Oxygen carrier in core-shell fibers synthesized by coaxial electrospinning enhances Schwann cell survival and nerve regeneration

Abstract

Rationale: Local hypoxia is a challenge for fabrication of cellular grafts and treatment of peripheral nerve injury. In our previous studies, we demonstrated that perfluorotributylamine (PFTBA) could provide short term oxygen supply to Schwann cells (SCs) and counteract the detrimental effects of hypoxia on SCs during the early stages of nerve injury. However, the quick release of oxygen in PFTBA compromised its ability to counteract hypoxia over an extended time, limiting its performance in peripheral nerve injury. Methods: In this study, PFTBA-based oxygen carrier systems were prepared through coaxial electrospinning to prolong the time course of oxygen release. Core-shell structures were fabricated, optimized, and the oxygen kinetics of PFTBA-enriched core-shell fibers evaluated. The effect of core-shells on the survival and function of SCs was examined in both 2D and 3D systems as well as in vivo . The system was used to bridge large sciatic nerve defects in rats. Results: PFTBA core-shell fibers provided high levels of oxygen to SCs in vitro , enhancing their survival, and increasing NGF, BDNF, and VEGF expression in 2D and 3D culture systems under hypoxic condition. In vivo analysis showed that the majority of GFP-expressing SCs in the PFTBA conduit remained viable 14 days post-implantation. We found that axons in PFTBA oxygen carrier scaffold improved axonal regeneration, remyelination, and recovery. Conclusion: A synthetic oxygen carrier in core-shell fibers was fabricated by the coaxial electrospinning technique and was capable of enhancing SC survival and nerve regeneration by prolonged oxygen supply. These findings provide a new strategy for fabricating cellular scaffolds to achieve regeneration in peripheral nerve injury treatment and other aerobic tissue injuries.

Systematic review of the therapeutic use of Schwann cells in the repair of peripheral nerve injuries: Advancements from animal studies to clinical trials

“…They observed a significantly greater survival of GFP labeled SCs within the PFTBA conduit up to 28 days after implantation as compared to the conduit with SCs but without the hydrogel. In Ma et al (2020), the authors demonstrated further enhancement of SC survival in a conduit designed with a core-shell structure containing encapsulated PFTBA. The new scaffold coupled with the PFTBA hydrogel allowed for greater oxygen carrying capacity and increased SC survival during the initial hypoxic phase of nerve regeneration.…”

“…There were 15 studies (Aszmann et al, 2008;Sun et al, 2009;McGrath et al, 2010;Berrocal et al, 2013;Jesuraj et al, 2014;Hoben et al, 2015;Liu et al, 2017;Wang et al, 2017;Gonzalez-Perez et al, 2018;Ma et al, 2018Ma et al, , 2020Huang et al, 2019;Burks et al, 2021;Yao et al, 2021) that evaluated the number of myelinated axons within the graft through light microscopy and/or through immunostaining. Among those, 14 studies demonstrated significant improvement in myelinated axon counts in the graft with SCs as compared to the graft alone (Aszmann et al, 2008;Sun et al, 2009;McGrath et al, 2010;Berrocal et al, 2013;Jesuraj et al, 2014;Hoben et al, 2015;Liu et al, 2017;Wang et al, 2017;Gonzalez-Perez et al, 2018;Ma et al, 2018Ma et al, , 2020Huang et al, 2019;Burks et al, 2021;Yao et al, 2021). The presence of regenerated myelinated axons in the middle of a 10-mm gap were observed as early as 10-14 days after surgery (Huang et al, 2019;Yao et al, 2021) and in the distal end of a 10-mm gap as early as 3-4 weeks (McGrath et al, 2010;Liu et al, 2017;Huang et al, 2019).…”

“…In nearly all studies that employed a reversed autograft group as a positive control (McGrath et al, 2010;Berrocal et al, 2013;Liu et al, 2017;Ma et al, 2018Ma et al, , 2020Burks et al, 2021;Muangsanit et al, 2021) the repair group with implanted SCs demonstrated statistically similar number of myelinated axons as the reversed autograft group that regenerated to the distal segment of the graft used to repair gaps ranging from 10 to 17 mm between 4 and 16 weeks after surgery. Of note, although Aszmann et al (2008) observed that the number of myelinated axons at the distal segment of a much longer gap, about 30 mm, bridged with a homologous nerve graft that was seeded with harvested SCs were significantly fewer, smaller in diameter and had thinner myelination as compared to the autograft group at 12 weeks after surgery, they performed significantly better than the empty grafts, which did not have any axons reach the distal end.…”

Recent applications of electrical, centrifugal, and pressurised emerging technologies for fibrous structure engineering in drug delivery, regenerative medicine and theranostics

“…The ever-increasing process understanding in this remit has enabled the ES process to evolve, yielding complex and innovative systems; including coaxial systems containing multiple concentrically arranged needles (yielding multi-layered fibers) [186,[219][220][221][222][223][224][225][226][227][228][229][230][231][232][233] and electrohydrodynamic printing [2,57,142,[234][235][236][237][238][239][240][241]; enabling the fabrication of prepatterned, aligned fibers. An emerging development includes systems utilising a needleless approach; yielding fibers within the nanometer range without the use of a conductive nozzle [242][243][244][245][246][247][248][249][250][251].…”

“…Whilst there are many advantages to current polymeric biomedical implants, they do not possess the ability to provide sufficient contrasting for imaging and theranostics. These limitations have been overcome by incorporating contrasting agents or markers into electrospun fibrous matrices [220]. By incorporating magnetic complexations or actives, the resulting fibrous systems can be spatiotemporally controlled via a magnetic field which is operated externally [408].…”