Efficacy of the Application of a Purified Native Collagen With Embedded Antimicrobial Barrier Followed by a Placental Allograft on a Diverse Group of Nonhealing Wounds of Various Etiologies: A Case Series

George J. Koullias, MD, PhD

Disclosures

Wounds. 2021;33(1):20-27. 

In This Article

Abstract and Introduction

Abstract

Introduction: Invoked by the presence of biofilm, upregulation of tissue-destroying proteases is the hallmark of continuous inflammation in nonhealing wounds. Preventing biofilm re-formation and quenching protease activity in the wound bed, followed by providing regenerative factors to the area may aid in triggering a wound healing trajectory.

Objective: In this case series, the author evaluated a multimodal approach in patients with wounds that did not respond to conventional therapy. These patients were initially treated with purified native cross-linked extracellular matrix (ECM) with polyhexamethylene biguanide (PHMB) antimicrobial barrier (PCMP) followed by placental allografts.

Materials and Methods: Wounds underwent once-weekly debridements, followed by application of PCMP and subsequent applications of hypothermically stored amniotic membrane (HSAM) and/or dehydrated amnion/chorion membrane (dACM) placental allografts.

Results: Sixteen wounds were included in the study, but 1 patient died before healing rates were calculated. Of the remaining 15 wounds, 13 (86.67%) closed at or before week 12, with the remaining 2 wounds achieving complete wound closure by week 17. A subgroup analysis of larger wounds (> 25 cm2) also was conducted. Of the 16 wounds, 6 (37.5%) were present for 8.5 weeks; these wounds ranged in size from 31 cm2 to 78 cm2, with mean baseline area (standard deviation) of 43.5 cm2 (15.99) and median baseline area of 42 cm2. Of the 5 larger wounds, 3 (60%) closed before 12 weeks. All wounds achieved complete wound closure by week 17 following application of PCMP and subsequent application of HSAM or dACM.

Conclusions: Applications of PCMP to nonhealing wounds, followed by application of dACM or HSAM placental allograft, in conjunction with the standard of care provided at the author's institution, resulted in satisfactory wound closure rates in a diverse group of wounds in a patient group with multiple comorbidities.

Introduction

Acute wounds progress through stages of healing over a predictive time course and usually heal completely within 1 month. Occasionally, however, acute wounds may become chronic. Many factors can result in the stalling of the wound healing cycle in the inflammatory or proliferative stage.[1–3] These factors are divided into 2 broad categories—local (ie, oxygenation, infection, venous sufficiency, uncontrolled biofilm formation) and systemic (ie, age and sex, coexisting diseases, various immunocompromised states).[1] In particular, these factors can trigger the release of pro-inflammatory molecules, which, subsequently, can promote increased protease activity.[1,4] The upregulation of proteases (ie, collagenases, gelatinases A and B, serine proteases) in the wound bed can degrade the extracellular matrix (ECM) components, including fibronectin, as well as various pro-healing growth factors, all of which are essential in crosstalk between cells involved in ECM remodeling.[6,7] The final common denominators of all these factors are prolongation or full arrest of the wound at the inflammatory phase and chronicity.[5]

Biofilm is an example of a local factor that may stimulate an intense inflammatory response in a chronic wound.[1,8] Microbes, encapsulated by a defensive polysaccharide barrier, form biofilm communities that strongly attach to the wound bed.[9] In response to the presence of persistent biofilm, host immune cells (eg, neutrophils) infiltrate the area of infection and release cytokines, oxygen species, and proteases in an attempt to eradicate biofilm.[2,8,10,11] At this stage, the release of pro-inflammatory molecules and the activation of proteases culminate in ECM degradation and a reduction in the pro-healing activities of keratinocytes and other cell types, thereby interrupting the normal course of wound healing.[8,10,12] Although debridement removes biofilm and necrotic tissue, debridement alone is not adequate, owing to rapid biofilm re-formation, usually within 24 hours, with full re-formation within 3 days.[13,14]

Preclinical and clinical studies have demonstrated the effectiveness of the topical antimicrobial agent polyhexamethylene biguanide (PHMB).[15–17] As a cationic topical antimicrobial agent that interferes with catabolic functions in both gram-positive and gram-negative biofilm-forming bacteria, PHMB gains entry to bacterial cells by strongly binding to and disrupting the integrity of bacterial walls and membranes.[15–19] The broad-spectrum microbial activity of PHMB extends not only to both gram-positive and gram-negative biofilm-forming bacteria but also to methicillin-resistant Staphylococcus aureus and many fungal pathogens.[20,21] Polyhexamethylene biguanide has 2 extremely favorable clinical characteristics; it has no recorded resistance to any known bacterial species, and it does not exhibit significant local toxicity or systemic uptake.[16,22]

Collagen matrices can effectively mitigate protease imbalances by serving as substrates for these enzymes.[23–25] Specifically, native type I collagen matrices can strongly bind proteolytic enzymes, such as matrix metalloproteinases and elastase, which are prevalent in nonhealing wounds, thereby effectively reducing both inflammation and destruction of native tissue.[24–26]

Purified native cross-linked ECM with PHMB is an antimicrobial barrier comprising native, bilayered, cross-linked type I collagen, which is saturated with topical antimicrobial PHMB (purified collagen matrix with embedded PHMB, further referenced as PCMP). It is believed that PCMP lessens pro-inflammatory protease activity and prevents biofilm recurrence through its native type I collagen and PHMB components.[19,27,28]

One critical feature of a successful wound healing strategy is the quick transition to the proliferative and remodeling phases. Placental allografts, which have been used for more than a century for the treatment of various wound types and which have low immunogenicity, contain ECM proteins, regenerative growth factors, and cytokines essential for healing and promoting proliferation and remodeling.[29–34]

Dehydrated amnion/chorion membrane (dACM) is a dehydrated placental allograft containing all native layers of placental membrane. In addition to regenerative growth factors and anti-inflammatory cytokines, dACM also includes the spongy layer, which has high concentrations of specific growth factors and provides proteoglycans, glycoproteins, and hyaluronic acid, as well as a rich collagen network.[31,33–35]

Another type of placental allograft that has been applied as a wound covering for the treatment of both acute and chronic wounds is hypothermically stored amniotic membrane (HSAM). This placental allograft consists of a fresh amnion layer of the placenta, including the spongy layer, viable cell populations (ie, stem cells, epithelial cells, fibroblasts), and a vast array of angiogenic, regenerative, and anti-inflammatory factors and cytokines that are believed to assist in the wound healing process.[33,36,37] In addition, HSAM contains multiple ECM proteins important for scaffolding, including collagen types I, III, V, and VI, as well as proteoglycans.[36,37]

In this case series, PCMP was used to treat 16 wounds of various etiologies prior to bridging to placental allografts. The approach was based on the treatment hypothesis that PCMP, in combination with aggressive debridements and optimal wound care practices, would reduce biofilm re-formation along with levels of local proteolytic enzymes, which would help transition the wound from the inflammatory phase, thus triggering the reparative process. This initial treatment with PCMP would be followed by applications of dACM and HSAM that would provide regenerative factors necessary for progression of the wound through the proliferative phase.

Sixteen wounds were treated with the aforementioned treatment algorithm, with most treatment provided by 1 vascular surgeon in a single wound care center. Treatment included PCMP (PuraPly AM; Organogenesis, Inc) followed by either dACM (NuShield; Organogenesis, Inc) or HSAM (Affinity; Organogenesis, Inc). In addition, each wound also was managed per the standard of care at the institution; at the discretion of the surgeon, adjunct tests were performed to detect and manage any arterial or venous insufficiency after initiation of wound care treatments.

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