Hydrogel-based scaffolds to support intrathecal stem cell transplantation as a gateway to the spinal cord: clinical needs, biomaterials, and imaging technologies

Abstract

The prospects for cell replacement in spinal cord diseases are impeded by inefficient stem cell delivery. The deep location of the spinal cord and complex surgical access, as well as densely packed vital structures, question the feasibility of the widespread use of multiple spinal cord punctures to inject stem cells. Disorders characterized by disseminated pathology are particularly appealing for the distribution of cells globally throughout the spinal cord in a minimally invasive fashion. The intrathecal space, with access to a relatively large surface area along the spinal cord, is an attractive route for global stem cell delivery, and, indeed, is highly promising, but the success of this approach relies on the ability of cells (1) to survive in the cerebrospinal fluid (CSF), (2) to adhere to the spinal cord surface, and (3) to migrate, ultimately, into the parenchyma. Intrathecal infusion of cell suspension, however, has been insufficient and we postulate that embedding transplanted cells within hydrogel scaffolds will facilitate reaching these goals. In this review, we focus on practical considerations that render the intrathecal approach clinically viable, and then discuss the characteristics of various biomaterials that are suitable to serve as scaffolds. We also propose strategies to modulate the local microenvironment with nanoparticle carriers to improve the functionality of cellular grafts. Finally, we provide an overview of imaging modalities for in vivo monitoring and characterization of biomaterials and stem cells. This comprehensive review should serve as a guide for those planning preclinical and clinical studies on intrathecal stem cell transplantation.

Fig. 1

Injection routes of stem cell/biomaterial constructs into the spinal cord

Fig. 2. Effect of immobilization of GRGDS peptide on HAMC hydrogels for the differentiation of rat NSPCs.

Confocal images of rat NSPCs after encapsulation in 0.5/0.5 wt% HAMC gels for 7 days. Cells were stained for anti-RIP (for oligodendrocytes, red) and counterstained with DAPI (for cell nuclei, blue). Reprinted from Tam et al.

Fig. 3. Internalization experiments within cortical glial cell cultures.

a Astrocytes were able to internalize the FITC-labeled CMCht/PAMAM dendrimer nanoparticles after 48 h of incubation. b Oligodendrocytes also were able to internalize the FITC-labeled CMCht/PAMAM dendrimer nanoparticles. Representative image of the nanoparticles distributed along the intracellular compartment. Adapted from Salgado et al.

Fig. 4

Non-invasive imaging of intrathecally injected cell/biomaterial constructs