Hydrogels are a class of biomaterials widely implemented in medical applications due to their biocompatibility and biodegradability. Despite the many successes of hydrogel‐based delivery systems, there remain challenges to hydrogel drug delivery such as a burst release at the time of administration, a limited ability to encapsulate certain types of drugs (i.e., hydrophobic drugs, proteins, antibodies, and nucleic acids), and poor tunability of geometry and shape for controlled drug release. This review discusses two main important advances in hydrogel fabrication for precision drug release: first, the incorporation of nanocarriers to diversify their drug loading capability, and second, the design of hydrogels using 3D printing to precisely control drug dosing and release kinetics via high‐resolution structures and geometries. We also outline ongoing challenges and discuss opportunities to further optimize drug release from hydrogels for personalized medicine. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies

We report the formulation and mechanical characterization of double network (DN) composite hydrogels. The first network consists of covalently crosslinked poly(ethylene glycol diacrylate) (PEGDA), which forms a strong, brittle network that provides elasticity to the gel. The second network, sodium alginate, is ionically crosslinked with Ca 2+ to allow increased dissipation of mechanical energy. The novelty of this system over existing DN hydrogels is the additional incorporation of a third mesoscale network, composed of thermoresponsive poly(dimethyl siloxane) (PDMS) nanoemulsions, which undergo colloidal gelation through the bridging of the PEGDA hydrophobic end groups into the PDMS droplets. The colloidally gelled microstructures are photopolymerized into a solid hydrogel by crosslinking the precursors with ultraviolet (UV) light. Tensile mechanical experiments performed on the crosslinked DN nanoemulsion hydrogels show that their rupture stress (0.17-0.34 MPa), fracture energy (144-421 J/m 2 ), and Young's modulus (1-2.1 MPa) are comparable to similar systems in the literature. These mechanical measurements suggest that the gels may be suitable for manufacturing processes in which large shear rates and deformations are encountered. K E Y W O R D S composite hydrogels, double network hydrogels, nanoemulsions, thermoresponsive 1 | INTRODUCTION Hydrogels are a class of biomaterials that are widely used in biomedical applications, such as diagnostic devices, 1,2 tissue engineering, 3,4 and drug delivery, 5,6 due to their hydrophilicity and biocompatibility. 7-9 The physical and chemical properties of hydrogels can be tailored to specific biopharmaceutical applications. However, the adoption of conventional hydrogels composed of a single hydrophilic polymer, so-called single network (SN) hydrogels, are often limited in such applications due to a lack of mechanical strength as characterized by low Young's modulus values 10 of E~10 kPa and low fracture energies 11 of Γ = 10 0 -10 1 J/m 2 . Enhancing the mechanical strength of hydrogels is therefore important in expanding the applications of hydrogels to manufacturing processes in which large deformations are often encountered. 12 Double network (DN) hydrogels, 13 which are composed of two interpenetrating polymeric networks, are promising in overcoming the traditional mechanical limitations of SN hydrogels. The first network is typically made of a low-molecular weight polymer that provides rigidity to the system by tight covalent crosslinking. The second network is typically a polymer with high-molecular weight which is loosely crosslinked and provides flexibility to the system. 12 In 2003, Gong et al 13 developed a two-step sequential free-radical polymerization method to synthesize the first DN hydrogels, consisting of poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) as the first network and polyacrylamide (PAAm) as the second network. These DN gels achieved Γ = 10 2-3 J/m 2 and fracture tensile stresses σ rup = 10 0-1 MPa. Later, Sun et al 14 developed toug...

Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for antitumor payloads. However, the in vivo persistence of iNSCs limits their therapeutic potential. We hypothesized that by encapsulating iNSCs in the FDA‐approved, hemostatic matrix FLOSEAL®, we could increase their persistence and, as a result, therapeutic durability. Encapsulated iNSCs persisted for 95 days, whereas iNSCs injected into the brain parenchyma persisted only 2 weeks in mice. Two orthotopic GBM tumor models were used to test the efficacy of encapsulated iNSCs. In the GBM8 tumor model, mice that received therapeutic iNSCs encapsulated in FLOSEAL® survived 30 to 60 days longer than mice that received nonencapsulated cells. However, the U87 tumor model showed no significant differences in survival between these two groups, likely due to the more solid and dense nature of the tumor. Interestingly, the interaction of iNSCs with FLOSEAL® appears to downregulate some markers of proliferation, anti‐apoptosis, migration, and therapy which could also play a role in treatment efficacy and durability. Our results demonstrate that while FLOSEAL® significantly improves iNSC persistence, this alone is insufficient to enhance therapeutic durability.

Therapeutic neural stem cells (tNSCs) are a promising new platform for the treatment of glioblastoma (GBM). tNSCs exhibit a characteristic known as tumor tropism, in which they can migrate towards distant GBM foci via cytokine signaling. Complementarily, genetic engineering of NSCs may be performed to turn the cells into drug-producing therapeutics. Together, this results in NSCs that act as targeted drug delivery vehicles that can seek out and kill invasive GBM lesions post-resection. However, one limitation of this cell therapy platform is that tNSCs delivered directly into the GBM resection cavity are rapidly cleared. We hypothesized that the commercially available, FDA-approved hemostat FLOSEAL® may be used as a drug delivery system for improving cell persistence in the brain, thus resulting in improved therapeutic efficacy. It was found that tNSCs encapsulated in FLOSEAL® were detectable in the brain for over 95 days in mice, a drastic improvement compared to directly injected cells and cells encapsulated in other existing hemostat systems, which persisted 2 weeks or less. However, two in vivo efficacy studies of tNSCs encapsulated in FLOSEAL® yielded contrasting results. While the FLOSEAL®-tNSC system was significantly more efficacious against a GBM8 tumor model in mice compared to directly injected tNSCs, it was not significantly more effective against a U87 tumor model. This could be due to a variety of factors, including the tumor type (diffuse vs. solid for GBM8 and U87, respectively) and negative impacts of FLOSEAL® on tNSC markers of proliferation, migration, drug production, and anti-apoptosis. While FLOSEAL® is a promising material for the delivery of tNSCs in the treatment of post-operative GBM, alternative systems that allow for improved persistence while maintaining the therapeutic activity of the cells would be optimal for long-term treatment with tNSCs.

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