Leading OpinionPeripheral nerve regeneration: An opinion on channels, scaffolds and anisotropy☆
Section snippets
The problem
Peripheral nerve regeneration is a serious clinical problem. In 1995, there were in excess of 50,000 peripheral nerve repair procedures performed in the United States [1]. The data, however, probably underestimates the number of nerve injuries, as not all surgical or traumatic lesions can be repaired. Coaptation of the two nerve ends is commonly used to repair short nerve defects. When larger nerve gaps exist (20 mm or longer in humans), the current clinical gold standard for repairing larger
Nerve guidance channels (NGCs)
To date, much of the research effort has focused on nerve guidance channels to enhance regeneration across nerve gaps. While they improve regeneration when compared to no intervention, guidance channels rarely approach or match the performance of autografts when the gaps are 10 mm or longer (in rats). This includes numerous studies with varying permeability of the guidance channels [4], [5], involving electrically active channels [6], [7], as well as degradable guidance channels [8], [9]. While
Nerve guidance channels may need to carry other scaffolds
The rationale for filling NGCs with ‘engineered’ constructs is the following. When nerve gaps are short and inherent regeneration is possible, a fibrin cable forms across the nerve gap [10], [11] allowing for Schwann cell infiltration and the formation of the Bands of Bungner, which are oriented columns of laminin-1 and aligned Schwann cells. Regenerating fibers then enter the gap and follow these Bands of Bungner, reach the distal end of the severed nerve, enter it and go on to re-innervate
Rational design of scaffolds for peripheral nerve repair
Pursuing this logic, several groups have implanted natural and synthetic biomaterials, cells, microfibers, nanofibers, chondroitinase ABC digested autografts, and Schwann cells seeded in Matrigel to enhance regeneration across peripheral nerve gaps. An analysis of these various approaches reveals that 4 essential components of grafts are typically manipulated to enhance regeneration across peripheral nerve gaps. These components are the growth permissive substrates (hydrogels or nano/micro
A case for anisotropy in scaffold design
Anisotropic distribution of the four components influencing peripheral nerve regeneration may enable faster or better regeneration, by exploiting the differential response of growth cones to changes in structural (oriented scaffolds vs. non-oriented scaffolds) or biochemical features (gradients of trophic or ECM proteins). Prof. Letourneu's pioneering work suggests that growth cone extension across gradients (even if it is down an LN-1 gradient) is superior to growth across uniformly
The third dimension: a closer look
Another important consideration in designing strategies for enhancing peripheral nerve regeneration are the kinds of approaches one takes to fill the NGCs with bioactive features (physical/structural as well as biochemical/biological). There has been a vigorous debate on the need for the development of 3D substrates/gels/scaffolds because they are more ‘biomimetic’. However, in general, neurite extension on 2D surfaces, including tissue culture plates, is better than when cells are embedded in
Animal models and evaluation of regeneration
Integral to designing and characterizing the ideal engineered constructs for peripheral nerve regeneration are the animal models used, the methods of analysis that determine success, and the criteria used to define success. In rat models, it is imperative that two factors be involved, a gap greater than 15 mm, and controls involving autografts. Secondly, should regeneration in such models be successful, it is important to test the engineered scaffolds in larger animals, with gaps greater than 40
Conclusion
In conclusion, although a definitive engineered alternative to autografts has yet to be identified, several promising methods are approaching the performance of autografts. Engineered constructs whose design is inspired by an understanding of the distribution of structural, and biochemical features of autografts are more likely to succeed. Examples of such design include constructs that mimic autografts’ anisotropic physical features, including the oriented columns of Schwann cells and
Acknowledgements
The author acknowledges several former and current post-docs, research engineers and graduate and undergraduate students, including Dr. Xiaojun Yu, Dr. Young-tae Kim, Mr. Michael Tanenbaum and Mr. Mahesh Dodla. Mr. Dodla is also acknowledged for the illustrations. Funding from NIH NS44409 and GTEC, an NSF funded Engineering Research Center at Georgia Institute of Technology/Emory University is acknowledged.
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Editor's Note: Leading Opinions: This paper is one of a newly instituted series of scientific articles that provide evidence-based scientific opinions on topical and important issues in biomaterials science. They have some features of an invited editorial but are based on scientific facts, and some features of a review paper, without attempting to be comprehensive. These papers have been commissioned by the Editor-in-Chief and reviewed for factual, scientific content by referees.