Research into microfluidic devices to aid in cancer diagnosis promises huge leaps in making diagnostics easier and faster. Much of this research is focused on chips that can trap circulating tumor cells (CTCs) which are present in blood samples. CTCs are released from a primary tumor and can form metastases in other sites in the body, a process which is responsible for more than 90% of cancer-related deaths.
Being able to easily detect and assess CTCs in the blood would provide clinicians with the ability to minimally-invasively diagnose cancer and provide researchers with a window on cancer metastasis and progression. At present, if scientists wish to find CTCs in a blood sample, they have to search for them manually using a microscope, like looking for a needle in a haystack.
The microfluidic chips designed by Professor Fatih Sarioglu of Georgia Tech are conceived as a streamlined replacement for such manual techniques. They require only a small volume of blood and employ a bifurcated design to trap CTC clusters, while allowing healthy single cells to pass through.
The trapped cells remain viable, and can be removed from the chip for culturing and further analysis. So far, Sarioglu and his research team have tested the chips with blood samples from patients with a variety of metastatic cancers, including non-small cell lung cancer, melanoma, breast, and prostate cancers. Massachusetts General Hospital has licensed the chip technology, and it is currently being used in both basic cancer research and clinical studies.
Medgadget had the opportunity to ask Prof. Sarioglu some questions about his research.
Conn Hastings, Medgadget: Please give us some background on how metastatic cancers are generally diagnosed and monitored at present.
Fatih Sarioglu: Cancer is typically diagnosed during a doctor’s visit triggered by its symptoms being felt by the patient. At that point, unfortunately it might have already metastasized. The primary and secondary sites are identified through imaging and the tumor tissue is resected and sent for a biopsy to identify the type of the cancer. Following the cancer diagnosis, the patient is given chemotherapy and is followed up with periodic imaging of the tumor sites for a potential relapse.
Medgadget: How would a simple blood test be useful in terms of rapid diagnosis, a reduction in invasive procedures, and point-of-care analysis?
Sarioglu: Diagnosing and monitoring cancer through a simple blood analysis offers great opportunities for non-invasive management of cancer. A blood test is already central to many medical decisions and can be performed in almost any clinic at the point-of-care. It is also minimally invasive and can be performed as many times as needed unlike a surgical biopsy. Therefore, a blood-based biopsy, also called the liquid biopsy, can provide a way not only to diagnose cancer from simple blood work as part of a check-up well before its symptoms appear, but also to monitor patient response to the therapy by providing longitudinal information about the tumor state through a series of non-invasive biopsies.
Medgadget: Was it a challenge to design a device that selectively isolates CTCs, given how rare they are in blood samples?
Sarioglu: The challenge in identifying CTCs is not only that they are extremely rare in the blood but also even those from the same tissue are very heterogenous. Therefore, any technology for CTC detection needs to be extremely sensitive to the level that it can identify a single tumor cell among a billion blood cells and it should be able to achieve this specifically to prevent false positives. To address these challenges, we developed a microfluidic device that screens a blood sample at the individual cell level so that none of these rare tumor cells are missed. We also do this very quickly so that we can scan a tube of blood containing ~50 billion cells in reasonable time.
Medgadget: Please give us an overview of how these microfluidic chips work. How are they selective for CTCs? What volume of blood is required?
Sarioglu: Our device targets clusters of CTCs, which have long been known to have greater metastatic propensity than single CTCs and therefore uses the multicellularity of the CTC-clusters to discriminate them from the blood cells. We designed credit-card sized single use plastic chips that accept unprocessed blood sample. Inside the device, these highly metastatic CTC-clusters are held at what we call the bifurcating trap, while all other cells run unimpeded. The bifurcating trap divides the sample flow at a junction so that different cells in a cluster balance each other similar to a fulcrum. We placed tens of thousands of these bifurcating traps running in parallel over the chip so that it can process clinically relevant volumes of blood samples. We typically use a tube (~10 mL) of blood.
Medgadget: What types of characterization are possible once CTCs have been isolated within a chip? Do you envisage that the technique could lead to personalized medicine, whereby clinicians could find the most effective treatments by characterizing the cells?
Sarioglu: The device isolates CTC clusters when they are on their way to metastasis. Therefore, a lot can be learned about the metastasis process besides using these cells in the clinic for personalized cancer treatment. The chip allows phenotypical and molecular analysis of isolated tumor cells. For basic research, isolated tumor cells can be studied to identify diagnostic and therapeutic targets. They can also be used in animal models for functional studies. In the clinic, RNA and DNA of isolated cells can be sequenced to identify the prevalent mutations to guide new targeted therapies. Drugs can potentially be tested on these patient-derived tumor cells in a petri dish, before they are administered to the patient.
Medgadget: Please give us an overview of how the chips are being used in clinical and basic research studies at present.
Sarioglu: We have already used the chip in clinical studies on blood samples collected from patients with breast, prostate cancers and melanoma in a collaboration with Massachusetts General Hospital. We are currently working to apply the technology to other cancer types as well and collaborate with clinicians from Emory University to investigate the clinical utility of CTC-clusters. In terms of fundamental science applications, we work with cancer biologists to investigate the role of CTC-clusters in the metastatic process to identify ways to interfere with and impede the process.