Severe traumatic injuries and invasive surgical procedures such as tumor resection often create peripheral nerve gaps, accounting for 200,000 injuries in the US annually. The clinical """"""""gold standard"""""""" for bridging peripheral nerve gaps is autografts (typically using sensory sural nerve), where 40~50% of patients regain useful function. However, the use and effectiveness of autografts is limited by several issues, including their limited availability, collateral damage at the donor site, and the presence of inhibitory chondroitin sulfate proteoglycans within the grafts. Therefore, it is critical to develop alternative approaches that match or exceed the performance of autografts. However, the leading bioengineering strategy of using nerve guidance channels has limited efficacy and has not been successful in bridging gaps longer than 10mm in rat models. In the previous grant period, we proposed to design 3D hydrogel based scaffolds with either isotropically or anisotropically distributed ECM (laminin-1) or nerve growth factor (NGF) to bridge gaps longer than 15mm in rats. We successfully designed and fabricated isotropic and anisotropic 3D hydrogels, demonstrated that indeed growth cones extend processes significantly faster in immobilized ECM gradients in vitro and that anisotropic scaffolds with gradients of laminin-1 and NGF are able to bridge 17-20mm gaps, whereas isotropic scaffolds with uniformly distributed LN-1 and NGF do NOT. Though, unfortunately, anisotropic hydrogel scaffolds only meet success 44% of the time in bridging 17-20mm gaps in rats. Therefore, we have developed a new approach to anisotropic scaffolds - using aligned electrospun polymeric nanofibers (diameter 200- 600nm). In our preliminary data, we demonstrate that this novel oriented nanofiber-based 3D scaffold enhances peripheral nerve regeneration across long nerve gaps (17mm rat model) and matches the performance of autografts by anatomical and histological measures. A critical finding of this study was that oriented nanofibers enabled efficient Schwann cell migration into the scaffolds, which was a precursor to realizing the endogenous regenerative potential of severed peripheral nerves. The central hypothesis of this proposal is that functionalizing the polymeric nanofiber based scaffolds with factors that enhance Schwann cell migration and tropic/trophic functions will enable nanofiber based scaffolds to exceed the performance of autografts. We propose testing this hypothesis in a challenging 17mm nerve gap in rodents. In this next generation design, the oriented scaffolds will be biodegradable and `functionalized'to include biochemical cues, such as growth stimulatory extracellular matrix (laminin-1) and trophic protein (Neurotrophin 3, NT-3). We suggest that by concentrating the pro- regenerative cues (structural and biochemical) we can design engineered scaffolds that out-perform autografts in rigorous, clinically relevant animal models of peripheral nerve injury. When complete, this research will represent a significant step in the direction of providing alternatives to autografts for peripheral nerve repair.

Public Health Relevance

200,000 peripheral nerve injuries occur every year in the US alone. This research will advance our understanding of the mechanisms of peripheral nerve regeneration, and develops 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 #
2R01NS044409-07A2
Application #
7531716
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Kleitman, Naomi
Project Start
2002-08-15
Project End
2011-06-30
Budget Start
2009-07-17
Budget End
2010-06-30
Support Year
7
Fiscal Year
2009
Total Cost
$384,796
Indirect Cost
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
Rangavajla, Gautam; Mokarram, Nassir; Masoodzadehgan, Nazanin et al. (2014) Noninvasive imaging of peripheral nerves. Cells Tissues Organs 200:69-77
Mokarram, Nassir; Bellamkonda, Ravi V (2014) A perspective on immunomodulation and tissue repair. Ann Biomed Eng 42:338-51
Mukhatyar, Vivek; Pai, Balakrishna; Clements, Isaac et al. (2014) Molecular sequelae of topographically guided peripheral nerve repair. Ann Biomed Eng 42:1436-55
Valmikinathan, Chandra M; Mukhatyar, Vivek J; Jain, Anjana et al. (2012) Photocrosslinkable chitosan based hydrogels for neural tissue engineering. Soft Matter 8:1964-1976
Mokarram, Nassir; Merchant, Alishah; Mukhatyar, Vivek et al. (2012) Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 33:8793-801
Mokarram, Nassir; Bellamkonda, Ravi V (2011) Overcoming endogenous constraints on neuronal regeneration. IEEE Trans Biomed Eng 58:1900-6
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
Hoffman-Kim, Diane; Mitchel, Jennifer A; Bellamkonda, Ravi V (2010) Topography, cell response, and nerve regeneration. Annu Rev Biomed Eng 12:203-31
Johnson, Mela R; Lee, Hyun-Jung; Bellamkonda, Ravi V et al. (2009) Sustained release of BMP-2 in a lipid-based microtube vehicle. Acta Biomater 5:23-8
Clements, Isaac P; Kim, Young-tae; English, Arthur W et al. (2009) Thin-film enhanced nerve guidance channels for peripheral nerve repair. Biomaterials 30:3834-46

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