Oxi-HA/ADH Hydrogels: A Novel Approach in Tissue Engineering and Regenerative Medicine

Abstract

Hyaluronic acid (HA) is a natural polyelectrolyte abundant in mammalian connective tissues, such as cartilage and skin. Both endogenous and exogenous HA produced by fermentation have similar physicochemical, rheological, and biological properties, leading to medical and dermo-cosmetic products. Chemical modifications such as cross-linking or conjugation in target groups of the HA molecule improve its properties and in vivo stability, expanding its applications. Currently, HA-based scaffolds and matrices are of great interest in tissue engineering and regenerative medicine. However, the partial oxidation of the proximal hydroxyl groups in HA to electrophilic aldehydes mediated by periodate is still rarely investigated. The introduced aldehyde groups in the HA backbone allow spontaneous cross-linking with adipic dihydrazide (ADH), thermosensitivity, and noncytotoxicity to the hydrogels, which are advantageous for medical applications. This review provides an overview of the physicochemical properties of HA and its usual chemical modifications to better understand oxi-HA/ADH hydrogels, their functional properties modulated by the oxidation degree and ADH concentration, and the current clinical research. Finally, it discusses the development of biomaterials based on oxi-HA/ADH as a novel approach in tissue engineering and regenerative medicine.

Statistical optimization of hydrazone-crosslinked hyaluronic acid hydrogels for protein delivery

“…A wide range of Young's moduli have been observed with hydrazone-crosslinked HA hydrogels with values ranging between 1–2000 Pa reported in the literature. 36 In comparison, our HA hydrogels exhibited relatively low compressive moduli within a narrow range of 4.5–42.2 Pa. Others have found that a higher degree of modification for HA-ADH led to stiffer hydrogels, which was similar to what we observed for the 40 kDa hydrogels. 35 …”

“…A wide range of Young's moduli have been observed with hydrazone-crosslinked HA hydrogels with values ranging between 1-2000 Pa reported in the literature. 36 In comparison, our HA hydrogels exhibited relatively low compressive moduli within a narrow range of 4.5-42.2 Pa. Others have found that a higher degree of modification for HA-ADH led to stiffer hydrogels, which was similar to what we observed for the 40 kDa hydrogels. 35 Ultimately, our method of fabricating hydrazone-crosslinked HA hydrogels yielded hydrogels with a wide range of physicochemical properties, including large ranges in hydrogel gelation time and mass change, with the capacity to swell, degrade, or maintain a relatively constant mass over 28 days depending on the molecular weight and concentrations of HA-ADH and HA-Ox used (Table 2).…”

“…[30][31][32] We formed HA hydrogels using dynamic covalent hydrazone crosslinks as this approach can yield a wide range of physicochemical properties, making them an attractive hydrogel platform for numerous regenerative medicine applications. [33][34][35][36][37][38][39][40] The properties of hydrazone-crosslinked HA hydrogels can be easily tuned by adjusting the ratios of the two dynamic covalent crosslinking polymers: oxidized HA (HA-Ox) and HA adipic acid dihydrazide (HA-ADH). Thus, we narrowed our input parameters to HA molecular weight, HA-Ox concentration, and HA-ADH concentration.…”

Statistical Optimization of Hydrazone-Crosslinked Hyaluronic Acid Hydrogels for Protein Delivery

“…A wide range of compressive moduli have been observed with hydrazone-crosslinked HA hydrogels with values ranging between 1-2000 Pa reported in the literature. (36) In comparison, our HA hydrogels exhibited relatively low compressive moduli within a narrow range of 4.5-42.2 Pa. Others have found that a higher degree of modification for HA-ADH led to stiffer hydrogels, which was similar to what we observed for the 40 kDa hydrogels. (35) Ultimately, our method of fabricating hydrazone-crosslinked HA hydrogels yielded hydrogels with a wide range of physicochemical properties, including large ranges in hydrogel gelation time and mass change, with the capacity to swell, degrade, or maintain a relatively constant mass over 28 days depending on the molecular weight and concentrations of HA-ADH and HA-Ox used (Table 2).…”

“…(30)(31)(32) We formed HA hydrogels using dynamic covalent hydrazone crosslinks as this approach can yield a wide range of physicochemical properties, making them an attractive hydrogel platform for numerous regenerative medicine applications. (33)(34)(35)(36)(37)(38)(39)(40) The properties of hydrazonecrosslinked HA hydrogels can be easily tuned by adjusting the ratios of the two dynamic covalent crosslinking polymers: oxidized HA (HA-Ox) and HA adipic acid dihydrazide (HA-ADH). Thus, we narrowed our input parameters to HA molecular weight, HA-Ox concentration, and HA-ADH concentration.…”