Abstract
Over the past few years, different in vitro and in vivo studies have been highlighting the great potentiality of hyaluronic acid (HA) as a biomaterial in wound healing treatment thanks to its good capability to induce mesenchymal and epithelial cell growth and differentiation, angiogenesis, and collagen deposition. However, the need to improve its mechanical properties as well as its residence time has led scientists to study new functionalization strategies. In this work, chemically modified HA-based hydrogels were obtained by methacrylic and maleic functionalization. Methacrylated (MEHA) and maleated HA (MAHA) hydrogels have shown important physico-chemical properties. The present study provides a deeper insight into the biocompatibility of both synthesized materials and their effects on tissue inflammation using in vitro and in vivo models. To this aim, different cell lines involved in wound healing, human dermal fibroblasts, human adipose-derived stem cells and human umbilical vein endothelial cells, were seeded on MEHA and MAHA hydrogels. Furthermore, an inflammation study was carried out on a murine macrophage cell line to assess the effects of both hydrogels on inflammatory and anti-inflammatory interleukin production. The results showed that both MAHA and MEHA supported cell proliferation with anti-inflammation ability as highlighted by the increased levels of IL-10 (57.92 ± 9.87 pg mL−1 and 68.08 ± 13.94 pg mL−1, for MEHA and MAHA, respectively). To investigate the inflammatory response at tissue/implant interfaces, an in vivo study was also performed by subcutaneous implantation of the materials in BALB/c mice for up to 28 days. In these analyses, no significant chronic inflammation reaction was demonstrated in either MEHA or MAHA in the long-term implantation.
Highlights
It was determined from the ratio of the peak areas corresponding to the methacrylate (5.6 and 6.1 ppm) and maleated (5.9 and 6.6 ppm) moieties with the protons of methyl (–CH3 – 1.9 ppm) that belong to the N-acetyl group and served as the reference
The functionalized hyaluronic acid (HA) with higher degrees of substitution (DS) represented the best compromise in terms of physico-chemical and mechanical properties with an elastic modulus of 20.1 kPa and 41.2 kPa for maleated HA (MAHA) and MEHA, respectively.[47]
MEHA and MAHA hydrogels were cultured with HUVEC, HDF and human amnion-derived mesenchymal stem cells (HAD-MSC), examining the in ammation chemokines and in ammation response in vitro and in vivo models
Summary
Hydrogels are hydrophilic polymer networks capable of absorbing a high quantity of water, up to thousands of times their dry weight.[1,2,3] Due to their hydrophilic nature, they allow diffusion of small molecules, nutrients and oxygen, providing an ideal 3D microenvironment for cell proliferation and differentiation.[4,5] Since hydrogels have structural similarities with the extracellular matrix (ECM), they have been extensively used in various biomedical applications as drug delivery agents,[6] bio-adhesives,[7] and as scaffolds for regenerative medicine.[8,9,10] Among natural hydrogels, hyaluronic acid (HA) called hyaluronan, plays a central role in maintaining cell and tissue integrity, promoting cell proliferation, intracellular signaling and wound repair.[11] HA is a linear polysaccharide, consisting of alternating b-1,4-linked units of b-1,3-linked glucuronic acid and N-acetyl-D-glucosamine suitable for formulating hydrogels.[12] It is the main constituent of the ECM in human connective tissue and allows a structural assembling of aggrecan components.[13,14,15,16,17] Thanks to its biological properties such as biocompatibility and being non-allergenic, HA represents a suitable material for application to the skin or dermis layer.[18,19,20,21] bene ting from its physicochemical performances such as unique water retention capacity, hydrophilicity, rheological, and viscoelastic behavior, HA affects cellular response in terms of cell attachment, growth, migration and differentiation.[13,22] several in vitro and in vivo studies have demonstrated the good potential of HA in wound healing treatment by inducing mesenchymal and epithelial cell migration and differentiation, improved angiogenesis, and collagen deposition.[23] it has been described that metabolic degradation by-products of HA are able to stimulate endothelial cell proliferation and migration, tailoring the in ammatory processes and angiogenesis at different stages of wound
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