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A Systems Biology Approach to Peripheral Nerve Regeneration
Hilton M Kaplan, MBBCh FCSSA PhD1; Joseph M Rosen, MD2; D. Kacy Cullen, PhD3; Omar F Khan, PhD4; E. Thomas Pashuck, PhD1; Daniel G Anderson, PhD4; Robert S Langer, ScD4; Joachim Kohn, PhD FBSE1
1Rutgers University, Piscataway, NJ, 2Dartmouth College, Lebanon, NH, 3Neurosurgery, University of Pennsylvania, Philadelphia, PA, 4Massachusetts Institute of Technology, Cambridge, MA
Introduction: Most peripheral nerve research focuses on short gaps (<3 cm in humans). The most urgent clinical need is the treatment of large gaps (5-15 cm). This challenge requires coordinated integration of multiple components, to address: nerve gap; distal effects of axonotmesis and Wallerian degeneration; functional deficits at motor/sensory targets. True clinical solution requires combining state-of-the-art technologies to provide a comprehensive nerve regeneration treatment.
Methods: We have developed: (1) A neurotrophic, guiding conduit across the defect: Nerve guidance wraps (NGWs) were braided from tyrosine-derived polycarbonate microfibers, with optimized wall porosity and hyaluronic acid (HA) coating. They have been used for rapid screening of fillers and biologically active mimetics for driving preferential motor reinnervation (assessed by retrograde labeling of rat/rabbit spinal cord motoneurons). Cell-selective hydrogels are being developed, that are permissive to axons and Schwann cells (SCs) but resist fibroblasts. (2) A neuro-biologically active, structurally-aligned filler across the defect and for maintaining neuromuscular junctions (NMJs): Tissue-engineered nerve graft (TENG) "living scaffolds" are 3D constructs embedded in collagen, comprising highly aligned axonal tracts developed by stretching motor/sensory axons spanning discrete neuronal populations. (3) Electrical stimulation of the proximal repair, NMJs, and denervated muscles, to facilitate regeneration and maintain viability: Stretchable microelectrode arrays (sMEAs) were manufactured using multistep microfabrication patterning of gold electrodes (in space-filling/Peano curve manner to increase flexibility) onto flexible polydimethylsiloxane backing.
Results: (1) NGWs were found to be (a) neurotrophic (improved regeneration vs. non-porous conduits in 1.5 cm rat model; and vs. commercial conduits in 5 cm pig model with TENGs); (b) kink- and compression-resistant; (c) a barrier to scar infiltration while facilitating mass exchange (due to microporous, HA-coated walls); (d) bioresorbable over tunable periods. (2) TENGs were found to accelerate axonal regeneration and functional recovery in rats and pigs across 1-5 cm gaps ("axon-mediated axonal regeneration"); and to promote SC infiltration from stumps to maintain distal structures. (3) sMEAs are capable of stimulating denervated muscles to prevent atrophy, while providing real-time muscle/nerve health assessment through telemetry of neural recordings. Initial biocompatibility testing showed no significant changes in host response when compared to unmodified polydimethylsiloxane controls.
Conclusions: To our knowledge, this is the first proposed application of a systems biology approach to nerve regeneration: a truly comprehensive approach from spinal cord roots to target organs. The current status of each technology will be presented, with plans for their integration.
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