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

项目摘要 这项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 用于在体内监测可植入生物材料。组织工程支架是一种再生医学 范例，其创建3D环境以诱导各种组织中的组织形成，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测量真实的体内 生物降解速率，并评估植入后的内部微观结构。连续成像和数据分析 可以用比组织学更简单可靠的方法来完成。此外，这种新的造影剂 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是临床上重要的放射技术，提供具有安全辐射水平的高分辨率扫描， 几乎每家医院和放射科都有成像系统， 在学术界和工业界普遍存在的系统。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体内生物降解。我们的早期研究 通过用不透射线的钆和铋纳米颗粒掺杂TES来实现这一点，然而，钆纳米颗粒 和铋显示出折衷的毒性，从而避免了它们的临床转化和继续开发。 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， 在这项研究中，我们提出要充分研究TaOx纳米粒子，使生物材料在体内连续成像 和TES。我们有关于TaOx纳米颗粒容易结合到聚合物中的广泛的初步数据， TES用于神经再生，具有强大的microCT成像和分析协议。 在目标1中，我们将制造和表征具有不同TaOx含量的聚合物TES的集合， 降解速率，具有良好的特性。将进行一系列体外评估， 最大化TaOx含量同时最小化影响物理性质或引起不良毒性的目标。 在目标2中，我们将通过测量TaOx包埋的可生物降解TES的微CT来证明其有用性。 植入不同生理环境中的TaOx嵌入的聚合物TES的真实体内生物降解， 确定1）植入部位生理环境对TES生物降解速率的影响，和2）植入部位生理环境对TES生物降解速率的影响如何。 体外降解研究预测了体内生物降解和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， 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TaOx包埋的PLGA TES成功证明功能性神经再生将合理化 在人类中TaOx嵌入的TES的体内CT评价的转化研究。

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.