Anti-inflammatory drug delivery from hyaluronic acid hydrogels

Abstract

Two different types of hyaluronic acid (HA) hydrogels were synthesized by crosslinking HA with divinyl sulfone (DVS) and poly(ethylene glycol)-divinyl sulfone (VS-PEG-VS). Vitamin E succinate (VES), an anti-inflammatory drug, and bovine serum albumin (BSA), a model of anti-inflammatory protein drugs, were loaded into the gels and their release kinetics were measured in vitro. VES and BSA released with a burst from both HA hydrogels during the first few hours, and release continued gradually for several days. The rate of release from HA-VS-PEG-VS-HA hydrogels was faster than that from HA-DVS-HA hydrogels, presumably due to the lower crosslink density in the former. The anti-inflammatory action of released VES was tested by incubating peripheral blood mononuclear cells (PBMC) on HA hydrogels with and without VES in the gel. The number of cells adhering on HA hydrogels was very low compared to that on tissue culture polystyrene (TCPS), which might be one of the important advantages of using HA hydrogels for implant coatings or tissue engineering applications. ELISA test results showed that the tumor necrosis factor-alpha (TNF-alpha) concentration was very low in the supernatant of the wells containing the HA hydrogel with VES in contact with the activated macrophages compared to that without VES. This is probably the effect of the released VES reducing the production of anti-inflammatory cytokine, TNF-alpha. HA hydrogels containing anti-inflammatory drugs may have potential for use in tissue engineering and also as biocompatible coatings of implants.

Chemically Modified Natural Polysaccharides to Form Gels

“…In addition to direct divinyl sulfone, a variety of sulfone-terminated PEGs have been used for this as well. The presence of the hydrophilic PEG spacer leads to an overall lower cross-linking density which allows for greater swelling and faster drug release (Hahn et al 2004). HPC has also been reacted with divinyl sulfone at high pH (pH~12) to form a temperature-responsive hydrogel which shrinks upon warming.…”

Structurally Versatile Glycosaminoglycan Hydrogels for Biomedical Applications

“…[16] The combination of these two components provides a stress energy absorption mechanism. [17][18][19][20] Although collagen fibrils are not extensible, they transfer the applied stresses while water-swollen proteoglycans absorb the stress energy and prevent the tissue from collapse. [16] Due to the presence of sulfate and carboxyl groups, glycosaminoglycans are highly negatively charged.…”

“…[15] Since then, other groups have adopted this technique and applied it to other GAGs such as hyaluronic acid (HA) to make photocrosslinkable precursors. [10,[16][17][18] In these networks, the methacrylate side groups polymerize via free radical chain polymerization. If the groups are on different functionalized GAGs, the GAGs become linked via the polymerized polymethacrylate kinetic chains.…”

Hyaluronic Acid in Drug Delivery Systems

“…It also constitutes the backbone of cartilage proteoglycan. Because of its unique physicochemical properties and various biological functions, HA and modified HA have been extensively investigated and widely used for pharmaceutical and medical applications, (Balazs and Denlinger, 1993;Illum et al, 1994;Hahn et al, 2004;Ohri et al, 2004) such as for arthritis treatment (Balazs and Denlinger, 1993), ophthalmic surgery (Bothner and Wik, 1987), drug development , and tissue engineering (West et al, 1985;Ohri et al, 2004). HA is known to be involved in wound healing, promoting cell motility and differentiation during development (Laurent, 1998).…”

“…HA is known to be involved in wound healing, promoting cell motility and differentiation during development (Laurent, 1998). A number of strategies for the chemical modification of HA for improving its physicochemical properties through carboxyl and hydroxyl groups have been developed (Balazs and Leshchiner, 1987;Kuo et al, 1991;Illum et al, 1994;Luo et al, 2000;Hahn et al, 2004;Ohri et al, 2004).…”