Ultrasound‐stimulated peripheral nerve regeneration within asymmetrically porous PLGA/Pluronic F127 nerve guide conduit

Abstract

Recently, we developed a novel method to fabricate a nerve guide conduit (NGC) with asymmetrical pore structure and hydrophilicity using poly(lactic-co-glycolic acid) (PLGA) and Pluronic F127 by a modified immersion precipitation method. From the animal study using a rat model (sciatic nerve defect of rat), we recognized that the unique PLGA/Pluronic F127 tube provided good environments for nerve regeneration. In this study, we applied low-intensity pulsed ultrasound as a simple and noninvasive stimulus at the PLGA/F127 NGC-implanted site transcutaneously in rats to investigate the feasibility of ultrasound for the enhanced nerve regeneration through the tube. The nerve regeneration behaviors within the ultrasound-stimulated PLGA/Pluronic F127 NGCs were compared with the NGCs without the ultrasound treatment as well as normal nerve by histological and immunohistochemical observations. It was observed that the PLGA/Pluronic F127 tube-implanted group applied with the ultrasound had more rapid nerve regeneration behavior (approximately 0.71 mm/day) than the tube-implanted group without the ultrasound treatment (approximately 0.48 mm/day). The ultrasound-treated tube group also showed greater neural tissue area as well as larger axon diameter and thicker myelin sheath than the tube group without the ultrasound treatment, indicating better nerve regeneration. The better nerve regeneration behavior in the our NGC/ultrasound system may be caused by the synergistic effect of the asymmetrically porous PLGA/Pluronic F127 tube with unique properties (selective permeability, hydrophilicity, and structural stability, which can provide good environment for nerve regeneration) and physical stimulus (stimulation of the Schwann cells and activation of the neurotrophic factors).

A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery

“…The use of low-intensity US indicated a significant increase in nerve regeneration rates (0.72 mm d -1 in the UStreated group versus 0.48 mm d -1 in the non-treated group) [25]. Likewise, US resulted in increased myelination, axon diameter and thicker regenerative nerve cable [25]. The effects of US stimulation have exhibited comparable results in a number of studies and may hold potential to improve current clinical nerve therapies especially when used in combination with additional regenerative factors, i.e.…”

“…Early attempts of improvements for NGCs involved variations in material design and fulfilling a number of criteria for the ideal hollow conduit. These criteria included: (i) limiting scar infiltration, while allowing diffusion of nutrients into the conduit and wastes to exit the conduit; (ii) providing sufficient mechanical properties for structural support; (iii) exhibiting a low immune response; and (iv) biodegradability, to remove the need for secondary surgery and to prevent chronic inflammation and pain caused by nerve compression due to the eventual collapse of implanted NGCs [25]. For the first criterion, adequate nutrient exchange and waste removal in an NGC can be achieved, if the material is permeable with a molecular weight limit of approximately 50 kDa [26][27][28].…”

“…[ 25] within their conduit design. A bi-layered laminin-coated PLLA conduit, used in combination with intraluminal PLGA fibres, was demonstrated to enhance the modified outer NGC.…”

“…In later studies, these bi-layered coated conduits were combined with external ultrasound stimulation (US), a novel non-invasive approach. The use of low-intensity US indicated a significant increase in nerve regeneration rates (0.72 mm d -1 in the UStreated group versus 0.48 mm d -1 in the non-treated group) [25]. Likewise, US resulted in increased myelination, axon diameter and thicker regenerative nerve cable [25].…”

The Body Acoustic: Ultrasonic Neuromodulation for Translational Medicine

“…Several studies have noted that under the right conditions, application of US stimulation increases the rate of nerve regeneration and restoration of function, as verified by the analysis of animal gait and toe spreading, conduction velocity changes, and immunohistochemistry [Mourad et al, 2001;Tyler et al, 2008;Park et al, 2010].…”