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

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 pre-clinical and clinical studies on intrathecal stem cell transplantation.Funds provided under the project NanoTech4ALS (ref. ENMed/0008/2015, 13/EuroNanoMed/2016), funded under the EU FP7 M-ERA.NET program, Strategmed 1/233209/12/NCBIR/2015, and NIH R01 NS091100. The FCT distinction attributed to J.M.O. under the Investigator FCT program (IF/01285/2015) is also gratefully acknowledgedinfo:eu-repo/semantics/publishedVersio

Translational considerations in injectable cell-based therapeutics for neurological applications: concepts, progress and challenges

Significant progress has been made during the past decade towards the clinical adoption of cell-based therapeutics. However, existing cell-delivery approaches have shown limited success, with numerous studies showing fewer than 5% of injected cells persisting at the site of injection within days of transplantation. Although consideration is being increasingly given to clinical trial design, little emphasis has been given to tools and protocols used to administer cells. The different behaviours of various cell types, dosing accuracy, precise delivery, and cell retention and viability post-injection are some of the obstacles facing clinical translation. For efficient injectable cell transplantation, accurate characterisation of cellular health post-injection and the development of standardised administration protocols are required. This review provides an overview of the challenges facing effective delivery of cell therapies, examines key studies that have been carried out to investigate injectable cell delivery, and outlines opportunities for translating these findings into more effective cell-therapy interventions

Photoreceptor Transplantation and Regeneration

A recent study showed that an electronic chip implanted under the human retina restored some extent of vision to a blind patient. Because the device was implanted where the light sensitive cells, the photoreceptors, should have been, this study demonstrated that it is possible to take advantage of the internal circuitry of the retina even in the absence of photoreceptors and in the presence of extensive glial and neuronal reorganization. This result strongly supports the development of cell replacement therapies for the cure of photoreceptor degeneration, provided that the cells are implanted in the same anatomical location. Similarly to other sensory neurons but differently from neurons lost in most degenerative diseases, photoreceptors are the first neurons of the circuit and only have to make efferent connections. Secondly, photoreceptors are histologically located in a restricted region of the organ. These features make them the most immediately transplantable type of neuron and interesting candidates for clinical trials involving cell transplantation. In cell replacement therapies the identification of the source of cells able to integrate and connect to the host tissue needs to be defined. For the retina, cells showing the best survival and integration rates are post-mitotic rod precursors, rather than immature retinal progenitors. Given the difficulty of obtaining human fetal cells, many studies are undergoing to differentiate cells with such features starting from stem cells. Three main classes of stem cells are under investigation to be sources for in vitro photoreceptor generation. They are embryonic stem cells, induced pluripotent stem cells and adult retinal stem cells. This chapter will describe the current preclincal studies for in vitro generation and subsequent transplantation of photoreceptor precursors

The Axolotl Limb Regeneration Model as a Discovery Tool for Engineering the Stem Cell Niche

Purpose of reviewRecent advances in genomics and gene editing have expanded the range of model organisms to include those with interesting biological capabilities such as regeneration. Among these are the classic models of regeneration biology, the salamander. Although stimulating endogenous regeneration in humans likely is many years away, with advances in stem cell biology and biomedical engineering (e.g. bio-inspired materials), it is evident that there is great potential to enhance regenerative outcomes by approaching the problem from an engineering perspective. The question at this point is what do we need to engineer?Recent findingsThe value of regeneration models is that they show us how regeneration works, which then can guide efforts to mimic these developmental processes therapeutically. Among these models, the Accessory Limb Model (ALM) was developed in the axolotl as a gain-of-function assay for the sequential steps that are required for successful regeneration. To date, this model has identified a number of proregenerative signals, including growth factor signaling associated with nerves, and signals associated with the extracellular matrix (ECM) that induce pattern formation.SummaryIdentification of these signals through the use of models in highly regenerative vertebrates (e.g. the axolotl) offers a wide range of possible modifications for engineering bio-inspired, biomimetic materials to create a dynamic stem cell niche for regeneration and scar-free repair