Single stage surgical intervention for treatment of severe traumatic brain injury

项目摘要 这项应用的长期目标是彻底改变严重创伤性脑损伤（TBI）的治疗方法。 通过在前所未有的单阶段减压中使用新型成骨水凝胶材料， 颅骨切除术（DC）。DC是对TBI患者进行的常见救生神经外科手术 闭合性头部损伤和/或中风移除颅骨可缓解颅内压升高 让大脑膨胀到封闭的颅顶之外在手术后，患者目前 留下一个大的颅骨缺损（即，他们的头骨上有一个大洞）持续数周或数月，需要第二次手术， 用保存下来的颅骨或定制的3D打印材料替换缺失的颅骨。以这样 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的，前所未有的， TBI患者接受一期外科手术。 我们的方法的关键是一类新的水凝胶材料，其中脱矿骨的天然材料 基质、失活软骨或失活肌腱本身是水凝胶的交联剂。我们的物质 由组织颗粒和透明质酸的糊状前体溶液组成， 外科医生可以容易地雕刻到开放的颅骨缺损区域中。只有2分钟的紫外线照射， 颗粒与透明质酸交联，以产生一种新的材料，该材料是固体的，但具有柔性，并且可以允许 大脑开始肿胀，然后随着脑肿胀的消退过渡到骨骼。的创新之处 交联后的材料的一个优点是，它可以通过释放抗炎剂来局部缓解肿胀 分子，以改善和加速神经恢复，而且还提供了一个保护层之间 头皮和身体最不可或缺的器官主要假设是我们的柔性药物洗脱水凝胶 在大鼠中TBI和DC之后立即放置的植入物将转变为跨越颅骨的完整骨 缺陷和减轻与TBI相关的神经功能缺损。为了验证这一假设，以下具体目标 建议：1）调整水凝胶刚度和骨再生应用于TBI，和2）评估局部 TBI后抗炎药物递送以减少水肿/脑损伤体积，从而改善行为 复苏 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， 引入动态材料作为第一个也是唯一的过程的一部分。在这样做的过程中，我们有可能 通过前所未有的单阶段手术减轻与严重TBI相关的神经功能缺损。

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.