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: 10318506
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 98.18万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318506
• 关键词: 3-Dimensional; 3D Print; Acute; Address; Affect; Alzheimer' s Disease; Animals; Astrocytes; Biological Assay; Biological Models; Biomechanics; Biomimetics; Blood; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Vessels; 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; 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; 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; neuropsychiatry; neurovascular; neurovascular coupling; neurovascular unit; programs; psychosocial; relating to nervous system; response; response to brain injury; response to injury; shear stress; simulation; spatiotemporal; tau Proteins; tau-1

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.

摘要 持久影响：动态、全天然生物打印3D人体神经血管仿生研究创伤 脑损伤病理生理学 据估计，每年有250万人遭受创伤性脑损伤，许多幸存者经历了 随后的长期认知缺陷、感觉运动障碍和神经精神残疾，导致 对受影响的个人造成深刻的心理社会和经济后果。的急性和慢性影响 在美国和世界各地，神经创伤是导致死亡、发病和长期残疾的主要原因 世界。尽管脑外伤在神经病理学上有明确的定义，但不太清楚的是早期脑损伤与脑损伤之间的关系 创伤相关神经血管病理学的影响和由此导致的进展。这是一项多学科、多专业的 提案响应跨机构血脑接口计划(RFA-HL-20-021、R61/R33)和 建立在波士顿大学劳伦斯·利弗莫尔国家实验室 医学院和NIH/NIA资助的波士顿大学阿尔茨海默病中心 神经创伤，包括创伤所致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伏性tau蛋白神经退行性病变 脑病(CTE)。该项目将开发并表征一种可在体外灌流的人类神经血管单位。 (NVU)模型，首要目标是识别生物力学触发因素和分子细胞反应 决定创伤性微血管损伤(TMI)的位置、严重程度和进展的脑损伤，血液- 脑屏障(BBB)破坏和磷酸化tau蛋白病变。为了实现这一目标，这项工作将 利用现有的BBB平台来丰富3D多细胞动态人类NVU仿生体 可灌流的内皮化血管系统。由此产生的光学清晰的NVU平台将使系统 具有时空控制的人类脑血管系统的询问，包括所有人类NVU细胞类型 和结构功能的实时测量。在R61阶段，我们将修改我们现有的3D打印BBB 模型包括培养人诱导多能干细胞(IPSC)来源的内皮细胞、周细胞、星形胶质细胞、 和神经元。细胞组成、结构-功能关系、流体流动动力学(血管内， 以及培养条件对IPSC成熟的影响。在R61阶段，我们将 开发一种与平台兼容的伤害仪器，通过计算模拟来匹配使用的负载 活体动物研究。3D打印模型中嵌入的标记将支持直接测量和 可视化的时间变化的应变在撞击过程中作为血管，神经胶质和神经细胞的病理和 功能受损(R33阶段)。此外，我们还将研究分子、细胞和功能的影响。 颅脑损伤后的二次损伤。结果将通过对实验动物和 临床病理与独特的人脑标本的相关性。这个项目将有助于从根本上 脑损伤生物力学及其与神经损伤急、慢性影响的关系 人脑。