Strategies for inducing the formation of bands of Büngner in peripheral nerve regeneration

Abstract

Peripheral human nerves fail to regenerate across longer tube implants (>2 cm), most likely because implants lack the microarchitecture of native nerves, including bands of Büngner. Bands of Büngner comprise longitudinally aligned Schwann cell strands that guide selectively regrowing axons. We aim to optimize tubular implants by integrating artificial bands of Büngner. Three principle strategies for inducing the formation of bands of Büngner were investigated: (a) an aligned extracellular matrix, (b) polarizing differentiation factors, and (c) microstructured biomaterial filaments. In vitro oriented collagen and a combination of differentiation factors (NGF, neuregulin-1, TGF-β) induced Schwann cell alignment to some extent. The most pronounced Schwann cell alignment was evident on ultrathin, endless poly-ɛ-caprolactone (PCL) filaments with longitudinal microgrooves. Precoated PCL filaments proved to be non-cytotoxic, displayed good cell attachment, and supported Schwann cell proliferation as well as guided axonal outgrowth. In vitro on PCL filaments Schwann cells displayed a polarized expression of the cell adhesion molecule L1 similar to that seen in vivo in bands of Büngner after sciatic nerve crush in adult rats. In summary, the integration of bioengineered bands of Büngner based on microstructured polymer filaments in nerve conduits promises to be the most valuable approach to initiating a more efficient regeneration across longer nerve lesions.