Last month, University of Southern California’s Prof. Keyue Shen was awarded the prestigious Trailblazer Award from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (NIH), the latest in a long line of recognition he’s received for his groundbreaking cancer and stem cell research.
Dr. Shen specializes in studying cell and tissue microenvironments, the ecosystems that cells live within in the body. He explains, using tumor microenvironments as an example, “Usually with cancer cells, most people think of a very malicious cell sitting in the body like a parasite, but actually they are constantly interacting with the surrounding normal cells and matrix proteins.” By studying how to better control these microenvironments, we inch closer to being able to suppress the cancer cells’ ability to metastasize.
With a background in mechanical engineering, biophysics, and biomedical engineering, Dr. Shen is an Assistant Professor of Biomedical Engineering at USC’s Viterbi School of Engineering, an Associate Member of the Norris Comprehensive Cancer Center, and a Principle Investigator of USC Stem Cell. He also leads the Laboratory for Integrative Biosystems Engineering (the “Shen Lab”), which has four PhD students, one masters students, five undergraduates, a technician, and an array of tools, including an Othermill.
Dr. Shen’s team recently published a paper in the journal Technology entitled “A cost-effective micromilling platform for rapid prototyping of microdevices,” in which they characterized the Othermill and assessed its applicability to microdevice production. The paper is freely available on the Technology and NCBI sites. We spoke with Dr. Shen to learn more.
Tell us about your research.
Our research primarily focuses on creating engineered cell culture models to study the signaling and cell-cell interactions that occur in tumors and bone marrow that control cell behaviors and fates. Through our studies, we hope to understand the mechanisms of important biological processes in cancer disease and stem cell regeneration so that novel therapies can be discovered.
How do you use milling in your work?
Milling is one of the techniques that we use to fabricate microdevices for our studies. Some of our devices are directly milled, while others are created from molds made by the mill. These devices perform a variety of functions, such as trapping cells for culture in specific areas, flowing antibodies past cells to label them, and so on. As such, we largely focus on operating our Othermill at high precision and accuracy to produce the complex micro-scale features of these devices.
Why are you interested in microfluidics? What are its applications?
Our interest in microfluidics stems from its application in organ-on-a-chip devices, microchips that have engineered structures and features that recapitulate certain characteristics of native organ environments. These devices offer great value as platforms for cell studies because they're economical (cells may grow on trees, but the cells we’re interested in studying do not! The micro scale of these systems helps conserve cells, media, and other related inputs), closely mimic the cells natural environment, offer a high level of control in terms of isolating variables to study, and allow for drug test/screening under a real human organ-like context (thus gaining more relevance and saving animals).
Microfluidics is employed in a wide variety of ways in these organ-on-a-chip devices. For example, microfluidic channels can be used to load cells into the device, to flow media or soluble signaling molecules at controlled rates past cells in culture, mimicking the flow of blood and its constituents past tissues in the body, and to form obstacles to investigate cell movement in response to stimuli.
These are just a few of the applications that microfluidics can do in organ-on-a-chip devices. However, it should be noted that microfluidics is widely employed in a variety of other fields as well, such as physics and chemistry, as a part of lab-on-a-chip devices.
How did you hear about the Othermill?
We became interested in 3D milling because we were looking for flexible fabrication techniques for organ-on-a-chip devices. Soft lithography, which is most commonly a combination of photolithography and polydimethylsiloxane (PDMS) molding, has long been the golden standard for fabricating microdevices, but it has limitations in the material properties. We're particularly interested in the fast prototyping capabilities, relatively high-precision (although not as high as photolithography), and flexible material options of micromilling, and thus, we decided to purchase our own milling machine to serve our production purposes.
We discovered the Othermill in our search for a suitable entry-level 3D mill for our purposes. We did a comparison of different options on the market and eventually settled on the Othermill for a number of reasons:
- We had an impressive demo at the Westec tradeshow;
- The software interface is really intuitive and has good compatibility with CAD software;
- There is a large collection of training videos on YouTube and knowledgebase on OMC’s website to provide superior training and learning experience; and
- OMC seems to be working on establishing a vibrant community to facilitate idea exchanges.
What kind of materials did you mill in your research and what were you testing for?
We sought to characterize the milling capabilities of our Othermill V2 in terms of accuracy, precision, surface roughness, and optical quality. These four factors were selected because they're the most pertinent factors that could potentially affect the reliability of our experimental results.
Accuracy and precision were assessed for the X, Y, and Z axes at both the millimeter and micrometer range. Surface roughness and optical quality were assessed for native milled surfaces, as well as for mechanically polished and vapor-polished surfaces. Mechanical polishing and vapor polishing were considered in our tests because they represent potential means for improving both the surface roughness and optical quality. The latter is related to the microscopic observations in our lab.
We performed our milling characterization tests using polycarbonate, as polycarbonate is a bio-friendly polymer that can be directly implemented in organ-on-a-chip devices. We also performed some follow-up resolution tests using machining wax for ease.
What's next for you in your research?
Beyond the published paper, we have also worked with HDPE, Delrin, and Teflon and are interested in expanding to other materials such as acrylic, polystyrene, polypropylene, etc. As of now, we’re using the milling machine in two of our main areas of interest: tumor hypoxia and the hematopoietic stem cell (HSC).
For the tumor hypoxia, we’re developing a device that models the oxygen gradient seen in tumors to understand the development of malignancy and drug resistance. For the HSC project, we’re developing a device that mimics the bone marrow for culturing hematopoietic stem cells, which will greatly benefit clinical transplantation of HSCs to treat blood diseases.
Thank you, Dr. Chen! We salute you in your efforts and are thrilled the Othermill has been able to help in your research.
For more on Dr. Shen, watch his faculty profile: