Preclinical and Clinical Studies of Hyaluronic Acid in Wound Care

A Case Series and Literature Review

Harry P. Schneider, DPM; Adam Landsman, DPM, PhD


Wounds. 2019;31(2):41-48. 

In This Article

Abstract and Introduction


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.


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 al[4] 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 research[4] 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]