- University of California, Los Angeles, CA, U.S., Research Fellow in Chemistry and Biochemistry, 2003-2005.
- Stanford University, Stanford, CA, U.S., PhD in Chemistry, 2003.
- Furman University, Greenville, SC, U.S., BSc in Chemistry, 1997.
- Department of Chemistry, University of Toronto.
- Institute of Biomedical Engineering (BME), University of Toronto.
MY RESEARCH OVERVIEW (GO TO SCIENTIFIC OVERVIEW)
Microfluidics for Chemistry, Biology, and Medicine
I have to think small to think big. My research focuses on creating “labs-on-a-chip” (LOCs)—miniaturized, automated devices that are capable of conducting several laboratory experiments at once. LOCs use tiny amounts of reagents (a material that can start a chemical reaction) and other materials, which results in less environmental waste, reduced lab costs and overall increased efficiency.
In developing LOCs, we take advantage of a wide range of tools, including microfabrication, fluorescence microscopy, chemical separations, mass spectrometry, and in vitro cell culture and analysis. A key technology that we use is called digital microfluidics (DMF). In DMF, discrete liquid droplets are manipulated on the surface of an insulated array of electrodes. DMF facilitates an unparalleled level of control over microchemical reactions, and we are exploring the unique capabilities of DMF for applications ranging from chemical synthesis to clinical sample preparation to tissue engineering. We are fortunate to be surrounded by top-notch biologists from the Donnelly Centre, who have more interesting problems than we can possibly ever solve!
This environment is perfect for my research. If you take a quick stroll through the building, you are liable to run into a geneticist, chemist, molecular biologist, chemical engineer, and computer scientist. Members of the Donnelly Centre were pre-selected for their willingness to participate in unconventional collaborations and our physical proximity allows scientists from different worlds to bump into each other and dream up new research projects.
SCIENTIFIC RESEARCH OVERVIEW
Our research group is engaged in a diverse range of projects using microfluidics to solve problems in chemistry, biology, and medicine. Vignettes describing four current projects are described below.
1. Analysis of Tiny Tissue Samples
The front-line treatment for breast cancer in post-menopausal women is aromatase inhibitor therapy (AIT), which prevents local synthesis of estrogen in breast tissue. Until recently, however, there have been no convenient methods to quantify local breast estrogen (and thus, the efficacy of AIT) without invasive surgical biopsies of >500 mg tissue samples. Our group recently worked with Dr. Bob Casper (an endocrinologist at Mount Sinai Hospital) to develop a method to extract and quantify hormones in 1 mg samples of breast tissue. A paper describing this work was featured on the front cover of the inaugural issue of the AAAS journal, Science Translational Medicine, and was covered extensively in the international news media. This innovation is notable in that (i) it is the first method (of any kind) capable of measuring hormones in such tiny samples, and (ii) is the first microfluidic method to accept unprocessed tissue samples as device input. We are currently applying the method to evaluating ~1 mg samples collected by core needle biopsies (a much less invasive sampling procedure than surgical biopsies) from >200 patients in a study funded by the Canadian Breast Cancer Research Foundation. After suitable validation and certification, variations of these methods may prove to be useful for personalized medicine, in which regular CNB sampling and analysis will guide the administration of therapeutic dosing of aromatase inhibitor therapy.
2. Miniaturized Chemical Synthesis
Chemists have long been interested in miniaturizing organic synthesis to take advantage of favorable scaling of diffusion and heat exchange over small distances. Unfortunately, the dominant technology used to date (relying on enclosed microchannels) is not an ideal match for all manifestations of this application because of clogging of solid reagents and precipitates, complex plumbing issues, and material incompatibilities. Our group recently demonstrated an alternative to microchannels for miniaturized organic synthesis ‑ the first method of its kind. A paper describing this work was featured on the inside cover of Angewandte Chemie. The device was designed to handle solid and liquid reagents with diverse properties for up to thirty reaction steps in parallel. Working with Prof. Andrei Yudin (U of T Dept. of Chemistry), the new devices and methods were applied to synchronized synthesis of peptide-based macrocycles and their analogues with side chains appended during aziridine ring-opening. In on-going work, we are continuing to collaborate with the Yudin group to develop a method capable of combinatorial synthesis of peptidomimetics. Future generations of such systems may represent an important advance for laboratory chemists, allowing for automated synthesis of libraries of compounds for applications in drug discovery and high-throughput screening.
3. Microfluidic Cell Culture and Screening
In vitro cell culture and analysis is omnipresent in modern biology labs, but this comes at a cost, with world-wide activities requiring an annual expenditure of billions of dollars and hundreds of thousands of laboratory hours. Our group was the first to explore the compatibility of digital microfluidics with cell culture, with the goal of automating the processes and reducing the reagent costs. One paper describing this work, reported a system capable of detachment and collection of cells from an origin site and delivery to a destination site for sub-culture. Despite widespread interest in applications involving cells in the microfluidics community for more than a decade, this paper was the first to describe a method cell culture with multigenerational passaging. Recent work has featured extensions of these techniques to primary cells, non-mammalian cells, multiplexed cell assays, and three-dimensional cell constructs. Perhaps most importantly, our group recently completed comprehensive genome-level study of the effects of digital microfluidic actuation on cell health and phenotype, characterized with cell-based sensors, single-cell COMET assays, DNA microarrays, and qPCR, concluding that effects on cells (if any) exposed to standard DMF operating conditions are negligible (Integr. Biol. 2013, 5, 1014-1025).
4. Dried Blood Spot Analysis
Dried blood spot (DBS) samples stored on filter paper are becoming popular for applications ranging from pre-clinical screening in the pharmaceutical industry, to point-of-care testing for infectious diseases in resource-limited settings. Despite this interest, there are few automated solutions for handling, extracting, and analyzing DBS samples, and in fact, most current methods are manual, tedious, and slow. Our group developed the first microfluidic technique capable of extracting and quantifying analytes from DBS samples, as was described in a paper that was featured on the cover of Analytical Chemistry. Working with collaborators at the Ontario Newborn Screening Program (ONSP), DBS samples from neonates were screened for diagnostic markers for genetic diseases, and the results were comparable to those generated using conventional (manual and lab-scale) techniques. The technique has captured the attention of experts; for example, in a news story describing the technique (Chem. Eng. News, 2011, 89, 9), well-known DBS proponent Neil Spooner called the method a “revolutionary” advance for DBS analysis.
- Digital microfluidic immunocytochemistry in single cells. Ng AH, Dean Chamberlain M, Situ H, Lee V, Wheeler AR. Nat Commun. 2015 Jun 24;6:7513.
- A microfluidic technique for quantification of steroids in core needle biopsies. Kim J, Abdulwahab S, Choi K, Lafrenière NM, Mudrik JM, Gomaa H, Ahmado H, Behan LA, Casper RF, Wheeler AR. Anal Chem. 2015 May 5;87(9):4688-95.
- Microgels on-demand. Eydelnant IA, Betty Li B, Wheeler AR. Nat Commun. 2014 Feb 25;5:3355.
View Pubmed search of Dr. Wheeler's full list of publications.