ulcer of unknown etiology of the left medial upper thigh (Figure 2). The patient reported a small pimple that subsequently ulcerated and developed into a slowly enlarging tender ulcer over 1 year. She also reported that multiple previous topical treatments had been tried, including collagenase, silver sulfadiazine cream, and silver alginates, but they were ineffective.

Initial assessment in the wound clinic revealed an irregularly shaped ulcer in the left medial upper groin region. Wound cultures were initially positive for methicillin-resistant Staphylococcus aureus, and the patient received a course of antibiotic treatment with doxycycline. Tissue biopsy was negative for cutaneous malignancy and was consistent with a chronic pyogenic granulating ulceration; thus, a clinical diagnosis of PG was made. Initial wound management consisted of topical collagenase application followed by topical collagen with silver alginate. The patient was also started on long-term anti-inflammatory treatment with oral doxycycline and a short oral prednisone taper. However, poor clinical improvement of the ulceration was noted upon initiating topical treatment.

Following the poor progress with these initial treatments, BSA application was initiated. A total of 5 grafts were applied over an 18-week period. Complete resolution of the ulceration was achieved; at the 3-month follow-up visit, there was no ulcer recurrence.

Case 3

A male patient was referred to the wound clinic by another physician for a second opinion. The patient presented with a chronic nonhealing ulcer of the right lateral lower leg of 2 years’ duration (Figure 3). Previous workup for the ulceration included 2 tissue biopsies that tested positive for acute and chronic inflammation, as well as peripheral arterial angiography, which was unremarkable. Two previous attempts to manage the wound with multilayer compression wraps were unsuccessful.

The patient’s past medical history included significant type 2 diabetes mellitus, hypertension, asthma, sleep apnea, and coronary artery disease. Chronic medications included inhaled steroids, clopidogrel, oxycodone for chronic pain, lisinopril, hydrochlorothiazide, metformin hydrochloride, and simvastatin. Further review of the patient’s history did not elicit any findings of systemic inflammatory disease or joint inflammation.

Examination in the clinic revealed a large granulating ulcer with moderate necrotic slough, exuberant rolled edges, and moderate periwound inflammation. Significant tenderness was noted, out of proportion to the presenting findings. Given the patient’s symptoms and wound characteristics, a clinical diagnosis of PG was made based on the combination of minor criteria and a suspicious biopsy. Initial treatment consisted of topical collagenase and hydrocortisone. The patient was also treated with oral prednisone, tapered slowly. Repeat vascular angiography was performed, which confirmed no significant arterial insufficiency. Subsequently, BSAs were applied to the wound. A total of 6 grafts were applied from October 2017 through January 2018. The grafts were secured using multilayer compression wraps. Topical dressings applied between graft applications consisted of crushed prednisone with oil emulsion dressings and silver alginate with a compression wrap. Complete resolution of the ulceration was achieved 18 weeks after initial BSA application.

Case 4

A male patient was referred to the wound clinic by another physician for a second opinion. The patient presented with a nonhealing right anterolateral lower leg ulceration of several months’ duration (Figure 4). He had consulted a dermatologist for the ulceration, and 2 tissue biopsy specimens were positive for acute and chronic granulating inflammation. The patient reported that the ulceration initially started as a dime-sized chronic papule that subsequently began to ulcerate. Additionally, he reported significant worsening with several attempts at sharp debridement. There was also a significant increase in erythema and necrosis following the attempts at sharp debridement. Before referral to the senior author’s wound center, the initial topical treatments consisted of collagenase and silver sulfadiazine cream with a nonadherent gauze dressing. Minimal to no improvement was achieved with these topical dressings. A diagnosis of PG was made.

The patient’s past medical history was positive for Sjögren syndrome diagnosed 6 months previously, hyperlipidemia, hypertension, and chronic obstructive pulmonary disease. There was no history of inflammatory bowel disease. The patient’s regular medications included apixaban, inhaled corticosteroids, diltiazem hydrochloride, hydrochlorothiazide, an albuterol and ipratropium bromide inhaler, pravastatin sodium, prednisone tablets on a suppressive dose of 15 mg daily prescribed by the dermatologist, quinapril hydrochloride, and ranitidine. Significant allergies included penicillins, ciprofloxacin, hydroxychloroquine, and doxycycline. Vascular screening with ankle-brachial indices and arterial Doppler ultrasonography were unremarkable for significant arterial insufficiency. Initial treatment of the ulceration included oil emulsion dressing and 0.125% sodium hypochlorite solution-soaked gauze and 40 mg of crushed prednisone sprinkled on the wound bed. These dressings were changed daily. The patient did not want to increase the oral prednisone dosage.

Very limited debridement of the necrotic tissue was initiated following 1 week of topical prednisone wound therapy to remove the necrotic bioburden of the wound bed. After adequate wound bed preparation, BSA was applied and secured with a multilayer compression dressing. Dressings between BSA applications included crushed prednisone and oil emulsion dressing with silver alginate and multilayer compression. A total of 5 BSAs were applied between June 2019 and September 2019. Complete resolution of the ulcer was achieved 19 weeks after initial BSA application.

Case 5

A female patient with a complicated history of ankylosing spondylitis, Crohn disease, and refractory lower extremity ulcerations received a diagnosis of chronic PG of several years’ duration. A nonhealing intergluteal cleft ulceration also developed approximately 2 years before the patient presented to the wound care clinic (Figure 5). The diagnosis of PG was made following separate biopsies of the nonhealing ulceration of the right lower leg and the intergluteal cleft ulceration. Previously, under the care of a dermatologist, the patient was administered multiple courses of oral steroids and immunosuppressants, including methotrexate, adalimumab, and hydroxychloroquine, with no significant improvement in the chronic refractory ulcers.

The right leg ulceration was managed with topical collagenase and silver alginate dressings, with no significant improvement. The gluteal cleft ulcerations were initially managed using collagenase and silver sulfadiazine as well as silver alginate dressings with instructions for strict offloading of the buttocks and sacrum. There was no improvement with these topical treatments.

At the wound clinic, initial treatment of the lower leg ulcerations consisted of topical crushed prednisone with collagenase and multilayer compression wraps. A BSA was subsequently applied and resulted in closure of the right lower extremity ulcerations. Based on that treatment success, the patient requested a trial of split-thickness skin allograft to the refractory intergluteal cleft ulceration. The application of an allograft at this site was clinically challenging because of the proximity to the anal orifice as well as the inability to adequately offload the site and maintain an adequate dressing. The patient had been evaluated previously by a plastic surgeon for a possible autograft, but that was not done because of the potential for inducing a similar lesion at the harvest site. Because of a similar concern, the patient was not a candidate for placement of a diverting colostomy, either.

Ultimately, a series of split-thickness BSAs were applied between January 2019 and May 2019. A total of 4 allografts were applied. The grafts were secured to the wound bed using surgical staples and nonadherent gauze with a rolled gauze bolster. Significant patient adherence to offloading (ie, no sitting for 1–2 weeks after graft application) was instrumental to achieving good graft adherence. Complete resolution of the intergluteal cleft ulceration was achieved with the BSAs. Close follow-up after wound closure has demonstrated no evidence of ulcer recurrence.

Clinical treatment notes

Several clinical points should be noted concerning the 5 cases presented herein. No other advanced cell tissue products were used in the management of these ulcerations, including becaplermin, amniotic tissue products, or other acellular tissue products. Negative pressure wound therapy was used in only 1 case to secure the allograft after application. No negative pressure wound therapy was used in wound bed preparation or after allograft application. Topical steroids were used in most cases during wound bed preparation; crushed prednisone tablets were the most tolerated preparation. The authors were also able to perform wound bed debridement following the initiation of topical steroid treatment in most cases with no significant clinical worsening and no evidence of pathergic reaction. No new PG lesions were observed in any patient during the treatment periods, and all prior medications were continued during treatment.

In the 5 cases reported herein, the average wound area measurement at presentation was 42.6 cm². The mean wound duration at the start of treatment was 14 months. An average of 5.2 grafts were applied per wound. The average time to complete wound healing was 18.8 weeks. These findings are not statistically significant, because the sample size is not large enough for statistical analysis. The wound measurements illustrate a general frame of reference of wound sizes.

Options for the management of PG are limited and choosing the optimal treatment is difficult, because no clearly defined pathogenesis has been identified. The intensity of treatments is often associated with the level of disease progression, ie, the more rapid the expansion of the PG lesion, the more aggressive therapeutic treatment must be.¹ Because prognosis mostly relies on identifying and managing any underlying systemic disease processes, that should be the focus of initial treatment efforts. Most treatment plans concerning PG involve a combination of systemic medications, topical agents, and wound care. Treatment involving a combination of topical and systemic corticosteroids is the most common approach.^1,3,21 Immunosuppressive agents such as cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, infliximab, and minocycline are also commonly used in conjunction with corticosteroids; evidence suggests the addition of these agents helps facilitate complete healing of PG.^3,22 The successful treatment of PG with combination allograft and biologic therapy has also been described in the literature.^23,24 This success can be presumed to be largely because of improved graft incorporation because of a reduced immune response against the allograft.^23,24 Studies have shown overexpression of proinflammatory cytokines in PG in addition to notable clinical improvement with the use of immunosuppressive agents.^25-29 A reduction in proinflammatory markers in serum levels has been shown to coincide with clinical improvement of PG when systemic treatment of various immunologic therapies are used.^25-29 This suggests a reduction in proinflammatory mediators using systemic anti-inflammatory therapies in PG with the concomitant use of allografts to aid in graft acceptance and the prevention of recurrence.^23,24 With adequate treatment, complete resolution of a PG lesion occurs within approximately 7 months.³

Pathergy results in a profound and often difficult-to-heal skin injury secondary to minor trauma or a surgical procedure. It can occur in up to 20% to 30% of patients with PG and is most closely associated with PG resulting from systemic diseases.^1,30 There is a known association between skin trauma and the development of PG as well as the subsequent worsening of the lesion after sharp debridement.^31-33 Some studies have shown that when used judiciously, surgical intervention can help facilitate healing of larger ulcers or those refractory to conventional treatment.³⁴ Surgical interventions such as light surgical debridement for wound bed preparation can be performed with adequate immunosuppression and control of any underlying systemic disease.^34,35 Traditional autografts would likely be contraindicated because of the risk of pathergy and the potential for PG at the graft harvest site. This complication can be avoided by using allografts (ie, human tissue grafts not taken from the recipient).

The BSA studied herein shows promise in facilitating the healing of PG ulcerations. Bioactive skin allografts are efficacious in wound healing because of their ability to promote revascularization of the wound bed and to provide the essential constituents required for the natural healing process.³⁶ These components also maintain the architectural structure of the human extracellular matrix (ECM).³⁶ It has been shown that the BSA used in the patients in this case series contains the same amount of collagens (type I and III), growth factors, and cytokines present in fresh, normal human tissue that stimulate natural tissue healing.³⁶ This distinctive characteristic is important and makes this particular BSA unique because most skin substitutes function only to supply wounds with cytokines and some limited cellular components (eg, fibroblasts) but do not replicate the structural and physiologic qualities of fresh human skin.³⁶ The skin used in this BSA is obtained from an organ donor within 24 hours after death to preserve tissue viability.³⁷ The tissue is then cleansed and preserved via cryopreservation with minimal manipulation, with the aim of preserving as much of the natural components within the skin as possible. After cryopreservation, the allograft is ready for implantation. Up to 70% of the cells within the BSA are viable at implantation.³⁶ Landsman et al³⁶ found that the cell viability of this particular BSA was favorable to that of fresh unprocessed skin, which typically produces optimal healing results. The authors of that study found that the BSA maintained the skin characteristics necessary for wound healing, including ECMs, native growth factors, and viable cells. This characteristic allows the allograft to more closely resemble the skin it is meant to restore, resulting in more effective wound healing.

Wound healing traditionally begins by vertically filling the wound with granulation tissue, followed by horizontal closure via epithelialization. This natural process is reproduced when treating wounds with BSA by revascularizing the ECM framework, which typically occurs approximately 72 hours after the application of the product. This process is then followed by horizontal epithelialization, which is aided by the natural components (ie, growth factors, intact basement membrane, collagen) inherent within the graft.³⁸ Like split-thickness skin grafts, the BSA used in this case series, when applied to an optimally prepared wound bed, imbibes nutrients and oxygen during the first 24 hours of allograft application.³⁹ This process is followed by the formation of a fibrin seal generated between the allograft and wound bed.³⁹ Inosculation, a process in which a vascular network is formed between the wound bed and graft for nutrient exchange, occurs over the next 24 hours (48 hours after initial graft placement).⁴⁰ The final step in BSA incorporation is revascularization, which begins approximately 72 hours after the initial graft application and functions to establish blood flow through the already formed vascular network created during inosculation. Successful revascularization allows full graft incorporation to the wound bed because of the presence of living cells and the essential wound healing components found naturally within these cells. The process clears all cellular components of the allograft of inflammatory rejection by the host within approximately 14 days after graft application.⁴¹ However, the fresh human collagen can be fully incorporated into the wound bed because collagen by itself is nonimmunogenic to the recipient wound bed. Because of this, the authors of this case series believe that incorporation of the BSA studied herein appears to be particularly efficacious in facilitating healing of PG ulcers because of the strength of the revascularization that occurs during graft implementation.

This case series provides compelling evidence for the efficacy of the BSA studied in healing complex cases of PG ulcerations. Several mechanisms for the success of this treatment are suggested, but further clinical and laboratory studies are necessary to evaluate them. The BSA used in these cases clinically incorporates the wound bed of the patient with PG to a greater extent than other available treatments. The disease process of PG involves a considerably altered host immune system response, and thus, there is a substantially altered immunologic response to the application of an allograft. The authors of this case series speculate that the efficacy of this particular BSA is a direct result of the altered immune system of the host and perhaps a delay in the ability of the host to clear the cellular components of the allograft, thereby promoting a much stronger inosculation and revascularization process following application of the allograft.

Another potential mechanism for the success of this BSA is the immediate and adequate coverage over an extensive wound without deep tissue exposure. Because no graft harvesting from the host is required for BSA application, pathergy is not of clinical concern with its use, and multiple allografts can be applied over time, thus increasing the efficacy of wound treatment and healing. The successful integration of collagen into the wound bed is another mechanism by which this BSA promotes successful wound healing. The collagen component of the ECM of this BSA is identical to that of the host wound bed; thus, incorporation of the collagen is nearly complete with the application of the allograft. This results in much more robust granulation of the wound bed and facilitates more rapid and complete reepithelialization compared with other allograft options.

Although this case series attests to the utility of a particular BSA in the healing of PG ulcerations, it has limitations. This is a small series of cases with no randomization and no control group. Further study is needed, perhaps with randomization and including a control group that does not undergo application of the BSA. Although the patients discussed herein had a very long duration of treatment with standard wound care dressings before the initial applications of BSA (and application of this product was likely the definitive factor in the ultimate wound resolution), it is impossible to determine causality without a control group. Additionally, the sample size of this study is small, with 5 patients total, and further studies with larger numbers of patients are needed to validate the findings presented herein. Another major limitation is that no comparison has been made with patients in whom systemic steroids or immunosuppressive treatments were not used. Thus, it is not known whether systemic agents are the reason for improved graft uptake. Further research is warranted to study this issue as well.

Pyoderma gangrenosum is a rare, painful ulcerating disease that can seriously affect patients’ lives and may be chronic. These ulcerations can be refractory to healing despite current treatments. This is largely because of incomplete understanding of the pathophysiology of PG ulcerations. Although these ulcerations are often associated with inflammatory disorders, PG can arise in any individual. This case series aims to illustrate how the BSA studied better facilitates wound healing for PG ulcerations compared with other allograft options. The authors of this study think that the alterations of the immune system that cause PG allow for enhanced graft adherence and nutrient exchange, thus leading to improved lengths of time to wound healing; in this case series, the mean wound duration at the start of BSA application was 14 months. All of the wounds had been present for more than 1 year had received standard wound therapy alone, but all healed in a matter of weeks after BSA application. This BSA and other similar allografts consist of living human cells from donors and therefore contain all the natural components essential in the wound healing process. These allografts cannot cause pathergy, which is common in patients with PG, because they are not taken from the recipient. Bioactive skin allograft can be reapplied at multiple intervals to help reinvigorate the wound healing process during each application. The BSA studied herein also appears to establish robust revascularization between the allograft and the ulceration, allowing optimal nutrient exchange. These healing mechanisms result in a shortened overall wound healing time. From the results reported herein, the BSA studied showed value in facilitating the healing process of PG ulcerations, and may stimulate future studies to elucidate the cellular and microbiologic pathways for this activity.