Long-Term Efficacy and Safety Outcomes of Transplantation of Induced Pluripotent Stem Cell-Derived Neurospheres with Bioabsorbable Nerve Conduits for Peripheral Nerve Regeneration in Mice

Abstract

The induced pluripotent stem cell (iPSc) offers great potential for cell-based therapy in regenerative medicine. We previously developed tissue-engineered bioabsorbable nerve conduits coated with iPSc-derived neurospheres for use in peripheral nerve repair. Here, we examine the long-term efficacy and safety of using nerve conduits with iPSc technology for peripheral nerve repair in mice. The nerve conduit consisted of an outer layer of a poly <smlcap>L</smlcap>-lactide mesh and an inner layer of porous sponge composed of 50% <smlcap>L</smlcap>-lactide and 50% ε-caprolactone. Secondary neurospheres were derived from mouse iPScs, resuspended and cultured within the conduit for 14 days. Conduits were implanted within surgically administered 5-mm defects in the left sciatic nerve of mice (iPSc group; n = 14). The defects in the control group (n = 13) were reconstructed using the nerve conduit alone. At 4, 8, 12, 24 and 48 weeks postsurgery, motor and sensory functional recovery in the iPSc group had improved significantly more than in the control group. At 24 and 48 weeks, histological analysis revealed axonal regeneration in the nerve conduits of both groups. However, axonal regeneration and myelination were significantly enhanced in the iPSc group. No teratomas were identified in the iPSc group at any time point. Therefore, we here demonstrate that bioabsorbable nerve conduits coated with iPSc-derived neurospheres promote enhanced regeneration of peripheral nerves and functional recovery without teratoma formation in the long term. This combination of iPSc technology and bioabsorbable nerve conduits has the potential to be a safe future tool for the treatment of peripheral nerve defects.

A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity

“…Very few in vitro models have been developed that can capture the myelination process and most of them are derived from primary rodent cells (Lari- osa-Willingham et al, 2016; Schott et al, 2016; Bourre et al, 1979). Some recent studies demonstrate human myelinating oligodendrocytes derived from iPSC (Uemura et al, 2014; Wang et al, 2013), however, only by introducing the cells into mice in vivo. Altogether, cell morphology, immunostaining and cell-cell interactions shown by neuronal and glial cell populations demonstrate that the BMPS recapitulates cellular types and patterns of interactions seen in the human CNS and can therefore be considered organotypic.…”

Protective effect of biodegradable nerve conduit against peripheral nerve adhesion after neurolysis

“…2,9,31 The PLA-PCL material used in the present study has also been used for nerve conduits and has suitable flexibility and gentleness for nerves. 22,30,[55][56][57] As mentioned above, it is important to protect peripheral nerves from scar formation during the initial healing stage, which continues for several weeks after neurolysis. The present study proved that the morphological properties of axons in the nerves wrapped with the nerve conduits were preserved because the PLA-PCL conduit prevented scarring and adhesion of the nerve beyond the initial healing stage without being completely absorbed and while maintaining its flexibility.…”

“…We used the same biodegradable polymer tube for the treatment of peripheral nerve defects as previously reported. 22,30,[55][56][57] The conduit (outer diameter 3 mm; inner diameter 2 mm; length 15 mm) was sized so that it was 1 to 2 mm larger than the diameter of the rat sciatic nerves, which were less than 1 mm, to ensure that no nerve constriction was induced. 25,29 The nerve conduit comprises an outer layer composed of a PLA multifilament fiber mesh and an inner layer composed of a 50% PLA and 50% PCL porous sponge with pores of 10 to 50 mm (Fig.…”

“…In particular, the PLA and PCL copolymer sponge of the inner layer has a honeycomb structure that is minimally damaging to the nerve. 22,30,[55][56][57]…”

“…1). 55 We hypothesized that this biodegradable nerve conduit is useful for both nerve regeneration and protective wrapping of the nerve to prevent scar and adhesion formation. In the present study, we used a rat nerve adhesion model to compare protective nerve wrapping with this nerve conduit versus hyaluronic acid (HA), which has been shown to protect nerves from adhesion formation, by examining the efficacy of each materials to prevent nerve adhesion.…”