Hyaluronic Acid-Based Products Are Strictly Contraindicated in Scleroderma-Related Skin Ulcers

Giulio Gualdi, MD; Paola Monari, MD; Daniele Cammalleri, MD; Laura Pelizzari, MD; Piergiacomo Calzavara Pinton, PhD


Wounds. 2019;31(3):81-84. 

In This Article

Abstract and Introduction


Introduction: Evidence of the role of hyaluronic acid (HA) in the tissue repair process is extensive. Hyaluronic acid produces a positive effect on skin ulcer healing, so many companies produce it in various topical applications.

Objective: This retrospective, observational study examined the use of different HA-based products in patients with chronic skin ulcers of various etiologies (vascular, scleroderma, postoperative) to assess the indication, effectiveness, and possible adverse reactions.

Materials and Methods: A retrospective case review was conducted on 79 patients presenting to the Department of Dermatology of the Spedali Civili (Brescia, Italy) with multiple chronic skin ulcers of the legs of various etiologies. The authors counted a total of 106 chronic wounds with granulating appearance but not responsive to common wound dressings; for this reason, these wounds were treated with a HA-based product. The efficacy of the treatment was evaluated by dividing the population into 2 groups: sclerodermic (41 ulcers) and nonsclerodermic (65 ulcers).

Results: Initial results confirmed HA-based products were effective for healing chronic skin wounds. However, when wounds are grouped by etiology, it was evident that patients with sclerodermic ulcers showed a rapid inflammatory response that led to a clinical deterioration and worsening of skin ulcers (92.7%). In contrast, patients with noninflammatory ulcers (vascular, postoperative) had the severe inflammatory event reduced to 1.5%, with a recovery of 98.5%. Conclusions. The negative effects of HA-based products on a patient with scleroderma could be explained by the fact that HA can produce a proinflammatory effect causing keratinocyte migration.


Evidence of the role of hyaluronic acid (HA) in the tissue repair process is extensive. It is well known that HA is produced by various cell types at different stages of their life cycle and that it performs many functions within the wound healing process due to its polysaccharide structure in the extracellular matrix (ECM).[1] As a glycosaminoglycan of the ECM that is normally produced by mesenchymal cells, HA is strongly elevated during embryogenesis and tissue injury inflammation and repair as well as in tumor invasion and metastasis. Hyaluronic acid is closely involved in keratinocyte migration and may act positively upon endothelial and fibroblast cells through the adhesion molecule CD44.[1,2] Due to hygroscopic, rheological, and viscoelastic properties, HA influences the surrounding extracellular environment through complex molecular interactions with both cellular and matrix surface receptors.

Hyaluronic acid exists in 3 forms based on molecular weight that act in different directions on tissue.[3] Higher molecular weight HA (1000 kDa) has an anti-angiogenic effect.[4] Intermediate-sized HA oligomers (200 kDa) are involved in tissue repair through an inflammatory effect; in fact, they stimulate the expression of inflammatory chemokines, macrophages, eosinophils, endothelial cells, and epithelial cells.[3] Finally, lower molecular weight HA fragments (20 kDA) stimulate dendritic cells and upregulate both collagen I and III gene expression in fibroblastic cells.[3] Due to its biocompatibility, HA has found wide use in the medical and cosmetic fields, including the healing of chronic skin wounds. It appears that HA produces a positive effect in the healing of chronic skin ulcers of various etiologies such as venous leg ulcers, burns, and postsurgical wounds.[5,6] Many companies produce HA in various topical applications, including pads, creams, and substrates, as HA has been shown to improve healing time. Hyaluronic acid also has been shown to exhibit an important analgesic effect on pain that influences patient quality of life.[7]

Indeed, chronic wounds significantly decrease quality of life in a number of ways, such as reduced mobility, pain, unpleasant odor, sleep disturbances, social isolation and frustration, and inability to perform everyday duties.[8] Psychological factors may not only be a consequence of delayed healing but also may be influenced by choosing the right treatment between the variety of products on the market.

The authors conducted a retrospective observational study on the use of HA-based products, prescribed in the year 2011, for patients with chronic ulcers of various etiologies (vascular, scleroderma, and postoperative) consecutively presenting to the Department of Dermatology of the Spedali Civili (Brescia, Italy) in order to assess indication, effectiveness, and possible adverse reactions.