Early Clinical Performance of an Adaptive Self-Assembling Barrier Scaffold in Nonhealing Chronic Wounds

A Review of Six Cases

Daniel Kapp, MD, PA; Laura Pfendler, PT, DPT, CWS; Lou D'Oro, MD; Randall Wolcott, MD

Disclosures

Wounds. 2022;34(1):20-30. 

In This Article

Discussion

Wound healing is a complex and dynamic process. It can be delayed for many reasons, including intrinsic factors, such as wound characteristics (location, wound size), patient characteristics (advanced age, obesity, poor nutrition), and systemic comorbidities (diabetes, compromised renal function, vascular disease), and exposure to extrinsic factors that adversely affect wound repair, such as microorganisms, physical aggravation, and administered medications or treatments. The currently accepted paradigm for delayed wound healing involves the wound becoming stuck in a hostile environment during the inflammatory phase of healing.[20]

Manifestations of healing complications may include dehiscence, hypertrophic scars, scar contracture, exudation, infection, tissue ischemia, and necrosis; in some cases (eg, diabetic foot ulcers), these may lead to recurrence, amputation, or mortality.[21–23] Despite the number of wound management options available, many wounds do not respond to treatment. The burden on the families and caretakers of patients resulting from failed treatment should not be minimized.[24] Advances on multiple fronts, including biomaterials, biologics, novel procedures, and the tools and markers to better understand wound pathophysiology, have aided the development of novel wound care and skin regeneration technologies. The advanced treatment modalities include bioactive molecules, growth factors, gene and cell therapies, skin substitutes, collagen or similar biopolymers, hyperbaric oxygen, lasers, electrical stimulation, and negative pressure wound therapy.[21–23] The potential for these approaches to influence the healing of chronic, refractory wounds hinges on their ability to interrupt the stalled healing process and promote resumption of the normal healing process.

Previous studies in various preclinical models have shown the ability of aSABS to affect multiple events in the wound repair process. Csukas et al[8] reported on rapid hemostasis with use of aSABS regardless of anticoagulation status in a rat liver punch biopsy model. In porcine models of second-degree burn wounds and full-thickness wounds, application of aSABS resulted in reduced inflammation, lower total bacterial counts, and higher rates of both granulation tissue formation and reepithelialization compared with controls.[10–12] The anti-inflammatory effects of aSABS were also demonstrated in a lipopolysaccharide-induced inflammation model of eye injury.[13] An increase in the steady-state mRNA levels of epidermal growth factor, keratin 6, keratin 17, and vascular endothelial growth factor was observed in wounds managed with this self-assembling peptide compared with those managed with saline (control group), which correlated with the histological findings of higher reepithelialization rates and increased granulation tissue formation.[10] The clinical results and quality-of-life outcomes in the cases described in the present study, which were observed by the clinicians and patients alike, could be explained by the unique attributes of aSABS noted in the aforementioned preclinical studies.

The use of debridement prior to application of subsequent dressings or procedures has been widely recognized as the optimal strategy to achieve improved healing outcomes in the management of chronic wounds.[1,21,25] As discussed in the individual case studies in the present study, aSABS better enabled the use of aggressive debridement procedures necessary to completely remove the necrotic wound tissue by providing a remarkable degree of wound management and bleeding control. As a result, it was possible to complete wound management in a low-acuity clinic setting and without the need for thrombin or sutures, which would otherwise have been used for many of these procedures. The immediate bleeding control afforded by aSABS, even in the presence of antiplatelet therapy, was demonstrated in a prior clinical study of acute shave excision wounds.[26] The cases presented herein further support those findings, even in the presence of more challenging chronic wounds and complex patient subsets, as well as regardless of the wound age, depth, or severity (eg, a 10-year-old pressure ulcer with ongoing repetitive trauma or a 1-year-old refractory post-TMA wound in a patient with diabetes). Of note, bleeding cessation was also observed long after the debridement procedure, alleviating the patient's at-home routine, as seen in the case of the patient with the extremely friable open wound secondary to an extensive burn sustained 20 years earlier.

Furthermore, by facilitating aggressive debridement, use of aSABS also allowed near-complete removal of the biofilm of surface-associated bacteria and the infected wound tissue, thus reducing the wound bioburden, which is among the major culprits in wound chronicity. Although the clinical diagnosis of wound biofilm remains controversial, it is now recognized that biofilms are present in 60% to 100% of chronic wounds, a position supported by the World Union of Wound Healing Societies.[27] These biofilms maintain a state of chronic inflammation that can damage surrounding tissue. The hyperactivation of local inflammatory processes and the physical obstruction to wound closure caused by the bacterial biofilms pose a serious threat to healing, thus making both the removal of biofilm and control of excessive inflammation a high priority.[28–31] A broad range of biofilm management strategies, including local and systemic antibiotics, surgical debridement, and recent technologies, such as topical oxygen therapy, have been used in an attempt to address the problem of wound biofilm.[28] Although the wound microbiota were not quantified for all cases in the present study, treatment with aSABS appeared to have had a favorable effect on the bioburden in cases in which such evaluations were made, which suggests that aggressive debridement of the wound allowed for the removal of the infected tissue, thus helping return the wound to the normal healing cycle.

The ability of aSABS to form a clear, conforming seal of a nanofibril network that remained affixed to the surface of an irregular wound bed provided a protective moisture-donating barrier on and around the wound tissue. The effect of a moist wound environment on multiple wound healing elements has been documented in the literature; this would include augmenting the epithelialization process by faster and easier migration of epidermal cells, encouraging prolonged presence of proteinases and growth factors, improving the inflammatory and proliferative phase, and enhancing angiogenesis.[32–34] Consequently, several types of advanced wound dressings have been developed, including occlusive or semi-occlusive advanced wound dressings, odor-absorbent dressings, scaffold dressings, bioactive dressings, and antibacterial dressings.[20] Achieving moisture balance that allows for wound reepithelialization without excessive exudate is essential to reducing inflammation and promoting healing. In at least 2 of the cases studied herein in which such observations were made, a reduction in wound drainage and exudate levels was noted while the protective barrier function was maintained and granulation tissue was formed.

In addition to the reduction of infection and inflammation, other distinguishing features of normal wound healing (ie, reduction of wound hypertrophic margins, wound contracture, or granulation bed formation) were noted, supporting that aSABS becomes an ECM-like network, thus creating a microenvironment for favorable cellular events, such as adhesion, migration, and proliferation of healthy host cells in the wound milieu and subsequently facilitating repair of the damaged wound tissue. In the context of the etiopathology of the wounds, it is important to note that more than half the cases reported here represented lower extremity wounds. They comprised a surgical site wound from local infection and dehiscence after emergency vascular bypass surgery for tibial ischemia, a wound after Mohs microscopic surgery, a stalled chronic wound after TMA, and a trophic ulcer on the lateral malleolus. The latter 2 cases were also compounded by systemic comorbidities.

Management of lower extremity wounds can pose an enormous challenge to the surgeon. For instance, the repair of below-the-knee lower extremity defects after Mohs surgery that are not amenable to primary closure leads to challenges given the high propensity for complications. Postoperative reactive edema and inflammation can result in a painful and protracted healing course.[35] In the context of TMA, many patients often have comorbidities or risk factors such as diabetes mellitus, infrapopliteal disease, history of smoking, and end-stage renal disease; in such cases, wound management can be arduous. Failure rates associated with TMA have been well-documented in the literature and manifest as postoperative complications requiring further surgery, a need for a more proximal amputation, or perioperative hospital mortality.[36–38] The management of trophic ulcers poses substantial difficulty because of the recurrent and nonhealing nature of these ulcers. Management is further complicated by associated systemic pathologies, which often have a disabling effect with devastating complications, such as amputation.[39] Desired outcomes are often elusive, despite the current availability of multiple options to treat lower extremity wounds. Consequently, the need for improved technologies to reduce the need for amputation procedures and potential mortality remain.

Even among the complex lower extremity wounds reported in the present study, aSABS demonstrated remarkable healing progression, which was particularly impressive considering the presence of multiple systemic comorbidities or medication nonadherence, either of which could hinder wound repair. The adaptive self-assembling barrier scaffold offered 2 valuable and practical benefits in the management of chronic wounds. First, the hemostasis and wound management properties enabled aggressive surgical debridement. Second, the assembled aSABS intercalated with the wound bed, providing a barrier scaffold that augmented host healing. In this study, aSABS demonstrated marked efficacy in the patients with stalled wounds.

The translation of the multipronged mechanistic effects of aSABS to the observed clinical effects reported in these case studies (ie, improved wound quality and tissue appearance, reduced wound size, reduced exudate or accumulation of slough, improved wound granulation, and improved epithelialization), underscores its performance. In addition to the clinical outcomes, the observations reported by the patients during the at-home intervals between the clinic visits included cessation of intermittent bleeding episodes, a noteworthy reduction in wound drainage, and reduced burden of at-home care on patients' families and caretakers. Finally, in addition to the improvements in healing outcomes, use of aSABS seems to have improved patients' quality of life and adherence to prescribed treatment regimens.

The clinical performance of aSABS, albeit early and in limited numbers of patients, points to its potential as a single multimodal solution. Self-assembly of the peptide into aSABS as a result of the ionic local wound environment was observed consistently, and the cited benefits occurred independent of the complexity, age, or location of the wounds; the sex, age, or comorbidities of the patients; and the variety of therapeutic approaches to wound management across the 3 clinics. These wounds had not previously healed despite prior attempts to treat them with a variety of wound care modalities, including skin grafts, placental-based products containing human amnion and chorion membrane, and skin substitutes, in addition to standard products and treatment regimens, such as topical antibiotics, antibiofilm gel, or ointments, offloading, and debridement procedures. Given that use of aSABS reinitiated the previously stalled healing processes and facilitated repair in a short duration in these exceedingly complex wounds, it is easy to postulate the effect it could have on healing progression if used as an elective wound healing product at the onset of wound care, rather than or in addition to its use as a rescue product to address the failure of prior treatments, as was done in these cases. More important, use of aSABS allowed management of these complex wounds in an outpatient setting without the need for an operating room; this is a valuable feature both during the COVID-19 pandemic, and any time when resource constraints can lead to negative outcomes by limiting access to operating rooms or resource-intensive technologies. Furthermore, use of aSABS can enable clinicians the ability to better deploy the Wound Center Without Walls strategy proposed by Rogers et al,[40] in which wound care is untethered from a physical location while allowing aggressive triage and wound care.

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