Injectable biopolymer gel compositions for neural tissue repair

Injuries to the brain, spinal cord or other central nervous system (CNS) tissues trigger a cascade of biochemical events that result in an environment that is unfavorable for axonal regeneration and re-establishment of functional connections. Advances in understanding of the cellular and molecular mechanisms underlying spinal cord injury (SCI) over the past twenty years have resulted in the development of a number of therapeutic approaches to treating this critical problem. Biomaterial constructs represent an important and perhaps essential component of spinal cord repair strategies; however the functional and restorative potential of these approaches has not yet been realized.;This research focused on the development, synthesis and properties of biopolymer gel compositions for neural tissue repair. The primary goal was to prepare injectable gels which could function to bridge the lesion, prevent development or progression of a cystic cavity and provide a favorable terrain for axonal regeneration by delivering cells or other growth-promoting factors to the injured spinal cord. Homogeneous alginate (ALG), alginate-carboxymethylcellulose (ALG-CMC) and alginate-hyaluronic acid (ALG-HA) gels suitable for soft tissue engineering applications were synthesized via ionic crosslinking. Gradual gelation was achieved by slow liberation of calcium ions from calcium carbonate by reaction with D-glucono-delta-lactone (GDL). In situ-forming ALG, ALG-CMC and ALG-HA gels have not previously been studied as biopolymer matrices for SCI repair.;All compositions were injectable through a 22-gauge needle prior to crosslinking. Gelation timing was evaluated as a function of biopolymer composition, calcium content, and temperature, and ranged from one to three hours for the conditions studied. Swelling and stability of gels were evaluated in vitro, and oscillatory tests were used to examine rheological properties. The potential for ALG, ALG-CMC and ALG-HA gels as transplantation matrices was investigated by incorporating Schwann cells in gel compositions in vitro.;A pilot animal study was conducted to demonstrate proof of concept in vivo using a clinically relevant SCI model in adult rats. Study animals received midline cervical contusion injuries at C3/C4 using an Infinite Horizon impactor and were treated with an ALG-CMC gel one week later. Histology revealed that the compositions integrated well with host spinal cord tissue and did not initiate a significant inflammatory response. Treated animals also showed minimal evidence of cystic cavitation. Results suggest that injectable alginate-based compositions have significant potential for minimally-invasive treatment of SCI and should undergo further investigation and optimization for neural tissue repair.