Tissue-Engineered Approaches for Complex Wounds: A Case Series Using Esterified Hyaluronic Acid Matrix

Robin Evans¹, William Starr¹, Shreyash Pradhan¹, Javier Romero¹, Graal Diaz¹

1. Anacapa Surgical Associates Ventura County Health Care Agency 300 Hillmont Ave., Ventura, CA, USA, 93003
2. Graduate Medical Division Community Memorial Healthcare System 147 N. Brent St., Ventura, CA, 93003

OPEN ACCESS

PUBLISHED: 31 August 2025

CITATION: Evans, R., Starr, W., Prahdan, S., et al. Tissue-Engineered Approaches for Complex Wounds: A Case Series Using Esterified Hyaluronic Acid Matrix. Medical Research Archives, [online] 13(8).
https://doi.org/10.18103/mra.v13i8.6614

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v13i8.6614

ISSN 2375-1924

Abstract

Tissue specific injuries are difficult to heal and costly to treat. Current solutions are often insufficient to heal complex wounds. Tissue engineering for acute wounds is a new approach. Tissue engineering focuses on regenerating tissue based on the use of biologic scaffolds and cell signaling. Normal wound healing is a dynamic, multiple-phase process that requires coordinated interactions between inflammatory factors, growth factors, angiogenesis, and collagen formation. New technologies use a tissue engineering approach to ensure a smooth transition between the phases of wound healing. If an acute wound fails to progress through normal healing, the phases can become chronic.

Keywords

Tissue engineering, complex wounds, hyaluronic acid, wound healing, scaffolds.

Introduction

Complex soft tissue injuries are difficult to heal and costly to treat. Current solutions are often insufficient to heal complex wounds. Tissue engineering for acute wounds is a new approach¹. Tissue engineering focuses on regenerating tissue based on the use of biologic scaffolds and cell signaling. Normal wound healing is a dynamic, multiple-phase process that requires coordinated interactions between inflammatory factors, growth factors, angiogenesis, and collagen formation². New technologies use a tissue engineering approach to ensure a smooth transition between the phases of wound healing. If an acute wound fails to progress through normal wound healing phases, it can become a chronic wound³.

For example, negative wound pressure therapy has gained popularity because of its effects on angiogenesis⁴. Through inducing angiogenesis, the time to healing is improved, and chronic wounds have been shown to develop healthy granulation tissue⁵. However, negative wound pressure dressings require specialized care, and significant community support structures unavailable to many patients. As well, stimulating angiogenesis is only one component of successful wound healing. As such, a new tissue engineering approach is required to treat a wider variety of wounds at all stages.

Hyaluronic Acid (HA) has become a recent focus of interest. HA is a critical component in healthy skin⁶. HA is a non-sulfated glycosaminoglycan (GAG) found in the extracellular matrix of the skin and soft tissue. It is comprised of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic β (1–3) bond⁷. Depending on the HA size, salt concentration, pH, and associated cations, HA has a different physiologic effect⁸,⁹.

HA is a key component in successful wound healing¹⁰, as it modifies cell signaling. HA is involved in several different roles. Immediately after injury, hemostasis needs to occur. To accomplish this, high-molecular-weight hyaluronic acid (HMW-HA) is released from platelets. HA recruits neutrophils to perform phagocytosis of debris and dead tissue and release tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-8¹¹. HA has also been shown to interact with the toll-like receptors (TLR2 and TLR4) on lymphocytes and macrophages¹²,¹³. Fibronectin and HA help to guide fibroblasts to the wound¹⁴ and support the formation of type III collagen and a new ECM¹⁵. HA has also been noted to have a role in scarless, fetal wound healing¹⁶.

Uniquely, HA also has excellent properties as a scaffold. Esterified HA has been developed to utilize this characteristic¹³,¹⁷. Esterification allows for improved hydrophobicity and reduces HA degradation¹⁸. The electrospun membrane of esterified HA is covered with silicone sheeting. Currently marketed as Hyalomatrix by Medline, this esterified hyaluronic acid matrix was initially used to treat burns¹⁹. The objective of the current study is to review our current experience to determine future research directions.

Methods:

This was a single-center, prospective case-series conducted at a Level II trauma center over 16 months (February 2021 to September 2022). Eligible participants were consecutive adults aged 18 years or older treated with eHAM for wounds during the study window; exclusions included use of eHAM outside the study indications, incomplete medical records preventing key data extraction, or loss to follow-up before healing could be ascertained. Intervention details followed the manufacturer’s protocol and local practice, with documentation on whether eHAM served as the primary modality or an adjunct, frequency of dressing changes, device settings, and any adjunctive therapies (debridement, antibiotics, negative-pressure therapy, grafting) with timing relative to eHAM. Clinician training adhered to institutional guidelines, and deviations from the protocol were recorded. Data were abstracted.

from the electronic medical record and wound-care logs by trained staff using a predefined form and data dictionary. Quality assurance included double data entry for critical fields and regular source-note verification with adjudication of discrepancies. Variables collected encompassed demographics and wound characteristics (location, mechanism, injury date, size in cm2, depth, prior treatments, skin grafting dates and type, dates of eHAM applications and re-applications). Outcomes included the primary time to wound healing (defined as complete epithelialization with no drainage) and secondary outcomes such as percent wound size reduction, need for grafting, complications, and days to milestones. Follow-up extended from the first eHAM application to healing or last contact. Wound size and depth were measured using standardized methods; clinicians determined healing. Statistical analyses used SAS 9.4. Descriptive statistics described variables; time-to-event analyses employed Kaplan-Meier estimates with median time to healing and 95% CIs, and bivariate tests for subgroup comparisons. The study received IRB approval, with no external funding.

Figure 1. Participants by gender

Table 3 provides the overall picture: mean age was 52.25 years (SD 23.44). Time from wound onset to first eHAM averaged 27.4 days (SD 26.4). Initial wounds averaged 244.6 cm2 (SD 562.1), with post-first-eHAM wounds averaging 187.6 cm2 (SD 448.1) and a mean delta of −56.99 cm2 (SD 12.46). The mean percent decrease after the first eHAM was 30.47% (SD 25.76), and the time from eHAM to healed averaged 69.1 days (SD 36.5).

Table 4 describes treatments: all patients received a first eHAM, eight (66.7%) received a second, and three (25%) a third. First skin grafts were performed in 7 patients (58.3%), with a second graft in 5 patients (41.7%).

Discussion:

The development of eHAM. Tissue engineering is an emerging interdisciplinary field that applies principles of bioengineering and life sciences to develop substitutes that guide tissue regeneration. Langer and Vacanti²⁰ categorized three components that govern the outcome of tissue-engineered constructs: scaffolding, instructive environment, and responsive cells. Tissues are engineered in one of two ways: fabricated matrices or the use of cultured human epithelial cells. In the 1980s, the replacement of skin with cells in collagen-glycosaminoglycan scaffolds to facilitate tissue formation was gaining traction. Burke et al.²¹ successfully used porous collagen-chondroitin fibrillar dermis to physiologically promote wound healing in burn patients. Most of the early foundations of tissue engineering relied on the use of human cell cultures.

The development of cultured human epithelial autografts (CEA)²² was a major advance in tissue engineering. However, cultured autografts were found to be fragile and expensive²³. The dermal-epidermal junction requires a biocompatible scaffold to help these cells grow effectively. Hyaluronic acid was a biocompatible molecule and potential scaffold for CEA. Initially, the ethyl and n-propyl esters of hyaluronic were used to create a polymer film and show the biocompatibility of the approach²⁴. Zacchi et al.²⁵ cultured fibroblasts and keratinocytes on a non-woven scaffold of a benzylester of hyaluronic acid to re-create the epidermal-dermal junction seen in normal skin. Galassi et al.²⁶ used this approach to show an increase in the reconstruction of autologous ECM in both acute and chronic wounds.

Biodegradable temporizing matrices (BTM) have gained popularity in the treatment of acute burn wounds. Early burn debridement has been shown to improve outcomes²⁷–³¹. However, the extent of debridement can be limited by the availability of skin graft donor sites, especially in large burns. BTM such as eHAM provides alternatives for early coverage. Gravante et al. demonstrated eHAM use in deep partial thickness³² and full thickness¹⁸ burn patients. Some of these patients went on to heal without skin grafting. A silicone sheet bilayer in these patients theoretically improves fluid loss and granulation tissue formation monitoring. Osti and Enzo³³ found an improvement in wound pH after eHAM application, suggesting improvement in burn healing through alteration of cell signalling. Specifically, it appears that hyaluronic acid plays a role via specific HA receptors, inflammation, cellular migration, and angiogenesis³⁴.

The clinical use of eHAM for complex wounds. Even complex wounds benefit from eHAM application. Complex wounds include wounds with exposed bone, tendon, or other difficult-to-heal clinical situations such as diabetic foot wounds. These unique wounds pose a challenge to any clinician. Notably, the exposure of tendon or bone can lead to tendon necrosis and osteomyelitis, respectively. Ultimately increased delayed healing, morbidity, and mortality. As well, there are often limited dressing and clinical options. A skin graft does not have the ability to take without a blood supply from its recipient site and a local, regional, or free flap is often required. Although negative wound pressure therapy (NWPT) has been successfully employed in the treatment of complex wounds³⁵, it is painful, expensive, and requires a bulky machine to be attached to the wound at all times.

Figure 4. Full thickness skin loss of calf after cast removal for a closed tibial fracture: A. Eschar managed with Silvadene dressing (20 cm × 8 cm); B. Sloughed off eschar; C. Calf after removal of eHAM for 3 weeks (14.5 cm × 6 cm); D. Calf 60 days after eHAM application.

Liu et al. illustrated the effectiveness of eHAM in patients with exposed tendon or bone from trauma, chronic wounds, diabetic foot wounds, and burns³⁶. In this series, eHAM was used for approximately three weeks and followed by coverage with split-thickness skin grafting. However, multiple applications of eHAM have also been used. Vaienti et al. has shown that multiple applications of eHAM improve wound healing outcomes³⁷. This includes healing by secondary intention and preparation for skin grafting.

The primary therapeutic aim of esterified hyaluronic acid matrix (eHAM) in complex wounds is to induce the formation of a neodermis—a dermal-like, organized tissue that serves as an integrative bed for subsequent healing steps. This neodermis was first identified through work by Myers and colleagues, who described a distinct

issue resulting from the interaction of the eHAM scaffold with host tissue. The neodermis forms as a product of HA signaling within the matrix, promoting a cascade of cellular events that culminate in a highly vascularized, structurally organized layer that more closely resembles native dermis than conventional granulation tissue.

Histologically, the neodermis appears more organized and vascular than typical granulation tissue, with Aballey and colleagues reporting that the dermal characteristics within the neodermis resemble those of normal skin dermis. The extended vascular network supports robust perfusion and nutrient delivery, which is particularly important in wounds with exposed structures such as tendons and bones, where a stable, well-vascularized bed is essential for protection and healing. The neodermis thus provides a durable, scaffold-like foundation that accommodates re-epithelialization and enhances graft take, enabling skin grafts to adhere and integrate more reliably and potentially reducing the need for more complex flap coverage in some cases.

In essence, eHAM’s value lies not only in temporary wound coverage but in actively guiding tissue remodeling toward a dermal substitute that supports stability, vascularity, and subsequent epidermal regeneration. While the precise extent and kinetics of neodermis formation can be influenced by factors such as infection, perfusion, and patient comorbidities, the concept underscores how HA-based matrices create a dermal analogue that bridges the gap between the wound bed and definitive closure.

Conclusion:
Our experience demonstrates that the electrospun non-woven esterified hyaluronic acid matrix (eHAM) is a valuable tool in the treatment of complex wounds. The nanofibrous scaffold provides increased opportunities for cell adhesion and growth. Matrix revascularization allows for healing by secondary intention or coverage with a skin graft. In our study, many patients were able to heal using eHAM therapy alone. Clinical benefit was demonstrated after the first eHAM application, where wound size was markedly reduced for all patients. Multiple eHAM applications showed improved efficacy in larger wounds. Further investigation will allow us to improve our tissue engineering paradigm to optimize outcomes for patients with complex wounds.

Conflict of Interest:
None.

Funding Statement:
This study did not receive funding. Dr. Evans is a member of the Advisory Board of True Digital Surgery, and the rest of the authors have nothing to disclose.

Acknowledgements:
None.

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