Novel, injectable hydrogels were developed that solidify through a dual-gelation, physical and chemical, mechanism upon preparation and elevation of temperature to 37°C. A thermogelling, poly(N-isopropylacrylamide)-based macromer with pendant epoxy rings and a hydrolytically-degradable polyamidoamine-based diamine crosslinker were synthesized, characterized, and combined to produce in situ forming hydrogel constructs. Network formation through the epoxy-amine reaction was shown to be rapid and facile, and the progressive incorporation of the hydrophilic polyamidoamine crosslinker into the hydrogel was shown to mitigate the often problematic tendency of thermogelling materials to undergo significant post-formation gel syneresis. The results suggest that this novel class of injectable hydrogels may be attractive substrates for tissue engineering applications due to the synthetic versatility of the component materials and beneficial hydrogel gelation kinetics and stability.

Injectable, dual-gelling hydrogels were successfully developed through the combination of physical thermogellation at 37°C and favorable amine:epoxy chemical crosslinking. Poly(N-isopropylacrylamide)-based thermogelling macromers with a hydrolyzable lactone ring and epoxy pendant groups, and a biodegradable diamine-functionalized polyamidoamine crosslinker were synthesized, characterized, and combined to produce non-syneresing and bioresorbable hydrogels. Differential scanning calorimetry and oscillatory rheometry demonstrated the rapid and dual-gelling nature of the hydrogel formation. The post-gelation dimensional stability, swelling, and mechanical behavior of the hydrogel system were shown to be easily tuned at the synthesis and formulation stages. The leachable products were found to be cytocompatible at all conditions, while the degradation products demonstrated a dose- and time-dependent response due to solution osmolality. Preliminary encapsulation studies showed MSC viability could be maintained for 7 days. The results suggest that injectable, thermally and chemically crosslinkable hydrogels are promising alternatives to prefabricated biomaterials for tissue engineering applications, particularly for cell delivery.

The impact of synthesis and solution formulation parameters on the swelling and mechanical properties of a novel class of thermally and chemically gelling hydrogels combining poly(N-isopropylacrylamide)-based thermogelling macromers containing pendant epoxy rings with polyamidoamine-based hydrophilic and degradable diamine crosslinking macromers was evaluated. Through variation of network hydrophilicity and capacity for chain rearrangement, the often problematic tendency of thermogelling hydrogels to undergo significant syneresis was addressed. The demonstrated ability to easily tune post-formation dimensional stability at both the synthesis and formulation stages represents a significant novel contribution towards efforts to utilize poly(N-isopropylacrylamide)-based polymers as injectable biomaterials. Furthermore, the cytocompatibility of the hydrogel system under relevant conditions was established, while demonstrating time- and dose-dependent cytotoxicity at high solution osmolality. Such injectable in situ forming degradable hydrogels with tunable water content are promising candidates for many tissue engineering applications, particularly for cell delivery to promote rapid tissue regeneration in non-load-bearing defects.

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