EAGER: Preliminary Study on Novel self-assembled Toroidal-Spiral MicroParticles (TSMPs) for sustained release of therapeutic proteins and peptides: theory and experiments

该提案的研究目的是检验以下假设：通过粘性沉降、扩散和交联动力学的相互作用进行的自组装可以产生具有环形螺旋内部结构的新型聚合物微粒，该内部结构为药物持续释放提供优势。更具体地，在颗粒形成期间，治疗性蛋白质和肽同时包封到环形螺旋通道中。与流行的蛋白质递送方法相比，环形螺旋微颗粒（TSMP）可以在良性条件（室温、低剪切和低界面张力）下完全在水相中形成并装载蛋白质，所述条件保持精细的大分子构象，从而使生物活性和生物利用度最大化。为了验证这一新颖的想法，从而减轻长期项目的概念风险，我们请求支持为期一年的研究，为未来的定期提案提供更多的初步结果。在这里提出的一年时间内，将解决两个关键方面：（1）蛋白质自加载到环形螺旋颗粒中，以及（2）将环形螺旋颗粒从毫米级（目前可实现）缩小到微米级。在初步的实验和理论工作的基础上，我们期望在这两方面的努力取得成功。下面的研究计划包括应急计划，以防最初的方法不按预期工作。 智力优势。将实验室研究与通用的计算机模拟相结合，该提案解决了基本的流体力学和传质问题，使一类新的聚合物药物递送颗粒能够局部持续释放治疗性蛋白质和肽。TSMP将通过复杂缠绕的液体结构的光触发闪光聚合产生。当水混溶性聚合物液滴在低雷诺数下通过水溶液沉积时，这些液体结构通过水动力形成。对于任意粘度比和非牛顿流变学，聚合物液滴进入水池（形成钟形涡环）的初始影响代表了流体力学中很大程度上未探索的制度，将应用定量可视化实验和计算机建模。预期的发现将大大提高我们对新的自组装过程的定量理解，从而为生产具有新结构的微粒提供了一个量子飞跃。 更广泛的影响。该项目提供了一个技术平台，可以转化为许多复杂疾病的医学治疗。研究将通过一个新的研究生微流体课程，两个模块的本科运输现象序列和本科研究项目的序列影响化学工程课程。一个专门的网站（www.example.com）将发布一套为大学和大学预科学生设计的基于Java的教育模块，这些模块也将在教育期刊文章中描述。实验和理论结果的高度可视化性质，以及生物医学应用的社会相关性，代表了通过与芝加哥土地高中正在进行的部门关系被招募到化学工程的学生的自然吸引力。该项目利用了Liu和Nitsche在妇女和代表性不足的少数民族学生中正在进行的外联、招聘和保留工作。

The research objective of the proposal is to test the hypothesis that self-assembly by interaction of viscous sedimentation, diffusion, and cross-linking kinetics can produce a new category of polymeric micro-particles with a toroidal-spiral internal structure that offers advantages for sustained drug release. More specifically, during the particle formation, therapeutic proteins and peptides are simultaneously encapsulated into the toroidal-spiral channels. In contrast with prevailing protein delivery methods, toroidal-spiral micro-particles(TSMPs) can be formed and loaded with proteins entirely within the aqueous phase, under benign conditions (room temperature, low shear and low interfacial tensions) that preserve delicate macromolecular conformations and thereby maximize bioactivity and bioavailability. To validate this novel idea, and thereby mitigate conceptual risk for the longer project, we request support for one-year of research to provide more preliminary results for a regular proposal in future. Within the one-year period proposed here, two key aspects will be addressed: (1) protein self-loading into the toroidal-spiral particles, and (2) scaling down toroidal-spiral particles from the millimeter scale (currently achievable) to micron dimensions. On the basis of preliminary experimental and theoretical work, we expect success in both endeavors. The research plan below includes contingency plans in case the initial approach does not work as anticipated. Intellectual Merit. Integrating laboratory investigation with versatile computer simulations, this proposal addresses the fundamental fluid mechanics and mass transfer that enable a new category of polymeric drug-delivery particles for local sustained release of therapeutic proteins and peptides. TSMPs will be generated by light-triggered flash polymerization of intricately wound liquid structures. These liquid structures form by hydrodynamic forces when a water-miscible, polymeric drop sediments at low Reynolds number through an aqueous solution. The initial impact of the polymeric droplets into the aqueous pool (forming bell shapes of vortex rings) for arbitrary viscosity ratio and non-Newtonian rheology represents a largely unexplored regime in fluid mechanics, to which both quantitative visualization experiments and computer modeling will be applied. The anticipated findings will greatly enhance our quantitative understanding of new self-assembly processes, thereby providing a quantum leap in producing microparticles with novel structures. Broader Impacts. This project provides a technological platform that can potentially be translated into medical treatments for many complex diseases. Research will impact the ChE curriculum through a new graduate microfluidics course, two modules for the undergraduate Transport Phenomena sequence and a sequence of undergraduate research projects. A dedicated website (www.microfluidtech.org) will publish a suite of Java-based educational modules designed for college and pre-college students, also to be described in an educational journal article. The highly visual nature of the experiments and theoretical results, as well as the societal relevance of the biomedical applications, represent a natural draw for students being recruited into chemical engineering through ongoing departmental relationships with Chicago land high schools. This project leverages ongoing outreach, recruitment and retention efforts by Liu and Nitsche among women and underrepresented minority students.