A Retrospective Analysis of Clinical Use and Outcomes Using Viable Placental Membrane Allografts in Chronic Wounds

As of 2018 in the United States, an estimated 8.2 million people had chronic wounds, with an estimated annual health care cost of $28.1 to $96.8 billion annually.^1,2 Chronic wounds, especially of the lower extremities, negatively affect quality of life, have considerable associated costs, and can result in negative outcomes, including cellulitis, osteomyelitis, amputation, and death. The prevalence of chronic wounds is expected to increase due to increasing rates of obesity and diabetes mellitus (DM) as well as an aging population. Healing chronic wounds in a timely manner while avoiding negative outcomes can be challenging.

Acute wounds progress through the phases of wound healing in sequence: hemostasis, inflammation, proliferation, epithelialization, and remodeling. Chronic wounds commonly become stalled in the inflammatory phase; the cellular events occurring during this stagnation can vary, including tissue ischemia and/or destruction, deficiencies in the extracellular matrix (ECM) (eg, inadequate fibrin matrix, growth factors), large volumes of necrotic tissue, failed angiogenesis, and bioburden.³ The percentage change in wound area is an accepted marker of healing potential. Wounds that do not decrease in size by 50% in the first 4 weeks of care are less likely to achieve complete closure by 12 weeks,⁴ and only about 24% of wounds heal after 12 weeks.⁵ The longer a wound has been present, the less likely it is to heal, indicating possible support for early and aggressive wound management.⁶

The viable placental membrane (vPM) under review (Grafix; Smith+Nephew) is a human placental membrane with viable cells including mesenchymal stem cells. It donates growth factors, fibroblasts, epithelial cells, mesenchymal stem cells, and a collagen-rich ECM to chronic wounds. Multiple growth factors are associated with the ECM vPMs provide including epidermal growth factor, fibroblast growth factor ß, keratinocyte growth factor, vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor ß1 and ß3, hepatocyte growth factor, tissue inhibitor of metalloproteinases, and neutrophil gelatinase-associated lipocalin.

A differentiation between viable amniotic products and other cellular and/or tissue-based products (CTPs) is that vPMs include living fibroblasts, keratinocytes, and mesenchymal stem cells. Mesenchymal stem cells regulate immune response and inflammation, recruit host cells to secrete growth factors and matrix proteins, and are capable of differentiating into different mesenchymal lineage cells.⁷ Although some controversy exists regarding the benefit of amniotic tissue that retains living cell types vs other preparation methods that do not retain cell viability, the purpose of this study was to describe the clinical use and outcomes of a specific product.

The use of vPM products has been shown to decrease time to healing of diabetic foot ulcers and decrease adverse wound events and wound-related infections.⁵ Although the etiology of wound chronicity varies, the vPM reviewed herein addresses multiple potential issues that limit wound healing.

Purpose
This retrospective research study evaluated the clinical use and outcomes of the viable human amniotic CTP with living mesenchymal stem cells used in the management of chronic wounds in the community hospital outpatient department setting, with the goal of comparing real-world use and outcomes of the product with use and outcomes described in the chronic wound literature.

Human patients consideration
This retrospective research analysis required submission to an institutional review board (IRB).⁸ Such approval was requested because the research results may be generalizable and the primary purpose is to add to a shared fund of knowledge. Approval was granted by the Froedtert and the Medical College of Wisconsin IRB.

Human patients participating in this project are safeguarded through the IRB process, which ensures protection of their safety, rights, and welfare.⁸ As an additional protection for human subjects, the project lead has completed CITI Human Subjects Research Training on the rules, regulations, and ethical principles governing research involving human subjects for interacting with research participants (eg, consenting, recruiting, data collecting).

The safety of the product studied herein, including manufacturing and distribution, is regulated by the US Food and Drug Administration as a CTP under 21 CFR Part 1271.⁹ This product has an established safety and efficacy profile and has been used in the Froedtert Health System since 2016.

Setting and sample
This study was conducted at the Froedtert Community Hospital Division Wound Healing Program, which represents 2 community hospital-based wound centers in southeastern Wisconsin: Froedtert Menomonee Falls Hospital and Froedtert West Bend Hospital. These facilities are designated hospital outpatient departments. Participants include all patients who underwent therapy at these locations between July 1, 2016, and August 21, 2019.

Inclusion criteria
Inclusion criteria consisted of all patients who had undergone and completed therapy with the vPM at Froedtert Community Hospital Division outpatient care centers between July 1, 2016, and August 21, 2019 (n = 89).

Exclusion criteria
Exclusion criteria consisted of all patients who had not received vPM therapy between July 1, 2016, and August 21, 2019, or who had begun but not completed such therapy during the study period. No exclusions were made regarding wound type, wound location, exposed structures, patient age, comorbidities, or adherence.

Data collection and analysis
Data collection occurred through retrospective chart reviews. Data analysis was performed via Excel (version 2016, Microsoft Corporation) using simple linear regression and descriptive statistics. For the purposes of this study, time to healing was defined as complete wound closure, 100% epithelialization of the wound bed, or documented dimensions of 0 × 0 × 0. Time to healing was calculated from the first day of treatment (day 0) to documented wound closure and the first day of vPM therapy to documented wound closure. Data collected included demographics, wound size, wound etiology, use of additional advanced therapies, the number of applications of vPM, use of compression, use of offloading, and adverse wound events. Results were compared with those reported in the literature, using literature results as the hypothetical means to compute t-statistics.

Protocol
All patients received standard of care prior to vPM application, including debridement, cleansing of the affected location or extremity and wound with soap and water, applying hypochlorous acid for 5 minutes, and applying no-sting skin protectant to the periwound as well as moisturizing cream. The vPM was applied using aseptic technique. A silicone mesh contact layer was applied and secured with sterile strips of medical tape. Appropriate secondary dressings were applied, including those with antimicrobial agents, per provider discretion. All patients were offered offloading and compression as indicated. Patients with moderate drainage were offered cover dressing changes midweek, with vPM grafts applied weekly.

A total of 89 patients received vPM treatment during the observed study period. The mean patient age was 70 years (range, 28–89 years; 69% male [n = 61], 31% female [n = 28]). Wound types were diabetic or neuropathic foot ulcers (54% [n = 48]), venous leg ulcers (VLUs) (17% [n = 15]), pressure injuries (7% [n = 6]), and atypical wounds (22% [n = 20]). The average wound duration prior to vPM initiation was 104 days. Average wound size at presentation was 6.9 cm². Of all the study participants, 54% had peripheral arterial disease (PAD) (n = 48) (Figure 1), 63% had diabetes mellitus (DM) (n = 56), 37.5% had DM and PAD (n = 30), and 17% had exposed bone or tendon (n = 15). All were full-thickness wounds (N = 89).

The average number of vPM applications was 5.6 for all patients and also 5.6 applications for participants remaining after those who did not achieve healing were excluded. Participants who experienced healing by 12 weeks received an average of 4.2 vPM applications.

Of patients receiving vPM therapy, 48% (n = 43) did not receive additional advanced therapy during the study period. Negative pressure wound therapy (NPWT) was used in 19% of cases (n = 17), low-frequency noncontact ultrasound was used in 25% (n = 22), and both NPWT and low-frequency noncontact ultrasound were used in 7% (n = 6). In 1 case, both NPWT and hyperbaric oxygen were used.

Twenty-four study participants did not achieve healing during the study period. The adverse events and scenarios associated with nonhealing included osteomyelitis (n = 6), cellulitis or chronic wound infection (n = 6), amputation (n = 8), wound surgical closure (n = 1), nonadherence with offloading or compression (n = 6), deceased (non-wound-related) (n = 4), deceased (wound-related sepsis) (n = 1), and lost to follow-up (n = 3). A single patient could experience multiple adverse events and scenarios. Forty-five percent of patients who did not achieve healing were nonadherent with offloading or compression. Overall, 20% of all participants were nonadherent with compression or offloading. Of study participants who did not achieve healing, 75% (n = 18) had some degree of PAD.

Adverse wound events were recorded during the entire treatment course, not only during vPM therapy. The total number of events was recorded, with the events primarily occurring in the following sequence: infection, osteomyelitis, and amputation. Adverse events included wound infection (n = 15), cellulitis (n = 2), osteomyelitis (n = 11), stasis dermatitis (n = 3), sepsis and death (n = 1), amputation (n = 8), and epidermolysis bullosa flare (n = 1).

The average adjusted time to healing after initiation of vPM was 81.2 days. The shortest time to healing was 16 days, and the longest was 541 days. At 12 weeks, 57% of wounds had healed.

A literature review identified 3 similar studies (Table) in which this vPM therapy was applied to chronic wounds in the outpatient or clinic setting. A 2014 study by Lavery et al⁵ included only diabetic foot ulcers. The median time to wound closure was 42 days, and the 12-week closure rate was 62%. A 2017 study by Johnson et al¹⁰ did not include Wagner grade 4 or 5 ulcers or patients with Charcot deformity. Mean time to closure was 59.7 days, and the 12-week closure rate was 63%. In a 2013 study that required standard of care to include compression and offloading, Regulski et al¹¹ reported a mean time to closure of 41 days and a 12-week closure rate of 76%. Inferential statistical analysis utilizing independent t tests compares differences between 2 groups with the use of means from the groups. Independent t tests with means utilized from these 3 previously published similar studies were not significantly different from the observed results in the current study (P =.99 for all).

Despite broad inclusion criteria including patients with PAD, uncontrolled DM, autoimmune conditions, nonadherence, and exposed bone and tendon (Figure 2), use of the vPM under review resulted in wound healing rates similar to those observed in the literature. The comparison studies were selected for product matching and study design; however, these studies were more limited in terms of inclusion and exclusion criteria, excluding wound types, wound depths, wound complications, exposed structures, Charcot deformity, comorbidities, and adherence.

Effectiveness research allows for direct observation of existing interventions in the desired setting. In translational research, effectiveness refers to a result obtained in an average clinical or real-world environment. Studies such as this one assist clinicians in justifying product cost to the facility and health care system.¹² Knowing the clinical use, effectiveness, and outcomes of products used in the clinic setting also assists clinics in choosing among the more than 120 CTPs currently on the market to maximize positive outcomes and provide safe, quality care for patients with chronic wounds.

Current wound research does not commonly include the diverse wound etiologies and patient presentations encountered in wound centers.¹² Wound types other than diabetic foot ulcers and VLUs are commonly excluded in wound research even though 20% to 30% of wounds are atypical (ie, those not classified into the typical wound categories of VLUs, diabetic foot ulcers, pressure ulcers, or arterial ulcers).^12,13 Patients with comorbid conditions and variables common to wound centers, including exposed bone, peripheral vascular disease, elevated A1C level, autoimmune disorders, and poor nutrition, are excluded from most wound research. The exclusion of these patient types may artificially inflate healing rates and negatively influence coverage of advanced therapies. One multisite study comparing VLUs presenting to wound centers with those presented in randomized controlled trials (RCTs) found that real-world VLUs were 5 times larger and presented with comorbid conditions excluded in VLU RCTs.¹⁴ Managed care organizations report clinical evidence from published studies as the most important factor when selecting which CTP to cover.¹⁵ Therefore, excluding these wound etiologies and clinical presentations results in insurance denials of coverage for these wound types. Healing rates reported in chronic wound clinical research may be artificially inflated because of the exclusion of these patient types. Some research studies have reported wound healing rates as high as 95%,^16,17 although data from research with more inclusive criteria demonstrate healing rates closer to 30% to 45%.^17,18 When managed care organizations transition to episode of care and performance-based payment plans, healing rates reported in the literature will not match real-world healing rates, which may affect reimbursement. Wound care providers are encouraged to participate in the research process and to include typical patients treated in wound centers, including the response of atypical wounds to advanced therapies.

Limitations of this study include the retrospective, nonrandomized, nonblinded study design. Inherent in this design is the potential for missing data. No official matching was completed between the samples of this study and the 3 studies results were compared to, potentially limiting statistical comparison. Similar to previously published studies, this study included a small sample size.

The effectiveness of vPMs observed in RCTs was also observed in this study of real-world use of vPMs for multiple wound types, including atypical wounds, wounds in patients with comorbidities including PAD and uncontrolled DM, and wounds involving exposed bone or tendon. The results of this study were not statistically different from those reported in the literature (P =.99), despite the broad inclusion criteria in this study. Healing results in this study are similar to those reported in the literature. More RCTs are needed to explore the efficacy of vPM in managing wounds in the setting of patient presentations common to wound healing centers.

Author: Laura Swoboda, DNP, APNP, FNP-C, FNP-BC, CWOCN-AP

Affiliation: Froedtert and the Medical College Community Hospital Division, Menomonee Falls, WI; Clinical Translational Science Institute of Southeastern Wisconsin, Milwaukee, WI

Correspondence: Laura Swoboda, DNP, Froedtert and the Medical College of Wisconsin Community, Hospital Division, Outpatient Care Center, N180 W8085 Town Hall Rd, Menomonee Falls, WI 53051; laura.swoboda@froedtert.com

Disclosure: The author discloses no financial or other conflicts of interest.