Dynamics of tissue ingrowth in SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores after bridging a spinal cord transection

Abstract

While many types of biomaterials have been evaluated in experimental spinal cord injury (SCI) research, little is known about the time-related dynamics of the tissue infiltration of these scaffolds. We analyzed the ingrowth of connective tissue, axons and blood vessels inside the superporous poly (2-hydroxyethyl methacrylate) hydrogel with oriented pores. The hydrogels, either plain or seeded with mesenchymal stem cells (MSCs), were implanted in spinal cord transection at the level of Th8. The animals were sacrificed at days 2, 7, 14, 28, 49 and 6 months after SCI and histologically evaluated. We found that within the first week, the hydrogels were already infiltrated with connective tissue and blood vessels, which remained stable for the next 6 weeks. Axons slowly and gradually infiltrated the hydrogel within the first month, after which the numbers became stable. Six months after SCI we observed rare axons crossing the hydrogel bridge and infiltrating the caudal stump. There was no difference in the tissue infiltration between the plain hydrogels and those seeded with MSCs. We conclude that while connective tissue and blood vessels quickly infiltrate the scaffold within the first week, axons show a rather gradual infiltration over the first month, and this is not facilitated by the presence of MSCs inside the hydrogel pores. Further research which is focused on the permissive micro-environment of the hydrogel scaffold is needed, to promote continuous and long-lasting tissue regeneration across the spinal cord lesion.

Modified Methacrylate Hydrogels Improve Tissue Repair after Spinal Cord Injury

“…Previous studies have also shown that fibronectin enhances axonal ingrowth after SCI but the studies were restricted to a short time evaluation period. This may not, however, reflect long-term data as we have shown in our recent paper [ 39 ]. In our study, fibronectin modification of the HEMA scaffold showed some increased but statistically insignificant difference in the ingrowth of axons into the peripheral and also central parts, while there were no axonal sprouts present in the plain HEMA 3 months after SCI.…”

Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis

“…The hydrogels, either empty or seeded with rat MSCs, were implanted in the spinal cord transection. However, MSCs seeded in the scaffold did not enhance tissue infiltration into the pores, and only rare axons crossing the hydrogel bridge were observed after 6 months, which suggests that this type of scaffold did not provide an optimal environment for neural tissue repair ( Hejcl et al, 2018 ).…”

Biomaterials reinforced MSCs transplantation for spinal cord injury repair

“…The therapeutic system exhibited significant potential for the rehabilitation of SCI. In addition to PLGA scaffolds, a SIKVAV-modified highly superporous poly(2-hydroxyethyl methacrylate) (HEMA) hydrogel with oriented pores was constructed by Aleš Hejčl's team [126] . Their results indicated that connective tissue and blood vessels quickly infiltrated the scaffold within the first week after therapeutic intervention, and axons gradually infiltrated from the first month.…”

“… Types Biomaterials Mechanisms/Functions Ref. Scaffolds collagen Regulating adhesion, proliferation, and differentiation through focal adhesion kinase-Src (FAK-Src) and RhoA/ROCK signaling pathway [101] , [102] , [103] , 153] HA Promoting cellular adhesive growth through reacting with CD44; Restoring protective microenvironment via anti-inflammation and reducing glia scar [112 , 130] RGD/fibrinogen modified HA-PH Enhancing adhesion and proliferation [116] gelatin Mitigating inflammation; Inhibiting necrosis and apoptosis; Promoting neuron-like differentiation [56 , 80 , 139 , 141] RGD ECM Integrin binding [124] fibrin Inducing oriented adhesion, promoting neuron-like differentiation and axonal sprouting/regeneration [121 , 123] alginate Axonal sprouting/regeneration [122] chitosan Rheological properties similar to nerve tissue contributed to MSCs viability; Synergistically modulating inflammation with MSCs [155] PLGA Maintaining stemness [8 , 15] p(HEMA-AEMA) Promoting integration to host tissue [126] RGD modified agarose/carbomer RGD motif increased MSCs adhesion; ECM deposition maintained MSCs viability [125] Inorganic nanoparticles MnO 2 Scavenging ROS [130] …”