Drug delivery, cell-based therapies, and tissue engineering approaches for spinal cord injury

Abstract

Spinal cord injury (SCI) results in devastating neurological and pathological consequences, causing major dysfunction to the motor, sensory, and autonomic systems. The primary traumatic injury to the spinal cord triggers a cascade of acute and chronic degenerative events, leading to further secondary injury. Many therapeutic strategies have been developed to potentially intervene in these progressive neurodegenerative events and minimize secondary damage to the spinal cord. Additionally, significant efforts have been directed toward regenerative therapies that may facilitate neuronal repair and establish connectivity across the injury site. Despite the promise that these approaches have shown in preclinical animal models of SCI, challenges with respect to successful clinical translation still remain. The factors that could have contributed to failure include important biologic and physiologic differences between the preclinical models and the human condition, study designs that do not mirror clinical reality, discrepancies in dosing and the timing of therapeutic interventions, and dose-limiting toxicity. With a better understanding of the pathobiology of events following acute SCI, developing integrated approaches aimed at preventing secondary damage and also facilitating neuroregenerative recovery is possible and hopefully will lead to effective treatments for this devastating injury. The focus of this review is to highlight the progress that has been made in drug therapies and delivery systems, and also cell-based and tissue engineering approaches for SCI.

Keywords: CNS injury; Drug therapy; Gene therapy; Growth factors; Inflammation; Polymers; Scaffold.

Figure 1

Progression of spinal cord injury response with time and different therapeutic and regenerative strategies.

Figure 2. Neuroprotective efficacy of SOD-NPs in human neurons

(A) SOD-NPs (superoxide dismutase-loaded nanoparticles) using different doses of SOD at 6 hrs in neurons under hydrogen peroxide-induced oxidative stress; (B) Comparative neuroprotective effect of SOD-NPs with pegylated-SOD (PEG-SOD) in neurons under hydrogen peroxide-induced oxidative stress, Dose of SOD = 100 U (Data as mean + s.e.m.; n = 3; *P < 0.05). Figure reproduced with permission from reference (81).

Figure 3. Nano-CAT-NPs protect human neuronal cells from oxidative stress

Primary human neurons were challenged with hydrogen peroxide-induced oxidative (50 μM, 24 h) with or without 200 μg/ml Nano-CAT (catalase-loaded NPs) or Nano-CON (control NPs without CAT) and stained for microtubule associated protein 2 (MAP-2). Immuno-staining micrographs (a–f) show MAP-2 staining (red, neuronal marker; specific cytoskeletal proteins that are enriched in dendrites and essential to stabilize its shape); Glial fibrillary acidic protein (GFAP, green, astrocyte marker); and 4′,6-diamidino-2-phenylindole (DAPI, blue, nuclei). Arrow represents loss of MAP-2, neurite network or fragmented nuclei. Arrowhead represents MAP-2 enriched neurons. Images are representative of five random fields of at three donors. Scale bar = 50 μm. Reproduced with permission from reference (82).