PROJECT SUMMARY The long-term objective of this application is to revolutionize the treatment of severe traumatic brain injury (TBI) by employing a novel osteogenic hydrogel material in an unprecedented single-stage decompressive craniectomy (DC) procedure. DC is a common life-saving neurosurgical procedure performed on TBI patients with either closed head injury and/or stroke. Removing the cranial bone mitigates rising intracranial pressures by allowing the brain to swell outside the closed calvarial vault. Following the procedure, patients are currently left with a large cranial defect (i.e., a large hole in their skull) for weeks or months and require a 2nd surgery to replace the missing cranial bone with their preserved cranial bone or a custom 3D-printed material. In such cases, this 2nd surgical procedure is currently unavoidable. Our strategy is unique and unprecedented by treating TBI patients with a single-stage surgical procedure. The key to our approach is a new class of hydrogel materials, where natural materials of demineralized bone matrix, devitalized cartilage, or devitalized tendon are themselves the crosslinkers of the hydrogel. Our material consists of a paste-like precursor solution of tissue particles and hyaluronic acid that behaves as a paste that a surgeon can easily sculpt into the open calvarial defect area. With only 2 minutes of UV light exposure the particles are crosslinked with the hyaluronic acid to create a new material that is solid, yet flexible, and can allow the brain to swell initially, and then transition into bone as the brain swelling subsides. The innovation of this material after crosslinking is that it can provide localized relief of swelling by releasing anti-inflammatory molecules to improve and accelerate neurological recovery, and moreover provide a protective layer between the scalp and the body’s most indispensable organ. The chief hypothesis is that our flexible, drug-eluting hydrogel implants placed immediately following TBI and DC in rats will transition to complete bone spanning the cranial defect and mitigate neurologic deficits associated with TBI. To test this hypothesis, the following Specific Aims are proposed: 1) Tune hydrogel stiffness and bone regeneration for application to TBI, and 2) Evaluate localized anti-inflammatory drug delivery after TBI to reduce edema/brain injury volume and thereby to improve behavioral recovery. Our approach is unique in that we are leveraging musculoskeletal regenerative medicine as a tool to usher in a new paradigm for severe TBI treatment. While a primary debate in the neurosurgery field for treatment of TBI revolves around the amount of time between the 1st (DC) and 2nd (cranioplasty) procedures, we challenge whether that debate is even necessary. Instead, we ask whether the 2nd surgery can be eliminated altogether by introducing a dynamic material as part of the first, and only procedure. In so doing, we hold the potential to mitigate neurologic def...