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.

Defined Alginate Hydrogels Support Spinal Cord Organoid Derivation, Maturation, and Modeling of Spinal Cord Diseases.

In the process of generating organoids, basement membrane extracts or Matrigel are often used to encapsulate cells but they are poorly defined and contribute to reproducibility issues. While defined hydrogels are increasingly used for organoid culture, the effects of replacing Matrigel with a defined hydrogel on neural progenitor growth, neural differentiation, and maturation within organoids are not well-explored. In this study, the use of alginate hydrogels as a Matrigel substitute in spinal cord organoid generation is explored. It is found that alginate encapsulation reduces organoid size variability by preventing organoid aggregation. Importantly, alginate supports neurogenesis and gliogenesis of the spinal cord organoids at a similar efficiency to Matrigel, with mature myelinated neurons observed by day 120. Furthermore, using alginate leads to lower expression of non-spinal markers such as FOXA2, suggesting better control over neural fate specification. To demonstrate the feasibility of using alginate-based organoid cultures as disease models, an isogenic pair of induced pluripotent stem cells discordant for the ALS-causing mutation TDP43G298S is used, where increased TDP43 mislocalization in the mutant organoids is observed. This study shows that alginate is an ideal substitute for Matrigel for spinal cord organoid derivation, especially when a xeno-free and fully defined 3D culture condition is desired.

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.

Bottom-up design of hydrogels for programmable drug release.

Hydrogels are a promising drug delivery system for biomedical applications due to their biocompatibility and similarity to native tissue. Programming the release rate from hydrogels is critical to ensure release of desired dosage over specified durations, particularly with the advent of more complicated medical regimens such as combinatorial drug therapy. While it is known how hydrogel structure affects release, the parameters that can be explicitly controlled to modulate release ab initio could be useful for hydrogel design. In this review, we first survey common physical models of hydrogel release. We then extensively go through the various input parameters that we can exercise direct control over, at the levels of synthesis, formulation, fabrication and environment. We also illustrate some examples where hydrogels can be programmed with the input parameters for temporally and spatially defined release. Finally, we discuss the exciting potential and challenges for programming release, and potential implications with the advent of machine learning.

Dynamic Grafting of Carboxylates onto Poly(Vinyl Alcohol) Polymers for Supramolecularly-Crosslinked Hydrogel Formation.

Supramolecular hydrogels have attracted considerable interest due to their unique stimuli-responsive and self-healing properties. However, these hydrogel systems are usually achieved by covalent grafting of supramolecular units onto the polymer backbone, which in turn limits their reprocessability. Herein, we prepared a supramolecular hydrogel system by forming dynamic covalent crosslinks between 4-carboxyphenylboronic acid (CPBA) and polyvinyl alcohol (PVA). The system was then further crosslinked with either calcium ions or branched polyethylenimine (PEI) to generate hydrogels with distinctly different properties. Incorporation of calcium ions resulted in the formation of hydrogels with higher storage modulus of 7290 Pa but without self-healing properties. On the other hand, PEI-crosslinked hydrogel (PVA-CPBA-PEI) exhibited >2000% critical strain value, demonstrated high stability over 52 days and showed sustained antibacterial effect. A combination of supramolecular interactions and dynamic covalent crosslinks can be an alternate strategy to fabricate next-generation hydrogel materials.

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.

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.

Progress in drug-delivery systems in cardiovascular applications: stents, balloons and nanoencapsulation.

Drug-delivery systems in cardiovascular applications regularly include the use of drug-eluting stents and drug-coated balloons to ensure sufficient drug transfer and efficacy in the treatment of cardiovascular diseases. In addition to the delivery of antiproliferative drugs, the use of growth factors, genetic materials, hormones and signaling molecules has led to the development of different nanoencapsulation techniques for targeted drug delivery. The review will cover drug delivery and coating mechanisms in current drug-eluting stents and drug-coated balloons, novel innovations in drug-eluting stent technologies and drug encapsulation in nanocarriers for delivery in vascular diseases. Newer technologies and advances in nanoencapsulation techniques, such as the use of liposomes, nanogels and layer-by-layer coating to deliver therapeutics in the cardiovascular space, will be highlighted.