In Vivo Monitoring of Oxygenation in Implants: Applications to Tissue Engineering

植入物中氧合的体内监测：在组织工程中的应用

• 批准号: 8068250
• 负责人: NICANOR I. MOLDOVAN
• 金额: $ 38.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068250
• 关键词: Address; Angiogenic Factor; Biocompatible Materials; Biotechnology; Blood Vessels; Bone Marrow; Cell physiology; Cells; Clinical; Communities; Device or Instrument Development; Devices; Diagnostic; Diffusion; Drug Delivery Systems; Electron Spin Resonance Spectroscopy; Encapsulated; Engineering; Goals; Hydrogels; Image; Implant; In Situ; Intercellular Fluid; Location; Logistics; Measures; Membrane; Methods; Modeling; Molecular; Monitor; Mus; Oxygen; Oxygen saturation measurement; Partial Pressure; Penetration; Perfusion; Radial; Regenerative Medicine; Reporting; Resolution; Signal Transduction; Stem cells; Surface; System; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Translating; Vascularization; angiogenesis; base; biomaterial compatibility; caprolactone; clinical application; density; design; glucose sensor; implantable device; improved; in vivo; microwave electromagnetic radiation; millimeter; minimally invasive; nanocrystal; neovascularization; novel; particle; public health relevance; research study; scaffold; sensor; subcutaneous; tool; tumor

DESCRIPTION (provided by applicant): Long term monitoring of oxygen concentrations at the level of biomedical implants, and optimizing its availability are key issues in diagnostics, tissue engineering and biotechnology. Recent advances in the use of EPR detectable, oxygen-sensitive probes with excellent sensitivity, accuracy and remote accessibility, opened a new era of opportunity for real-time monitoring of oxygenation in vivo. However, for many applications these probes need to be encapsulated behind a semi-permeable membrane. We developed a nanofilter-limited, implantable model device with dual EPR-based oxygen sensor and drug delivery capabilities, and we tested its capacity to track oxygenation in a tissue engineered construct containing bone marrow progenitor cells. Using a quantitative model of oxygen diffusion in the vicinity of implants, we also demonstrated that our oxygen sensor provides a proportional relationship between the reported local pO2 and microvascular density, supported by in situ observations at the end of the experiment. Furthermore, we synthesized a novel class of biomaterials, incorporating by electrospinning the EPR sensitive nano-crystals directly into a poly-caprolactone microfibrillar scaffold. Using EPR imaging, we showed the in vivo distribution of oxygen within this scaffold and found that the determined average pO2 was compatible with its subcutaneous location. In addition, we demonstrated the capacity of this scaffold to support proliferation and endothelial differentiation of bone marrow progenitor cells. Here we propose to further validate, improve the design and expand the applications of this device. This project will take into consideration, besides the development of the device and the logistics of its use, also the design of its interface with the tissue, with the goal to develop a tool for studying and optimizing implant oxygenation as dependent on nearby neovascularization. Specific Aims: 1. Determine oxygenation within tissue engineering constructs as dependent on their vascularization. 2. Test the hypothesis that oxygenation within a filter-limited implant is sensitive to pharmacological modulation of nearby angiogenesis. 3. Demonstrate that stimulation of neovascularization in peri-implant space using tissue engineering methods could also improve implant oxygenation. The progress in the use of implanted oxygen probes will be readily translated into novel clinical applications such as monitoring available oxygen in tissue engineering constructs, with improved perfusion, optimized cell encapsulation, or better functioning of oxygen or glucose sensors. PUBLIC HEALTH RELEVANCE: We propose to develop a method and an implantable device for minimally invasive, in vivo monitoring of local oxygen concentrations in biomedical implants. These will be useful for monitoring oxygenation in oxygen- dependent sensors, in encapsulated cells, in tissue engineering constructs, and for other branches of regenerative medicine.

描述（由申请人提供）：长期监测生物医学植入物水平的氧气浓度并优化其可用性是诊断、组织工程和生物技术中的关键问题。 EPR 可检测氧敏感探头的使用取得了最新进展，具有出色的灵敏度、准确性和远程可访问性，为实时监测体内氧合开启了新时代。然而，对于许多应用，这些探针需要封装在半透膜后面。我们开发了一种纳米过滤器限制的可植入模型装置，具有基于 EPR 的双氧传感器和药物输送功能，并测试了其在含有骨髓祖细胞的组织工程结构中跟踪氧合的能力。使用植入物附近的氧扩散定量模型，我们还证明了我们的氧传感器提供了报告的局部 pO2 和微血管密度之间的比例关系，并得到实验结束时的现场观察的支持。此外，我们合成了一类新型生物材料，通过静电纺丝将 EPR 敏感纳米晶体直接整合到聚己内酯微纤维支架中。使用 EPR 成像，我们显示了该支架内氧气的体内分布，并发现确定的平均 pO2 与其皮下位置相符。此外，我们还证明了该支架支持骨髓祖细胞增殖和内皮分化的能力。在此我们建议进一步验证、改进设计并扩展该装置的应用。除了设备的开发及其使用的物流外，该项目还将考虑其与组织界面的设计，目标是开发一种工具，用于研究和优化依赖于附近新生血管的植入物氧合。具体目标： 1. 确定组织工程结构内的氧合取决于其血管化。 2. 检验以下假设：过滤器限制的植入物内的氧合对附近血管生成的药理学调节敏感。 3. 证明使用组织工程方法刺激种植体周围空间的新生血管也可以改善种植体氧合。植入式氧探针的使用进展将很容易转化为新的临床应用，例如监测组织工程结构中的可用氧，改善灌注、优化细胞封装或改善氧或葡萄糖传感器的功能。 公共健康相关性：我们建议开发一种方法和植入式设备，用于微创体内监测生物医学植入物中的局部氧气浓度。这些将有助于监测氧依赖性传感器、封装细胞、组织工程结构以及再生医学的其他分支中的氧合。