Review Article
Managing Wounds with Exposed Bone and Tendon with an Esterified Hyaluronic Acid Matrix (eHAM): A Literature Review and Personal Experience

https://doi.org/10.1016/j.jccw.2018.04.002Get rights and content

Abstract

The loss of extracellular matrix in combination with the exposure of structures such as bone and tendon pose a major challenge; the development of granulation tissue and subsequent reepithelialization over these structures is extremely slow and often may not happen at all. Replacement of the matrix has been shown to significantly increase the chances of healing since, with revascularization of the matrix, a wound bed is created that may either heal by secondary intention or via the application of a skin graft.

A literature search on an esterified hyaluronic acid-based matrix (eHAM) returned five articles on the treatment of wounds with tendon and bone loss in which the eHAM was used. The etiologies of the wounds described varied among the articles, as did treatment modalities. However, all of them received proper debridement of necrosis with subsequent (although not always immediately) application of the eHAM. A very high percentage of all wounds reached the different primary endpoints in the studies, which were complete reepithelialization, complete coverage with granulation tissue and/or 10% coverage of the original wound size with epithelium, the latter being a strong indicator of the wound continuing to heal. The individual authors concluded that the esterified hyaluronic acid matrix (eHAM) is a valuable tool to assist in the complete healing of difficult to heal wounds.

Introduction

Debridement, removal of devitalized tissue, is a crucial step in wound healing and an essential part of the initiation of the wound healing process,1, 2, 3 as reflected in acronyms such as DIMES.4

In lesions such as Wagner stage III and IV diabetic foot ulcers,5 debridement may extend into the subcutaneous tissues, often with exposure of tendon and/or bone. While grafting on other clean, subcutaneous tissues (i.e. fat or fascia) is possible and may lead to good results,6 direct coverage of tendon and bone is difficult without the development of granulation tissue over these structures.7 Because of the exposure of deep structures, typical wound management is often insufficient, and the lesion may not reach complete, or even partial, reepithelialization.8 It is estimated that these so-called “hard to heal wounds” represent a growing economic burden on Western society of approximately $25B annually.9

It has been shown that reconstruction or replacement of lost extracellular matrix (ECM) is beneficial, since it improves the development of granulation tissue, the speed of healing and overall quality of the tissues.10, 11 The first “replacement matrix” was made of a mixture of collagen and a glycosaminoglycan (chondroitin sulfate). It was developed in the 1980's for the treatment of large, full-thickness, excised burns12, 13 and was first tested in a clinical trial14 in the same decade, receiving wider acceptance and usage in the 1990's.15, 16 In the burn and trauma literature, it was shown that a matrix based on a glycosaminoglycan can also be used successfully in hand, foot, and ankle reconstruction and their associated tendon and joint exposures.17, 18, 19

Many matrices, including acellular dermal-epidermal matrices and bioengineered skin substitutes, are now available and all aim at replacing the lost ECM with a matrix that will allow and encourage the production of granulation tissue and a “neodermis”.20, 21, 22, 23 The matrices become vascularized from both the wound margins and the underlying tissues,24, 25, 26, 27 eventually covering the poorly vascularized wound bed with a vascularized scaffold, which can then support a skin graft or go on to closure via secondary intention.

Some of the newer matrices are based on hyaluronic acid (also called hyaluronan or HA), another glycosaminoglycan. Glycosaminoglycans, also called mucopolysaccharides, are long, unbranched polysaccharides consisting of repeating disaccharides. Among them, hyaluronic acid has a unique structure; it does not contain any sulfate groups and is not covalently attached to proteins. It is, however, a component of non-covalently formed complexes with proteoglycans in the ECM. The disaccharides in hyaluronic acid are d-glucuronic acid and D-N-acetylglucosamine units, and the molecule can reach a molecular mass of up to 107 daltons28 It has a unique mode of synthesis in which the molecule is extruded directly into the extracellular space upon formation.29

Hyaluronic acid is completely and consistently conserved throughout a large span of the evolutionary tree,30 indicating its fundamental biological importance. It is identified in all vertebrates and present in many tissues, but more than 50% of hyaluronan resides in the dermis where it is associated with versican.28

HA plays a multifaceted role through its complex biological and physicochemical interactions with matrix components and cells.31 This ranges from a purely structural function in the extracellular matrix to controlling cellular behavior via its influence on the tissue macro- and microenvironments, as well as through direct receptor-mediated effects on gene expression.32 Hyaluronic acid is a major component of synovial tissues and fluids, as well as other soft tissues, and endows their environments with remarkable rheological properties such as changing viscosity depending on shear stress within the joint.33, 34 Hyaluronan also takes part in the partitioning of plasma proteins between vascular and extravascular spaces. This way it affects solubility of macromolecules in the interstitium, changes chemical equilibria, and stabilizes the structure of collagen fibers.34

Through complex signaling mechanisms, HA plays a major role in promoting angiogenesis.35 Indeed, hyaluronan content in skin is elevated transiently in granulation tissue during the wound healing process.32

Hyaluronic acid is metabolically very active; for example, its half-life in skin is less than one day.28 To avoid this rapid turnover when used in, for example, a matrix, hyaluronic acid can be esterified, and the level of esterification “controls” the half-life of the product. HYAFF®a is an esterified form of hyaluronic acid36 and Hyalomatrixa, b is an esterified hyaluronic acid matrix (eHAM) featuring HYAFF as the primary layer. eHAM acts as a 3-dimensional scaffold for cellular invasion and capillary growth, thus creating a vascularized wound bed. It has a protective outer silicone layer that can be removed upon incorporation of the matrix.

eHAM has been used in different indications for deep tissue loss, such as deep partial- and full-thickness burns37, 38, 39 and other full-thickness trauma,40, 41, 42, 43, 44, 45 as well as in the reconstruction of the scalp. Other indications include the reconstruction of contracted and hypertrophic scars,46, 47 the correction of syndactyly48 and as a matrix in the repair of wounds with exposed tendons and bone.45 In addition, its clinical efficacy has been evaluated in ulcers of various etiology, including large venous leg ulcers and diabetic foot ulcers with critical limb ischemia lesions.41, 42, 44

In lesions with exposed tendons and bone, the use of flaps for wound closure is generally considered the best option; fasciocutaneous flaps are the first choice for the repair of lesion with exposed tendon, since they provided the best functional repair with superior gliding properties for the underlying tendons.49, 50, 51 Myocutaneous flaps or muscle flaps in combination with a (split-thickness) skin graft (STSG) are a good choice for the coverage of exposed bones.52, 53, 54 However, due to several local and systemic conditions, not all patients and their wounds may be appropriate candidates for (extensive) surgery, in which case the use of an extracellular matrix may play an essential role in reconstructing the ECM, thus contributing to wound healing.

The aim of this article is to analyze and review clinical research on eHAM as an ECM in the repair of ulcers and other (surgical) lesions with exposed bone and/or tendon.

Section snippets

Method

An online search, using search engines such as PubMed, Google Scholar, Embase and Endnote, was initiated. (English) search terms included “hyaluronic acid,” “hyaluronan,” “ulcer,” “chronic wound,” “exposure,” “tendon,” “bone,” “matrix” and “Hyalomatrix.” Search results were limited to those articles that described ulcers with exposed bone and tendon, and for which eHAM was used as part of the treatment.

Results

Five articles, describing only lesions with exposed tendon and/or bone or with some exposed bone/tendon lesions among a more extensive series of deep ulcers, were found in the literature, with patient populations ranging from one (a case history) to 262. Evidence levels55 ranged from 2a42 (essentially a multicenter, non-comparative, prospective, observational study) to 456 (a single case study). Inclusion and exclusion criteria showed a significant diversity among the studies. At the same time,

Limitations

A review article has inherent limitations since, as is the case here, it is highly unlikely that the different case series and trials described in articles found through (web) searches all have the same format and generate the some type of parameters. This implies that results cannot necessarily be combined or extrapolated, since study protocols, patient populations, indications and endpoints vary among the different studies. The level of evidence55 also usually varies among the different

Discussion and conclusion

144 lesions of different etiologies, but all with exposed bone and/or tendon, were treated with proper and extensive debridement (ulcers) or primary excision (malignancies). The wounds were subsequently covered with eHAM, comprised of a hyaluronan based material (HYAFF) with a protective silicone top-layer. The matrix, allows for cellular ingrowth, thus creating a viable wound bed. In a number of lesions, the “reconstructed” dermis was then covered with a split thickness skin graft.

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