3D Printed Collagen Tracheal Scaffolds with Biomimetic Microstructure

项目概要/摘要 大约每2000名儿童中就有1名出生时患有先天性气道畸形， 由于疾病或创伤导致的缺损;这些患者中的一个重要子集需要气管移植物来恢复气道 通畅性许多有影响力的发现和创新战略都来自于75年来的研究， 但是仍然需要患者特异性的气管移植物， 可以提供长期的、无干预的治疗，同时与患者一起成长。本研究的目的是 该奖学金旨在设计一种患者特异性的3D生物打印胶原蛋白气管移植物， 天然气管的特性，包括仿生微结构。3D生物打印是一种理想的技术， 适合应对这一挑战，因为它允许我们使用天然生物材料，如I型胶原蛋白， 脱细胞气管ECM，以构建与患者解剖结构完全匹配的移植物。范伯格实验室 开发了新一代悬浮水凝胶的自由形式可逆嵌入（FRESH）生物打印 这将使我能够控制打印支架的微观结构， 在原生气管中发现的组织。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，该提案将朝着持久的，患者特异性的， 无免疫抑制治疗长段气管缺损在第一个目标中，我将使用高分辨率 容积成像以询问天然气管细胞外基质微观结构。这些数据集将用于 为了设计用于气管不同部分的区域适当的仿生微结构（例如环， 结缔组织）。这些微观结构模式预计将重演生理力学 在有限元分析（FEA）模型和3D生物打印胶原蛋白构建体中，第二个目标 我将使用特定年龄的气管测量数据和去识别的医学成像数据集来生成患者- 使用开放源代码成像分割工具的特定儿科气管移植物几何形状。区域 适当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 气管移植物将在FEA中建模，然后在胶原蛋白中打印并进行机械表征（例如， 塌陷力、顺应性、可缝合性），以证明生理学上必需的天然血管的重现。 气管力学为了完成这项研究，我组建了一个具有重要专业知识的团队， 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 制定严格的培训计划，充分利用卡内基梅隆大学世界一流的环境， 大学和匹兹堡大学帮助我建立必要的技术和专业技能， 一个多产的医学科学家这个建议将启动我的长期目标，研究再生， 用于治疗先天性、创伤性和肿瘤性头颈部组织缺损的功能性组织支架 同时是一名耳鼻喉科医生，专攻头颈外科。

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.