Dense fibroadhesive scarring and poor blood vessel-maturation hamper the integration of implanted collagen scaffolds in an experimental model of spinal cord injury

Abstract

Severe spinal cord injury (SCI) results in permanent functional deficits, which despite pre-clinical advances, remain untreatable. Combinational approaches, including the implantation of bioengineered scaffolds are likely to promote significant tissue repair. However, this critically depends on the extent to which host tissue can integrate with the implant. In the present paper, blood vessel formation and maturation were studied within and around implanted micro-structured type-I collagen scaffolds at 10 weeks post implantation in adult rat mid-cervical spinal cord lateral funiculotomy injuries. Morphometric analysis revealed that blood vessel density within the scaffold was similar to that of the lateral white matter tracts that the implant replaced. However, immunohistochemistry for zonula occludens−1 (ZO-1) and endothelial barrier antigen revealed that scaffold microvessels remained largely immature, suggesting poor blood-spinal cord barrier (BSB) reformation. Furthermore, a band of intense ZO-1-immunoreactive fibroblast-like cells isolated the implant. Spinal cord vessels outside the ZO-1-band demonstrated BSB-formation, while vessels within the scaffold generally did not. The formation of a double-layered fibrotic and astroglial scar around the collagen scaffold might explain the relatively poor implant-host integration and suggests a mechanism for failed microvessel maturation. Targeted strategies that improve implant-host integration for such biomaterials will be vital for future tissue engineering and regenerative medicine approaches for traumatic SCI.

Dual‐Cues Laden Scaffold Facilitates Neurovascular Regeneration and Motor Functional Recovery After Complete Spinal Cord Injury

“…implanted micro‐structured type‐I collagen scaffolds in adult rats with mid‐cervical spinal cord lateral funiculotomy injury; however, spinal cord vessels within the scaffold generally did not regenerate. [ 30 ] In this study, we observed some RECA + vessel regeneration at the lesion site where the hydrogel scaffold was implanted, which indicated that our scaffold is more conducive to the growth and regeneration of spinal cord vessels.…”

Injectable hydrogels in stroke and spinal cord injury treatment: a review on hydrogel materials, cell–matrix interactions and glial involvement

“…It often leads to the formation of fibrous scarring and cystic cavity which obstructs potential neuronal ingrowth. 64,117 Proper integration between the tissue and scaffold often results in a high degree of cell infiltration to modulate the microenvironment in the lesion, given that the architectures of the scaffold are permissive to cell infiltration. 118 In addition, tissue integration is also related to supporting axonal growth by facilitating endogenous cell infiltration and migration and deposition of laminin.…”

Biomaterial and Therapeutic Approaches for the Manipulation of Macrophage Phenotype in Peripheral and Central Nerve Repair

“…More recently, it has been demonstrated that macrophages are responsible for fibroblast recruitment to the injury site and depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation in the lesion site, and this is associated with increased axonal growth [80]. Furthermore, the proliferation of fibroblasts can induce fibrosis around biomaterial implants [81][82][83] a particular caveat of biomaterial use [84], and have been implicated in the relatively poor implant-host integration in some implanted scaffolds [65,85].…”