3D Printed Collagen Tracheal Scaffolds with Biomimetic Microstructure

项目摘要/摘要 2000年约有1名儿童出生时患有先天性呼吸道畸形，其他儿童则发展为气管畸形。 由于疾病或创伤造成的缺陷；这些患者中的一个重要亚群需要气管移植来恢复呼吸道 通畅性。在超过75年的研究中，许多有影响力的发现和创新战略产生了 气管置换的发展，但仍然需要一种针对患者的气管移植 可以提供长期的、无干预的治疗，同时与患者一起成长。本课题的研究目标是 联谊会是设计一种针对患者的、3D生物打印的胶原蛋白气管移植物，它重述了机械 结合仿生微结构的天然气管的特性。3D生物打印是一项理想的技术 适合于应对这一挑战，因为它允许我们使用本地生物材料，如I型胶原和 脱细胞的气管细胞外基质，以构建完全符合患者解剖的移植物。范伯格实验室已经 开发新一代自由形式可逆包埋悬浮水凝胶(新鲜)生物印花 这将使我能够控制打印支架的微观结构，以复制细胞外基质 在天然气管中发现的组织。通过使用3D将局部气管力学与生理负荷相匹配 图案化的仿生微结构，这一提议将朝着持久的、针对患者的、 长段气管缺损的免免疫抑制治疗。在第一个目标中，我将使用高分辨率 体积成像以询问天然气管细胞外基质的微结构。将使用这些数据集 为了为气管的不同部分设计区域性合适的仿生微结构(例如环， 结缔组织)。这些微结构模式预计将概括生理机械 在有限元分析(FEA)模型和3D生物打印的胶原结构中的特性。在第二个目标中 我将使用特定年龄的气管测量数据和已识别的医学成像数据集来产生患者- 使用开源影像分割工具确定特定的儿科气管移植物几何形状。按地区划分 合适的仿生微结构将在这些移植物几何形状中形成图案。这些仿生生物 气管移植物将在有限元分析中建模，然后用胶原蛋白打印并进行机械表征(例如： 塌陷力、顺应性、可缝合性)以演示生理上必需的自然状态的重现 气管机械师。为了完成这项研究，我组建了一个具有丰富专业知识的团队 生物力学、发育生物学、组织工程和细胞外基质。我和这个团队一起工作过 制定严格的培训计划，充分利用卡内基梅隆大学的世界级环境 大学和匹兹堡大学帮助我建立必要的技术和专业技能 一位多产的内科医生兼科学家。这项提议将启动我研究再生能源的长期目标， 功能性组织支架修复先天性、创伤性和肿瘤性头颈部组织缺损 同时以耳鼻喉科医生的身份执业，并获得头颈外科专业学位。

PROJECT SUMMARY/ABSTRACT Approximately 1 in 2000 children are born with a congenital airway malformation and others develop tracheal defects due to disease or trauma; an important subset of these patients needs a tracheal graft to regain airway patency. Many impactful discoveries and innovative strategies have resulted from over 75 years of research into development of a tracheal replacement, but there remains a need for a tracheal graft that is patient-specific and can provide long-term, intervention free treatment while growing with the patient. The research goal of this fellowship is to engineer a patient-specific, 3D bioprinted collagen tracheal graft that recapitulates the mechanical properties of native trachea by incorporating biomimetic microstructure. 3D bioprinting is a technology ideally suited for tackling this challenge, as it allows us to use native biological materials, like collagen type I and decellularized tracheal ECM, to construct grafts that exactly match patient anatomy. The Feinberg lab has developed a new generation of Freeform Reversible Embedding of Suspended Hydrogels (FRESH) bioprinting that will allow me to control the microstructure of printed scaffolds to reproduce the extracellular matrix organization found in native trachea. By matching regional tracheal mechanics to physiologic loading using 3D patterned biomimetic microstructure, this proposal will take an important step towards a durable, patient-specific, immunosuppression free treatment for long-segment tracheal defects. In the first aim I will use high resolution volumetric imaging to interrogate native tracheal extracellular matrix microstructure. These data sets will be used to design regionally appropriate biomimetic microstructures for different sections of the trachea (e.g. ring, connective tissue). These microstructural patterns are expected to recapitulate physiologic mechanical properties in both finite element analysis (FEA) models and 3D bioprinted collagen constructs. In the second aim I will use age-specific tracheal measurement data and deidentified medical imaging datasets to produce patient- specific pediatric tracheal graft geometries using open-source imaging segmentation tools. Regionally appropriate biomimetic microstructure will be patterned throughout these graft geometries. These biomimetic tracheal grafts will be modelled in FEA and then printed in collagen and mechanically characterized (e.g. collapsing forces, compliance, suturability) to demonstrate recapitulation of physiologically essential native tracheal mechanics. To accomplish this research, I have assembled a team with significant expertise in biomechanics, developmental biology, tissue engineering, and extracellular matrix. I have worked with this team to develop a rigorous training plan that will take advantage of the world class environment of Carnegie Mellon University and the University of Pittsburgh to help me build the technical and professional skillsets necessary for a productive physician-scientist. This proposal will jumpstart my long-term goals of investigating regenerative, functional tissue scaffolds for treatment of congenital, traumatic, and oncologic head and neck tissue defects while practicing as an otolaryngologist with a subspecialization in head and neck surgery.