A Novel Vehicle for the Delivery of Exogenous Neurotrophic Factors in Spinal Cord Injury

The relatively permanent nature of central nervous system injury is a great scientific dilemma, specifically as it pertains to spinal cord injury (SCI). Over the past several decades, significant advances have been made in the understanding of the pathophysiological mechanisms of SCI. Furthermore, the basic science literature is rife with promising studies investigating the effects of novel therapeutic interventions targeted to alter the disease process and to restore neurological function. Unfortunately, translating this progress into effective clinical treatment modalities has proved to be a major challenge and lags far behind. Despite the advances in basic science research, severe SCI continues to carry a poor prognosis with respect to restoration of neurological function and creates a major burden on our society.

As is the case for any disease process, to develop effective therapeutic interventions for SCI, it is first necessary to gain a thorough understanding of the pathophysiology of SCI. In broad terms, neurological recovery after SCI is impeded by a multitude of processes that occur both immediately after the injury and in a delayed fashion. Such processes include myelin-associated inhibitors, a paucity of neurotrophic factors, the inability of mature neurons to overcome inhibitory signals, and delayed formation of glial scar. No single process is responsible for blocking neuronal regeneration; therefore, effective therapies should be multimodal. Methods to promote neuronal regeneration range from genetic alterations and stem cell transplantation to administration of exogenous neurotrophic factors. However, the lack of feasible and realistic strategies for successful administration of these interventions in humans has limited their translation to clinical medicine.

In a recent article, Wang et al¹ explored the advantages and effectiveness of administering exogenous neurotrophic factors, specifically ciliary neurotrophic factor (CNTF), to promote neuroregeneration after SCI. The development of realistic application strategies for genetic and stem cell--based therapies, although potentially effective, is rather challenging. Comparatively, delivery of exogenous neurotrophic factors is theoretically less complicated. The authors have focused on the cytokine CNTF because dramatic increases in expression of CNTF after central nervous system injury have been detected and because it may play an important role in neuroregeneration. Simple injection of exogenous compounds generally leads to poor results owing to rapid diffusion, insufficient concentration at the site of injury, and systemic side effects. One solution to this dilemma involves implantation of a pump to deliver high concentrations of the desired cytokine to the injury site. Alternatively, the authors used sodium hyaluronate as a vehicle for sustained CNTF release by implanting gelatinous particles directly into the site of SCI in rats. These implants were created by dissolving CNTF and sodium hyaluronate gelatinous particles in phosphate-buffered saline.

In their experiments, rats were anesthetized and underwent T8-9 laminectomies, followed by direct injury to the spinal cord. The rats were divided into 4 groups based on the type of implant: sodium hyaluronate-CNTF particles, sodium hyaluronate alone, CNTF alone, and controls. They were then subjected to locomotive testing, electrophysiological assessment, and eventually sacrificed to perform immunohistochemistry and tissue analysis. The sodium hyaluronate--CNTF group demonstrated significantly better results on locomotive testing compared with the other 3 groups. Additionally, electrophysiological improvement in the sodium hyaluronate--CNTF group, as measured with cortical motor evoked potentials and sensory evoked potentials, was greater than in the other 3 groups. On immunohistochemistry analysis, the authors found that expression of neuron-specific intermediate filaments and β-tubulin III was significantly higher in the sodium hyaluronate-CNTF group, suggesting increased axonal growth and neurogenesis (Figure). Subsequently, they demonstrated that this result was related to the promotion of proliferation and differentiation of endogenous neural progenitor cells in response to the sodium hyaluronate--CNTF particles.

Figure

Quantification of neurotrophic factor- and β-tubulin III–positive neuronal fibers in the lesion area at 2 months postoperatively. A and B, macroscopic images of the dorsal surfaces of the lesion control (A) and sodium hyaluronate-ciliary neurotrophic factor (CNTF; B) cords at 2 months postoperatively. C, Nissl staining of the sodium hyaluronate-CNTF cord showed that the complete resection operation had made no neural residue left in the lesion area. The sodium hyaluronate-CNTF gelatinous particles are indicated by an asterisk. D and E, quantification of neurotrophic factor- (D) and β-tubulin-III–positive (E) neuronal fibers in the rostral, middle, and caudal segments of the lesion area at 2 months postoperatively. Error bars represent ±2 SE. Scale bars: A and B, 2 mm; C, 200 μm. Reprinted by permission from Macmillan Publishers Ltd: [Spinal Cord] (Wang N, Zhang S, Zhang AF, Yang ZY, Li XG. Sodium hyaluronate-CNTF gelatinous particles promote axonal growth, neurogenesis and functional recovery after spinal cord injury. Spinal Cord. 52(7):517-523, copyright 2014.

The authors' novel method of introducing an effective exogenous neurotrophic factor into the site of SCI holds great promise as a useful means of translating important basic science research in SCI to the clinical setting. The concept behind this research highlights the importance of closing the gap between successful bench therapies and realistic applications in the treatment of human disease. Translating bench science to the bedside is often limited by the challenge of establishing an effective and safe vehicle for drug administration. From a neurosurgical standpoint, the potential usefulness of this technique extends well beyond the realm of SCI, providing an important means of bypassing the blood-brain barrier, avoiding systemic side effects, and delivering high concentrations of therapeutic agents for sustained periods of time directly to the targeted area. This conceptual design has given rise to implantable carmustine-impregnated biodegradable copolymers for the treatment of gliomas.

As a result in large part of advances in genetics, proteomics, and molecular biology, scientists and physicians have enhanced understanding of the pathophysiological mechanisms of SCI. Disease processes are rapidly being broken down to the molecular level, and understanding the critical steps in a disease process permits the development of targeted therapies. Surgical intervention is only a minor part of the comprehensive care required in patients with severe or complete SCI. This work by Wang et al sheds new light on an old problem. In the future, development of biodegradable vehicles for the delivery of effective pharmaceuticals directly to site of injury could improve the long-term outlooks for patients with SCI.