Hyaluronan is a major carbohydrate component of the extracellular matrix and can be found in skin, joints, eyes and most other organs and tissues. It has a simple, repeated disaccharide linear copolymer structure that is completely conserved throughout a large span of the evolutionary tree, indicating a fundamental biological importance. Amongst extracellular matrix molecules, it has unique hygroscopic, rheological and viscoelastic properties. Hyaluronan binds to many other extracellular matrix molecules, binds specifically to cell bodies through cell surface receptors, and has a unique mode of synthesis in which the molecule is extruded immediately into the extracellular space upon formation. Through its complex interactions with matrix components and cells, hyaluronan has multifaceted roles in biology utilizing both its physicochemical and biological properties. These biological roles range from a purely structural function in the extracellular matrix to developmental regulation through effects of cellular behavior via control of the tissue macro- and microenvironments, as well as through direct receptor mediated effects on gene expression. Hyaluronan is also thought to have important biological roles in skin wound healing, by virtue of its presence in high amounts in skin. Hyaluronan content in skin is further elevated transiently in granulation tissue during the wound healing process. In this review, the general physicochemical and biological properties of hyaluronan, and how these properties may be utilized in the various processes of wound healing: inflammation, granulation and reepithelization, are presented.

Functions of hyaluronan in wound repair

Applications and Emerging Trends of Hyaluronic Acid in Tissue Engineering, as a Dermal Filler, and in Osteoarthritis Treatment

Hyaluronic acid (also known as hyaluronan or hyaluronate) is naturally found in many tissues and fluids, but more abundantly in articular cartilage and synovial fluid (SF). Hyaluronic acid (HA) content varies widely in different joints and species. HA is a non-sulfated, naturally occurring non-protein glycosaminoglycan (GAG), with distinct physico-chemical properties, produced by synoviocytes, fibroblasts, and chondrocytes. HA has an important role in the biomechanics of normal SF, where it is partially responsible for lubrication and viscoelasticity of the SF. The concentration of HA and its molecular weight (MW) decline as osteoarthritis (OA) progresses with aging. For that reason, HA has been used for more than four decades in the treatment of OA in dogs, horses and humans. HA produces anti-arthritic effects via multiple mechanisms involving receptors, enzymes and other metabolic pathways. HA is also used in the treatment of ophthalmic, dermal, burns, wound repair, and other health conditions. The MW of HA appears to play a critical role in the formulation of the products used in the treatment of diseases. This review provides a mechanism-based rationale for the use of HA in some disease conditions with special reference to OA.

Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory.

https://hal.archives-ouvertes.fr/hal-03035503/document

Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies.

Hyaluronan (HA) is a biocompatible and biodegradable linear polysaccharide which is of interest for tumor targeting through cell surface CD44 receptors. HA binds with high affinity to CD44 receptors, which are overexpressed in many tumors and involved in cancer metastasis. In the present study, we investigated the impact of HA molecular weight (MW), grafting density, and CD44 receptor density on endocytosis of HA-grafted liposomes (HA–liposomes) by cancer cells. Additionally, the intracellular localization of the HA–liposomes was determined. HAs of different MWs (5–8, 10–12, 175–350, and 1600 kDa) were conjugated to liposomes with varying degrees of grafting density. HA surface density was quantified using the hexadecyltrimethylammonium bromide turbidimetric method. Cellular uptake and subcellular localization of HA–liposomes were evaluated by flow cytometry and fluorescence microscopy. Mean particle sizes of HA–liposomes ranged from 120 to 180 nm and increased with increasing size of HA. HA–liposome upta...

Characterization of CD44-Mediated Cancer Cell Uptake and Intracellular Distribution of Hyaluronan-Grafted Liposomes

Perfusion imaging of skin island flap blood flow by a scanning laser-Doppler technique

The extracellular matrix macromolecule, hyaluronan, is thought to modulate wound healing. However, the molecular size of hyaluronan and contaminating associated proteins may be important determinants of these effects. We have examined the results of seven daily topical treatments of full-thickness skin wounds in pigs with ultrapure hyaluronan of defined molecular size. High molecular weight hyaluronan (>1000 kd) enhanced, whereas low molecular weight hyaluronan decreased, the rate of early wound contraction as compared with intermediate hyaluronan (molecular weight = 100 kd) and saline solution controls. Fracture strength at 21 days was reduced by high and intermediate molecular weight hyaluronan but not by low molecular weight hyaluronan. Wound perfusion, measured by means of a scanning laser-Doppler technique as a noninvasive indicator of angiogenesis, showed depression by high and intermediate molecular weight hyaluronan on day 3, but all forms of hyaluronan caused elevated blood flow on day 7. The architecture of granulation tissue in this wet healing model was highly organized, but no gross histologic differences were seen because of treatment. Different molecular species of hyaluronan have differential effects on contraction, angiogenesis, and the evolution of wound strength. Where hyaluronan is used as a treatment or vehicle for wounds, its precise composition should be specified.

Hyaluronan, heterogeneity, and healing: the effects of ultrapure hyaluronan of defined molecular size on the repair of full-thickness pig skin wounds.

Objective To obtain information about the quality of scars of healed venous leg ulcers compared with intact skin on the opposite leg by using high-frequency ultrasound. Methods Twenty-eight patients (16 women, 12 men, aged 31 - 89 years) whose venous ulcers had healed and scars formed were included in this study. The echogenicities of scars were measured with a 20 MHz high-frequency ultrasound Dermascan. The thickness of epidermis and dermis was assessed and the number of low echogenic pixels (LEPs) in the papillary dermis and reticular dermis were counted using image analysis software. Results The average epidermal thickness of the scars after 1 week to 20 years of healing was significantly increased compared to those of the control ( P < 0.01), whereas the average dermal thickness of scars after healing was significantly decreased compared to the control ( P < 0. 01). The numbers of LEPs and the distributions of LEPs between scars and controls had no statistically significant differences. There were no correlations among scar echogenicities, age of healed venous ulcers, initial ulcer areas, age of venous ulcers or age of patients. In the control skin samples, the young group aged 31 - 69 years had fewer LEPs than did the elderly group aged 70 - 89 years. Conclusion Our study demonstrates that after the healing of venous leg ulcers, there are significant differences in the thickness of the epidermis and dermis, but no significant alterations in water content and distribution in the dermis when compared to the controls.

Chiyu Jia

Papers

Perfusion imaging of skin island flap blood flow by a scanning laser-Doppler technique

Hyaluronan, heterogeneity, and healing: the effects of ultrapure hyaluronan of defined molecular size on the repair of full-thickness pig skin wounds.

Long-term mortality of ultrasound structure in patients with venous leg ulcers-healed from one week to twenty years.