Preclinical and Clinical Studies of Hyaluronic Acid in Wound Care: A Case Series and Literature Review

Introduction. Esterified hyaluronic acid is part of a unique dressing that can be used for the treatment of difficult, nonprogressive wounds, including venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). Objective. The data presented herein represent a small retrospective sample of the authors’ clinical experience with this unique material. Materials and Methods. Data were collected from 6 patients with DFUs and 3 patients with VLUs. Patients were assessed at regular intervals, and the change in wound size as well as the percentage of necrotic versus granular tissue were tracked. Results. The average time for evaluation was 55.25 days (SD = 2.76 days). During this period, the average change in wound size decreased by 6.43 cm² (SD = 7.55 cm²), from 7.93 cm² (SD = 8.12 cm²) to 1.50 cm² (SD = 0.92 cm²), and developed an increase of 74.38% (SD = 32.01%) coverage with granulation tissue from 46.11% (SD = 22.05%), representing about a 50% increase in granulation tissue over the 55 days of evaluation. Conclusions. The presented literature supports the contention that hyaluronic acid is a critical component in the complex cascade of wound healing and most likely is responsible for the clinical wound improvement in the case series presented.

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Hyaluronic Acid in Inflammation and Tissue Regeneration

Dermal and epidermal wound healing is a highly orchestrated cascade of events. For academic purposes, the process has been stratified into 3 distinctive, overlapping stages: (1) inflammation, (2) proliferation, and (3) remodeling. During the inflammatory phase, there is an initial vascular injury, resulting in platelet and complement activation. Once successful clotting has been achieved, neutrophils and macrophages are sent to the wounded region to phagocytize bacteria and debris.¹ The inflammatory phase normally lasts a few days. In the proliferative phase, there is angiogenesis, extracellular matrix (ECM) formation by fibroblasts, and early epithelialization. The remodeling phase consists of remodeling, contraction, and increased tensile strength of the skin.²

Chronic wounds remain in the inflammatory stage of wound healing due to a defect in systemic or local factors.² Systemic factors that impede wound healing include immunosuppression, diabetes, peripheral vascular disease, chronic renal insufficiency, vitamin deficiencies, and protein deficiency, among others. Local wound factors that cause wound healing to stall include necrotic or hyperkeratotic tissue, foreign debris, localized edema, bony prominences, absence of growth factors, bacterial overgrowth, infection, biofilm, and lack of moisture equilibrium.²

The goal of healing a chronic wound has led to a plethora of products used to control the local wound environment. Prior to adding any advanced product to a wound, the appropriate surgical or mechanical debridement must be utilized to remove any infected, hyperkeratotic, or necrotic tissue. Once the wound has been properly prepared, various specialized dressings, growth factors, collagen grafts, or skin substitutes can be added.³ Sheehan et al⁴ noted that, as a negative predictor of healing, if a wound does not close by about 50% in the first 4 weeks of treatment, there is less than a 10% chance that the wound will be closed after 12 weeks. Their research⁴ also showed that if a wound closes by 50% in the first 4 weeks of treatment, it is likely to be completely closed by 12 weeks. Therefore, in nonhealing wounds, it is imperative to identify and correct the factors preventing further wound healing and employ an engineered wound product.

Hyaluronic acid (HA; also called hyaluronan) is an anionic, non-sulfated glycosaminoglycan present in numerous tissues, including connective and epithelial tissues. It is a linear polymer of D-glucuronic acid and D-N-acetylglucosamine disaccharides, linked via alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronic acid is highly hygroscopic (ie, attracts and holds water from the surrounding environment) and absorbent. However, its native form is a gel, which is difficult to keep within a wound. Natural polymers of HA can range in size from 5000 to 20 million Dalton.⁵ Hyaluronic acid is synthesized in the cellular plasma membrane by HA synthases. Several reservoirs of HA exist within the body, including one associated with the cell surface, one bound to other components of the ECM, and a largely mobile pool. In the ECM, HA plays an essential role in migration and proliferation of cells as well as in tissue hydrodynamics.⁶ A number of cell receptors for HA have been identified, including CD44, receptor for HA-mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1).⁷ CD44 mediates cell interaction with HA, and their binding plays an important role in a number of physiologic events, such as cell aggregation, migration, proliferation, and activation.⁸ In addition, ICAM-1 serves as a cell adhesion molecule, and the binding of HA to ICAM-1 contributes to the control of ICAM-1-mediated inflammatory activation.⁹ The RHAMM plays a role in the generation and organization of granulation tissue.¹⁰ The principal of dynamic reciprocity describes wound healing as a series of steps in which cells and the extracellular microenvironment continually interact. In many of these steps, HA plays a critical role, including hydration, anti-inflammation, and cellular migration.¹¹

The Cambridge Health Alliance Institutional Review Board (Cambridge, MA) approved this retrospective patient review. Charts from 9 patients with either a diabetic foot ulcer (DFU) or a venous leg ulcer (VLU), previously treated with an esterified HA matrix dressing (EHAM; Hyalomatrix; Medline Industries, Inc, Mundelein, IL), were examined. Patients were selected in reverse chronologic order, and they had to meet several criteria in order to be included in this evaluation, which are listed in Table 1.

Case series
Based on the inclusion/exclusion criteria described in Table 1, 9 patients were identified. Three of the patients had VLUs and 6 had DFUs. There were 5 men and 4 women with an average age of 56.8 years (range, 47–72 years). All patients had diabetes including those with ulcers of venous etiology. The average hemoglobin A_1C was 9.82% (SD = 1.45). Wound size averaged 14.47 cm² (range, 6.00 cm²–27.00 cm²) in the VLU group and 4.60 cm² (range, 1.98 cm²–12.60 cm²) in the DFU group. The overall average wound size was 7.93 cm² (SD = 8.12 cm²).

Treatment consisted of surgical debridement of the wound when there was obvious periwound callus or superficial necrotic tissue present. Following debridement, the wound was cleansed thoroughly with saline, and the EHAM was applied with the fibrous surface facing the wound. In cases in which there was significant exudate, the silicone portion of the dressing was fenestrated to allow for drainage. The EHAM normally was secured with plain gauze, and a multistage compression dressing was applied on top of this for all 3 VLUs. One of the DFU cases also included an absorbent alginate dressing on top of the EHAM due to a large amount of exudate.

At each visit, wound size was recorded via standard paper ruler. In addition, an estimation of the relative amounts of fibrous or necrotic tissue compared with the amount of granular, well-vascularized tissue was documented in the patient’s clinical record. This ratio always totaled 100% and was a crude estimate of the relative increase or decrease in granulation tissue present.

The analysis included a measure of the change in wound size with time as well as the relative amount of granulation tissue present across the wound bed. Typically, patients were evaluated at baseline, day 7 (1 week), day 14 (2 weeks), day 28 (4 weeks), day 42 (6 weeks), and day 56 (8 weeks), ± 4 days for each visit. Table 2 illustrates the change in wound size and increase in the presence of granulation tissue observed at each time point.

An example of wound progression can be seen in Figure 1, where the decrease in wound size and formation of granulation tissue is apparent.

Hyaluronic acid in wound repair
Hyaluronic acid plays a multifaceted role in all stages of wound healing. The wound tissue in the early inflammatory phase of wound repair is abundant in HA, which is a reflection of increased synthesis.⁸ Hyaluronic acid enhances cellular infiltration⁸ and assists in the mobilization of important proinflammatory cytokines such as tumor necrosis factor alpha and interleukin 8.¹²

The early stage of granulation tissue is dominated by a HA-rich ECM. During the formation of granulation tissue, locally produced HA facilitates cell proliferation and migration into the provisional wound matrix. Hyaluronic acid also plays a major role in the organization of the granulation tissue matrix, with RHAMM probably being the most influential receptor.¹⁰

Stabilization of the granulation tissue matrix occurs at a somewhat later stage. Hyaluronic acid stabilizes the matrix by scavenging free radicals¹³ with proinflammatory cytokines,¹⁴ preventing destruction of the ECM. Finally, at the proliferation stage of wound healing, HA sustains basal keratinocytes, both with regard to cellular support and regulation.⁸

Hyaluronic acid ester
In mammals, the half-life of HA in different tissue ranges from < 24 hours to several days.¹⁵ Esterification changes the physical properties of HA and prolongs its half-life based upon the level of esterification. Semisynthetic polymers¹⁶ allow for esterification on different levels, resulting in products with different half-lives. With this ability, new classes of HA-derived biopolymers, also known as HA ester), have been created. Hyaluronic esters have controllable degradation rates that can be optimized depending on the medical indication. The biopolymers can be produced into a variety of physical forms, such as meshes and perforated membranes, while maintaining the safety profile of native HA. All HA-based products in this case series are HA ester-based compounds.

The EHAM is a bilayered dermal matrix comprised of a wound contact layer made of hyaluronic acid ester with an outer barrier layer comprised of a semipermeable silicone membrane (Figure 2). The dermal matrix contact layer is biodegradable and creates a 3-dimensional scaffold for cellular invasion and capillary growth. The outer silicone layer controls water vapor loss, provides protective coverage of the wound, and adds increased tear strength to the device. The EHAM product is a 510(k) cleared medical device and CE-marked (known as Hyalomatrix PA) as a dermal substitute for the management of different types of partial- and full-thickness wounds. Examples of clinical indications include second-degree burns, ulcers (pressure, venous, diabetic, chronic vascular), tunneling/undermining and draining wounds, surgical wounds (donor sites/grafts, post-Mohs micrographic surgery, post-laser surgery, podiatric surgery, wound dehiscence), and trauma (abrasions, lacerations, skin tears).

Review of current literature
Hyaluronic acid was first described as part of wound healing in the 1930s.¹⁷ There are numerous laboratory, animal, and human studies published reviewing the positive effect of HA on healing chronic wounds. In tests on physical and chemical properties of the esterified HA materials, HA ester was found to be beneficial as a scaffold for tissue engineering.¹⁸ The material was shown to form a weak gel network. This change in rheological properties (vs. native HA), in combination with improved elasticity and residence times, was stated to provide an expansion of the possible applications of HA in the biomedical field.¹⁹ The results of this theoretical analysis have been confirmed in a series of experiments with mammalian (including human) cells and tissues.^20-31

Preclinical studies
Several cell culturing studies have demonstrated the importance of HA in the wound healing cascade. Hyaluronic acid ester was used as a scaffold for culturing murine mesenchymal stem cells.^20,21 The scaffold was shown to support the adhesion, migration, and proliferation of the stem cells, as well as the synthesis and delivery of ECM components.^20,21 This finding demonstrated the ability to attract and produce cells necessary for the propagation of wound healing. Stark et al²² demonstrated an improved stabilized in vitro model for long-term growth and differentiation of human keratinocytes by combining collagen hydrogels reinforced by modified HA fibers. The authors stated that this scaffold-based substrate not only allows for studying homeostasis control but also, for the first time, provides proper experimental conditions for establishing a stem cell niche in vitro.²² Additionally, endothelialized skin was prepared successfully by culturing keratinocytes, fibroblasts, and endothelial cells obtained from human full-thickness skin samples in scaffolds produced from HA ester.²³ The in vitro engineered skin developed into a well-differentiated upper layer of stratified keratinocytes that lined a dermis-like structure in which fibroblasts, ECM, and a microvascular network were present. The ultimate goal is the for the aforementioned successful in vitro models to translate into in vivo wound healing supplementation.

Animal model studies
The wound healing attributes of 5 acellular dermal skin substitutes — Integra Matrix Wound Dressing (product A; Integra LifeSciences, Inc, Plainsboro, NJ), ProDerm (product B; Laboratoire Genevrier, Antibes Juan les Pins, France), Renoskin (product C; Symatese, Chaponost, France), MatriDerm (product D; MedSkin Solutions, Billerbeck, Germany) 2 mm, and the EHAM product — were compared in a porcine wound model in a prospective randomized study.²⁴ Full-thickness lesions were created and dermal substitutes were implanted. An autologous split-thickness skin graft (STSG) was applied on postoperative day 21 after removal of the silicone top layer of the matrix (if applicable). Wounds were followed-up for 2 to 6 months. Results showed significant differences between groups in dermis incorporation and in early wound contraction, but at 2- and 6-months post grafting, no difference was observed with regard to wound contraction and quality of the scar (pliability, height, vascularity, pigmentation).²⁵ However, in this study, all dermal components were grafted on day 21 post application; the authors commented that product D and the EHAM could be grafted earlier and that this might have made a difference with regard to the final results.

Myers et al²⁶ applied the EHAM to the wound bed of full-thickness burns on miniature pigs and removed it in subsequent weeks. The EHAM appeared to support keratinocyte grafting by providing a temporary epidermal barrier, delivering HA to the wound bed, and inducing neodermis formation. The silicone top layer of the dressing was found to assist in limiting wound bed colonization.²⁶ A separate but similar study by a different group²⁷ used the same experiment but with a follow up of 5 months. This study demonstrated similar results with an improved dermal wound bed in the presence of the EHAM. The optimal pretreatment time was 2 weeks after induction of the injury with 2 applications of the EHAM at weekly intervals.²⁷

Human studies
Human wound studies have demonstrated success in improving patient outcomes. A brief review of wound healing studies subdivided into clinic scenarios is presented.

Use of HA for traumatically induced wounds. In a prospective trial, Vaienti et al²⁸ evaluated full-thickness traumatic wounds in 15 patients treated with the EHAM. Eight wounds were on the lower limbs and 7 on the upper. The average size of the lesions was 104.4 cm² (range, 6 cm²–490 cm²). Two wounds had tendon and bone exposure, 10 only had tendon exposed, and 3 lesions had no exposed bone or tendon. Wounds were surgically excised and/or debrided, after which the dermal matrix was applied and sutured into place.²⁸ On postoperative day 15, the silicone top layer of the EHAM was removed and, when indicated clinically (depending on the level and type of granulation tissue present in the wound bed), a second application was used. A STSG was used for final closure in 5 cases (33.3%). The assessment of the quality of the new skin was optimal/normal for 5 cases (33.3%), good in 7 (46.7%), and moderate in 3 (20.0%). The mean time to complete healing was 26.8 days (range, 16–60 days). All patients went on to successful repair with 6 patients requiring a second application of the EHAM and 5 (33.3%) needing STSGs.²⁸

Secondary healing following skin loss. Onesti et al²⁹ evaluated 20 patients with an average age of 73.6 years (range, 20–90 years). All had a skin lesion due to the surgical excision of different types of skin malignancies (ranging from basal cell carcinomas to melanomas). The average wound size after excision was 6.5 cm² ± 6.4 cm². Primary closure of the lesion (ie, with the use of flaps) was considered contraindicated in their patients. After excision, the lesions were covered with the EHAM, and wound inspection took place every 3 to 5 days. At 3 weeks postop, the wounds in 9 patients (45%) showed such improvement (level of reepithelialization) that grafting was not deemed necessary and the EHAM was applied again until healing was complete. In 11 patients (55%), a proper dermis-like wound bed had developed and wounds were closed with a STSG. In 2 patients, dermal regeneration was insufficient; these patients received a second application of the EHAM.

Nicoletti et al³⁰ assessed skin properties after reconstruction of skin loss, comparing product A and the EHAM as dermal templates. Twenty-seven patients (10 males, 17 females; mean age, 62.85 years [range, 15–88 years]) underwent reconstruction of 36 skin-loss sites with either a full-thickness skin graft (n = 7), a STSG (n = 10), (fenestrated) EHAM and sequential STSG (n = 8), or product A and sequential STSG (n = 11). Anatomical areas included the head (n = 19), trunk (n = 7), upper limbs (n = 5), and lower limbs (n = 5). Split-thickness skin grafting was performed based on the clinical appearance (regenerated tissue growth) of the matrix/wound bed. For the EHAM, this occurred, on average, 19 days after the excision (range, 13–27 days). For product A-treated lesions, the average “waiting period” was 25 days (range, 15–45 days). There was no statistically significant difference among the 4 treatment methodologies. The EHAM had the best approximation (to normal skin) with regard to corneal hydration, transepidermal water loss, and hemoglobin and melanin index, while none of the closure techniques matched normal skin with regards to colorimetry. The EHAM-treated wounds demonstrated better cell regulation and stimulation activity, with subsequent production of a better regenerated ECM, while product A-treated wounds allowed the formation of a more elastic-regenerated dermis, with overall better physical, mechanical, and optical properties. Unfortunately, due to the small number of patients, the study³⁰ was underpowered to establish statistical significance.

A multicenter, prospective, noncomparative, observational study by Caravaggi et al³¹ evaluated patients with different types of wounds that were treated with the EHAMsubsequent to standard wound care. Two hundred sixty-two mostly elderly patients (mean, 70 years; range, 33–103 years) participated in the trial. Of those, 121 (46.2%) lesions were vascular (of which 50% were venous, 15% arterial, and 35% arterial/venous) and 66 (25.2%) were DFUs (of which 56% were neuroischemic, 27% ischemic, and 17% neuropathic) in origin. Five wounds (1.9%) were pressure ulcers, 39 (14.9%) were classified as “other” (eg, vasculitis, iatrogenic ulcers), and 31 (11.8%) were traumatic in nature.³¹ Of all ulcers, 31% were < 15 cm², 44% were between 15 cm² and 50 cm², and 25% were > 50 cm². In 64% of all cases, the ulcers were partial-thickness, 24% had exposed tendons and/or bones, and 12% involved bones and joints. All wounds had been present for more than 2 months without a healing response; 45% had a duration of < 6 months, 19% between 6 and 12 months, and 36% were > 1 year. The presence of a clinical infection was the only exclusion criterion. The main endpoints of the study were coverage of the lesion with healthy dermal tissue, suitable for autografting, or until the growth of new epithelium was enough evidence for allowing healing by secondary intention. Wounds were surgically debrided and covered with the EHAM. The matrix stayed on the wound for a period of 8 to 15 days until it clinically incorporated into the wound. Nonadherent dressings were changed weekly if clinically indicated. The median number of EHAM applications was 2. Compression was used for VLUs and offloading for DFUs. Reepithelialization of 10% of the original surface of the lesion (the threshold value) occurred in 83% of ulcers in a median time of 16 days (range, 10–26 days), while 26% of wounds achieved 75% reepithelialization within the maximum follow-up period of 60 days. Long-term follow-up showed that, of the total 262 wounds, 220 (84%) healed completely by secondary intention. In a population of mostly elderly patients, many of whom were suffering from multiple comorbidities, and including patients being treated with steroids and other immunosuppressive and cytotoxic medications, the EHAM largely was effective for all wound etiologies and wound types, including many large and full-thickness chronic wounds.³¹

Hypertrophic scar, scar contracture, and keloids
Erbatur et al³² described 10 patients with mature hypertrophic scars or keloids and 10 patients with full-thickness soft tissue loss (secondary to burns, trauma, or excision). In both groups, after excision, the EHAM was applied and sutured. In the nonelective soft tissue loss surgery group, silver sulfadiazine 1% cream was used over the matrix. The EHAM was left in situ for 28 days, after which a split-skin autograft was applied. In the full-thickness skin loss group of patients, no hypertrophy or keloid was observed. Skin biopsies demonstrated collagenization scores of preoperative skin biopsies and were significantly higher than 3-month postoperative scores (P < .0001), while vascularization scores of preoperative skin biopsies were significantly lower than postoperative scores (P < .00001). The authors³² concluded that the use of HA ester provided the desired clinical healing in the 6-month follow-up period and stated that HA application as an alternative to other treatment modalities led to a durable skin coverage in full-thickness tissue loss in adult patients. Since hypertrophic scars, keloids, and significant scar contractures are due to a defect in the dermal layer,^33-35 this study³² strongly indicated the use of EHAM may create a more anatomic neodermis to prevent abnormal dermis formation.

Faga et al³⁶ performed elective reconstructive plastic surgery on 6 consecutive patients with an average age of 42 years (range, 6–60 years) and with a total of 11 mature contracted scars that were contraindicated clinically for more extensive reconstructive interventions such as skin expansion or flap surgery. After excision of the contracted scar, the EHAM was applied and sutured to the wound. At postoperative day 6, sutures were removed and, on average, on day 19 (range, 13–27 days) an autologous STSG was applied. Biopsies were performed at least 3 weeks after grafting. Clinically, stable skin coverage of the lesions was observed in all of the treated wounds at the 1-month (post grafting) period and at 12-month follow-up, though the authors³⁶ note an average retraction rate of 51% to 62% at that time. Histological observation and immunohistochemical analysis displayed integration of the graft within the surrounding tissues. The authors stated that the EHAM proved to be a good and reliable dermal substitute, promoting the regeneration of a skin-like tissue, clinically and histologically better than scarred skin, though still unable to control the eventual collagen contraction.³⁶

Desyndactyly
In a paper hoping to improve clinical results following desyndactyly, Landi et al³⁷ released 26 webspaces in 23 patients (14 boys, 9 girls; mean age, 50 months [range, 6–116 months]). Surgery was performed without grafting to fill the skin defects, since grafting may lead to complications such as web creep,³⁸ secondary deformities, and poor scar formation. Instead of grafting, the defects were covered with EHAM. All patients healed by postoperative day 31 and were followed for 24 months. No secondary lateral, rotation, or flexion deformities were noted at follow-up, and there was no hypertrophic scar or keloid formation. All patients had close to normal pigmentation and normal to good pliability. All patients and parents were satisfied by the avoidance of skin grafts.³⁷

Diabetic foot ulcers
Caravaggi et al³⁹ looked to limit the level and severity of amputations in patients with severely infected DFUs and critical limb ischemia. All 23 patients required excision of infected soft tissue as well as bone. The type of amputations performed were transmetatarsal (n = 3), Chopart (n = 5), partial calcanectomy (n = 8), and forefoot/ray (n = 7). Wounds were left open and treated with the EHAM. On day 21 following application, the top silicone layer of the matrix was removed. Complete coverage of the exposed cancellous bone was reached in 21 of 23 patients in a period of 28 ± 17 days of treatment. The study did not meet the primary endpoint of preventing more proximal amputations in patients with severe ischemia. However, the results demonstrate rapid post amputation dermal repair in wounds with exposed bone and a complete healing percentage of 43% of all post amputation lesions in severely infected and ischemic wounds.³⁹

Uccioli et al⁴⁰ completed a prospective, comparative study comparing a 2-step, HA ester product-based approach compared with standard care (offloading, nonadherent dressing) in the treatment of Wagner grade I or II DFUs. The ulcers enrolled were ≥ 2 cm² in size. One hundred sixty patients with dorsal or plantar DFUs (unhealed for ≥ 1 month and 8.8 cm² ± 9.4 cm² in size) were randomized to receive Hyalograft-3D (Anika Therapeutics Inc, Bedford, MA) autograft, followed by Laserskin (Anika Therapeutics Inc) autografts after 2 weeks (N = 80; treatment group; average age, 61 years) or nonadherent paraffin gauze (Jellonet; Smith & Nephew, Hull, UK) (N = 80; control group; average age, 62 years). At 12 weeks, complete ulcer healing was similar in both groups (24% treated vs. 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group than the control (mean, 40 vs. 50 days, respectively; P = .018), while the weekly percentage of ulcer reduction also was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treatment group as compared with 43% of controls. Ulcers had a 2.17-times better chance of wound healing per unit time after grafting with the treatment product (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of DFUs (P = .035). The study results demonstrated the potential of this bioengineered substitute to manage hard-to-heal dorsal DFUs.⁴⁰

In a study⁴¹ of 36 patients (26 men, 10 women; average age, 60.0 ± 10.7 years), Vasquez et al debrided 36 DFUs, then applied a HA-containing material (Hyalofill; Anika Therapeutics, Inc). The lesions measured 2.2 cm² ± 2.2 cm². Dressings were changed every other day until the lesion was completely covered with granulation tissue, then the dressing regimen was changed to an occlusive dressing. Seventy-five percent of the lesions healed with a 20-week evaluation period. Of those that healed in this period, healing took place in a mean of 10.0 ± 4.8 weeks. The average duration of the HA-containing material therapy in all patients was 8.6 ± 4.2 weeks. The authors⁴¹ concluded that use of the HA ester dressing to generate granulation tissue, followed by occlusive treatment, may be a useful adjunct to appropriate DFU care.

Venous leg ulcers
In a multicenter trial by Motolese et al,⁴² 16 elderly patients (7 males, 9 females; average age, 77 years; range, 64–88 years) with large venous ulcers underwent EHAM grafting for reconstructive surgery, with the average area grafted per procedure measuring 153 cm² (range, 55 cm²–275 cm²). Wounds were treated with the EHAM and regularly assessed. In 12 patients (75%), the EHAM application was followed by (autologous) skin grafting. After a 6-month follow-up period, no recurrences were observed in 15 patients. In 1 patient (6%), complete closure never occurred, but a reepithelialization rate of 70% was achieved. The final results (at 6 months–1 year) were considered to be good in 12 cases, fair in 3, and poor in 1.

There are several limitations to this study. The first limitation is that this is a case series and not a randomized, controlled study. Essentially, the primary exclusion criteria were the presence of significant comorbidities or concomitant intervention with another biologic modality. There was no direct comparison to a control group. The authors did not attempt to provide either a matched or unmatched control for this study because they felt the sample size was too small to provide a statistically valid comparison. The objective was to review the use of HA-derived treatments and demonstrate its use on patients with diabetes and chronic foot ulcers. Future studies will be designed to make this direct comparison. The case series allows exposure to a broader group of real-world patients. The second limitation is that the follow-up time was only 8 weeks. Therefore, only 1 wound had time to close completely. Clearly, a longer period of follow-up is essential to gauge closure and recurrence rates in this patient population.

Although there is no control for comparison, a recent large meta-analysis publication⁴³ indicated treatment of foot ulcers in people with diabetes using biologics resulted in an improvement in healing rates over treatment with standard of care and the difference was statistically significant. Though HA was not analyzed specifically as an ingredient in any of the biologics examined in this study,⁴³ HA is a component in most of the connective tissue-derived biologics discussed here.⁴³

Anecdotally, the present authors clearly observed progression of healing when the EHAM was used to treat the wounds in this case series. The authors attribute this in part to the idea of dynamic reciprocity, due to the fact that HA plays a critical role in so many aspects of wound healing.¹¹

In the present study, the authors found that the EHAM worked best with mild to moderately exudative wounds. Wounds with a significant amount of drainage will require fenestration of the silicone layer, more frequent EHAM dressing changes, and/or hydrocolloid outer dressings.

In the present study, the authors found that HA is a viable option for dermal wound healing; it works as a substrate to promote production of ECM. With appropriate offloading and local wound care, dermal-thickness wounds can epithelialize via secondary intention or act as a wound bed for a STSG. Numerous animal and clinic trials have shown that HA is equivalent or superior to standard of care in the treatment of wounds. Thus, HA is another adjunct to help heal difficult wounds.

Authors: Harry P. Schneider, DPM; and Adam Landsman, DPM, PhD

Affiliation: Cambridge Health Alliance, Harvard Medical School, Cambridge, MA

Correspondence: Harry Schneider, DPM, Podiatric Medicine and Surgery Residency Director, Cambridge Health Alliance, Department of Surgery, 1493 Cambridge Street, Cambridge, MA 01867; hschneider@cha.harvard.edu

Disclosure: Dr. Schneider is on the Speakers Bureau of Osiris Therapeutics, Inc (Columbia, MD). Dr. Landsman is on the Speakers Bureau of Medline Industries (Northfield, IL), a Key Opinion Leader of Soluble Systems Key (now Solsys Medical, Newport News, VA), Chief Medical Officer of Kent Imaging (Calgary, Alberta, Canada), and a member of the Board of Directors of LifeNet Health (Virginia Beach, VA).