Fully injectable hydrazone-thiosuccinimide and hydrazone-disulfide interpenetrating polymer network (IPN) hydrogels by kinetically orthogonal cross-linking of functionalized poly(N-isopropylacrylamide) (PNIPAM) and poly(1-vinyl-2-pyrrolidone) (PVP) precursors

摘要

Introduction: IPNs are produced by interlocking two chemically distinct networks in each other's free volume fraction. This interlocking and the potential for segregation of the IPNs into inhomogeneous domains can cause mechanical properties and microstructures distinct from single network controls. Prior IPNs reported as injectable (desired for minimally invasive delivery) were polymerized in situ with cross-linkers, raising potential concerns of high temperature / UV initiation / chemical toxicity. Networks may instead be formed by simple mixing of injected functionalized polymers. To thus produce an IPN, the two bonding reactions must be highly specific, such as hydrazide-aldehyde with thiol-maleimide or the slower thiol to disulflde reaction. Materials and Methods: Hydrogel IPNs were based on thermosensitlve PNIPAM functionalized to produce hydrazones and hydrophilic networks produced from PVP-thiol and -maleimide (Figure 1). Samples were characterized by shear rheometry, freeze-fracture SEM and small-angle neutron scattering (SANS). Thermoresponsive swelling, network degradation and model drug release were evaluated. Results and Discussion: Polymer concentrations were chosen to match storage moduli of single network PNIPAM and PVP controls. IPNs showed enhanced (p＜0.05) G' relative both to the sum of the single networks and to semi-IPN controls with one linear polymer embedded in the other network (Figure 2), attributed to elastic interlocking of the two distinct networks, and suggesting IPN hydrogels as potential reinforced tissue engineering scaffolds. SEM and SANS studies showed differences in IPN microstructure, particularly dependent on the cross-linking rate of the PVP network relative to hydrazone formation in the PNIPAM one, with slower gelling disulfides permitting more phase separation than the faster thiosuccinimide cross-linking. The IPN reflects the PNIPAM component's LCST behaviour, but with slower transitions and reduced hysteresis after the initial thermal cycle (Figure 3a,b), attributed to the PVP phase' elastic contribution to re-swelling. Hydrolytic degradation in the IPN is also both slower and less extensive overall (Figure 3c,d), with IPNs retaining their shape and at least half their initial mass weeks longer than the single network controls in an accelerated hydrolysis model. Conclusions: Distinctive mechanical and thermoresponsive behaviour and degradation kinetics between IPN, semi-IPN and single network hydrogels clearly demonstrate the effects of network interpenetration on biomaterial properties. Interlocking also modulates the hydrogel microstructure, dependent on rates of crosslinking between the constitutive networks. We anticipate utility for these hydrogels as reinforced tissue engineering scaffolds, and for reducing burst release in hydrogel drug loading, wherein the initial de-swelling typically elutes a large proportion of stored drug by convection.