Injectable PEG-analogue hydrogels based on poly(oligoethylene glycol methacrylate) have been developed based on complementary hydrazide and aldehyde reactive linear polymer precursors. These hydrogels display the desired biological properties of PEG, form covalent networks in situ following injection, and are easily modulated for improved control over their functionality and physiochemical properties.

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Degradable, covalently in situ gelling analogues of thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) hydrogels have been designed by mixing aldehyde and hydrazide-functionalized PNIPAM oligomers with molecular weights below the renal cutoff. Co-extrusion of the reactive polymer solutions through a double-barreled syringe facilitates rapid gel formation within seconds. The resulting hydrazone cross-links hydrolytically degrade over several weeks into low molecular weight oligomers. The characteristic reversible thermoresponsive swelling−deswelling phase transition of PNIPAM hydrogels is demonstrated. Furthermore, both in vitro and in vivo toxicity assays indicated that the hydrogel as well as the precursor polymers/degradation products were nontoxic at biomedically relevant concentrations. This chemistry may thus represent a general approach for preparing covalently cross-linked, synthetic polymer hydrogels that are both injectable and degradable.T hermoresponsive hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) that switch from a hydrated, expanded state at low temperature to a collapsed state at high temperature have been extensively investigated in the literature. The proximity of the ∼32°C volume phase transition temperature (VPTT) of PNIPAM hydrogels with physiological temperature (37°C) has sparked particular interest in the biomedical applications of these hydrogels as "smart", environmentally tunable drug delivery vehicles, 1 tissue engineering scaffolds, 2 cell growth/separation supports, 3 and biomolecule separation and recovery matrices, 4 among other applications. 5 Despite their significant potential in biomedical applications, PNIPAM hydrogels have not achieved clinical success, primarily due to concerns regarding the ultimate fate of PNIPAM inside the body. Though toxic in its monomeric form, 5 poly(N-isopropylacrylamide) has been shown to be effectively noncytotoxic at concentrations realistic to many medical applications. 6 However, possible depolymerization and/or chronic bioaccumulation of PNIPAM represent significant regulatory barriers to medical use. An additional practical barrier is the need to fabricate current PNIPAM hydrogel formulations outside of the body, as the free radical chemistry and thermal or UV initiation 3 required to form the hydrogels can induce significant cell toxicity and cannot be performed in deep tissues. While weakly cross-linked hydrogels may be sufficiently viscous to facilitate injection, 4 injection of more highly elastic hydrogels is impractical. As a result, there is a need for mechanically robust PNIPAM-based hydrogels that can be introduced into the body through minimally invasive means and subsequently degrade into safe and clearable products.While many studies have explored the formation of injectable and degradable thermoresponsive hydrogels via physical association 1,7,8 or space-filling, 9 relatively few studies have addressed the challenge of creating injectable and degradable covalently cross-linked PNIPAM hydrogels. Hydrolytically degradab...

A series of synthetic oligomers (based on the thermosensitive polymer poly(N-isopropylacrylamide) and carbohydrate polymers (including hyaluronic acid, carboxymethyl cellulose, dextran, and methylcellulose) were functionalized with hydrazide or aldehyde functional groups and mixed using a double-barreled syringe to create in situ gelling, hydrazone-cross-linked hydrogels. By mixing different numbers and ratios of different reactive oligomer or polymer precursors, covalently cross-linked hydrogel networks comprised of different polymeric components are produced by simple mixing of reactive components, without the need for any intermediate chemistries (e.g., grafting). In this way, hydrogels with defined swelling, degradation, phase transition, drug binding, and mechanical properties can be produced with properties intermediate to those of the mixture of reactive precursor polymers selected. When this modular mixing approach is used, one property can (in many cases) be selectively modified while keeping other properties constant, providing a highly adaptable method of engineering injectable, rapidly gelling hydrogels for potential in vivo applications.

Hydrogels that can form spontaneously via covalent bond formation upon injection in vivo have recently attracted significant attention for their potential to address a variety of biomedical challenges. This review discusses the design rules for the effective engineering of such materials, and the major chemistries used to form injectable, in situ gelling hydrogels in the context of these design guidelines are outlined (with examples). Directions for future research in the area are addressed, noting the outstanding challenges associated with the use of this class of hydrogels in vivo.