Base assumptions for illustration series:
Interstump gap length of approximately 10-15mm
o Transected nerve repaired
within 90 days of original injury
o Transected nerve endings
resected back to healthy tissue
Repair of a 3-4mm diameter nerve
Cross section illustration is at midgraft
Hours is ~0-48 hours
Days is about 2-7 days
Weeks is ~1-8 weeks
Months is ~2-12 months
Years are ~1+ years.
Sural nerve is the most commonly used donor nerve but it is typically small diameter which often results in a size mismatch to the nerve being repaired. Furthermore, because they are smaller caliber, fascicular patterns (number and size of fascicles) often do not match fascicular patterns of the nerve being grafted1. Upon implantation, the tubes of the autograft are filled with debris (e.g. axons and myelin) and cells from the site where it was harvested. Within hours following implantation of a nerve autograft, the graft is revascularized and the cells begin clearing out debris in the tubes and preparing the structure to serve as a scaffold for regenerating axons (see Hours). Within days the tubes have been completely cleared, Schwann cells (SCs) line up in each tubes and regenerating axons begin spouting trying to find tubes to grow into (see Days). While some tubes remain empty, axon regeneration is well distributed throughout the entire cross section of the graft because of the organization of tubes in the nerve tissue that serves as an optimum physical scaffold for cell and axon in growth (even distribution of tubes throughout). Within weeks, the regenerating axons that have found a tube to guide it are close to bridging the entire length of the nerve gap (see Weeks). Over time these axons regenerate across the entire length of the graft then continue on to the target site e.g. muscle or skin. Over the next several months, these axons continue to mature (get thicker) and remyelinate (see Months) resulting in a new nerve segment that, depending on the injury and nerve being repaired, may be thinner then the recipient’s own nerve yet is functional (see Years).2
Within hours following implantation of a conduit, fluid containing inflammatory cells and secreted trophic factors fills the conduit (see Hours). Within days, a fibrin cable forms inside the tube. Regeneration cannot successfully occur within a conduit without the formation of this fibrin matrix, which serves an essential function as a physical bridge across the nerve gap and provides contact guidance for cells. Notably the thickness and quality of the cable, which effectively provides the total available regeneration area, is inversely related to the size of the conduit and often does not fill the entire volume of the tube or does not even form at all if the gap length is too long (see Days). Over the next several weeks following implantation, SCs infiltrate from both stumps and grow along the fibrin cable. Some of the SCs are able to line up and form aligned tubes making a structure that can physically guide regenerating axons across the nerve gap. Axon regeneration is centralized to where the fibrin cable forms. Some of these SC tubes remain empty and any regenerating axons that do not locate a SC tube to guide it get pruned back and die (see Weeks). Over time, axons that are able to find and regenerate within a SC tube grow across the entire length of the conduit and continue on to the target site e.g. muscle or skin (see Months). Timing for the stability of conduits is crucial. Conduits need to remain stable until regeneration occurs across the nerve gap but once regeneration has occurred, the conduit is useless and its continued presence is only a potential hazard which is why the majority of nerve conduits are composed of non-permanent materials that degrade or resorb over time.1 Depending on the size of the nerve discontinuity and on the type of injury, adequate nerve repair can be achieved but often the resulting new nerve segment is thinner and its function is highly variable (see Years).3,4
Since Avance® is available in a range of sizes; it can more readily be sized to match the nerve being repaired. Immediately upon implantation, Avance® provides multiple empty open tubes that provide a physical scaffold for axon and cell in growth. Within hours, axons may begin sprouting but the decellularized matrix must first revascularize and repopulate with cells before any meaningful regeneration can occur (see Hours). Within days, SCs infiltrate from both stumps, grow into the empty tubes and align forming tube structures that guide axon regeneration across the nerve gap (see Days). Within weeks, many but not all of the SC tubes are filled with regenerating axons that have remyelinated. Axon regeneration is well distributed throughout the entire cross section of Avance® because of the organization and even distribution of tubes throughout the tissue matrix (see Weeks). Over time these axons regenerate across the entire length of Avance® and continue on to the target site e.g. muscle or skin. Over the next several months, these axons continue to mature (get thicker) and remyelinate (see Months) resulting in a new nerve segment that, depending on the injury and nerve being repaired, is closely sized to the recipient’s own nerve and is functional (see Years).3,5,6,7
||Meek MF and Coert JH. Clinical Use of Nerve Conduits in Peripheral Nerve Repair: Review of the Literature. J Reconstruct Microsurg. Feb 202; 18(2):97-109.
||Lundborg G. A 25 Year Perspective of Peripheral Nerve Surgery: Evolving Neuroscientific Concepts and Clinical Significance. J Hand Surg. 2000; 25A: 391-414
||AxoGen Internal Report: RD-001
||Dahlin LB and Lundborg G. Use of Tubes in Peripheral Nerve Repair. Neurosurg Clin N Amer. Apr 2001; 12(2): 341-352.
||Karabekmez FE, Duymaz A, Moran SL. Early Clinical Outcomes with the use of Decellularized Nerve Allograft for Repair of Sensory Defects Within the Hand. Hand (NY) 2009; 4(3): 245-9
||Whitlock EL, Tuffaha SH, Luciano JP, Yan Y, Hunter DA, Magill CK, Moore AM, Tong AY, Mackinnon SE, Borschel GH. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve. 2009; 39(6):787-99.
||Evans PJ, Midha R, Mackinnon S. The Peripheral Nerve Allograft: A Comprehensive Review of Regeneration and Neuroimmunology. Prog Neurobiol. 1994; 43: 187-23