PI Michael Steketee
Co PI Stephen Badylak
Title Applying extracellular matrix technology to neuroprotect and to repair injured retina and optic nerve
Description: ECM technology as an early preventative for reducing secondary ocular trauma. After ocular trauma, secondary injury due to inflammation and a default healing response that forms scar tissue, in injured central nervous system (CNS) tissues, are major factors contributing to permanent vision loss. To address this problem, we are developing an injectable, ECM hydrogel and an ECM biohybrid wrap. Both platforms are designed to stabilize trauma to the retina or to the optic nerve and limit inflammation, edema, and scarring. ECM technology uses natural ECM bioscaffolds, derived by decellularizing specific tissues or organs, to promote a positive healing response in tissues the body is unable to repair functionally by default. In both preclinical and clinical models, ECM bioscaffolds can facilitate site-specific, functional repair in various peripheral tissues, including heart, lung, esophagus, muscle, tendon, skin, and peripheral nerves among others. Though the exact mechanisms are unknown, ECM bioscaffolds act, in part, by attracting endogenous stem cells and promoting site-appropriate differentiation, vascularization, neurogenesis, and a pro-repair M2 phenotype in macrophage and microglia. We hypothesize ECM technology will preserve or restore visual function by altering the default healing response to retinal or optic nerve injury in four key areas: 1) Increase RGC survival and axon regeneration. 2) Increase endogenous stem cell recruitment to the wound. 3) Increase M2 polarization in macrophages and microglia at the wound site. 4) Decrease glial scarring.
Aim 1: To determine if ECM derived from fetal CNS tissue is more efficacious than ECM derived from adult, non-CNS tissues in vitro
Aim 2: To determine if tissue-specific ECM hydrogels can modulate the default immune and glial scarring responses to acute retinal trauma in vivo. Compared to controls, fetal ECM hydrogel will: Hypothesis 2.1: Increase M2 polarization in microglia and macrophage. Hypothesis 2.2: Decrease glial scarring at the wound.
Aim 3: To determine if tissue-specific ECM biohybrid nerve wraps can modulate the default immune response to acute optic nerve trauma in vivo. Compared to controls, ECM hydrogels will: Hypothesis 3.1: Increase M2 polarization in microglia and macrophage. Hypothesis 3.2: Increase stem cell recruitment. Hypothesis 3.3: Decrease glial scarring in the optic nerve. Hypothesis 3.4: Increase RGC survival and axon regeneration.
Aim 4: To determine if ECM biohybrid nerve wraps preserve visual function after optic nerve crush. Compared to controls, ECM biohybrid wraps will: Hypothesis 4.1: Slow or prevent RGC axon degeneration as measured by MRI. Hypothesis 4.2: Slow or prevent vision loss as measured by electroretinography.
Study Design: ECM bioscaffolds will be optimized for M2 microglia/macrophage polarization and retinal ganglion cell survival and axon regeneration. Optimized ECM bioscaffolds will then be used for pre-clinical in vivo studies as an injectable temperature sensitive hydrogel to repair acute retina incisional trauma and an ECM biohybrid wrap to repair acute optic nerve trauma. Controls will include untreated, injured only, sham, and groups receiving non-ECM collagen injections or non-ECM wraps.
Military Benefit: If successful, ECM hydrogel based technology will provide the filed combat ophthalmologist an easily administrable therapy to minimize secondary ocular trauma, increasing the potential to preserve visual function. Though outside the scope of this proposal, this technology is also applicable to various injuries throughout the body (i.e. peripheral nerve repair and corneal burns).
Term 2014 – 2018