Fetal Bovine Acellular Dermal Matrix in the Management of Chronic Nonhealing Lower Extremity Wounds

The management of chronic nonhealing venous foot and leg ulcers remains a challenging problem that substantially affects patients and significantly burdens the health care system. Medicare cost projections for wound care of up to $96.8 billion annually have been reported.¹ Three percent of adults 65 years or older (approximately 1.6 million people) in the United States are estimated to have open wounds.¹ Nonhealing wounds are associated with increased hospitalization, decreased quality of life, minor and major amputations, and increased risk of mortality.^2-4 Thus, it is important to address both the therapeutic modalities and wound factors that influence these treatments in order to maximize wound healing rates and subsequently reduce health care costs and improve patient outcomes.

The armamentarium for the management of chronic skin wounds has greatly expanded, but treatment remains a slow and challenging process. One of the greatest advances in wound healing is the development of dermal matrices. Acellular skin grafts, a specific subtype of dermal matrix, provide a scaffold for wound healing without contributing cells directly to the wound bed. In the early stages of wound healing, type III collagen is laid down first, followed by an increase in type I collagen as scar formation progresses and wound remodeling occurs.⁵

Fetal bovine acellular dermal matrix (FBADM) is an acellular dermal collagen repair scaffold derived from fetal bovine dermis that can be used in the management of challenging wounds.⁶ This dermal matrix is composed of type III collagen, which is active in developing and healing tissues. The FBADM consists of nondenatured biochemical components of the collagen fiber matrix in fetal bovine dermis,⁶ which provides an extracellular base for tissue regeneration.

The present retrospective study evaluated the effects of FBADM on wound healing in patients with chronic venous leg and foot ulcers, with a specific focus on the ability to achieve complete wound closure by 12 weeks using this product.

A single-center retrospective chart review was conducted to collect data on patients with chronic venous leg and foot ulcers treated with FBADM (PriMatrix;Integra LifeSciences) from January 1, 2013, through December 31, 2019. Data collection included demographic information, medical and surgical history, medication history, previous wound treatments, wound description, wound size, length of treatment, time to wound healing, number of product applications, dates of applications, complications, and recurrences. Demographic information included race and ethnicity to assess for any significant differences in healing rates. The primary endpoint was complete wound closure 12 weeks after initial application. The data were collected and analyzed using Microsoft Excel (Microsoft Corp), and StatTools, version 8.0 (Palisade Company, LLC). Multivariate regression analysis was employed to assess the correlation between wound healing outcomes and various patient characteristics (eg, history of diabetes, number of comorbidities, patient age) and various wound characteristics (eg, wound slough and wound drainage).  Statistical significance for all tests was set at the standard threshold of P <.05.

Demographics. A total of 43 patients were treated using FBADM. The mean patient age was 68.5 years ± 15.2 standard deviation, with a mean body mass index of 28.2 ± 7.8 (Table 1). Sex, race, and ethnicity were self-reported and study participants were categorized as Asian (n = 6 [14%]); Black (n = 10 [23.3%]); Hispanic (n = 5 [88.4%]); non-Hispanic (n = 38 [88.4%]); other (4 [9.3%]), including multiracial; and White (n = 23 [53.5%]). There were 24 males (55.8%) and 19 females (44.2%). Sixteen subjects were smokers (37.2%), and almost all patients had vascular disease (n = 39 [90.7%]). The 3 most common vascular diseases were peripheral vascular disease (n = 34), hypertension (n = 28), and hyperlipidemia (n = 14). Additional comorbidities identified included history of prior amputation (n = 3 [7%]), diabetes (n = 10 [23.3%]), and renal disease (n = 3 [7%]). In 17 patients (39.5%), other therapies had been unsuccessful.

Wound characteristics. The median wound area was 11.3 cm² (minimum, 1 cm²; maximum, 187 cm²) (Table 2). The median wound age was 8 months (range, 2–72 months). Most wounds were located on the leg (72.1%), with the remainder located either on the foot (20.9%) or the abdomen or scalp (7.0%).

Summary of wound closure. Complete closure of the wound occurred in 23 patients overall (53%) and occurred in 12 patients (28%) at 12 weeks (Table 3). The mean percent area reduction at 12 weeks was 87%. The median time to wound closure was 84 days (minimum, 28 days; maximum, 327 days). The average number of FBADM applications was 1.6 ± 1.8, with a maximum of 4. There was 1 wound recurrence, and there were no infections or amputations.

Characteristics of healers versus non-healers. There were no significant differences between healers and non-healers based on mean body mass index (26.8 vs 29.8, respectively; P = .21) or mean number of comorbidities (4 vs 3.1, respectively; P = .09) (Table 4). Similarly, there were no significant differences based on mean wound size (24.6 cm² vs 29.9 cm², respectively; P = .64) or mean wound age (12.4 months vs 19.1 months, respectively; P = .24). Patient age was the only statistically significant factor between healers and non-healers, with average age significantly higher in the healers compared with the non-healers (73.7 years and 62.6 years, respectively; P = .02).

Product utilization by size. Seven (41.2%) of the 17 patients with wounds larger than 20 cm² achieved complete closure. Interestingly, the matrix applied was smaller than the wound area in 12 (70.6%) of these 17 patients. For all patients in whom the product size used was smaller than the wound area, 46.7% (n = 15) of patients had complete wound closure. Most patients (n = 28 [65%]) required 1 or 2 applications of FBADM during the entirety of the treatment phase, with a mean baseline wound area of 19.6 cm² (range, 1.5–96.0 cm²) and 13.6 cm² (range, 1.0–62.0 cm²), respectively (Table 5). Twelve patients (28%) required 3 applications of FBADM (mean wound area, 44.9 cm² [range, 1.8–187.0 cm²]), and 3 patients (7%) required 4 applications (mean wound area, 41.8 cm² [range, 6.0–70.0 cm²]). For patients who had been previously treated with other skin substitutes without achieving closure, a complete closure rate of 35.3% was achieved with FBADM (6 of 17).

Risk factors for wound healing. Binary logistic regression for successful wound healing showed that absence of diabetes, lack of drainage, and lack of slough were independently associated with increased wound healing (P = .0128, P = .0146, and P = .0061, respectively) (Table 6). Neither number of comorbidities nor wound age affected the rate of successful wound healing.

In this single-center retrospective study, use of FBADM in the management of chronic venous leg ulcers resulted in improvement in wound healing. More than half of the patients achieved complete wound closure, and of those, many achieved complete wound closure within 12 weeks.

The standard of care for management of chronic wounds consists of monitoring for infections, cleaning, dressing, and performing debridement when necessary, as well as compression and elevation.^7,8 Even with standard of care therapy, chronic lower extremity venous stasis ulcers last an average of 12 to 13 months.⁹ In contrast, with the use of FBADM in the present study, more than half of the patients enrolled achieved complete wound closure in an average of 111 days (<4 months). The use of treatment adjuncts, such as cellular and acellular dermal matrices, can improve wound healing rates; however, this was not common practice as of the time of this writing. A recent consensus meeting on the management of chronic wounds mentioned the use of cellular- and tissue-based products only briefly to note that each product should be independently assessed for each wound type, further highlighting the need for research into the benefits of these therapies.¹⁰

The benefits of FBADM are likely derived from its unique composition. This acellular, bovine-derived skin scaffold is predominantly made of type I collagen but is uniquely rich in type III collagen (30%) compared with other allografts sourced from adult tissues.¹¹ The increased type III collagen supports the initial wound healing process, in which type III collagen is preferentially synthesized before conversion to type I collagen.⁵ By providing the building blocks in this process, FBADM provides an optimal environment for early developing tissues. Initial work by Kavros et al⁶ on the use of FBADM showed excellent healing of diabetic foot ulcers at 12 weeks, with a complete wound closure rate of 76%. A recent prospective randomized controlled trial evaluating the effect of FBADM on hard-to-heal diabetic foot ulcers demonstrated improved rates of complete wound closure at 12 weeks in the FBADM group compared with standard of care.¹¹ Both of these studies showed better wound closure rates than the present study. However, Kavros et al⁶ and Lantis et al¹¹ focused on diabetic foot ulcers with an average wound size of approximately 4 cm² and 3 cm², respectively, which is much smaller than the wounds in the present study (mean wound area, 27 cm²; maximum, 187 cm²). In a retrospective review, Paredes et al¹² evaluated patients with chronic, large venous leg ulcers measuring an average of 21.1 cm² ± 27.4 who were treated with FBADM. By 16 weeks, 38% of wounds were closed. This further reinforces the fact that even in patients with large and challenging ulcers initially thought to have a limited chance of healing, improvement in wound closure rates is possible with the use of FBADM.

Large wounds pose a particular challenge for wound healing owing to the extensive surface area, increased risk of infection, poor vascularization throughout, and a deregulated inflammatory response.^13,14 In the present study, 41.2% of wounds larger than 20 cm² closed completely with the use of FBADM. Even in situations in which the FBADM was smaller than the wound area, almost half of patients achieved complete wound closure. Fetal bovine acellular dermal matrix is rich in elastin, which is an integral component of the extracellular matrix that provides the structural integrity and elasticity required for mechanical stretching of the dermis.^15,16 This makes it possible to cover a large, irregular wound that is larger than the initial product size, demonstrating the economic benefit of the product. Additionally, FBADM may also be used as second-line therapy for difficult or nonhealing wounds that were previously treated with other skin substitutes; the present study demonstrated a significant closure rate of 35% in such cases.

The present study shows the utility of FBADM both as an initial treatment modality for large and small chronic lower extremity ulcers, and as a second-line therapy. The limited use of FBADM in other anatomic locations in the present study (ie, abdomen, scalp) suggests that there may be a role for its expanded use in other chronic wounds.

Given the economic burden of chronic wounds, it is important to develop treatments and solutions that not only improve patient outcomes, but are also efficient and cost-effective. The convenience of FBADM application, which can be performed easily in the outpatient setting, provides such a solution for venous ulcers of the leg and foot. In the present study, complete wound closure was achieved with a median of 1 application, which suggests that a single treatment is sufficient for complete healing. A decrease in the number of outpatient treatments has the potential to significantly reduce health care expenditures; a 2014 study showed that annual outpatient wound care costs were higher than inpatient costs, with estimated upper range costs of $35.8 billion and $24.3 billion, respectively.¹

Despite higher initial costs with acellular dermal matrix, studies have shown cost benefit with its use when the reduced cost associated with decreased wound closure time is taken into account.^17-19 Among cellular- and tissue-based products, acellular dermal matrices were found to be the most cost-effective compared with other cellular-based products.²⁰ Such evidence suggests that these novel techniques should not be discounted on the basis of upfront expenditure.

This was a single-center retrospective study with a small sample size, which limits the applicability of the results to the general population. Additionally, there is no direct comparison with wound healing rates using standard of care alone, or comparison with other treatment adjuncts (eg, other acellular or cellular dermal matrices), which limits the conclusions that can be drawn. A future randomized controlled trial stratified by wound size and etiology is necessary to further elucidate the effect of FBADM in the management of chronic nonhealing lower extremity wounds.

In the present study, application of FBADM was safe, efficient, and effective in the management of chronic venous leg ulcers, including large wounds and wounds that had not healed with other therapies, including prior application of other skin substitute products.

Affiliations: ¹Department of Surgery, Northwell Health, Manhasset, NY; ²Comprehensive Wound Healing & Hyperbaric Center, Northwell Health, Lake Success, NY; ³Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY

Address all correspondence to: Alisha Oropallo, MD, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; aoropallo@northwell.edu

Potential conflicts of interest: The authors have no conflicts of interest to declare that are relevant to the content of this study.

1.         Sen CK. Human wounds and its burden: an updated compendium of estimates. Adv Wound Care. 2019;8(2):39-48. doi:10.1089/wound.2019.0946

2.         Jupiter DC, Thorud JC, Buckley CJ, Shibuya N. The impact of foot ulceration and amputation on mortality in diabetic patients. I: From ulceration to death, a systematic review. Int Wound J. 2016;13(5):892-903. doi:10.1111/iwj.12404

3.         Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care. 2015;4(9):560-582. doi:10.1089/wound.2015.0635

4.         Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why venous leg ulcers have difficulty healing: overview on pathophysiology, clinical consequences, and treatment. J Clin Med. 2020;10(1):29. doi:10.3390/jcm10010029

5.         Mathew-Steiner SS, Roy S, Sen CK. Collagen in wound healing. Bioengineering. 2021;8(5):63. doi:10.3390/bioengineering8050063

6.         Kavros SJ, Dutra T, Gonzalez-Cruz R, et al. The use of PriMatrix, a fetal bovine acellular dermal matrix, in healing chronic diabetic foot ulcers: a prospective multicenter study. Adv Skin Wound Care. 2014;27(8):356-362. doi:10.1097/01.ASW.0000451891.87020.69

7.         Dreifke MB, Jayasuriya AA, Jayasuriya AC. Current wound healing procedures and potential care. Mater Sci Eng C. 2015;48:651-662. doi:10.1016/j.msec.2014.12.068

8.         Ren SY, Liu YS, Zhu GJ, et al. Strategies and challenges in the treatment of chronic venous leg ulcers. World J Clin Cases. 2020;8(21):5070-5085. doi:10.12998/wjcc.v8.i21.5070

9.         Optimal Care of Chronic, Non-Healing, Lower Extremity Wounds: A Review of Clinical Evidence and Guidelines. Canadian Agency for Drugs and Technologies in Health; 2013. Accessed December 11, 2022. http://www.ncbi.nlm.nih.gov/books/NBK195726/

10.       Eriksson E, Liu PY, Schultz GS, et al. Chronic wounds: treatment consensus. Wound Repair Regen. 2022;30(2):156-171. doi:10.1111/wrr.12994

11.       Lantis JC, Snyder R, Reyzelman AM, et al. Fetal bovine acellular dermal matrix for the closure of diabetic foot ulcers: a prospective randomised controlled trial. J Wound Care. 2021;30(Sup7):S18-S27. doi:10.12968/jowc.2021.30.Sup7.S18

12.       Paredes JA, Bhagwandin S, Polanco T, Lantis JC. Managing real world venous leg ulcers with fetal bovine acellular dermal matrix: a single centre retrospective study. J Wound Care. 2017;26(Sup10):S12-S19. doi:10.12968/jowc.2017.26.Sup10.S12

13.       Vowden P. Hard-to-heal wounds made easy. Wounds Int. 2011;2(4).

14.       Sawaya AP, Stone RC, Brooks SR, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun. 2020;11(1):4678. doi:10.1038/s41467-020-18276-0

15.       Cornwell KG, Landsman A, James KS. Extracellular matrix biomaterials for soft tissue repair. Clin Podiatr Med Surg. 2009;26(4):507-523. doi:10.1016/j.cpm.2009.08.001

16.       Wang Y, Armato U, Wu J. Targeting tunable physical properties of materials for chronic wound care. Front Bioeng Biotechnol. 2020;8:584. doi:10.3389/fbioe.2020.00584

17.       Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res. 2009;9(1):115. doi:10.1186/1472-6963-9-115

18.       L S, Sujit J. The use of Dermagraft in neuropathic foot ulcers in people with diabetes: an economic analysis for Australia. Prim Intent Aust J Wound Manag. 2002;10(2):49-50, 52-54, 56-57.

19.       Steinberg J, Beusterien K, Plante K, et al. A cost analysis of a living skin equivalent in the treatment of diabetic foot ulcers. Wounds. 2002;14:142-149.

20.       Carter MJ, Waycaster C, Schaum K, Gilligan AM. Cost-effectiveness of three adjunct cellular/tissue-derived products used in the management of chronic venous leg ulcers. Value Health. 2014;17(8):801-813. doi:10.1016/j.jval.2014.08.001