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.

Polyurea-urethane Temperature-responsive Hydrogels for Sustained Delivery of Anti-VEGF Therapeutics.

Temperature-responsive hydrogels, or thermogels, have emerged as a leading platform for sustained delivery of both small molecule drugs and macromolecular biologic therapeutics. Although thermogel properties can be modulated by varying the polymer's hydrophilic-hydrophobic balance, molecular weight and degree of branching, varying the supramolecular donor-acceptor interactions on the polymer remains surprisingly overlooked. Herein, to study the influence of enhanced hydrogen bonding on thermogelation, we synthesized a family of amphiphilic polymers containing urea and urethane linkages using quinuclidine as an organocatalyst. Our findings showed that the presence of strongly hydrogen bonding urea linkages significantly enhanced polymer hydration in water, in turn affecting hierarchical polymer self-assembly and macroscopic gel properties such as sol-gel phase transition temperature and gel stiffness. Additionally, analysis of the sustained release profiles of Aflibercept, an FDA-approved protein biologic for anti-angiogenic treatment, showed that urea bonds on the thermogel were able to significantly alter the drug release mechanism and kinetics compared to usage of polyurethane gels of similar composition and molecular weight. Our findings demonstrate the unrealized possibility of modulating gel properties and outcomes of sustained drug delivery through judicious variation of hydrogen bonding motifs on the polymer structure.

Biomedically-relevant metal organic framework-hydrogel composites.

Metal organic frameworks (MOFs) are incredibly versatile three-dimensional porous materials with a wide range of applications that arise from their well-defined coordination structures, high surface areas and porosities, as well as ease of structural tunability due to diverse compositions achievable. In recent years, following advances in synthetic strategies, development of water-stable MOFs and surface functionalisation techniques, these porous materials have found increasing biomedical applications. In particular, the combination of MOFs with polymeric hydrogels creates a class of new composite materials that marries the high water content, tissue mimicry and biocompatibility of hydrogels with the inherent structural tunability of MOFs in various biomedical contexts. Additionally, the MOF-hydrogel composites can transcend each individual component such as by providing added stimuli-responsiveness, enhancing mechanical properties and improving the release profile of loaded drugs. In this review, we discuss the recent key advances in the design and applications of MOF-hydrogel composite materials. Following a summary of their synthetic methodologies and characterisation, we discuss the state-of-the-art in MOF-hydrogels for biomedical use - cases including drug delivery, sensing, wound treatment and biocatalysis. Through these examples, we aim to demonstrate the immense potential of MOF-hydrogel composites for biomedical applications, whilst inspiring further innovations in this exciting field.

A Polyanionic Tartrate-containing Temperature-responsive Hydrogel.

Thermogels, a class of hydrogels which show spontaneous sol-gel phase transition when warmed, are an important class of soft biomaterials. To date, however, most amphiphilic polymers that are able to form thermogels in aqueous solution are uncharged, and the influence of ionisable groups on thermogelation are largely unknown. Herein, we report the first example of a polyanionic amphiphilic multi-block copolymer, containing multiple pendant carboxylate groups, that can form transparent thermogels spontaneously when warmed up to physiological temperature. We demonstrate that introducing negative charges onto thermogelling polymers could significantly alter the properties of the micelles and thermogels formed. Furthermore, the polymer's polyanionic character provides new options for modulating the gel rheological properties, such as stiffness and gelation temperatures, through electrostatic interactions with different cations. We also demonstrated that the polyanionic thermogel allowed slower sustained release of a cationic model drug compound compared to an anionic one over 2 weeks. The findings from our study demonstrate exciting new possibilities for advanced biomedical applications using charged polyelectrolyte thermogel materials.

UiO-66 metal organic frameworks with high contents of flexible adipic acid co-linkers.

Adipic acid, an industrially-important chemical that can be sustainably derived from biomass and post-consumer nylon, is traditionally overlooked as a linker for MOFs. Herein, we report the first direct one-pot method for synthesising UiO-66 MOFs with an unprecedented 69 mol% adipate content, as well as the feasibility of these materials for MOF defect engineering by rapid and selective adipate thermolysis.

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.

A bio-functional polymer that prevents retinal scarring through modulation of NRF2 signalling pathway.

One common cause of vision loss after retinal detachment surgery is the formation of proliferative and contractile fibrocellular membranes. This aberrant wound healing process is mediated by epithelial-mesenchymal transition (EMT) and hyper-proliferation of retinal pigment epithelial (RPE) cells. Current treatment relies primarily on surgical removal of these membranes. Here, we demonstrate that a bio-functional polymer by itself is able to prevent retinal scarring in an experimental rabbit model of proliferative vitreoretinopathy. This is mediated primarily via clathrin-dependent internalisation of polymeric micelles, downstream suppression of canonical EMT transcription factors, reduction of RPE cell hyper-proliferation and migration. Nuclear factor erythroid 2-related factor 2 signalling pathway was identified in a genome-wide transcriptomic profiling as a key sensor and effector. This study highlights the potential of using synthetic bio-functional polymer to modulate RPE cellular behaviour and offers a potential therapy for retinal scarring prevention.

Polymeric hydrogels as a vitreous replacement strategy in the eye.

Vitreous endo-tamponades are commonly used in the treatment of retinal detachments and tears. They function by providing a tamponading force to support the retina after retina surgery. Current clinical vitreous endo-tamponades include expansile gases (such as sulfur hexafluoride (SF6) and perfluoropropane (C3F8)) and also sislicone oil (SiO). They are effective in promoting recovery but are disadvantaged by their lower refractive indices and lower densities as compared to the native vitreous, resulting in immediate blurred vision after surgery and necessitating patients to assume prolonged face-down positioning respectively. While the gas implants diffuse out over time, the SiO implants are non-biodegradable and require surgical removal. Therefore, there is much demand to develop an ideal vitreous endo-tamponade that can combine therapeutic effectiveness with patient comfort. Polymeric hydrogels have since attracted much attention due to their favourable properties such as high water content, high clarity, suitable refractive indices, suitable density, tuneable rheological properties, injectability, and biocompatibility. Many design strategies have been employed to design polymeric hydrogel-based vitreous endo-tamponades and they can be classified into four main strategies. This review seeks to analyse these various strategies and evaluate their effectiveness and also propose the key criteria to design successful polymeric hydrogel vitreous endo-tamponades.

Thermogelling chitosan-based polymers for the treatment of oral mucosa ulcers.

Current treatments for oral mucosa-related ulcers use drugs to relieve pain and promote healing, but rarely consider drug resistance to bacterial infection in the microenvironment of the oral cavity or the prevention of bleeding from gingival mucosa ulcers. We herein report an injectable, thermogelling chitosan-based system to address these concerns. An aqueous solution of chitosan-based conjugates (chitosan-g-poly(N-isopropylacrylamide) [CS-g-PNIPAAM] including 1a [CS-g-PNIPAAM with less PNIPAAM] and 1b [CS-g-PNIPAAM with more PNIPAAM], and chitosan-g-poly(N-isopropylacrylamide)-g-polyacrylamide [CS-g-PNIPAAM-g-PAM] 3) could reversibly form semi-solid gels at physiological temperatures for easy application to oral cavity ulcer sites by injection. The chitosan-based conjugate thermogels prepared could inhibit both Gram-positive and Gram-negative bacteria and the two with higher chitosan and poly(N-isopropylacrylamide) contents (1a and 1b) promoted proliferation of gingival fibroblasts in vitro. These two thermogels also exhibited improved blood clotting in an in vivo rat study. Thermogels 1a and 1b effectively promoted ulcer healing and shortened ulcer healing times in an oral gingival mucosa ulcer model using Sprague Dawley (SD) rats. These thermogels showed no obvious toxicity to the main organs of SD rats undergoing gingival ulcer treatment. These results suggest that this antibacterial biomaterial could be a promising injectable therapeutic agent for the treatment for oral mucosa ulcers.