Host Response Impairs Tissue Integration of a Fibrin Hydrogel Scaffold Containing Poly(ε-caprolactone) Nanofibers for Peripheral Nerve Repair

The development of bioengineered conduits for the repair of large peripheral nerve defects remains challenging. Here, we introduce a biomimetic fibrin hydrogel scaffold containing stacked arrays of aligned poly(ε-caprolactone) (PCL) nanofibers that mimics the naturally forming fibrin cable seen in transection injuries. We further evaluated the additional encapsulation of Schwann cells (SCs) into the fibrin hydrogel. Nerve regeneration was examined in a 15 mm rat sciatic nerve resection model over a period of 12 weeks, comparing our scaffolds against the autograft, a collagen hollow tube, and a lesion-only control group. Functional and morphometric analyses revealed that the autograft supported the strongest regeneration, followed by the SC-seeded fibrin-nanofiber scaffold and the hollow tube. Unexpectedly, a macrophage-rich core devoid of SCs and regenerated axons formed within both fibrin-nanofiber scaffolds around persisting PCL nanofibers. This core impaired the regenerative potential of the non-SC-seeded fibrin-nanofiber scaffold to the extent that functional regeneration was comparable to that of the lesion-only control group. While the scaffolds were designed to closely mimic and support the natural regenerative environment following nerve transection, our results reveal that these theoretical considerations do not necessarily translate into practice.