Oxygen-eluting scaffolds for cranial bone regeneration

用于颅骨再生的氧气洗脱支架

基本信息

批准号：
10586040
负责人：
Warren L Grayson
金额：
$ 45.91万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586040
关键词：
3D Print Address Adipose tissue Adoption Anatomy Autologous Transplantation Biocompatible Materials Blood Vessels Bone Matrix Bone Regeneration Bone Transplantation Calvaria Cell Fraction Cell Separation Cell Survival Cell Transplantation Cells Cephalic Cessation of life Clinical Complex Computer Models Cues Data Defect Development Diameter Economic Burden Encapsulated Endothelial Cells Esthetics Fatty acid glycerol esters Feedback Fibrin Fluorescence Formulation Fracture Harvest Hindlimb Human Hydrogels Hypoxia Image Implant In Situ In Vitro Injury Lasers Microspheres Minerals Modeling Monitor Morphogenesis Multi-modal optical imaging Multimodal Imaging Mus Natural regeneration Operative Surgical Procedures Optics Osteogenesis Oxygen Patients Perfusion Permeability Phenotype Point of Care Technology Polymers Polyvinyl Alcohol Porosity Powder dose form Process Radial Rattus Regenerative capacity Shapes Signal Transduction Site Stem cell transplant Structure Technology Testing Thick Tissue Engineering Tissues Transplantation Treatment Efficacy Vascular remodeling Vascularization bioactive scaffold bioscaffold bone clinical translation controlled release craniofacial craniofacial bone design efficacy validation healing hemodynamics hyperbaric chamber in vivo in vivo optical imaging insight long bone manufacture meter multimodality next generation non-invasive monitor novel osteogenic point of care polycaprolactone pressure progenitor response restoration scaffold scale up simulation spatiotemporal standard of care stem cell survival stem cells tissue regeneration wound

项目摘要

Each year, there are approximately 200,000 craniofacial fractures requiring bone transplantation in the US with an economic burden of $2B. These injuries often require multiple complex surgeries, which do not achieve adequate functional or aesthetic restoration. To address this limitation, the field of tissue engineering has employed advanced approaches that combine a patient’s own cells with customized bioactive scaffolds to induce regeneration. For efficacious clinical translation of tissue engineering strategies, it is crucial to develop them as point-of-care technologies in which the harvesting of cells, their packaging into scaffolds, and immediate transplantation into the defect site will take place within a single surgical procedure. A major hurdle of this strategy is that the hypoxic wound microenvironment impedes the ability of surviving cells to orchestrate regeneration. To overcome this limitation, we propose to design scaffolds capable of delivering oxygen (O2) along with the cells. Specifically, we will embed O2-eluting microtanks (µtanks) – hollow, polymeric microspheres capable of ‘storing’ O2 at elevated pressures and slowly releasing it into the cellular microenvironment – into scaffolds comprised of polycaprolactone (PCL) and decellularized bone matrix (DCB) that are 3D-printed in precise, anatomic shapes. To effectively design O2-eluting, PCL-DCB-µtank scaffolds and track the enhanced viability and therapeutic efficacy of transplanted stromal vascular fraction (SVF) cells harvested from lipoaspirate, we will utilize multimodal in vivo optical imaging. This will provide quantitative data on the in vivo microenvironmental factors that impact stem cell survival and tissue regeneration following transplantation and uniquely inform the design process leading to more effective, next-generation biomaterial scaffolds. We hypothesize that the delivery of oxygen using our microtank technology for up to four days will enhance stem cell survival, vascularization and bone formation within the defect and that by non-invasively monitoring the effects of oxygen delivery via a cranial window, we can optimize the design of the scaffold. In Specific Aim 1, we will manufacture 10-50 µm diameter biodegradable polyvinyl alcohol microtanks, incorporate them into the struts of the 3D-printed scaffolds, and validate the spatiotemporal O2 gradients within the scaffolds in response to varying the microtank concentrations and loading pressures. In Specific Aim 2, we will integrate experimental data of O2 concentrations most favorable to vascular morphogenesis/osteogenic differentiation of SVF with numerical simulations to predict the scaffold designs that provide favorable spatiotemporal O2 gradients to promote tissue regeneration. In Specific Aim 3, we will utilize non-invasive, multimodal imaging to dynamically monitor transplanted cells and vascular assembly in PCL-DCB-µtank scaffolds and use this to enhance scaffold design. We will test the optimal designs in a scaled-up, stringent, vasculature-limited model of bone regeneration. The complementary tissue engineering/imaging strengths will provide unprecedented insight into bone regeneration and produce novel platform biomaterial technologies.

在美国，每年大约有 200,000 例颅面骨折需要骨移植，其中 $2B 的经济负担这些伤害往往需要多次复杂的手术，而这并不能实现。为了解决这个限制，组织工程领域已经进行了充分的功能或美学修复。采用先进的方法，将患者自身的细胞与定制的生物活性支架相结合诱导再生对于组织工程策略的有效临床转化至关重要。它们作为现场护理技术，其中收获细胞、将其包装到支架中，以及在一次手术中立即移植到缺损部位是一个主要障碍。该策略的核心在于，缺氧的伤口微环境会阻碍存活细胞协调的能力为了克服这一限制，我们建议设计能够输送氧气（O2）的支架。具体来说，我们将嵌入 O2 洗脱微型罐（μtanks）——中空的聚合物。能够在高压下“储存”氧气并缓慢将其释放到细胞中的微球微环境——由聚己内酯（PCL）和脱细胞骨基质（DCB）组成的支架以精确的解剖形状 3D 打印，以有效设计 O2 洗脱 PCL-DCB-μtank 支架。并追踪移植基质血管成分 (SVF) 细胞的活力和治疗效果的增强从脂肪抽吸物中收获，我们将利用多模态体内光学成像，这将提供定量数据。影响干细胞存活和组织再生的体内微环境因素移植并为设计过程提供独特的信息，从而产生更有效的下一代生物材料我们认为使用我们的微型罐技术可以输送氧气长达四天。通过非侵入性方法增强缺损处的干细胞存活、血管化和骨形成通过颅窗监测氧气输送的效果，我们可以优化支架的设计。具体目标1，我们将制造直径10-50微米的可生物降解聚乙烯醇微型罐，将它们合并到 3D 打印支架的支柱中，并验证其中的时空 O2 梯度在具体目标 2 中，我们研究了支架对不同微罐浓度和负载压力的响应。将整合最有利于血管形态发生/成骨的 O2 浓度的实验数据通过数值模拟对 SVF 进行微分，以预测提供有利的支架设计在特定目标 3 中，我们将利用非侵入性、时空 O2 梯度来促进组织再生。多模态成像动态监测 PCL-DCB-μtank 中的移植细胞和血管组装支架并用它来增强支架设计，我们将按比例放大、严格、测试最佳设计。骨再生的脉管系统限制模型将具有互补的组织工程/成像优势。提供对骨再生前所未有的见解并产生新颖的平台生物材料技术。