Spinal cord injury (SCI) is a serious problem that primarily affects younger and middle-aged adults at its onset. To date, no effective regenerative treatment has been developed. Over the last decade, researchers have made significant advances in stem cell technology, biomaterials, nanotechnology, and immune engineering, which may be applied as regenerative therapies for the spinal cord. Although the results of clinical trials using specific cell-based therapies have proven safe, their efficacy has not yet been demonstrated. The pathophysiology of SCI is multifaceted, complex and yet to be fully understood. Thus, combinatorial therapies that simultaneously leverage multiple approaches will likely be required to achieve satisfactory outcomes. Although combinations of biomaterials with pharmacologic agents or cells have been explored, few studies have combined these modalities in a systematic way. For most strategies, clinical translation will be facilitated by the use of minimally invasive therapies, which are the focus of this review. In addition, this review discusses previously explored therapies designed to promote neuroregeneration and neuroprotection after SCI, while highlighting present challenges and future directions.

Neural stem/progenitor cell (NS/PC)‐based therapies have shown exciting potential for regeneration of the central nervous system (CNS) and NS/PC cultures represent an important resource for disease modeling and drug screening. However, significant challenges limiting clinical translation remain, such as generating large numbers of cells required for model cultures or transplantation, maintaining physiologically representative phenotypes ex vivo and directing NS/PC differentiation into specific fates. Here, we report that culture of human NS/PCs in 3D, hyaluronic acid (HA)‐rich biomaterial microenvironments increased differentiation toward oligodendrocytes and neurons over 2D cultures on laminin‐coated glass. Moreover, NS/PCs in 3D culture exhibited a significant reduction in differentiation into reactive astrocytes. Many NS/PC‐derived neurons in 3D, HA‐based hydrogels expressed synaptophysin, indicating synapse formation, and displayed electrophysiological characteristics of immature neurons. While inclusion of integrin‐binding, RGD peptides into hydrogels resulted in a modest increase in numbers of viable NS/PCs, no combination of laminin‐derived, adhesive peptides affected differentiation outcomes. Notably, 3D cultures of differentiating NS/PCs were maintained for at least 70 days in medium with minimal growth factor supplementation. In sum, results demonstrate the use of 3D, HA‐based biomaterials for long‐term expansion and differentiation of NS/PCs toward oligodendroglial and neuronal fates, while inhibiting astroglial fates. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 704–718, 2019.

Originating in the brain, glioblastoma (GBM) is a highly lethal and virtually incurable cancer, in large part because it readily develops resistance to treatments. While numerous studies have investigated mechanisms enabling GBM cells to evade chemotherapy-induced apoptosis, few have addressed how their surrounding extracellular matrix (ECM) acts to promote their survival. Here, we employed a biomaterial-based, 3D culture platform to investigate systematically how interactions between patient-derived GBM cells and the brain ECM promote resistance to alkylating chemotherapiesincluding temozolomide, which is used routinely in clinical practice. Scaffolds for 3D culture were fabricated from hyaluronic acid (HA)a major structural and bioactive component of the brain ECMand functionalized with the RGD (arginine-glycineaspartic acid) tripeptide to provide sites for integrin engagement. Data demonstrate that cooperative engagement of CD44, through HA, and integrin α V , through RGD, facilitates resistance to alkylating chemotherapies through co-activation of Src, which inhibited downstream expression of BCL-2 family pro-apoptotic factors. In sum, a bioengineered, 3D culture platform was used to gain new mechanistic insights into how ECM in the brain tumor microenvironment promotes resistance to chemotherapy and suggests potential avenues for the development of novel, matrix-targeted combination therapies designed to suppress chemotherapy resistance in GBM.

Biomaterials are being developed as therapeutics for spinal cord injury (SCI) that can stabilize and bridge acute lesions and mediate the delivery of transgenes, providing a localized and sustained reservoir of regenerative factors. For clinical use, direct injection of biomaterial scaffolds is preferred to enable conformation to unique lesions and minimize tissue damage. While an interconnected network of cell-sized macropores is necessary for rapid host cell infiltration into—and thus integration of host tissue with—implanted scaffolds, injectable biomaterials have generally suffered from a lack of control over the macrostructure. As genetic vectors have short lifetimes in vivo , rapid host cell infiltration into scaffolds is a prerequisite for efficient biomaterial-mediated delivery of transgenes. We present scaffolds that can be injected and assembled in situ from hyaluronic acid (HA)-based, spherical microparticles to form scaffolds with a network of macropores (∼10 μ m). The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores (∼10 nm), significantly increases the expression of locally delivered transgene to the spinal cord after a thoracic injury. Maximal cell and axon infiltration into scaffolds was observed in scaffolds with more regularly sized macropores. The delivery of lentiviral vectors encoding the brain-derived neurotrophic factor (BDNF), but not neurotrophin-3, from these scaffolds further increased total numbers and myelination of infiltrating axons. Modest improvements to the hindlimb function were observed with BDNF delivery. The results demonstrate the utility of macroporous and injectable HA scaffolds as a platform for localized gene therapies after SCI.