Injectable In Situ Gellable Hydrogel-Microgel Composites For Drug Delivery

Abstract

<p>Hydrogels are water soluble polymer networks that are similar to the extra-cellular matrix of cells. Drug delivery systems based on hydrogels are of interest given their high biocompatibility. Obstacles with their use include their macroscopic dimensions (requiring surgical implantation) and quick elution of drugs from the swollen hydrogel matrix.<br /><br />These challenges can be addressed through the use of microgels, hydrogel particles with nanoscale dimensions. Microgels made from poly(N-isopropylacrylamide) (PNIPAM)) are of particular interest given that the effective diameter and water content of these microgels decreases at ~32°C. The degree of des welling and drug release rates can be tuned by controlling distributions of comonomers inside micro gels. Microgels can be immobilized within an injectable hydrogel network which is a liquid outside the body but quickly gels upon injection inside the body.<br /><br />The bulk, entrapping hydro gels were fabricated from carboxymethyl cellulose (CMC) and dextran modified with hydrazide (CMC A) and aldehyde (Dex B) functional groups. When mixed via co-injection through a needle at concentrations of 2 wt%, a hydrazone-crosslinked hydrogel network was formed. AA-NIPAM micro gels were synthesized via mixed precipitation-emulsion free radical polymerization in a dilute (~1 wt% monomer) aqueous solution and were co-injected with the B polymer for encapsulation inside the hydrogel.<br /><br />Current results show that the release of bupivacaine, a cationic local anesthetic, can be sustained over a period of up to 30 days using these composite hydrogel systems. Release rates scaled directly with the anionic functional group content of the micro gel. Release rates from the composite microgels appear to be driven by ion exchange between the microgel and drug as opposed to simple diffusion.<br /><br />The composite hydro gels, hydrogel pre-polymers, and microgels all showed no significant cytotoxicity to fibroblasts or myoblasts at concentrations up to 2mg/mL according to the MTT assay, suggesting their utility as effective in vivo drug delivery vehicles.</p>