Outcomes of an Esterified Hyaluronic Acid Matrix in the Treatment of Chronic Lower Extremity Wounds: A Case Series

Objective. This case series evaluates the outcomes of persons with chronic lower extremity wounds treated with an esterified hyaluronic acid matrix (EHAM). Materials and Methods. Data were abstracted from 12 consecutive patients with a total of 14 evaluated chronic wounds (12 [100%] men, mean age 58.72 years) presenting for care at a multidisciplinary wound care center. Nine of the 12 patients had diabetes. The mean wound duration was 39.2 weeks. All patients received surgical wound debridement and were started on therapy consisting of weekly to biweekly applications of the EHAM with a nonadherent, moisture-retentive dressing until complete epithelialization was achieved. Outcomes evaluated included time to complete wound closure and proportion of patients achieving wound closure in 20 weeks. Results. In total, 85.7% of wounds measuring a mean of 2.32 cm² healed in the 20-week evaluation period. Of those that healed, healing took place in a mean of 8.9 weeks. Conclusions. A regimen of moist wound healing using an EHAM, which provides a scaffold for in-growing cells, may be a useful adjunct in the treatment of chronic, noninfected, nonischemic wounds.

Clinical Assessment of a Biofilm-disrupting Agent for the Management of Chronic Wounds Compared With Standard of Care: A Therapeutic Approach

Venous Ulcers Treated With a Hyaluronic Acid ECM and Compression Therapy

Introduction

Wound healing is a global medical concern complicated by challenges such as obesity, type 2 diabetes, and an overwhelmingly aging population. A common complication of lower extremity wounds is chronicity. If left untreated, a chronic wound can lead to infections, hospitalizations, amputations, and their associated costs. Billions of dollars are spent treating chronic wounds annually in the United States alone.¹ Moreover, the loss of productivity and diminished quality of life mounts a priceless emotional toll on the individuals affected and the family members caring for them.

Normal wound healing begins with blood clotting and inflammation, which often characterize an acute injury. Following the inflammatory phase, the wound progresses toward the proliferative and eventual reepithelization and remodeling phases. These later events are characterized by fibroblastic migration and proliferation, extracellular matrix (ECM) synthesis and organization, and angiogenesis. The ECM is produced by increased fibroblastic production of glycoproteins, proteoglycans, collagen fibers, and glycosaminoglycans such as hyaluronic acid (HA).² However, in a chronic wound, the healing phases are either stunted or redundant.³ Thus, a goal of chronic wound treatment is to progress the healing process to facilitate complete healing.

There have been many attempted treatments to target chronic healing, specifically ECM production and organization. The ECM allows the exchange of nutrients and wastes as well as provides a scaffold for host immune cells to migrate to tissues to eliminate pathogens and progress cell turnover. Of the ECM components, hyaluronan is the most conserved and hygroscopic. As the principal component of ECM, HA is involved in cell division and tissue formation. Consequently, HA plays many important roles in tissue healing. It has been shown that HA attenuates the inflammatory response and contributes to the production of granulation tissue, increased production of proteoglycans and glycosaminoglycans, and neoangiogenesis.^4-9 During remodeling, HA contributes to reepithelization and organized deposition of collagen fibers.¹⁰ Naturally, the healing properties of HA and the need for more advanced wound healing dressings led to the design of various treatment modalities capitalizing on HA derivatives.¹¹

Esterified hyaluronic acid matrix (EHAM; Hyalomatrix Wound Matrix; Medline Industries Inc, Mundelein, IL) is comprised of a HA-derived matrix coupled with a layer of medical-grade silicone. The silicone layer controls water vapor loss, avoiding an excessive loss of fluids, and acts as a semipermeable barrier to external agents. The purpose of this case series is to evaluate outcomes of chronic lower extremity wounds treated with EHAM.

Materials and Methods

In this case series, data from 12 patients with 14 chronic lower extremity wounds treated with EHAM were abstracted. All patients presented for care at the Rosalind Franklin University Health Clinics (North Chicago, IL). Of the patients evaluated, 12 (100%) were men with a mean age of 58.72 years. Nine of the 12 (75%) patients had diabetes. The 9 patients with diabetes had a mean hemoglobin A_1C of 8.84 ± 2.04 and a mean diabetes duration of 26.1 ± 4.48 years. The diagnosis of diabetes was confirmed by either communication with primary care providers or a review of medical records. All patients had adequate vascularity as confirmed by noninvasive vascular studies and full-thickness lower extremity ulcerations. The mean wound duration prior to treatment with EHAM was 39.2 weeks. The evaluated patients presented with a mean wound size of 2.32 cm²± 1.2 cm². Wound size was evaluated by measuring the maximum length by the maximum width.

All patients received surgical debridement as part of wound bed preparation in which all necrotic and fibrotic tissues were removed from the wound and a granular wound base was created. The wounds then received weekly to biweekly applications of an EHAM with a nonadherent and moisture-retentive dressing until complete epithelization (Figures 1, 2). Outcomes included time to complete wound closure and proportion of patients achieving wound closure in 20 weeks.

Results

Descriptive characteristics for this population are summarized in Table 1. In total, 12 (85.7%) wounds measuring a mean wound size of 2.32 cm² healed in the 20-week evaluation period. The mean number of EHAM applications was 3.7 ± 1.1. Of those that healed, healing took place in a mean 8.9 weeks. Table 2 summarizes the wound types, locations, and mean healing times. Table 3 illustrates the percentage of wound closure at biweekly intervals for all wounds. There were no device-related adverse events for all wounds. Two of the 12 (16.7%) patients required oral antibiotics at some point during treatment for reasons unrelated to their wounds; both patients were among those whose wounds healed in the 20-week assessment period.

Discussion

Chronic, nonhealing wounds may be secondary to a plethora of underlying causes, including venous insufficiency, diabetic neuropathy, peripheral vascular disease, and pressure (ie, pressure ulcer/injury). These wounds affect one-fifth of the US population and are defined as those that have failed to heal through an orderly and timely reparative process¹² and are clinically identified by an inability to achieve 50% reduction in wound size by a period of 4 weeks using appropriate standard of care. Chronic wounds are difficult to treat and are often recalcitrant to healing via standard wound management methods often accompanied by abnormal fibroblast and matrix protein functions in skin, decreased blood flow, peripheral neuropathy, and a poor inflammatory response.^13,14 Cost-effective, time-sensitive advanced treatment modalities are often indicated for chronic, nonhealing wounds to facilitate wound closure. Recent advances in wound care technologies, especially the advent of bioengineered alternative tissue, have proven to offer an optimized wound environment but have demonstrated varying efficacy rates.^15-18

Hyaluronic acid is a nonsulfated glycosaminoglycan characterized by a highly polymerized chain of glucuronic acid and N-acetylglucosamine units.^19,20 It is a major component of the ECM and is found in almost all tissues. In the skin, HA is abundant, particularly in the dermis; the epidermal microenvironment is high in HA concentration due to synthesis by keratinocytes.²¹ In fact, HA synthesis is a biomarker of keratinocyte proliferation.²²

Esterified hyaluronic acid matrix is a bilayered, sterile, flexible dermal substitute. It is comprised of an inner wound contact layer and an outer protective layer. The inner wound contact layer is made of a biodegradable derivative of HA that serves as a scaffold for cellular invasion and capillary growth. The outer protective layer is comprised of a semipermeable silicone membrane that acts as a physical barrier against external contaminants, controls water vapor loss, and promotes capillary growth, optimizing the chances of reepithelization. Furthermore, the transparency of the silicone film allows for continuous wound monitoring.

In previous studies,^23-25 EHAM maintained a high HA environment and provided a healing environment similar to fetal healing, which heals via regeneration rather than adult healing by scarring.Indications of EHAM use include venous and diabetic ulcers as well as many other wound types.¹² Due to the silicone film on the top layer of the bilayered wound dressing, it acts as a dermal substitute to allow for cellular invasion and capillary growth. Thus, providing a high HA concentration in the microenvironment allows for enhanced promotion of the healing process.

Between 1 and 5 matrices (mean of 3.7 ± 1.1) were applied during the 20-week period. It is important to note that additional matrix applications were not necessarily in relation to the percentage of wound closure but to whether the EHAM was stable and well-adhered to the wound. If, for example, the matrix was well adhered to the wound bed, then the wound would not be disturbed. However, if the matrix was not adhered to the wound bed, then the wound was debrided and a new matrix was applied. An example of this can be seen in Figure 2D, in which the matrix was well-adhered to the wound bed and not disturbed. The findings of this case series help support the effectiveness of utilizing an EHAM in conjunction with standard wound management techniques.

Limitations

The limitations of this case series included the small sample size and lack of a control group available to compare outcomes. In addition, a retrospective uncontrolled case series, such as the present one, may include inherent biases; therefore, a large randomized controlled trial is needed to refute or support the initial findings here.

Conclusions

Chronic wounds have a significant adverse effect on a patient’s quality of life, thus wound healing is an important goal that significantly increases a patient’s quality of life and reduces associated costs. In this case series, the authors analyzed the results of 14 chronic lower extremity wounds of 12 consecutive patients treated with EHAM. The findings of this retrospective chart review suggest that a regimen of moist wound healing using an EHAM may provide a scaffold for in-growing cells and be a useful adjunct in the treatment of chronic, noninfected, nonischemic wounds.

Acknowledgments

Authors: Timothy Cheung, MS¹; Zachary Laidley, BS¹; Jacob Jones, BS¹; and Stephanie Wu, DPM, MS²

Affiliations: ¹Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL; and ²Center for Lower Extremity Ambulatory Research (CLEAR), Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science

Correspondence: Timothy Cheung, MS, Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, Center for Lower Extremity Ambulatory Research, 3333 Green Bay Road, North Chicago, IL 60064; timothy.cheung@my.rfums.org

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

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