Single stage surgical intervention for treatment of severe traumatic brain injury - DIVERSITY SUPPLEMENT

项目总结[PANOR 01 NS 123051] 这项应用的长期目标是彻底改变严重创伤性脑损伤的治疗 (TBI)通过在前所未有的单阶段中使用新的成骨水凝胶材料 去骨瓣减压术（DC）。DC是一种常见的挽救生命的神经外科手术， 对患有闭合性头部损伤和/或中风的TBI患者进行研究。移除颅骨可以缓解 通过允许大脑膨胀到封闭的颅骨穹窿之外来降低颅内压。后 手术中，患者目前留下大的颅骨缺损（即，他们的头骨上有一个大洞）， 个月，需要第二次手术，用保存下来的颅骨替换缺失的颅骨， 定制的3D打印材料。在这种情况下，第二次手术目前是不可避免的。我们的策略是 独特的和前所未有的治疗创伤性脑损伤患者的单阶段外科手术。 我们方法的关键是一类新的水凝胶材料，其中脱矿物质的天然材料 骨基质、失活的软骨或失活的肌腱本身是水凝胶的交联剂。我们 材料由组织颗粒和透明质酸的糊状前体溶液组成， 外科医生可以很容易地将其雕刻到开放的颅骨缺损区域。只有2分钟的紫外线照射 暴露颗粒与透明质酸交联，以产生固体的新材料， 灵活，可以让大脑最初膨胀，然后随着大脑膨胀过渡到骨骼 平息。这种材料在交联后的创新之处在于，它可以提供局部的 通过释放抗炎分子来改善和加速神经恢复， 而且在头皮和身体最不可缺少的器官之间提供了一层保护层。首席 假设我们的柔性药物洗脱水凝胶植入物在大鼠TBI和DC后立即放置， 将过渡到跨越颅骨缺损的完整骨，并减轻与 创伤性脑损伤为了检验这一假设，提出了以下具体目标：1）调节水凝胶刚度和骨强度。 用于TBI的局部再生，和2）评估TBI后局部抗炎药物递送， 减少水肿/脑损伤体积，从而改善行为恢复。 我们的方法是独一无二的，因为我们正在利用肌肉骨骼再生医学作为一种工具， 严重创伤性脑损伤治疗的新范例。虽然在神经外科领域的主要争论是治疗 TBI围绕着第一次（DC）和第二次（颅骨成形术）手术之间的时间量，我们质疑 这场辩论是否有必要相反，我们问是否可以完全消除第二次手术 通过引入动态材料作为第一个也是唯一的过程的一部分。在这样做时，我们认为， 有可能通过前所未有的单阶段治疗减轻与严重TBI相关的神经功能缺损 procedure.

PROJECT SUMMARY [PARENT R01NS123051] 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 deficits associated with severe TBI with an unprecedented single-stage procedure.