Fabrication and characterization of biomimetic multichanneled crosslinked‐urethane‐doped polyester tissue engineered nerve guides

Abstract

Biomimetic scaffolds that replicate the native architecture and mechanical properties of target tissues have been recently shown to be a very promising strategy to guide cellular growth and facilitate tissue regeneration. In this study, porous, soft, and elastic crosslinked urethane-doped polyester (CUPE) tissue engineered nerve guides were fabricated with multiple longitudinally oriented channels and an external non-porous sheath to mimic the native endoneurial microtubular and epineurium structure, respectively. The fabrication technique described herein is highly adaptable and allows for fine control over the resulting nerve guide architecture in terms of channel number, channel diameter, porosity, and mechanical properties. Biomimetic multichanneled CUPE guides were fabricated with various channel numbers and displayed an ultimate peak stress of 1.38 ± 0.22 MPa with a corresponding elongation at break of 122.76 ± 42.17 %, which were comparable to that of native nerve tissue. The CUPE nerve guides were also evaluated in vivo for the repair of a 1 cm rat sciatic nerve defect. Although histological evaluations revealed collapse of the inner structure from CUPE TENGs, the CUPE nerve guides displayed fiber populations and densities comparable with nerve autograft controls after 8 weeks of implantation. These studies are the first report of a CUPE-based biomimetic multichanneled nerve guide and warrant future studies towards optimization of the channel geometry for use in neural tissue engineering.

Citrate chemistry and biology for biomaterials design

“…By doping urethane bonds into the polyester chains between ester crosslinks, a new class of polymer named crosslinked urethane-doped polyesters (CUPEs) has been developed by reacting with hexamethylene diisocyanate (HDI) with pendant hydroxyl groups as a chain extender to possess enhanced hydrogen bonding within polymer network, thus significantly improving mechanical strength to be 41.07± 6.85 MPa with a corresponding elongation at break of 222.66 ±27.84%. Importantly, when fabricated into CUPE scaffolds [29, 30], the tensile strength of biophasic scaffolds remained 5.02±0.70MPa, which was greater than native blood vessels (1.43±0.60 MPa) [30], while fabricated CUPE nerve guides with biomimetic multichannel structure still display an ultimate peak stress of 1.38±0.22 MPa with a corresponding elongation at break of 122.76±42.17%, comparable to that of native nerve guides [31]. Even when fabricated into porous triphasic vascular scaffolds, a suture retention strength of 1.79±0.11N [32] was obtained meeting the standard (1.7 N) for surgical suturing.…”

Citrate-Based Biomaterials and Their Applications in Regenerative Engineering

“…Owing to their elasticity, strength, and biocompatibility, CBBs have been investigated as a potential material for the regeneration of peripheral nerves. Porous and elastic nerve-guide scaffolds based on CUPEs have been fabricated with multiple internal longitudinally oriented channels as well as an external nonporous sheath to mimic the native endoneurial microtubular structure and epineurium (124). The fabrication technique provides versatility for designing the scaffold channel geometry, porosity, and mechanical properties.…”

“…The fabrication technique provides versatility for designing the scaffold channel geometry, porosity, and mechanical properties. The authors (124) hypothesized that peripheral nerve guides fabricated using CUPEs would have the strength and elasticity required to withstand physiological tensions and strains as well as surgical handling. CUPE multichanneled scaffolds displayed an ultimate peak stress of 2.83 ± 0.24 MPa with corresponding elongations at break values of 259.60 ± 21.49%, which are in the range of native nerve mechanical properties.…”

The critical chemical and mechanical regulation of folic acid on neural engineering

“…In order to confirm the in vitro findings above and to examine the in vivo efficacy of locally-delivered folic acid to promote peripheral nerve regeneration, we prepared kink-resistant, soft, elastic, and biodegradable crosslinked urethane-doped polyester (CUPE) NGCs [18,28] (Figure 6a) by first 1) coating glass rods with a CUPE pre-polymer solution, 2) controlled, thermal post-polymerization of CUPE, and 3) leaching of the CUPE NGCs in DI water followed by freeze-drying. Folic acid-modified CUPE (fCUPE) NGCs were made by dip-coating CUPE NGCs in PBS of 100-mg/L folic acid.…”

“…CUPE NGCs have already shown successful morphological recovery in a 10-mm rat sciatic defect model [28] so folic acid was added to further enhance their performance in treating large nerve defects. Folic acid-coated CUPE NGCs resulted in the promising PNS regeneration and functional recovery that are comparable to those of the autografts.…”