Evaluation of tantalum oxide nanoparticles for in vivo X-ray computed tomography evaluation of implantable biomaterials

项目摘要 该资助提出了一种创新的造影剂和 X 射线计算机断层扫描 (CT) 成像方法 用于体内监测植入式生物材料。组织工程支架（TES）是一种再生医学 创建 3D 环境以诱导各种组织（包括皮肤、骨骼、 结缔组织和神经。 TES 研究和开发的关键是能够在体内真实测量 生物降解率，并评估植入后的内部微观结构。串行成像和数据分析 可以通过比组织学更容易、更可靠的方式来实现这一点。此外，这种新型造影剂 和成像方法可直接用于 TES 结构完整性和术后位置的临床监测 植入患者体内。 CT 是一种临床上重要的放射技术，可提供具有安全辐射水平的高分辨率扫描， 几乎每个医院和放射科都有成像系统，以及临床前 microCT 研究 整个学术界和工业界通用的系统。我们开创了使用 microCT 的策略 可视化 TES 并测量植入小鼠体内后的生物降解。我们的早期研究 这是通过在 TES 中掺杂不透射线的钆和铋纳米颗粒来实现的，但是，钆 和铋表现出较低的毒性，阻碍了它们的临床转化和持续发展。 氧化钽 (TaOx) 已成为一种更具生物相容性的替代品，具有增强的 CT 特性，因此， 在这笔资助中，我们建议全面研究 TaOx 纳米粒子，以实现生物材料的体内连续成像 和TES。我们拥有有关将 TaOx 纳米粒子轻松掺入聚合物中的大量初步数据 用于神经再生的 TES，具有强大的 microCT 成像和分析协议。 在目标 1 中，我们将制造并表征一系列具有不同 TaOx 含量和 降解率，具有良好表征的特性。将进行一系列体外评估 目标是最大化 TaOx 含量，同时尽量减少对物理特性的影响或引起不良毒性。 在目标 2 中，我们将通过测量来展示 TaOx 嵌入的可生物降解 TES 的 microCT 的实用性 植入不同生理环境的 TaOx 嵌入聚合物 TES 的真实体内生物降解， 确定 1) 植入部位生理环境对 TES 生物降解率的影响，以及 2) 体外降解研究预测体内生物降解和 TES 完整性。在目标 3 中，我们将确定体内 通过评估 TaOx 嵌入的可生物降解 TES 的体内性能来促进 TaOx 的影响 周围神经损伤中的功能性神经再生，测量体内生物降解并评估潜力 毒性。使用 TaOx 嵌入的 PLGA TES 成功演示功能性神经再生将合理化 对人类 TaOx 嵌入的 TES 进行体内 CT 评估的转化研究。

Project Abstract This grant proposes both an innovative contrast agent and X-ray computed tomography (CT) imaging method for monitoring implantable biomaterials, in vivo. Tissue engineered scaffolds (TES) are a regenerative medicine paradigm that create 3D environments to induce tissue formation in a variety of tissues, including skin, bone, connective tissue and nerves. Key to TES research and development is the ability to measure true in vivo biodegradation rates, and to assess internal microstructure post-implantation. Serial imaging and data analysis can accomplish this in ways that are easier and more reliable than histology. Further, this new contrast agent and imaging method are directly translatable for clinical monitoring of TES structural integrity and location post- implantation in patients. CT is a clinically important radiological technique, affording high resolution scans with safe levels of radiation, with imaging systems in nearly every hospital and radiology department, and preclinical microCT research systems common throughout academia and industry. We have pioneered strategies for using microCT to visualize TES and measure biodegradation in vivo following implantation into mice. Our early studies accomplished this by doping TES with radiopaque gadolinium and bismuth nanoparticles, however, gadolinium and bismuth exhibit compromising toxicity, obviating their clinical translation and continued development. Tantalum oxide (TaOx) has emerged as a more biocompatible alternative, with enhanced CT properties, and so, in this grant, we propose to fully investigate TaOx nanoparticles for enabling in vivo serial imaging of biomaterials and TES. We have extensive preliminary data on the facile incorporation of TaOx nanoparticles into polymer TES for nerve regeneration, with a robust microCT imaging and analysis protocol. In Aim 1 we will fabricate and characterize a collection of polymer TES with varying TaOx content and degradation rates, with well characterized properties. A battery of in vitro assessments will be performed with the goal of maximizing TaOx content while minimally impacting physical properties or causing adverse toxicity. In Aim 2 we will demonstrate the usefulness of microCT of TaOx-embedded biodegradable TES by measuring the true in vivo biodegradation of TaOx-embedded polymer TES implanted in varying physiological milieu, determining 1) the effect of implantation site physiological milieu on TES biodegradation rate, and 2) how well in vitro degradation studies predict in vivo biodegradation and TES integrity. In Aim 3 we will determine the in vivo impact of TaOx by evaluating the in vivo performance of TaOx-embedded biodegradable TES for promoting functional nerve regrowth in peripheral nerve injury, measuring in vivo biodegradation and evaluating potential toxicity. Successful demonstration of functional nerve regrowth with TaOx-embedded PLGA TES will rationalize translational studies towards in vivo CT evaluation of TaOx-embedded TES in humans.