On A Chip – BioMEMS in Clinical and Point-Of-Care Applications

By Nicholas Watkins, Daniel Irimia, Mehmet Toner, and Rashid Bashir

NOTE: This is an overview of the article, which appeared in the November/December 2011 issue of the IEEE Pulse magazine.
Click here to read the entire article.

Introduction

Biological or biomedical microelectromechanical systems (BioMEMS) are poised to have a significant impact on clinical and biomedical applications. These devices – also termed lab-on-chip or point-of-care (POC) sensors – represent a significant opportunity in various patient-centric settings, including at home, at the doctor’s office, in ambulances on the way to the hospital, in emergency rooms (ERs), at the hospital bedside, in rural and global health settings, and in clinical or commercial diagnostic laboratories. The potential impact of these technologies on the early diagnosis and management of disease can be very high for sensing and reporting on parameters ranging from physiological to biomolecular.

This article points out medical areas where BioMEMS can make a significant contribution to both patient care and the affordability of providing that care.For instance, in the case of non-communicable diseases, POC clinical BioMEMS can be used for the collection of circulating tumor cells (CTCs), detection of protein or deoxyribonucleic acid (DNA) cancer biomarkers from serum, collection of exosomes, and the detection of micro-ribo-nucleic acid (micro-RNA) for cancer detection and epigenetic analysis. For infectious diseases such as HIV/AIDS, with more than 33 million people living with HIV/AIDS in the world, obtaining accurate helper T cell and viral load counts at regular intervals is crucial in monitoring the health of an HIV-positive patient’s immune system. BioMEMS-enabled rapid, point-of-use detection of these infectious diseases could dramatically change how these diseases are managed and treated.

Attributes of Biochip Sensors

BioMEMS and biochips are built from silicon, plastics, or polymer by using micro and nanofabrication technologies. The devices include microfluidic elements such as channels and wells for fluid and sample transport and could employ a range of processing, separation, and sensing modalities (optical and electrical). These devices can also have integrated sample preparation modules and biological recognition elements such as antibodies or DNA molecules for selective capture on the same chip sensor.

The authors suggest that diagnostics and prognostics for diseases could represent the largest and most fruitful area in BioMEMS. The figure below depicts a schematic overview of such devices, highlighting the various steps for detection and analysis of biological targets for clinical or biomedical applications. In general, the use of micro- and nanoscale technologies can be justified because of the following reasons: 1) reduced time-to-result due to small volumes resulting in higher effective concentrations, 2) reducing the sensor element to the scale of the target species and hence providing a higher sensitivity, 3) reduced reagent volumes and associated costs, 4) providing one-time-use disposable sensors and cartridges, and 5) the possibility of portability and miniaturization of the entire system.

Submodules and functions that need to be performed inside a BioMEMS point-of-care (POC) lab-on-chip device. The sample is processed and target analytes, molecules, or cells are captured via recognition elements. The target molecules or the source of the target, e.g., cells, are amplified. Finally, the target is detected and identified using different possible approaches that could require a label or might be label-free.

The article discusses some of the difficulties associated with biological analysis, especially with regards to whole-blood samples, and sensor techniques that have been deployed. It then covers in some detail four examples of biological analysis where research and development work is underway. The biological contexts are provided, along with descriptions and diagrams ilustrating the techniques that are being tested.

Example 1. Complete Blood count on a Chip

Current CBC tests require multiple analysis tools and trained technicians, which not only make the tests prohibitively expensive for many patients but require patients to travel to centralized clinical facilities that may provide results in several days or even weeks. A killer application for POC clinical BioMEMS could be a CBC on a chip, which could revolutionize the health-care infrastructure by not only decreasing personal health-care costs but also providing a rapid and comprehensive assessment during a physician’s visit, or even at the convenience of one’s own home, regardless of geographic and economic constraints. They report on work that is underway to realize such a device.

Example 2: Measuring Neutrophil Motility on a Chip

Neutrophils are the first line of defense against infections. They represent the most numerous subpopulation of white blood cells in the blood and have the ability to migrate within minutes from the blood to the site of infection or injury in the tissues. The motility function of the neutrophils is of great medical interest. However, measuring the motility of neutrophils is not an easy task.

The authors note that, although some elementary functions have already been demonstrated, the integration of efficient separation, precise analysis, and high-throughput format functions in the same device is not a trivial task, and creative new protocols and technological developments are required to overcome current obstacles.

Example 3: Bacterial Detection on a Chip

The capture and detection of bacteria and viruses from body fluids at POC also represents a grand challenge. Integrated biochip devices that can capture, trap, and detect specific bacteria based on dielectrophoresis and antibody-mediated capture have been shown. In addition, to reduce the time for detection of bacteria culture and perform the detection electrically, microfluidic chips in which a small number of bacterial cells could be concentrated from a dilute sample into nanoliter volumes and then cultured have also been demonstrated.

Detection of Circulating Tumor Cells (CTC) for Cancer Diagnostics

Blood-borne metastasis is initiated by cancer cells that are transported through the circulation from the primary tumor to vital distant organs, and it is directly responsible for most cancer-related deaths. However, CTCs are extraordinarily rare (estimated at one CTC per billion normal blood cells in the circulation of patients with advanced cancer), and they have been proven to be too difficult to isolate in sufficient numbers in order to be clinically useful.

The most widely used CTC isolation techniques rely on antibody-based capture of CTCs, which express epithelial cell surface markers that are absent from normal leukocytes [28]. The article describes a ‘CTC-chip’ that the Toner group has developed for single-step isolation of CTCs from unprocessed blood specimens.

ABOUT THE AUTHORS

Nicholas Watkins (watkins7@illinois.edu) and Rashid Bashir (rbashir@illinois.edu) are with the Department of Electrical and Computer Engineering and Bioengineering, Bioengineering and the Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois.

Daniel Irimia (dirimia@hms.harvard.edu) and Mehmet Toner (mtoner@hms.harvard.edu) are with the Surgical Services and BioMEMS Resource Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.