Single stage surgical intervention for treatment of severe traumatic brain injury

项目总结 这一应用的长期目标是革新重型创伤性脑损伤(Tbi)的治疗。 通过在史无前例的单期减压术中使用新型成骨水凝胶材料 开颅手术(DC)。DC是脑外伤患者常见的挽救生命的神经外科手术 有闭合性头部损伤和/或中风。摘除颅骨可缓解颅内压升高 通过让大脑在关闭的头盖骨穹隆外面膨胀。在手术后，患者目前正在 留下一个大的颅骨缺陷(即，在他们的头骨上有一个大洞)数周或数月，需要第二次手术 用他们保存下来的颅骨或定制的3D打印材料替换丢失的颅骨。在这样的情况下 病例中，这第二次手术目前是不可避免的。我们的战略是独特的，前所未有的，通过治疗 颅脑损伤患者采用一期手术治疗。 我们方法的关键是一种新型的水凝胶材料，其中天然材料脱矿骨 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，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。只需2分钟的紫外线曝光， 颗粒与透明质酸交联，产生一种固体的、但又灵活的新材料，可以 大脑最初会肿胀，然后随着脑肿胀的消退而转变为骨骼。它的创新之处在于 交联后的材料是可以通过释放抗炎物质来局部缓解肿胀 分子，以改善和加速神经恢复，并提供保护层之间 头皮和身体最不可或缺的器官。主要的假设是我们灵活的药物洗脱水凝胶 大鼠颅脑损伤和DC术后即刻植入的种植体将过渡到横跨颅骨的完整骨 改善和减轻与脑外伤相关的神经功能缺陷。为了验证这一假设，以下是具体目标 建议：1)调整水凝胶硬度和骨再生用于颅脑损伤；2)评估局部性 颅脑损伤后应用抗炎药物减少脑水肿/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通过 作为第一个也是唯一一个步骤的一部分，引入动态材料。在这样做的过程中，我们拥有 通过史无前例的单期手术减轻与严重脑外伤相关的神经功能障碍。

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 deficits associated with severe TBI with an unprecedented single-stage procedure.