Despite significant efforts developing biomaterials to direct axon growth, decellularized nerve allografts and nerve autografts remain the only clinical alternatives for repairing peripheral nerve injuries with transected nerve gaps of 2-12 cm. It is our belief that this is because many biomaterials for nerve regeneration do not faithfully reproduce the tubular microstructure of natural nerve extracellular matrix. Specifically, success of decellularized nerve allografts in repairing nerve gaps of ~5 cm is in large part due to preservation of aligned ~10 m diameter basal lamina tubes that direct axon growth and nerve reconnection. Unfortunately, nerve allografts require expensive processing procedures, limiting broad patient access due to high cost, and pose the risk of disease transmission. On the other hand, nerve autografts result in donor site morbidity and only 40- 50% success rates. Hence, there is a critical need for novel approaches to engineer regeneration scaffolds that may replace allografts and autografts in peripheral nerve injury repair. The goal of this exploratory/development project is to develop and test a new approach to obtain nerve regeneration scaffolds consisting of naturally derived crosslinked hydrogels with embedded tubular microstructure mimicking the nerve basal lamina. The proposed approach, magnetic templating, consists of dispersion of magnetic alginate microparticles in a pre-hydrogel solution, alignment of the microparticles into gap-spanning columnar structures with a magnetic field, hydrogel crosslinking in the field, and dissolution of the magnetic alginate microparticles, leavin behind aligned, continuous and interconnected gap-spanning channels with diameters that make them suitable for directing axon growth. Magnetic templating has the advantages of: (i.) aligned continuous tubular microstructure that mimics nerve basal lamina tubes in diameter and length; (ii.) compatibility with natural-based hydrogels, resulting in scaffolds with minimal immunogenicity or toxicity; (iii.) compatibility with biomolecules, enabling future incorporation o chemical and biological cues to further guide nerve growth; (iv.) scalability to lengths in centimeters; and (v.) process simplicity and scalability that will reduce cost and broaden patient base. We will achieve the project's goal through two specific aims designed to test our hypotheses:
(AIM 1) that tubular structure alignment, diameter, and connectivity are determined by overall concentration, diameter and magnetic nanoparticle content of the magnetic alginate microparticles, and the magnitude and direction of the magnetic field applied during the templating process;
and (AIM 2) that incorporation of linearly oriented channels through magnetic templating will increase axonal extension into hyaluronan/collagen hydrogels in vitro and in vivo. Completion of these studies will inform and motivate future phases of research to develop and translate magnetically templated regeneration scaffolds as alternatives for nerve allografts and autografts in peripheral nerve injury repair. This approach also has broad applicability for other tissue repair applications.

Public Health Relevance

This project aims to develop and test a low-cost, scalable process based on magnetic templating of dissolvable magnetic microparticles in a crosslinked natural-based hydrogel to produce nerve regeneration scaffolds with gap-spanning, aligned microchannels that mimic the natural nerve basal lamina and are therefore more effective at guiding axon extension and nerve reconnection. The project is motivated by PI Schmidt's previous experience developing and translating technology that led to AxoGen Inc.'s Advance(r) nerve graft, for which low cost alternatives based on naturally-derived biomaterials are desirable. As such, the proposed work is the first step in a continuum of research and development efforts that will lead to clinical translation of alternatives to nerve allografts and autografts in peripheral nerve injury repair.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Jakeman, Lyn B
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University of Florida
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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Garcia, Andrew R; Lacko, Christopher; Snyder, Catherine et al. (2017) Processing-Size Correlations in the Preparation of Magnetic Alginate Microspheres Through Emulsification and Ionic Crosslinking. Colloids Surf A Physicochem Eng Asp 529:119-127