Unique combination of hyaluronic acid and amino acids in the management of patients with a range of moderate‐to‐severe chronic wounds: Evidence from international clinical trials

Abstract

Chronic wounds present a prolonged burden to patients, their families and healthcare systems. There is evidence that the unique combination of hyaluronic acid (HA) and amino acids (Vulnamin®) promotes re‐epithelialization of wounds and stimulates activation and proliferation of fibroblasts with a significant increase in the regeneration of epithelial cells. Tissue regeneration and tissue repair are considered to be the fundamental activities of this unique combination of HA and amino acids that distinguishes it from other wound healing products. A review of trials over the last 15 years indicates distinct advantages of the unique combination of HA and amino acids, in terms of healing rate and induction of granulation tissue production compared with HA alone.

1. INTRODUCTION

Healthcare professionals universally agree on the urgent need to improve wound healing times, to prevent chronicity and if wounds do become chronic to instigate effective treatment strategies. ¹ Chronic wounds have devastating consequences both for patients and their carers as well as having major financial consequences for already overstretched healthcare systems. ² , ³ , ⁴ Health‐related quality of life (QoL) is systematically worse in patients with chronic wounds compared with those who receive effective treatment at the outset. In the United Kingdom, after adjustment for comorbidities, the annual cost of managing wounds is more than £4.5 billion, and the cost of treating pressure ulcers (PUs) alone, in the United States is over $11 billion per year. ¹ , ⁵

The already high prevalence of chronic wounds—in Europe there are 1·5–2 million people living with a chronic wound, while in the United States, around 6·5 million people have a chronic wound at any one time—is on track to increase further due to evolving demographic changes. ¹ , ⁶ People are living longer and they are more fragile, elderly people at increased risk of developing wounds, coupled with the fact that because hard‐to‐heal wounds are more common with comorbidities such as diabetes, obesity, immune system deficiencies, peripheral vascular disease and cardiopulmonary disease, means that there will be even higher numbers of people requiring treatment. A case in point is PUs (international prevalence rates range from 9% to 14%), associated with a range of health conditions that cause prolonged bed rest, can significantly contribute to morbidity and mortality, particularly in the aged population. Given that chronic wounds present a prolonged, yet avoidable burden to patients, their families and health systems, the development and implementation of wound management strategies that focus on increasing health related QoL and effectively reduce costs are urgently required.

Wound healing is a complex process that involves numerous cell types, cytokines, chemokines, growth factors and extracellular matrix components that work synergistically to heal. ⁷ There are several stages in the process: haemostasis, inflammation, proliferation and remodelling. Chronic wounds, defined as wounds not responding to therapy in 2–4 weeks, include diabetic foot ulcers, PUs and leg ulcers (LUs), venous/arterial LUs and ulcers of mixed aetiology. Two of the most common problems associated with chronic wounds are inflammation and infection, with the latter usually exacerbating the former. ⁸ Wound healing is often delayed at the inflammatory stage, with excess and persistent inflammation creating a hostile wound environment. Inflammation, while necessary and essential to effective healing, is however detrimental to healing when prolonged. ⁹

Nutrition is recognized as a key factor in wound healing and under stress conditions the metabolic demand for nutrients increases (cell proliferation and protein synthesis) and if not available, may slow down/stop the wound from healing. It follows therefore that wound healing can be enhanced by the addition of certain agents. ¹⁰ , ¹¹ , ¹² , ¹³

1.1. Role of hyaluronic acid and amino acids in wound healing

Collagen deposition, essential in wound healing, requires the production of collagen proteins which in turn requires the formation of collagen chains and successive proline and lysine residue hydroxylation. The availability of a pool of amino acids, those known to be involved in collagen synthesis, may improve, and accelerate wound healing. ¹⁴ In one study the addition of amino‐acid precursors of collagen were shown to promote and accelerate wound healing. A gel containing collagen precursor amino acids, sodium hyaluronate and polyvinylpyrrolidone increased fibroblast proliferative activity in cultures of human fibroblasts. ¹⁴ , ¹⁵

Hyaluronic acid (HA), composed of repeating units of D‐glucuronate and N‐acetylglucosamine, is the most important glycosaminoglycan produced by fibroblasts during wound and ulcer healing and seems to be able to promote cell proliferation, differentiation and motility, blood vessel location, as well as being involved in wound repair. ¹⁶ It is the hydrophilic properties of HA that seem to promote cellular migration while also protecting cells and extracellular matrix components through its free radical scavenging and protein exclusion properties. One of the recurring features of chronic wounds is that the inflammatory phase is prolonged due to the production of reactive oxygen species and enzymes such as proteases and matrix metalloproteinases. HA is found in connective tissue and participates in wound healing. One study reported improved wound healing in HA‐treated rats within 7 days. ¹⁷

1.2. Management of chronic wounds

The availability of new products and strategies to manage wounds has taken a quantum leap in recent years. Healthcare professionals now have an extensive range of products to choose from, but while positive this also raises dilemmas in real‐world clinical practice to decide on the most appropriate treatment for a given patient. To address this issue, an international group of experts convened a meeting to present and discuss their clinical experience in wound management in general and in particular with the use of the unique combination of HA and amino acids (Vulnamin®) in difficult‐to‐treat chronic wounds. The objective was to reach a consensus on how and when to utilize the combination to provide a cost‐effective, convenient option, in all healthcare settings that improves QoL for patients and their carers.

2. EVIDENCE FROM INTERNATIONAL CLINICAL TRIALS

There is evidence that the unique combination of HA and amino acids (that act as collagen precursors in wound healing) promotes re‐epithelialization of wounds and stimulates activation and proliferation of fibroblasts with significant increase in the regeneration of epithelial cells. Tissue regeneration and tissue repair are fundamental activities of this unique combination of HA and amino acids that distinguishes it from other wound healing products.

Initial evidence of the beneficial effects of this combination product was seen in preclinical animal models investigating its effects compared with HA alone (see Table 1). The unique combination product improved healing and wound closure when compared to HA alone. ¹⁸ In addition, large‐scale, multicentre trials in patients with a wide range of wounds provide substantive evidence of the effectiveness and good tolerability of this combination in different formulations (cream, gel, spray, powder). ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ One of the key issues in wound management is to effectively prepare the wound bed to improve granulation and promote re‐epithelialization. The combination of amino acids and HA reduces granulation and re‐epithelialization times, while providing debridement (see Table 1). This is vital in the wound healing process particularly in necrotic wounds. ²⁰

TABLE 1.

Evidence from clinical development programme with the unique combination of hyaluronic acid (HA) and amino acids.

Study	Methods	Outcomes
18	Preclinical animal model. Combination product versus HA alone.	Combination product superior to HA alone with improved fibroblast density as early as 24 h. At Day 3 healing was 16% greater. Wound closure was 30% and 70% greater at Day 5 and 10, respectively.
18	Prospective observational, multicentre (15 centres) clinical trial in 160 patients with a range of non‐infected cutaneous chronic wounds.	Overall, 76% (n = 120) achieved positive outcomes (defined as a > 40% reduction in the ulcer size). A significant mean reduction reported in primary outcome (change in ulcer area during the 6‐week treatment period), after 2 weeks and at 6 weeks compared with baseline and at follow‐up.
19	Randomized trial in 30 patients with diabetes LUs, comparing combination gel (+ compression) versus compression alone. Healing rate at 3 months primary endpoint, with secondary endpoints: healing time, reduction in ulcer area and ulceration score at 4 weeks, number of infective complications and overall patient satisfaction.	Oedema, and ulcer area significantly reduced in the combination gel groups with significantly (p < 0.05) higher ulcer healing at 12 weeks. Combination gel also improved healing time, patients' satisfaction. Reduction in ulcer area and ulceration score in 4 weeks also higher in patients receiving combination. No significant differences in the prevalence of infections and other adverse events.
20	Effectiveness of combination gel to debride and heal investigated in 40 patients with chronic necrotic wounds, who received either hydrogel containing HA plus amino acids versus hydrogel alone.	Wound area reduction significantly greater in group treated with combination product gel than with hydrogel alone (13% vs. 3%) with a significant presence of granulation tissue after 14 days only in those patients treated with the combination gel.
21	Effectiveness and safety of combination powder in treatment of chronic LUs investigated in 52 patients—one group received combination powder plus CA while control group received CA alone. Both groups received compression bandages.	Complete healing achieved in over 60% of patients treated with the combination powder and CA, and in 27% of those treated with CA alone. At 70 days, ulcer area reduced by 78% from baseline in the combination group compared with 28% in CA alone group. Combination product and compression is well tolerated and more effective in inducing faster healing in chronic LUs than standard dressing plus compression.
22	Effectiveness of the combination product in a spray format as a coadjuvant in the prevention of PUs investigated in large‐scale study in 500 patients at risk of developing bedsores (Norton score < 12).	In patients treated with combination spray, 213 (85.2%) improved, 11 (4%) worsened and 10% showed no change. In those treated with silver spray 60% of patients worsened (after 4 weeks compared to baseline), 25% had no change and 15% improved. Study authors concluded combination spray can help prevent skin damage as evidenced by improved local oxygen saturation (mean SpO2 increased by 4.41% with combination spray and decreased by 0.98% with silver spray).
23	Histological changes following the local application of the combination product were studied in 10 patients with spinal cord injuries and chronic PUs. Combination product was applied and three biopsies (Days 0, 7 and 15) were taken from each patient.	Biopsies showed increase in granulation tissue evident from Day 7 with a progressive increase until Day 15.

Abbreviations: CA, calcium alginate; LUs, leg ulcers; PUs, pressure ulcers.

The effectiveness and safety of the combination product in a powder format in the treatment of chronic LUs was confirmed in a clinical trial in 52 patients—one group received the combination powder plus calcium alginate (CA) and the control group CA alone. Both groups received compression bandages. ²¹ Overall, results indicated that the combination product and compression is safe and more effective in inducing faster healing in chronic LUs than standard dressing plus compression (see Table 1).

The effectiveness of the combination product in a spray format as a coadjuvant in the prevention of PUs was confirmed in a large‐scale study in 500 patients at risk of developing bedsores (Norton score < 12). The authors concluded that the combination spray can help prevent skin damage as evidenced by improved local oxygen saturation (mean SpO₂ increased by 4.41% with the combination spray). ²²

Histological changes following the local application of the combination product in 10 patients with spinal cord injuries and chronic PUs were also studied. Following application of the combination product, three biopsies (Days 0, 7 and 15) were taken from each patient. Analyses of biopsies showed an increase in granulation tissue already evident on Day 7 with a progressive increase until Day 15. ²³

The review of data published over the last 15 years showed distinct advantages of the unique combination of HA and amino acids, in terms of healing rate and induction of granulation tissue production compared with HA alone. There was also a significant improvement in the quality of the scar. ¹⁸ Additional evidence and further well‐designed trials are needed to support this combination having an effect in vivo on all stages of the healing process.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors. Medical writing support was provided by Edra S.p.A., with an educational grant from Professional Dietetics S.p.A., www.professionaldietetics.com.

CONFLICT OF INTEREST STATEMENT

The author reports no conflicts of interest.

Romanelli M. Unique combination of hyaluronic acid and amino acids in the management of patients with a range of moderate‐to‐severe chronic wounds: Evidence from international clinical trials. Int Wound J. 2024;21(S1):4‐8. doi: 10.1111/iwj.14617

DATA AVAILABILITY STATEMENT

Available on request.