Biomaterials used in stem cell therapy for spinal cord injury

Abstract

Spinal cord injury (SCI) is a common, severe damage to the central nervous system. Here, we discuss the use of biomaterials for stem cell transplantation in preclinical and clinical studies for the treatment of patients with SCI, because cell culture materials could influence the differentiation fate of stem cells, and not act only as carriers or scaffolds for delivery of stem cells and their differentiated cells. Therefore, the effects of cell culture materials on stem cell differentiation fate have been discussed. A direct injection of stem cells is the easiest method to transplant stem cells into the site of SCI. However, the stem cell solution tends to leak out from the injection site. Biomaterials such as fibrin have been used to reduce scarring at the transplantation site and facilitate the integration of transplanted stem cells or progenitor cells in animal models of SCI. Transplantation of stem cells using biomaterials (scaffolds or hydrogels) has been reported to be effective for the treatment of SCI in animal models. It would be necessary to investigate the optimal chemical structure, porosity, and morphology of biomaterials used for the transplantation of stem cells.

Introduction

There is a shortage of organs and tissues for treating patients with damaged organs and tissues. Human pluripotent stem cells (hPSCs) such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are excellent candidates for regenerating and repairing damaged organs and tissues because of their ability to induce differentiation in any kind of somatic cell or tissue derived from the three germ layers of the embryo (endoderm, mesoderm, and ectoderm).

Currently, clinical trials involving stem cell therapy using hPSCs (mainly hESCs) have reportedly been developed for only four major diseases, according to the database available at ClinicalTrial.gov; these diseases include spinal cord injury (SCI), macular degeneration, diabetes, and acute myocardial infarction [1], [2]. Although several review articles on clinical trials involving stem cell therapy using hPSCs have been published [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], they did not focus on the bioengineering aspect, and especially on the biomaterials used, such as those for hPSC culture and differentiation, the method of hPSC transplantation and condition, and the hPSC status, such as suspension or monolayer transplantation with and without biomaterials (scaffold and hydrogels) at the injection sites. Therefore, in this review, we describe the current bioengineering approaches, and particularly the biomaterial usage in stem cell therapy with hPSCs, as well as fetal and adult stem cells such as bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of SCI.

SCI is a common, severe traumatic damage occurring in the central nervous system (CNS). SCI is caused by an accident or violence, and is mainly categorized as cervical or thoracic SCI, depending on the injury site (Fig. 1A) [12]. SCI leads to myelopathy and damage to the white matter and myelinated fiber tracts, which carry motor and sensory signals to and from our brain [13]. The SCI pathophysiology is divided into two complex phases, namely, the primary and secondary injury phases (Fig. 1B) [8], [12]. In the primary injury phase, the insult to upper motoneurons by SCI leads to muscle weakness, hypertonia, and hyperreflexia, whereas the damage to lower motoneurons causes muscle atrophy, hyporeflexia, and hypotonia [14]. When the CNS is damaged during SCI, the blood-brain barrier is broken, which allows blood cells to invade medullar tissues; this triggers an inflammatory response, which upregulates excitatory neurotransmitters and inflammatory cytokines, and generates free radicals (Fig. 1B) [8], [13].

The secondary injury phase follows the primary injury phase if there is complex damage at the cellular level, such as (1) massive cellular death because of the host’s immune response to injury, (2) oxidative damage, (3) axonal damage, (4) secondary apoptosis and necrosis, and (5) excitotoxicity [13]. The loss of neurons (glial scar formation in Fig. 1B) in the spinal cord leads to impaired motor function. Neuronal death and axonal demyelination in addition to inflammatory and immune responses impair signal transduction through the spinal cord [15].

There are three distinct therapeutic methods for SCI (Fig. 2) [12]: (1) treatment with drugs having trophic or immunomodulatory functions (e.g., methylprednisolone, 4-aminopyridine, and GM1 ganglioside (monosialotetrahexosylganglioside)) [16], (2) transplantation of scaffolds (nerve guide) to bridge the lesion site, and (3) transplantation of stem or neural cells derived from hESCs, hiPSCs, fetal stem cells, adult stem cells (e.g., mesenchymal stem cells (MSCs), and neural stem cells (NSCs)) or olfactory cells. Stem cell-based therapy is especially expected to bridge the lesion site by creating an environment for remyelination, axon elongation, and formation of new circuits for signal transduction with and without biomaterials. Adult or fetal stem cells, hESCs, and hiPSCs could possibly be used in the treatment of patients with SCI by stem cell-based therapy. Prior to the discussion about the current status of emerging therapies and preclinical trials using hESCs, hiPSCs, and adult or fetal stem cells for SCI with and without biomaterials, the effect of biomaterials used for cell culture on the differentiation of stem cells, and especially on hESCs and hiPSCs, is discussed in the following sections. Differentiated cells derived from hESCs and hiPSCs have typically been used in most clinical trials except a few [17], [18], and biomaterials have been known to guide the differentiation fate of stem cells [2], [19].