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.
With the support of an NSF EAGER grant we have established a self-assembly mechanism to form ring-shaped particles with well-defined, spiral-shaped internal channels, which we call toroidal-spiral particles (TSPs) (Figure1). The unique shape and preparation methodology of TSPs is intended to overcome the major challenges of local co-delivery of macromolecules (proteins or peptides) and small molecules (e.g., cytotoxic drug) and of independently manipulating their release kinetics to obtain synergistic therapeutic effects. Therefore, the potential treatment of many complex diseases (e.g. cardiovascular diseases, cancer, hemophilia, renal failure, Huntington’s disease, Parkinson’s disease, and diabetes) will benefit from this novel drug-delivery platform. We are now able to reproducibly generate 100 mm to mm size TSPs with controlled morphology and internal structure. In particular, particles in the current size regime can potentially be used as post-surgical or subcutaneous implants. Results of our research show how parametric tuning of the TSP formation process leads ultimately to adjustable drug release kinetics. The computational methodology allows accurate characterization of the fine structure of the TS channels and the diffusional release model developed can import both the computed versus measured channel profiles. Self-loading within the TS channels occurs under benign conditions that have been shown to preserve conformation and functionality of sensitive proteins and peptides. Two undergraduate and one high-school students have been working on the project under the co-supervision of the PhD student dedicated to this project. The research results were presented by the students in Gordon conference (Soft Condensed Matter Physics, Colby Sawyer, 2011), AIChE (Pittsburgh, 2012), and AAPS (Chicago, 2012) and have led to two journal publications (Soft Matter, 8 (29), 7556 - 7559, 2012 and Langmuir, 28 (1), 729–735, 2012) and two manuscripts in preparation to be submitted to Journal of Pharmaceutical Sciences and Applied Physics Letters.
