While in the past hyaluronic acid (HA) was considered a passive component with a primarily structural role in tissues, research over the past few decades has revealed its diverse and complex biological functions, resulting in a major ideological shift. HA is abundant during normal central nervous system (CNS) development and, although down-regulated, remains ubiquitous in adult extracellular matrix (ECM). Significant changes in HA content are associated with pathological conditions, including stroke, traumatic injury and multiple sclerosis, and these changes likely disrupt repair by endogenous neural stem cells (NSCs). In this review, we describe recent findings in HA biology relevant to NSCs-focusing on the potential of HA-NSC interactions to mediate CNS regeneration. Currently, HA biomaterials are being developed to counteract matrix changes associated with CNS injury and disease, thereby promoting NSC survival and directing differentiation. In parallel, HA-based biomaterials engineered to mimic the native CNS microenvironment are being used to investigate the relationship between NSCs and their HA-rich surroundings within a controlled experimental space. As our understanding of HA-NSC interactions improves, so will the therapeutic potential of HA-based biomaterials. Efforts to better understand the relationship between HA bioactivities and biomaterial design parameters are already underway. Although significant progress has been made improving techniques for controlled fabrication of HA-based hydrogels with precisely defined features, there is still much work to be done. Ideally, future designs will incorporate multiple types of microenvironmental cues - orthogonally tuned in time and space - to direct differentiation of NSCs into various specialized lineages within a single biomaterial platform.

Spinal cord injury (SCI) is a devastating condition that leaves patients with limited motor and sensory function at and below the injury site, with little to no hope of a meaningful recovery. Because of their ability to mimic multiple features of central nervous system (CNS) tissues, injectable hydrogels are being developed that can participate as therapeutic agents in reducing secondary injury and in the regeneration of spinal cord tissue. Injectable biomaterials can provide a supportive substrate for tissue regeneration, deliver therapeutic factors, and regulate local tissue physiology. Recent reports of increasing intraspinal pressure after SCI suggest that this physiological change can contribute to injury expansion, also known as secondary injury. Hydrogels contain high water content similar to native tissue, and many hydrogels absorb water and swell after formation. In the case of injectable hydrogels for the spinal cord, this process often occurs in or around the spinal cord tissue, and thus may affect intraspinal pressure. In the future, predictable swelling properties of hydrogels may be leveraged to control intraspinal pressure after injury. Here, we review the physiology of SCI, with special attention to the current clinical and experimental literature, underscoring the importance of controlling intraspinal pressure after SCI. We then discuss how hydrogel fabrication, injection, and swelling can impact intraspinal pressure in the context of developing injectable biomaterials for SCI treatment.

Spinal cord injury (SCI) often causes loss of sensory and motor function resulting in a significant reduction in quality of life for patients. Currently, no therapies are available that can repair spinal cord tissue. After the primary SCI, an acute inflammatory response induces further tissue damage in a process known as secondary injury. Targeting secondary injury to prevent additional tissue damage during the acute and subacute phases of SCI represents a promising strategy to improve patient outcomes. Here, we review clinical trials of neuroprotective therapeutics expected to mitigate secondary injury, focusing primarily on those in the last decade. The strategies discussed are broadly categorized as acute-phase procedural/surgical interventions, systemically delivered pharmacological agents, and cell-based therapies. In addition, we summarize the potential for combinatorial therapies and considerations.