Severe traumatic injuries and surgical procedures like tumor resection often create peripheral nerve gaps, accounting for over 250,000 injuries in the US annually. The clinical "gold standard" for repair is autografts, with which 40~50% of patients regain useful function. The effectiveness and use of autografts is limited by issues including limited availability and collateral damage at the donor site. So, it is critical to develop alternative bioengineered approaches that match or exceed autograft performance. We recently reported a breakthrough in bridging critically sized nerve gaps (e15mm) in rats using a thin film-based intra-luminal scaffold carried in a standard nerve guidance channel. This finding gives rise to two important questions. (1) How does intra-luminal presentation of minimal thin film-based cues (occupying just 0.3% of intra-luminal volume) have a dramatic effect on regeneration? (2) If we understood the mechanism underlying this effect, could we influence the process, and further enhance regeneration to match or exceed autograft performance? An understanding of the mechanistic interplay between polymer fiber-based topography (what may be termed the endogenous 'regenerative processes/sequence') is necessary for the rational design of intra-luminal scaffolds. This process spontaneously occurs during the successful bridging of short gaps (<10mm in rats), but fails to occur in the bridging of longer gaps (e15mm in rats). It involves a fibrin cable formation, extracellular matrix deposition/remodeling (eg., fibronectin), glial/support cell (fibroblasts and Schwann cells) and axonal infiltration into the gap. Our central hypothesis is that the mechanism by which thin films with topographical cues enhance regeneration is by serving as physical 'organizing templates'for Schwann cell infiltration, Schwann cell orientation, extra-cellular matrix deposition/organization, and axon infiltration, which in turn leads to successful regeneration.
Our specific aims are as follows:
Aim 1 : Investigate the interplay between polymer fiber-based thin film topographyand fibrin cable/ECM organization and glial cell migration during repair of critically sized nerve gaps in vivo.
Aim 2 : Determine the effect of local delivery of diffusible biochemical factors that influence the regenerative sequence to synergistically enhance the regeneration when combined with topographical cues. The innovation here is that we will investigate the previously under-explored interplay between early events of the regenerative/wound healing sequence and intra-luminal thin-film scaffolds that present topographical cues. In addition to this phyiscal template that modulates the regenerative sequence, we further propose to give it a 'biochemical boost'with the sustained local delivery of neurotrophin-3 [Aim 2]. We therefore address a significant clinical problem through the rational design of minimalist, intra-luminal film-based scaffolds that should a) enhance our understanding of intra-luminal scaffold design and b) result in significantly better performance than previously attainable from nerve guidance channels in briding critically sized nerve gaps.

Public Health Relevance

Over 250,000-300,000 peripheral nerve injuries occur every year in the US alone. This research will advance our understanding of the mechanisms of peripheral nerve regeneration that is promoted by intra-luminal scaffolds, and will develop technologies that are likely to improve clinical outcomes after peripheral nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065109-05
Application #
8517218
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Ludwig, Kip A
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$310,066
Indirect Cost
$91,509
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
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Mukhatyar, Vivek J; Salmeron-Sanchez, Manuel; Rudra, Soumon et al. (2011) Role of fibronectin in topographical guidance of neurite extension on electrospun fibers. Biomaterials 32:3958-68
Mokarram, Nassir; Bellamkonda, Ravi V (2011) Overcoming endogenous constraints on neuronal regeneration. IEEE Trans Biomed Eng 58:1900-6
Hoffman-Kim, Diane; Mitchel, Jennifer A; Bellamkonda, Ravi V (2010) Topography, cell response, and nerve regeneration. Annu Rev Biomed Eng 12:203-31