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

项目摘要[母公司R01NS123051] 这一应用的长期目标是革命性地治疗严重创伤性脑损伤。 (TBI)通过史无前例的单级使用新型成骨水凝胶材料 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 对于有闭合性颅脑损伤和/或中风的脑损伤患者。摘除颅骨可缓解上升症 通过使大脑在闭合的头盖骨穹隆外膨胀而产生的颅内压。紧随其后的是 手术后，患者目前会留下一个很大的颅骨缺陷(即头骨上的一个大洞)数周或 几个月后，需要进行第二次手术，用他们保存的颅骨或 定制3D打印材料。在这种情况下，第二次手术目前是不可避免的。我们的战略是 独一无二、史无前例的单期手术治疗脑损伤患者。 我们方法的关键是一种新型的水凝胶材料，在这种材料中，天然材料可以脱矿 骨基质、失活的软骨或失活的肌腱本身就是水凝胶的交联剂。我们的 材料由组织颗粒和透明质酸组成的糊状前体溶液组成，透明质酸的行为类似于 外科医生可以很容易地雕刻成开放的颅骨缺损区的糊状物。只有2分钟的紫外线照射 暴露这些颗粒与透明质酸交联，产生一种固体的新材料，但 灵活，可以让大脑开始肿胀，然后随着脑部肿胀而过渡到骨骼 平息下来。这种材料在交联后的创新之处在于，它可以提供局部缓解 通过释放抗炎分子来改善和加速神经恢复，以及 此外，在头皮和身体最不可或缺的器官之间提供一层保护层。酋长 假设我们的灵活的药物洗脱水凝胶植入物在大鼠脑损伤和DC后立即放置 将过渡到横跨颅骨缺损的完整骨并缓解与以下相关的神经功能缺陷 TBI。为了验证这一假设，提出了以下具体目标：1)调整水凝胶硬度和骨骼 应用于脑损伤的再生，以及2)评估脑损伤后局部抗炎药物的释放 减少水肿/脑损伤体积，从而改善行为恢复。 我们的方法是独特的，因为我们利用肌肉骨骼再生医学作为一种工具 这是一种治疗重型脑外伤的新模式。虽然神经外科领域关于治疗的初步辩论 颅脑损伤围绕着第一次(DC)和第二次(颅骨成形术)之间的时间量，我们挑战 这场辩论是否有必要。相反，我们问的是第二次手术是否可以完全取消 通过引入动态材料作为第一个，也是唯一一个程序的一部分。在这样做的过程中，我们持有 通过史无前例的单期手术缓解与严重脑外伤相关的神经功能障碍 程序。

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.