Polymerized Estrogen Microfibers in Injectable Hydrogels for Astrocyte-Mediated Neurite Guidance and Protection

Rensselaer Polytechnic Institute, Troy NY

Investigators

Abstract

Non-Technical Abstract The central nervous system (CNS), including the brain and the spinal cord, is a complex superhighway of information transport within the human body. The CNS is vital to conducting the many varied processes of life, but it is also a remarkably fragile, soft tissue. Traumatic injuries to the brain or spine can lead to swelling, inflammation, and scarring that prevent full functional recovery in nearly all patients. Many drugs are available to treat such injuries, but unfortunately the outcomes are still quite poor – in part because of the complexity of the response to the injury and difficulty in delivering the medicine precisely where and when it is needed. There is hence an urgent impetus for novel science and engineering approaches to figure out how to improve drug efficacy within the injured CNS. In this project, the team are building new materials that are composed of drug molecules strung together in long chains called “polymers”. These polymerized drugs can act as a structural implant for supporting the growth of cells such as neurons from the brain and spinal cord, while gradually releasing small amounts of drug molecules locally at the site of implantation. Specifically, they are using recently invented polymers of estrogen, which is known to promote regenerative effects in the spinal cord post injury. The team will examine the fundamental scientific relationships between the structure of these materials and how critically important cells from the central nervous system respond to them, including neurons and other cells that assist in controlling neuron behavior. Two material formulations will be studied: one is an array of microscopic fibers, which mimics the fibrillar proteins that often guide cell growth in the body and the other is a soft hydrogel material, which is basically like the pharmaceutical equivalent of Jello. They hypothesized that combining these two drug-containing materials together into a single hybrid conduit will help us understand how to coax cells in the injured CNS to avoid scarring and inflammation and promote healing and regeneration of healthy tissue. The information gleaned from this work could someday pave the way for new therapeutic approaches to spinal cord injury and traumatic brain injury. The team will engage undergraduates in science writing such as creating and editing Wikipedia pages and submissions to the open-source journal, Wiki. J. Sci. Technical Abstract Contusive injuries to the central nervous system provoke acute trauma, inflammation, and swelling, followed by a complex and chronic secondary injury cascade which ultimately prevents full functional recovery. The 17β-estradiol (E2) hormone has been shown to promote functional recovery in rodent models but requires repeated systemic administration. The team proposes to develop novel implantable biomaterials composed of polymerized pro-drugs of 17β-estradiol (E2), formulated as oriented electrospun microfibers embedded in a matrix of injectable hydrogel. These materials degrade slowly by hydrolysis to release E2 locally. The fibers are made from a linear copolymer of pro-17β-estradiol and a flexible chain linker unit. The hydrogel is formed from 4-arm star polyethylene glycol with terminal units of hydrophobic E2, which forms transient non-covalent crosslinks with poly(β-cyclodextrin) in aqueous solution. Chemically, these polymerized estrogen scaffolds slowly degrade by hydrolysis to release low (nanomolar) doses of E2 locally at the site of the scaffold, sustained for exceptionally long periods of time (months to years), and with the ability to be applied in a minimally invasive manner. The oriented microfibers are proposed to mimic the approximate mechanical properties of fibrillar proteins and will promote mechanical contact guidance cues for controlling the morphology, phenotype, and protein expression in astrocytes and neurons in vitro. The injectable hydrogel matrix surrounding the fibers is intended to mechanically match the stiffness of very soft tissue in the central nervous system. The central goal of this research project is to relate the material properties to the cell response. The team will synthesize a library of polymerized E2 variants with systematically tuned chemical structures. The hydrophobicity and chain flexibility will be varied, which in turn will influence mechanical properties, surface topology and the rate and mechanism of degradation and drug release. These materials will then be incubated with astrocytes and neurons to assess the impact of their properties on the cell behavior observed. The ultimate goal is to understand how to orchestrate cell response to biomaterials that can promote regenerative phenotypes and possibly improve the likelihood of functional recovery. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.