Lasting Impacts: Dynamic, Fully Natural Bioprinted 3D Human Neurovascular Biomimetic Model to Study Traumatic Brain Injury Pathophysiology

持久影响：用于研究创伤性脑损伤病理生理学的动态、完全自然的生物打印 3D 人体神经血管仿生模型

• 批准号: 10916751
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 60.82万
• 依托单位: LAWRENCE LIVERMORE NATIONAL SECURITY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10916751
• 关键词: 3-Dimensional; 3D Print; Acute; Address; Affect; Alzheimer' s Disease; Animal Experiments; Animals; Astrocytes; Biological Assay; Biological Models; Biomechanics; Biomimetics; Blood; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Vessels; Blood brain barrier dysfunction; Boston; Brain; Brain Injuries; Brain Pathology; Cell Maturation; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Coagulation Process; Cognitive deficits; Collaborations; Companions; Computer Simulation; Defect; Economics; Endothelium; Engineering; Functional disorder; Funding; Goals; Human; Impairment; In Situ; In Vitro; Incubated; Individual; Injury; Investigation; Laboratories; Life; Link; Liquid substance; Location; Maps; Measurement; Mechanics; Membrane; Memory impairment; Microscopic; Microvascular Dysfunction; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neurons; Optics; Outcome; Pathology; Patients; Percussion; Pericytes; Permeability; Persons; Phase; Phenotype; Physiological; Plasma; Preparation; Property; Public Health; Research; Risk; Role; Severities; Site; Slice; Specimen; Structure; Survivors; Tauopathies; Testing; Therapeutic; Time; Tissues; Trauma; Traumatic Brain Injury; United States National Institutes of Health; Universities; Variant; Vascular Diseases; Visualization; Work; behavioral impairment; biofabrication; biomaterial compatibility; biophysical properties; bioprinting; blood-brain barrier disruption; cell type; chronic traumatic encephalopathy; dementia risk; disability; experience; fluid flow; implantation; improved; in silico; in vitro Model; in vivo; indexing; induced pluripotent stem cell; innovation; instrument; instrumentation; interest; interstitial; medical schools; molecular pathology; mortality; multidisciplinary; neural; neuropathology; neuropsychiatry; neurovascular; neurovascular coupling; neurovascular unit; programs; psychosocial; response; response to brain injury; response to injury; shear stress; simulation; spatiotemporal; tau Proteins; tau-1; vascular contributions; vascular injury

ABSTRACT Lasting impacts: dynamic, fully natural bioprinted 3d human neurovascular biomimetic to study traumatic brain injury pathophysiology Every year an estimated 2.5 million people sustain a traumatic brain injury (TBI), and many survivors experience subsequent long-term cognitive deficits, sensorimotor impairments, and neuropsychiatric disability that result in profound psychosocial and economic consequences for affected individuals. Acute and chronic effects of neurotrauma represent leading causes of mortality, morbidity, and long-term disability in the US and around the world. Although TBI is clearly defined neuropathologically, less well-defined is the relationship between the initial impact and the resulting progression of trauma-related neurovascular pathology. This multidisciplinary multi-PI proposal is responsive to the Trans-Agency Blood-Brain Interface Program (RFA-HL-20-021, R61/R33) and builds on a longstanding collaboration between Lawrence Livermore National Laboratory, Boston University School of Medicine, and the NIH/NIA-funded Boston University Alzheimer’s Disease Center to address fundamental mechanisms underpinning acute and chronic effects of neurotrauma, including trauma-induced microvascular injury and latent tau protein neurodegenerative pathologies associated with chronic traumatic encephalopathy (CTE). This project will develop and characterize a human in vitro perfusable neurovascular unit (NVU) model with the overarching goal of identifying biomechanical triggers and molecular-cellular responses to brain injury that determine the location, severity, and progression of traumatic microvascular injury (TMI), blood- brain barrier (BBB) disruption, and phosphorylated tau proteinopathy. To accomplish this objective, this work will leverage an existing BBB platform to biofabricate a 3D multi-cellular dynamic human NVU biomimetic with perfusable endothelialized vasculature. The resulting optically clear NVU platform will enable systematic interrogation of the human cerebrovasculature, including all human NVU cell types, with spatiotemporal control and structure-function measurements in real-time. In the R61 phase, we will modify our existing 3D-printed BBB model to include culture of human induced pluripotent stem cell (iPSC)-derived endothelia, pericytes, astrocytes, and neurons. Effects of cellular composition, structure-function relations, fluid flow dynamics (intravascular, interstitial), and culture incubation conditions on iPSC maturation will be investigated. In the R61 phase, we will develop a platform-compatible injury instrument informed by computational simulations to match loads used in in vivo animal studies. Embedded markers in the 3D-printed model will enable direct measurement and visualization of time-varying strain during impact as a function of vascular, glial, and neuronal pathology and compromised function (R33 phase). In addition, we will investigate molecular, cellular, and functional effects of secondary damage post-TBI injury. Results will be informed by companion studies in experimental animals and clinicopathological correlation with unique human brain specimens. This project will contribute to fundamental understanding of brain injury biomechanics and relationship to acute and chronic effects of neurotrauma in the human brain.

抽象的 持久影响：动态、完全自然的生物打印 3D 人体神经血管仿生材料，用于研究创伤 脑损伤病理学 每年估计有 250 万人遭受创伤性脑损伤 (TBI)，许多幸存者都经历过 随后的长期认知缺陷、感觉运动障碍和神经精神障碍，导致 对受影响个人造成巨大的社会心理和经济后果。 神经创伤是美国及世界各地死亡、发病和长期残疾的主要原因 尽管 TBI 在神经病理学上有明确的定义，但最初与 TBI 之间的关系尚不明确。 创伤相关神经血管病理学的影响和由此产生的进展。 该提案响应跨机构血脑接口计划（RFA-HL-20-021、R61/R33）并且 建立在劳伦斯利弗莫尔国家实验室与波士顿大学之间的长期合作基础上 医学院和 NIH/NIA 资助的波士顿大学阿尔茨海默病中心致力于解决 神经创伤（包括创伤引起的）急性和慢性影响的基本机制 与慢性创伤相关的微血管损伤和潜在 tau 蛋白神经退行性病变 该项目将开发并表征人类体外可灌注神经血管单元。 （NVU）模型的总体目标是识别生物力学触发因素和分子细胞反应 脑损伤决定了创伤性微血管损伤（TMI）的位置、严重程度和进展，血液- 脑屏障（BBB）破坏和磷酸化 tau 蛋白病为了实现这一目标，这项工作将。 利用现有的 BBB 平台生物制造 3D 多细胞动态人类 NVU 仿生体 由此产生的光学透明 NVU 平台将实现系统化。 通过时空控制询问人类脑血管系统，包括所有人类 NVU 细胞类型 在 R61 阶段，我们将修改现有的 3D 打印 BBB。 模型包括人类诱导多能干细胞 (iPSC) 衍生的内皮细胞、周细胞、星形胶质细胞、 和神经元。细胞组成、结构功能关系、流体动力学（血管内、 间质），并在 R61 阶段研究 iPSC 成熟的培养孵化条件。 开发一种平台兼容的伤害仪器，通过计算模拟来匹配使用的负载 3D 打印模型中的嵌入标记将能够直接测量和 将撞击过程中随时间变化的应变可视化为血管、神经胶质和神经元病理学的函数 此外，我们将研究功能受损（R33 期）。 TBI 损伤后的继发性损伤将通过实验动物和同伴研究得出结果。 该项目将有助于研究与独特的人脑标本的临床病理学相关性。 了解脑损伤生物力学以及与神经外伤的急性和慢性影响的关系 人类的大脑。