Drug-Eluting Nanofibrous Patches Demonstrate Importance Of Release Kinetics In Spinal Cord Repair
Timothy L. Downing*†, Aijun Wang†, Zhi-Qiang Yan§, Andy Lee†, Song Li*†
*UC Berkeley – UCSF Graduate Program in Bioengineering, †Department of Bioengineering, University of California at Berkeley, Berkeley CA 94720-3220, §Institute of Mechanobiology & Medical Engineering, Shanghai Jiao Tong University, Shanghai, China
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Summary:This study presents the therapeutic utility of drug-eluting nanofibrous patches in the study and repair of spinal cord injury.
Recent studies have shown that spinal cord injury (SCI) is over five times more prevalent than previously estimated, bringing the total number of people living with SCI to 1,275,000 in the US alone.1 In addition, as palliative care continues to advance, this number will continue to rise. Most unfortunately, patients with SCI, who already experience higher levels of poverty likely due to truncated economic opportunities, often incur exorbitant health care costs. These costs are owed to length of hospital stay as well as the need for multiplecostly procedures.1 The development of novel spinal cord regeneration strategies that significantly reduce the cost of health care for patients is critical. The previously mentioned implications are the motivation for this work.
Severe spinal cord injury is marked by a disruption in the ascending and descending axons of the spinal tracts. This disruption prevents vital communication between the brain and other parts of the body. Following injury to the spinal cord inflammation occurs, a glial scar is formed, and molecules inhibitory to axon growth are secreted. To mitigate these effects researchers have utilized a variety of pharmacological interventions. These include the use of both small and large biomolecules.2 In this study we utilize drug-eluting nanofibrous patches to explore the effects of rolipram and chondroitinase ABC (chABC) drug-release kinetics on spinal cord repair. While both of these therapeutic agents have shown significant efficacy in vivo – through decreased inflammation, increased axon growth, and degradation of glial scar components, few studies illustrate the impact of drug-release kinetics on functional and anatomical recovery. Here we demonstrate these drastic effects using a rat C5 hemisection spinal cord injury model.
Fig.1. A) Schematic ofdrug-eluting nanofibro-us patch implanted into the subdural space of the injured spinal cord. B) 8-week animalfunc-tional recovery score based on the Martinez forelimb recovery scale.
Biodegradable poly L-lactic acid (PLLA) was used to fabricate nanofibrous patches by electrospinning. Nanofibrous patches were mechanically stretched to induce fiber alignment to help bridge new tissue formation.3 Rolipram or chABC was dissolved in a 2% alginate solution and layered over electrospun nanofibrous patches. The alginate layer was cross-linked using a calcium chloride-rich mist. Drug-loaded patches were dried overnight at 37oC in order to slow the elution of loaded drugs during rehydration. Patches were implanted subdurally into the spinal cord to allow for the direct delivery of therapeutic agents into the injury site(Fig 1. A). To study the degree of functional recovery, animals were scored based on the Martinez forelimb and hindlimb recovery scale. Figure 1B shows that drug-delivery kinetics play an important role in the degree of animal forelimb functional recovery. In the case of rolipram and chABC, higher drug-delivery rates show adverse effects on animal locomotor recovery. Notably, these results also suggest that the use of drug-eluting nanofibrous patches can lead to a faster and greater extent of recovery. Thus, this novel strategy could lead to significant reductions in health care costs for future patients living with SCI.
[1] One Degree of Separation - Paralysis and Spinal Cord Injury in the United States. 2009, Reeve Foundation. p. 1-28.
[2] Thuret, S., L.D. Moon, and F.H. Gage, Therapeutic interventions after spinal cord injury. Nat Rev Neurosci, 2006. 7(8): p. 628-43.
[3] Zhu, Y., et al., Nanofibrous Patches for Spinal Cord Regeneration. Advanced Functional Materials, 2010. 20(9): p. 1433-1440.