Selective detection and isolation of circulating tumor cells (CTCs) from blood provide valuable clinical insight into disease diagnosis and prognosis as CTCs have been demonstrated to be an independent predictor of disease progression and survival. Additionally, accurate CTC numbers can be used to manage the disease by monitoring changes in tumors during treatment. However, CTCs are extremely rare, comprising as few as one in 109 hematologic cells in the blood of patients with metastatic cancer, effective recognition and separation of the rare cells remain a tremendous challenge. The central objective of this proposal is to mimic physiological, cellular behaviors within a microfluidic chip that can separate and capture CTCs with high efficiency and specificity. To increase sensitivity and capturing efficiency of the rare cells, exploiting multivalent effects will be useful since the effect has been observed to result in an exponential increase of binding avidity. Controlled immobilization of anti-epithelial-cell-adhesion-molecule (anti-EpCAM) through polymeric nanolinkers composed of spherical poly(amidoamine) dendrimers and linear polyethylene glycol will allow control over the multivalent surface to maximize the trapping of CTCs. Furthermore, as the first step of metastasis is known to be "rolling" of the CTCs on the endothelia of blood vessels that express selectins, surfaces coated with the protein that induces the naturally occurring rolling process will promote recruitment of the targeted cells out of the flow, thereby further enhancing specificity against the cells. Hence, here the investigators propose a new design of a CTC capturing device that mimics two important biological processes: multivalent binding and cell rolling. In addition, engineered microfluidic channels will induce rotation of flow that will substantially increases the cell interactions with the functionalized capturing surfaces. Specifically, the objectives of this work will focus on: 1) design and fabrication of a biomimetic microfluidic chip to separate and capture CTCs using rolling and multivalent strong binding; 2) characterization and optimization of capturing efficiency and specificity of the microfluidic chip using tumor cell lines.

The present program is unique in that it will mimic naturally occurring processes for potential diagnostic applications of late-stage cancer patients. The combined strategies of using the biomimicry and engineered microchannels will have great implications and potentially high-reward in the emerging area of rare cell detection in blood. It is hypothesized that a biomimetic microfluidic chip based on iterative rolling and stationary adhesion of CTCs will effectively detect and isolate the rare cells. Essential parameters that will determine the efficiency of CTC trapping are: 1) multivalent binding between the targeted cells and anti-EpCAM that is locally concentrated via immobilization through flexible polymeric nanolinkers and 2) maximized interaction between cells and the functionalized substrate through flow rotation caused by grooves in the channel ceiling.

The research team will expand the existing education and outreach activities of the individual investigators, including a high-school internship program and a research experiences for undergraduates. The University of Illinois at Chicago (UIC) has a high proportion of women and racial minority undergraduates, as well as first-generation college students who are projected to be the backbone of the scientific progress made by U.S. in the 21st century. The research results and experimental techniques developed in this program will be integrated into classroom instruction, both at the undergraduate and graduate levels.

Project Report

Our results have impacted to a broad range of engineering, pharmaceutical, and cancer research areas. Given the detection of rare cells such as circulating tumor cells (CTCs) has attracted a great deal of scientific and clinical interests, our findings based on using biomimetic combinations, a new method of identifying ligands, and using biomimetic medium (alginate) all contribute the advances in the highly multidisciplinary areas. More specifically, significant progress has been made on surface functionalization for enhanced recognition and separation of tumor cells using a biomimetic combination of cell adhesive proteins [1, 2]. Other progress includes identification of CD24 on MCF-7 cells as a protein that induces E-selectin-specific rolling of the cells [3]. The surface immobilization technique of the proteins was translated into a much smaller-scale microfluidic device in which a faithful biomimetic simulation of blood viscosity and diffusivity were achieved using alginate solutions [4, 5]. Recently, we found, for the first time, that the naturally occurring process known as "multivalent binding" mediated by dendrimers substantially enhances the surface capture of tumor cells [6]. Among the 6 publications, the paper published in Angewandte Chemie was highlighted by the journal as a "hot paper", Faculty 1000, and UIC NEWS. The Analytical Chemistry paper published in 2011 was highlighted by C&EN. Our project has successfully drawn attention from multi-level students such as graduate, undergraduate, and high school students. For graduate students, this result was directly used for two PhD dissertations. The undergraduate and high school students obtained hands-on experience by participating this work, helping them determine their future careers in science and engineering. The three supplementary REU grants supported nine UIC, UIUC, and IIT undergraduates. Additionally, the PI and his research team have filed 1 patent application (WO/2010/124227, US2013/265916) and has delivered over 40 invited talks and more than 25 poster/oral presentations. Publications [1] J.H. Myung, C.A. Launiere, D.T. Eddington, and S. Hong, Langmuir 2010, 26(11), 8589-8596. [2] J.H. Myung, K.A. Gajjar, Y.E. Han, and S. Hong, Polymer Chemistry 2012, 3(9), 2336-2341. [3] J.H. Myung, K.A. Gajjar, R.M. Pearson, C.A. Launiere, D.T. Eddington, and S. Hong, Analytical Chemistry 2011, 83(3), 1078-1083. [4] C.A. Launiere, G.J. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington, Biomedical Microdevices 2011, 13(3), 549-557. [5] C.A. Launiere, M. Gaskill, G. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington, Analytical Chemistry 2012, 84(9):4022-8. [6] J.H. Myung, K.A. Gajjar, J. Saric, D.T. Eddington, and S. Hong, Angewandte Chemie International Edition 2011, 50(49), 11769-11772.

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