The effect of a polyurethane-based reverse thermal gel on bone marrow stromal cell transplant survival and spinal cord repair

Abstract

Cell therapy for nervous tissue repair is limited by low transplant survival. We investigated the effects of a polyurethane-based reverse thermal gel, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU) on bone marrow stromal cell (BMSC) transplant survival and repair using a rat model of spinal cord contusion. Transplantation of BMSCs in ESHU at three days post-contusion resulted in a 3.5-fold increase in BMSC survival at one week post-injury and a 66% increase in spared nervous tissue volume at four weeks post-injury. These improvements were accompanied by enhanced hindlimb motor and sensorimotor recovery. In vitro, we found that ESHU protected BMSCs from hydrogen peroxide-mediated death, resulting in a four-fold increase in BMSC survival with two-fold fewer BMSCs expressing the apoptosis marker, caspase 3 and the DNA oxidation marker, 8-Oxo-deoxyguanosine. We argue that ESHU protected BMSCs transplanted is a spinal cord contusion from death thereby augmenting their effects on neuroprotection leading to improved behavioral restoration. The data show that the repair effects of intraneural BMSC transplants depend on the degree of their survival and may have a widespread impact on cell-based regenerative medicine.

Recent advances in synthetic polymer based hydrogels for spinal cord repair

“…The latter allowed enzymatic degradation of the hydrogel in the presence of cholesterol esterases. They showed, in a spinal cord contusion model, that transplantation of bone marrow stromal cells (BMSCs) in hydrogel enhanced cell survival and led to superior locomotor and sensory-motor recovery [68]. In another study, Jones et al reported the preparation of PEG hydrogels containing a collagenase-sensitive peptide, allowing for hydrogel degradation in the ECM microenvironment [69].…”

Bone Marrow-derived Mesenchymal Stem Cell Transplant Survival in the Injured Rodent Spinal Cord

“…Neutrophils and macrophages may also cause MSC death by the formation of reactive oxygen species that cause membrane damage leading to death. Indeed, transplanting the cells within a polyurethane-based biogel with antioxidative properties increases short term (one week) survival of MSCs [6]. Longer term (4 week) survival however, is unaffected by this gel, probably due to biodegradation of the gel.…”

“…Table 1 provides an overview of studies that have reported on bone marrow-derived MSC survival after transplantation into animal models of spinal cord injury. Studies that provide quantitative data on MSC survival after SCI report survival rates between 0 [14,15] and 52% [8] one week after transplantation and between 0 [6,[16][17][18][19][20] and 8% [21] one month after transplantation without survival enhancing therapies. In some cases, presence of MSCs up to two months [2,13,[22][23][24][25] and even three months [11,26,27] was reported after transplantation into models of spinal cord injury, but usually no or very few cells survive at these time points.…”

“…However, survival of MSCs in the injured spinal cord is poor, limiting the availability of these trophic factors to the nearby nervous tissue and thus their effects that lead to repair. Because it has been shown that improved survival of MSCs is associated with improved anatomical and/or functional repair [5][6][7][8][9][10][11][12][13], it is important to understand mechanisms of transplanted cell death and to develop strategies to improve MSC survival. This review provides an overview of studies that have investigated MSC survival in the injured spinal cord and summarizes current MSC survival promoting strategies, specifically focusing on bone marrow-derived MSCs.…”

Positively Charged Oligo[Poly(Ethylene Glycol) Fumarate] Scaffold Implantation Results in a Permissive Lesion Environment after Spinal Cord Injury in Rat

“…Other investigators have used a variety of biomaterials in SCI as injectable, nonstructured delivery vehicles after partial lesions such as hemisection, [24][25][26][27][28][29] contusion, or compression injury. 30,31 These incomplete lesion models spare a degree of CNS tissue at the injury site, thus in these models it is difficult to differentiate between true regeneration and distal axonal sprouting or remodeling. The complete transection lesion followed by scaffold placement provides a model where regeneration can be studied functionally and anatomically and the local environment in and around the scaffold precisely controlled.…”