A Multicenter Retrospective Study Comparing a Polylactic Acid CAMP With Intact Fish Skin Graft or a Collagen Dressing in the Management of Diabetic Foot Ulcers and Venous Leg Ulcers

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VLUs and DFUs are chronic wound types that pose an ongoing health care challenge.¹ CAMPs are advanced wound care therapies consisting of living cells or tissues or engineered materials derived from different sources. These products are designed to promote wound healing and tissue regeneration by providing bioactive components, growth factors, and structural support to the wound bed.² These therapies have been shown to be effective in promoting healing, particularly in chronic wounds.³ CAMPs are a broad category that encompasses allografts, which are tissues from a human donor (ie, amniotic membranes or cadaveric skin); xenografts, which are tissues from animal sources (ie, different collagen membranes); and alloplastic grafts, which are fully synthetic biomaterials.⁴ Although collagen dressings are not classified as CAMPs, they have widely been considered the clinical standard of care for advanced wound management.⁵ This heterogeneous group of wound care products encompasses dressings that employ a variety of carriers or combining agents with mainly type I collagen derived from bovine, porcine, equine, or avian sources that are used to promote a moist environment, act as a tissue scaffold, and promote the regulation of cells within the wound bed.⁶ However, although collagen dressings have demonstrated consistent effects in increasing wound healing rates and serving as an effective and safe option for chronic wound management,⁷ success rates are lower with collagen dressings than with CAMPs. Therefore, alloplastic CAMP grafts are emerging as an attractive treatment option to circumvent the issues associated with allografts, xenografts, and collagen dressings.^8,9

PLA is a synthetic material that has been used in alloplastic CAMPs; it has demonstrated healing benefits, particularly in burns and traumatic injuries.^10-12 Notably, the results of a recent randomized trial demonstrated that compared with the standard of care, PLA wound closure matrices can reduce the time to healing of DFUs.¹³ However, because use of PLA is relatively new in wound care, there is a scarcity of scientific reports assessing its effectiveness in promoting chronic wound healing, particularly when compared with other well-established CAMPs. Therefore, the objective of the research presented herein was to perform a multicenter retrospective chart review to compare the effectiveness of collagen dressings as the standard of care, a xenograft (intact fish skin graft, FSG), and a PLA alloplastic CAMP in promoting closure of DFUs and VLUs.

A retrospective chart review was conducted of patients with a single chronic wound (either DFU or VLU) who received care at 1 of 3 treatment centers—2 in Ohio (WAFL, Circleville, OH; Foot and Ankle Physicians of Ohio, Circleville, OH) and 1 in New Jersey (The Wound Institute of Ocean County, Toms River, NJ). The 3 sites are high-volume wound care clinics that are considered regional referral centers. The methodology was reviewed by WCG IRB, and the need for IRB approval was waived due to the nature of the research.

Inclusion criteria included charts from patients with either a single Wagner grade 1 or 2 DFU or a Clinical-Etiology-Anatomy-Pathophysiology classification C6 VLU. The charts were identified through a database search. In all cases, wound duration of at least 12 to 52 weeks before treatment with CAMPs and size between 1 cm² and 20 cm² were required for inclusion. Patients were required to have undergone weekly treatments until healing with only 1 of 3 products: collagen dressings (Fibracol Plus; Solventum), FSG (MariGen; Kerecis), or an alloplastic PLA-guided closure matrix (Supra SDRM; PolyMedics Innovations).

Exclusion criteria included charts with incomplete data, patients who developed wound infections that required the use of systemic antibiotics, patients who were hospitalized for any reason, and patients lost to follow-up. In addition to receiving the active therapy, all patients received the standard of care, which included weekly follow-up visits with debridement, wound care, and offloading with a walking boot for DFU or lower leg compression therapy for VLU. Collagen dressings or CAMPs were applied every week up until the wound was deemed completely closed.

The primary outcome for this chart review was the time to achieve full healing, defined as complete (100%) wound reepithelialization without drainage and/or the need for a dressing. The secondary outcome was the proportion of ulcers healed at 12 weeks.

Continuous data are presented as either mean (standard deviation) or median (range). Discrete data are presented as proportions. Wilcoxon rank-sum tests, Fisher exact tests, and Gray competing risk models were used to analyze the data by a researcher blinded to the treatment at the 95% CI using the statistical R software (version 4.0.2; The R Core Team, 2022. R: A language and environment for statistical computing). Multiple comparisons were adjusted using Tukey post hoc tests where applicable.

A total of 131 wounds (patient charts) were included in the study: 49 in the collagen group, 40 in the FSG group, and 42 in the PLA group. Across the different treatment groups, 47 wounds (36%) were identified as VLUs. The patient and baseline wound characteristics are presented in Table 1. No significant difference in demographic or wound characteristics was found at baseline.

Overall, the median time to achieve full healing was 16 weeks in the collagen group (range, 8–29 weeks), 12 weeks in the FSG group (range, 5–21 weeks), and 9 weeks in the PLA group (range, 3–16 weeks). The differences across groups were statistically significant: collagen vs FSG (P = .008), collagen vs PLA (P < .001), and FSG vs PLA (P = .043). Compared with collagen, the use of FSG was associated with 3.8 (95% CI, 0.8–6.8) fewer weeks until healing, whereas the use of PLA was associated with 6.9 (95% CI, 3.9–9.8) fewer weeks until healing. Compared with FSG, PLA took 3.0 (95% CI, 0.9–6.3) fewer weeks to achieve complete healing.

By wound etiology, the median time to achieve full healing in DFUs was 15 weeks in the collagen group (range, 8–29 weeks), 12 weeks in the FSG group (range, 5–20 weeks), and 10 weeks in the PLA group (range, 4–16 weeks): collagen vs FSG (P = .011), collagen vs PLA, (P < .001), and FSG vs PLA (P = .049). The median time to achieve full healing in VLUs was 17 weeks in the collagen group (range, 8–27 weeks), 10 weeks in the FSG group (range, 7–21 weeks), and 6 weeks in the PLA group (range, 3–16 weeks): collagen vs FSG (P = .008), collagen vs PLA (P < .001), and FSG vs PLA (P = .026) (Figure 1). No significant difference in wound size or duration was found between groups at baseline.

Complete healing was achieved by week 12 in 15 of 49 patients treated with collagen (31%), compared with 24 of 40 patients treated with FSG (60%) and 36 of 42 patients treated with PLA (86%) (P < .001) (Table 2). By wound etiology, complete healing was achieved by week 12 in 11 of 34 DFUs managed with collagen (32%), compared with 13 of 24 DFUs managed with FSG (54%) and 22 of 26 DFUs managed with PLA (85%) (P < .001). Similarly, for VLUs, complete healing was achieved by week 12 in 4 of 15 patients treated with collagen (27%), compared with 11 of 16 patients treated with FSG (69%) and 14 of 16 patients treated with PLA (88%) (P = .002) (Figure 2). The competing risk and cumulative incidence for achieving full closure by 12 weeks with collagen, FSG, or PLA was 31% (95% CI, 18%–44%), 62% (95% CI, 45%–76%), and 86% (95% CI, 70%–93%), respectively (Figure 3). The median number of applications of each product was 15 for collagen dressings, 10 for FSG, and 8 for PLA. No complications or adverse events for any of the CAMPs were recorded in the charts.

The current study demonstrates that compared with collagen dressings, which are considered the advanced wound care product standard of care, or a well-established acellular xenograft (FSG), the PLA alloplastic CAMP studied was associated with reduced time to healing and significantly increased full healing rates by 12 weeks of treatment in DFUs and VLUs. The use of PLA matrices was associated with a 50% and 20% reduction in the time needed to heal DFUs compared with collagen dressings and FSG, respectively. In the case of VLUs, the reduction observed in the time to heal was even more impressive, at 95% and 40% compared with collagen and FSG, respectively. Furthermore, PLA allografts were associated with a 55% higher rate of full healing by 12 weeks compared with collagen dressings, and a 26% higher rate compared with FSG.

Collagen dressings have been used as the standard of care for wound healing in multiple studies.⁷ Several articles have shown a healing rate of approximately 30% by 12 weeks with the use of these materials,^13-16 which is consistent with the findings of the current study. The collagen in most of these products is usually denatured and does not conserve its native structure; therefore, these products are mainly used as wound modulatory dressings. Cells readily attach to these products, and their collagen content offers molecular targets to saturate and modulate ECM-degrading enzymes such as MMPs.⁶

In contrast, FSG is a novel xenograft that combines the benefits of the traditional collagen and ECM scaffolding with the anti-inflammatory properties of the unsaturated fatty acids present in cold-water fish tissues.¹⁷ A landmark study demonstrated that use of FSG results in a clinically and statistically significant difference in wound healing compared with the standard of care, with 63% of wounds managed with FSG fully healed by 12 weeks,¹⁵ which is also consistent with the results of the current study.

PLA alloplastic grafts are a relatively new tool in the chronic wound care armamentarium; however, they have been available for almost 20 years for burn care. The alloplastic graft used in the current study is manufactured as a jellified foam composed of 75% PLA, 15% to 20% ε-caprolactone, and 5% to 10% trimethylene carbonate. The material has a 90% open porosity rate and a bimodal pore distribution range with micropores of 6 µm to 20 µm that are well suited for cell attachment and migration, and macropores of 100 µm to 700 µm for ECM deposition and blood vessel ingrowth.^18-20 Therefore, this alloplastic PLA CAMP is initially designed to be used as a scaffold. However, it is also designed to undergo spontaneous hydrolysis upon contact with fluid from the wound bed. This process ultimately cleaves the PLA into lactide monomers, which are then converted into lactate molecules.

Lactate has traditionally been considered a waste product of cellular metabolism. However, recent research has demonstrated that it exerts pleiotropic effects that are beneficial to wound healing.²¹ These effects include robust increases in neoangiogenesis through direct stimulation of the vascular endothelial growth factor pathway^22,23; increases in cell survival; increases in collagen and ECM deposition; and modulation of MMP activity,^24-28 profound immunomodulatory effects,^29-31 and acidification of the extracellular environment.^21,32,33 Taken together, these effects modulate most of the components and main processes of wound healing, thereby changing nonhealing, chronically inflamed tissue into a proliferative wound.

Despite its promising results, the current study has some limitations. Its major limitation is the retrospective design. This methodology includes incomplete data sets and intrinsic treatment biases, including that in most cases the therapies were not contemporaneous. However, attempts were made to control recall bias by including data from 3 different centers and performing a blinded data analysis. The multicenter nature of the study is another limitation, because although wound care professionals at all centers generally treat their patients in the same way, there are inherent differences in treatment and management (ie, debridement protocols, nutritional assessment and management, secondary dressings, etc.). However, this limitation was addressed by including treatment arms from all centers in as balanced a way as possible. Nonetheless, a large multicenter randomized clinical trial is needed to control for these pitfalls and ultimately determine efficacy, and to provide insights into the mechanism of action of this novel PLA-based technology in chronic wounds beyond what has already been established in the literature.

The selection of an advanced wound treatment such as a CAMP requires consideration of several factors, including the wound characteristics and physiology, as well as the patient’s personal preferences, such as religious or personal beliefs that may prevent them from using allografts or xenografts. The ideal CAMP should promote rapid healing, be easily integrated into native tissues, avoid triggering an aggressive immune or anaphylactic response, and be easily degraded into nontoxic metabolites.³ Based on the findings of the current study, alloplastic PLA-based grafts fulfill all these criteria, reduce the time to achieve healing of DFUs and VLUs, and increase the odds of achieving full closure by 12 weeks. Thus, PLA-based grafts show promise as another tool in the wound care armamentarium.

Authors: Brock A. Liden, DPM¹; Tiffany Liu, DPM²; Matthew Regulski, DPM^3,4; Melissa Foster, DPM²; Ryan DeLeon, DPM²; Gina Palazzi, DPM²; and Jose L. Ramirez-GarciaLuna, MD, PhD⁵

Affiliations: ¹WAFL, Circleville, OH; ²Foot and Ankle Physicians of Ohio, Circleville, OH; ³The Wound Institute of Ocean County, Toms River, NJ; ⁴Ocean County Foot and Ankle Surgical Associates, Toms River, NJ; ⁵Division of Experimental Surgery, McGill University, Montreal, QC, Canada

Disclosure: B.A.L, M.R., and J.L.R.G. have received or receive honorariums as consultants for PolyMedics Innovations GmbH. All remaining authors disclose no conflicts of interest. This research was presented at the 2023 Symposium on Advanced Wound Care Fall in Las Vegas, Nevada (November 2-5, 2023).

ORCID: Liden, 0009-0007-6023-2582; Ramirez-GarciaLuna, 0000-0002-3953-9762

Correspondence: Jose L. Ramirez-GarciaLuna, MD, PhD; Division of Experimental Surgery, McGill University, 1650 Cedar Ave Suite C10-124, H3G 1A4 Montreal, QC, Canada; jose.ramirezgarcialuna@mail.mcgill.ca

Manuscript Accepted: June 14, 2024