Biomaterial Approaches to Enhancing Neurorestoration after Spinal Cord Injury: Strategies for Overcoming Inherent Biological Obstacles

Abstract

While advances in technology and medicine have improved both longevity and quality of life in patients living with a spinal cord injury, restoration of full motor function is not often achieved. This is due to the failure of repair and regeneration of neuronal connections in the spinal cord after injury. In this review, the complicated nature of spinal cord injury is described, noting the numerous cellular and molecular events that occur in the central nervous system following a traumatic lesion. In short, postinjury tissue changes create a complex and dynamic environment that is highly inhibitory to the process of neural regeneration. Strategies for repair are outlined with a particular focus on the important role of biomaterials in designing a therapeutic treatment that can overcome this inhibitory environment. The importance of considering the inherent biological response of the central nervous system to both injury and subsequent therapeutic interventions is highlighted as a key consideration for all attempts at improving functional recovery.

Figure 1

Immune response following SCI. Trauma to the spinal cord elicits an immune response, which begins almost immediately after injury. Neutrophils are the first immune cells to respond to the lesion site, arriving within the first few hours after injury, and remaining for up to 3 days after injury. Vascular macrophages are the second class of immune cell to arrive at the lesion, arriving after the initial infiltration of neutrophils. Activation and infiltration of vascular macrophages subsequently activate and recruit microglial cells, which can persist in the lesion site for months after injury [–7].

Figure 2

Upregulation and expression of CSPGs. Almost immediately following an SCI, astrocytes located within the area of trauma begin to undergo hypertrophy, synthesizing and secreting CSPGs, including neurocan, phosphacan, and brevican. Additionally, the infiltration of vascular macrophages, activated microglial cells, and OPCs results in the increase in the proteoglycans NG2 and versican. The temporal expression of these proteoglycans is important to factor into any treatment, as they have differential effects on the regenerative process. Neurocan and versican are upregulated quickly following injury, with maximal expression observed 2 weeks after injury. Their expression begins to wane at longer times, approaching base levels by 8 weeks after injury. Brevican is also upregulated after injury, reaching maximal expression 2 weeks after injury. However unlike neurocan and versican, brevican expression remains elevated over time. Phosphacan is initially downregulated following SCI, with significantly reduced levels 1 week after injury. The expression begins to increase at longer times after injury and peaks around 8 weeks after injury. NG2 expression can be generally correlated to the infiltration of vascular macrophages, activated microglia, and OPCs, with maximal expression being found 1 week after injury. This differential expression pattern of CSPGs plays a large role in governing the regenerative response as many CSPGs are inhibitory to both process of atonal regeneration and remyelination (adapted from [8]).

Figure 3

Chronology of postinjury events. The lesion site in an injured spinal cord is also a very dynamic environment that undergoes many different changes, as the lesion changes from an acute injury to a chronic injury. In addition to the inhibitory environment established after SCI, the ever-changing nature of these postinjury events needs to be factored into the design of any therapeutic treatment [4, 5, 7, 9, 10].