The Use of Fetal Bovine Collagen on Chronic Wounds Increases Limb Salvage: A Single-center Retrospective Analysis

Chronic wounds can significantly affect a patient’s psychosocial and physical well-being. It is well established that patients with a diabetic foot ulcer (DFU) have a 2-fold increase in mortality compared with those without such ulceration; this mortality rate is further increased if these nonhealing wounds result in later amputation.¹ Whether this is a marker of disease severity is not entirely clear; the cause and effect of this association remain to be elucidated. Chronic wounds have a large financial effect on the US health care system, with an annual estimated cost of $28.1 billion (low range) to $31.7 billion (midrange) in Medicare spending.² Management of a DFU is thought to account for up to $19 billion of this spending. Similarly, the long-term cost of a chronic wound that progresses to amputation may be higher than that of a chronic wound managed aggressively with limb salvage efforts.³

The mortality rate associated with chronic wounds coupled with the recent emphasis on limb salvage has resulted in an increased desire for superior wound healing products that are reliable; inexpensive; easy to use, obtain, and store; and devoid of serious adverse effects. To meet this need, a variety of cellular- and tissue-based products (CTPs) have been developed to promote healthy granulation tissue in chronic wounds.

As part of a quality assurance project in the department of vascular surgery at a large tertiary care center (New York, NY), the authors of the current study evaluated the use of debridement techniques, negative pressure wound therapy (NPWT), and CTPs in limb salvage efforts based on the following 3 outcomes: freedom from amputation, wound closure, and freedom from readmission. One of the CTPs specifically evaluated was fetal bovine collagen (Primatrix; Integra LifeSciences). This product is an acellular collagen matrix derived from fetal bovine dermis. It is rich in type III collagen and filled with blood-binding cells and growth factors, thereby supporting cellular repopulation and revascularization of the wound.

As part of a university-based quality assurance program, the authors retrospectively analyzed data from 256 patients who underwent debridement and/or placement of a CTP between January 2016 and June 2018 as part of the treatment course for chronic wounds. Current Procedural Terminology (CPT) codes 15271 and 15275 were used to identify these 256 unique patients. This represented care provided by 3 dual board-certified general and vascular surgeons. Of the 256 patients, 4 patients were excluded because of incomplete data. Chart review of the remaining 252 patients was performed. All interventions, types of dressings, debridement tools, and skin substitutes used were recorded for each wound. Outcomes such as wound infection, readmissions, and future amputations were also documented. All patient identifiers were excluded, and data were entered into a spreadsheet in Excel (Microsoft Corporation). The data set then was imported into SAS University Edition (now called SAS OnDemand for Academics; SAS Institute) to aid statistical analysis. A binary logistic regression model was developed using all-cause future amputation as the response to various explanatory variables.

Of the 252 patients with complete data, 34 ultimately required either minor or major all-cause amputation after the initial wound intervention. For the remaining 218 patients, no amputations were recorded between 2016 and 2018 after initial wound intervention. The reasons for amputation included overwhelming infection and worsening gangrene. The Figure demonstrates the wound healing process of a patient treated with fetal bovine collagen.

Fetal bovine collagen was applied to 109 (43.25%) of the 252 patients studied. The most common protocol for application was in conjunction with tangential hydrosurgery or wide debridement, followed by 4 days of NPWT. When fetal bovine collagen was evaluated as an explanatory variable regarding the need for future amputation, a statistically significant relationship between the variables was found (P <.05) (Table). Of all treatment modalities utilized, only fetal bovine collagen showed statistical significance with regard to freedom from reamputation when binary linear regression was performed (P =.04).

The odds ratio calculated with this logistic regression was 0.433 (95% CI, 0.193–0.970) with regard to all-cause future amputations, which demonstrated a negative correlation between the use of fetal bovine collagen and amputation.

Other therapies evaluated included normal saline wet-to-dry dressings, sodium hypochlorite wet-to-dry dressings, the addition of Integra Dermal Regeneration Template (Integra LifeSciences), a 2-layer skin regeneration system composed of a thin outer layer of silicone and an inner layer matrix of bovine collagen and glycosaminoglycan, and NPWT without CTPs.

Wound closure data were recorded for 89 patients. Of those patients, 39 experienced primary wound closure without any further surgical intervention, and 28 experienced wound closure after split-thickness skin grafting. Forty-four patients were readmitted to the hospital within 1 year for severe soft tissue infection; 11 of these patients were readmitted within 30 days, and 20 were readmitted within 60 days. Patients readmitted for scheduled skin grafting or other staged procedures were excluded from this data set.

There are many dedicated limb salvage centers in the United States with the goal of decreasing the rate of amputation, and evidence suggests that amputation rates are decreasing.⁴ It is thought that a reduction in amputations will result in reduced morbidity and mortality as well as decreased overall health care costs. However, the lack of an algorithmic approach to limb salvage because of the heterogeneity of chronic wounds and incomplete knowledge of the long-term effects of each modality can leave the practitioner overwhelmed by the myriad of options.

The goal of the current retrospective study was to identify factors in the wound treatment algorithm that may affect outcomes to reduce the need for amputation. In the current study, fetal bovine collagen was found to be a viable option. Previous studies have investigated different CTPs and their effects on amputation. Frykberg et al⁵ reported a statistically significant decrease in amputations and bony resection with use of human fibroblast-derived skin substitute (Dermagraft; Organogenesis, Inc [formerly Advanced BioHealing, Inc]) compared with conventional care (5.5% and 12.6% rate of amputation, respectively; P =.031). Veves et al⁶ examined the efficacy of a human skin equivalent (Graftskin [Apligraf; Organogenesis and Novartis Pharmaceuticals]) and as a secondary endpoint found a statistically lower rate of lower extremity amputations in the intervention group treated with the CTP (P =.028).

Various studies, including Frykberg et al⁵ and Veves et al,⁶ were included in a Cochrane Review evaluating the use of skin substitutes in the management of DFUs.⁷ This meta-analysis of 17 trials with a total of 1655 randomized participants found a statistically significant lower amputation rate at the 12-week follow-up visit among patients treated with skin substitutes (risk ratio, 0.42; 95% CI, 0.23–0.81) (absolute risk difference, −0.06; 95% CI, −0.10 to −0.01) (number needed to treat, 17; 95% CI, 10–100).

Unlike the aforementioned meta-analysis, which reported data obtained 12 weeks after intervention, the current study, in which 2.5 years of data were reviewed, evaluated potential longer-term effects. The drawback of the current study is that it included only the patients treated during those 2.5 years; thus, the 5-year data differ from the results reported herein. Another limitation of this study is that it is single-center and retrospective in nature. The data used in this study were derived from a database created for all patients at the center undergoing procedures involving placement of a dermal matrix over a 2.5-year period. Several patients were lost to follow-up; thus, wound closure data were incomplete. Additionally, patients with poor perfusion were not treated with dermal matrices; thus, no data regarding perfusion assessment were collected. Because of this, the authors were unable to comment specifically on the effect of each patient’s limb perfusion on wound healing.

The present data analysis suggests that an algorithm of care including appropriate antibiotic therapy, tangential hydrosurgery, application of fetal bovine collagen, and a short course of NPWT is optimal for limb salvage, freedom from readmission, and wound closure. Specifically, these results indicate that use of fetal bovine collagen in the treatment of chronic lower extremity wounds may help postpone or prevent amputation, as evidenced by the statistically significant negative correlation between use of fetal bovine collagen and amputation. Additional long-term data analysis or a prospective trial are needed, but the data from the current study may be useful in selecting therapies for the management of chronic wounds.

Authors: Crystal V James, MD¹; Munir Patel, MD¹; Scott Ellis, MD¹; Michael Dudkiewicz, MD²; Alan Benvenisty, MD²; and John C Lantis II, MD²

Affiliations: ¹General Surgery, Mount Sinai Morningside/West Hospitals, New York, NY; ²Division of Vascular Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside/West Hospitals, New York, NY

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Crystal V James, MD, 425 W 59th Street, Floor 7, Mount Sinai Morningside/West Hospitals, New York, NY 10025; Crystal.James2@mountsinai.org