Peripheral nerve injuries can result from tumor resection, reconstructive surgery or trauma and cause life-long disabilities in most affected patients. The current clinical approach is to use scarce nerve autografts, and when available, their performance is unsatisfactory with less than a 50% rate of full functional recovery. The use of bioengineering three-dimensional scaffolds to obviate the need for autografts is a promising approach. However, the current generation of scaffolds is not effective in matching the performance of autografts even when tested in short nerve gaps (<5-7mm) in rodents. We propose to design fabricate and evaluate the next generation of three-dimensional (3D) bioengineered scaffolds that will significantly enhance peripheral nerve regeneration. An understanding of the relevant molecular architecture of nerve autografts inspires the design criterion for these scaffolds. We propose an innovative anisotropic scaffold design to evoke directional stimulation of nerve regeneration. Our scaffolds are engineered to present an increasing concentration gradient of bound laminin-1 and diffusible nerve growth factor (NGF) in nerve growth permissive 3D scaffolds to present an anisotropic biochemical environment to the regeneration nerve stump. Novel methods for spatially controlled 3D presentation of laminin-l, and for the sustained, local delivery of NGF are proposed. Laminin-1 and NGF are the two most critical proteins responsible for nerve autografts' limited success. Our central hypothesis that biomimetic, amsotropic three-dimensional scaffolds that contain an increasing gradient of growth promoting proteins along the axis of the nerve gap will match or exceed the performance of nerve autografts. Specifically, our scaffolds are designed to a) perform better than nerve autografts in the 10 mm gap model in rodents; and b) at least match the performance of autografts in a larger, clinically relevant, 25 mm nerve gap in cats. Importantly, we propose a quantitative evaluation of functional recovery due to regeneration across our scaffolds (to complement standard histological analysis) in both of our animal models as the critical outcome measure of success. When successful, the proposed research will represent a significant advance in the state-of-the-art in 3D biomaterials scaffold design, and has the potential to significantly impact the clinical repertoire available for treating peripheral nerve defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS044409-02
Application #
6788564
Study Section
Special Emphasis Panel (ZRG1-SSS-M (01))
Program Officer
Kleitman, Naomi
Project Start
2002-08-15
Project End
2007-07-31
Budget Start
2003-07-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$49,659
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

Showing the most recent 10 out of 16 publications