Injectable Hybrid-Crosslinked Hydrogels as Fatigue-Resistant and Shape-Stable Skin Depots.

Injectable hydrogels have gained considerable attention, but they are typically mechanically weak and subject to repeated physiological stresses in the body. Herein, we prepared polyurethane diacrylate (EPC-DA) hydrogels, which are injectable and can be photocrosslinked into fatigue-resistant implants. The mechanical properties can be tuned by changing photocrosslinking conditions, and the hybrid-crosslinked EPC-DA hydrogels exhibited high stability and sustained release properties. In contrast to common injectable hydrogels, EPC-DA hydrogels exhibited excellent antifatigue properties with >90% recovery during cyclic compression tests and showed shape stability after application of force and immersion in an aqueous buffer for 35 days. The EPC-DA hydrogel formed a shape-stable hydrogel depot in an ex vivo porcine skin model, with establishment of a temporary soft gel before in situ fixing by UV crosslinking. Hybrid crosslinking using injectable polymeric micelles or nanoparticles may be a general strategy for producing hydrogel implants resistant to physiological stresses.

Orthogonally crosslinked alginate conjugate thermogels with potential for cell encapsulation.

Hydrogels with more than one mode of crosslinking have gained interest due to improved control over hydrogel properties such as mechanical strength using multiple stimuli. In this work, sodium alginate was covalently conjugated onto thermoresponsive polyurethanes to prepare hybrid polymers (EPC-Alg) that are responsive to both temperature and Ca2+, forming orthogonally crosslinked hydrogels which are non-toxic to cells. Notably, the crosslinks are fully reversible, allowing for gel strength to be modulated via selective removal of either stimulus, or complete deconstruction of the hydrogel network by removing both stimuli. Higher alginate fractions increased the hydrophilicity and Ca2+ response of the EPC-Alg hydrogel, enabling tunable modulation of the thermal stability, stiffness and gelation temperatures. The EPC-Alg hydrogel could sustain protein release for a month and encapsulate neural spheroids with high cell viability after 7-day culture, demonstrating feasibility towards 3D cell encapsulation in cell-based biomedical applications such as cell encapsulation and cell therapy.

Branched PCL-Based Thermogelling Copolymers: Controlling Polymer Architecture to Tune Drug Release Profiles.

Temperature-responsive hydrogels, or thermogels, are a unique class of biomaterials that show facile and spontaneous transition from solution to gel when warmed. Their high biocompatibility, and ease of formulation with both small molecule drugs and biologics have made these materials prime candidates as injectable gel depots for sustained local drug delivery. At present, controlling the kinetics and profile of drug release from thermogels is achieved mainly by varying the ratio of hydrophobic: hydrophilic composition and the polymer molecular weight. Herein, we introduce polymer branching as a hitherto-overlooked polymer design parameter that exhibits profound influences on the rate and profile of drug release. Through a family of amphiphilic thermogelling polymers with systematic variations in degree of branching, we demonstrate that more highly-branched polymers are able to pack less efficiently with each other during thermogel formation, with implications on their physical properties and stability towards gel erosion. This in turn resulted in faster rates of release for both encapsulated small molecule hydrophobic drug and protein. Our results demonstrate the possibility of exploiting polymer branching as a hitherto-overlooked design parameter for tailoring the kinetics and profile of drug release in injectable thermogel depots.

Injectable PTHF-based thermogelling polyurethane implants for long-term intraocular application.

BACKGROUND: Hydrogels show great potential to be used for intraocular applications due to their high-water content and similarity to the native vitreous. Injectable thermosensitive hydrogels through a small-bore needle can be used as a delivery system for drugs or a tamponading substitute to treat posterior eye diseases with clear clinical potential. However, none of the currently available thermosensitive hydrogels can provide intraocular support for up to 3 months or more. METHOD: In this study, an injectable polytetrahydrofuran (PTHF)-based thermosensitive hydrogel was synthesized by polyurethane reaction. We examined the injectability, rheological properties, microstructure, cytotoxicity, and in vivo compatibility and stability of the hydrogels in rabbit eyes. RESULTS: We found that the PTHF block type and PTHF component ratio could modulate thermogelation properties of the polyurethane polymers. The PTHF-based hydrogel implants retained normal retinal structure and function. Incorporating bioinert PTHF generated highly biocompatible and more stable thermogels in the vitreous cavity, with gel networks and the presence of polymer still observed after 3 months when other thermogels would have been completely cleared. Moreover, despite lacking hydrolytically cleavable linkages, the polymers could be most naturally removed from the native vitreous by bio-erosion without additional surgical interventions. CONCLUSION: Our findings suggest the potential of incorporating hydrophobic bioinert blocks to enhance the in vivo stability of supramolecularly associated hydrogels for long-term intraocular applications.

High molecular weight hyper-branched PCL-based thermogelling vitreous endotamponades.

Vitreous endotamponades play essential roles in facilitating retina recovery following vitreoretinal surgery, yet existing clinically standards are suboptimal as they can cause elevated intra-ocular pressure, temporary loss of vision, and cataracts while also requiring prolonged face-down positioning and removal surgery. These drawbacks have spurred the development of next-generation vitreous endotamponades, of which supramolecular hydrogels capable of in-situ gelation have emerged as top contenders. Herein, we demonstrate thermogels formed from hyper-branched amphiphilic copolymers as effective transparent and biodegradable vitreous endotamponades for the first time. These hyper-branched copolymers are synthesised via polyaddition of polyethylene glycol, polypropylene glycol, poly(ε-caprolactone)-diol, and glycerol (branch inducing moiety) with hexamethylene diisocyanate. The hyper-branched thermogels are injected as sols and undergo spontaneous gelation when warmed to physiological temperatures in rabbit eyes. We found that polymers with an optimal degree of hyper-branching showed excellent biocompatibility and was able to maintain retinal function with minimal atrophy and inflammation, even at absolute molecular weights high enough to cause undesirable in-vivo effects for their linear counterparts. The hyper-branched thermogel is cleared naturally from the vitreous through surface hydrogel erosion and negates surgical removal. Our findings expand the scope of polymer architectures suitable for in-vivo intraocular therapeutic applications beyond linear constructs.