Challenges in Personalized Medicine
Author: Dr. Moritz Kneipp, Product Manager Liquid Flow Sensors
Modern medicine has been able to drastically improve the quality of life of the global population. Diseases such as polio, syphilis, tuberculosis or the plague have been almost eradicated and are successfully treatable or curable. The next milestone for modern medicine is personalized medicine. This novel discipline does not target the broad population, but focuses on the individual for the diagnosis and beyond. Personalized medicine takes the individual’s disease pattern, the patient’s constitution and gender and the resulting implications for the therapies and medicines into account. The overall goal is to create a therapy tailored to the individual that can, if necessary, be adjusted and fine-tuned according to the disease progression.
The combination of a plethora of modern technologies is required to enable such specialized treatments. As such, a tailored cancer therapy could be designed using flow cytometers, DNA sequencing and organ-on-a-chip applications.
Flow cytometer for analysis and diagnosis
Flow cytometers are used for high throughput cell analysis. In these devices, cells flow past an analysis unit (e.g. voltage or fluorescence read-out) at high velocity. The recorded voltage or light signal depends on the shape, structure, size and/or color of the cells. This way, cells with the desired properties can be identified and isolated using cell sorter technology.
Flow cytometers have received special attention with regard to circulating tumor cells (CTCs) in the blood of cancer patients. CTCs can be isolated from the patients’ blood and can therefore be a minimally invasive alternative to potentially complex and invasive traditional biopsies. These liquid biopsies have the potential to reduce the patients’ pain level, the overall risk and the total costs. In cases where the position of the primary tumor or the patient’s constitution does not allow for a traditional procedure, the CTCs can be used to gather the critical data required for a complete diagnosis.
CTCs, which were found in a cancer patient’s blood for the first time in 1869, typically originate from the primary tumor and are leaked into the blood stream or the lymphatic system. CTCs can be found in a blood sample even at early stages of the disease. At 1-10 CTCs per mL whole blood compared to millions of white and billions of red blood cells, their concentration is extremely low and highly sensitive flow cytometers and cell sorters are required to detect and isolate them.
DNA sequencing and characterization
Following detection and isolation of the CTCs, the next step is the characterization. This characterization can and must go down to the molecular level and even the DNA of a single tumor cell can be sequenced. Next Generation Sequencing (NGS) is used to generate the data reliably and quickly.
NGS is able to record the nucleotide sequence of DNA with significantly increased throughput compared to traditional sequencing methods such as Sanger sequencing. The DNA sequence can yield information about the type of tumor, the CTC-specific mutations and thus enable a specific prognosis on disease progression and help in therapy design. Combining NGS and CTCs can therefore be a viable alternative to traditional invasive biopsies.
The next step could lie in employing organ-on-a-chip (OOC) technologies. OOCs are a high-tech iteration of cell cultures. Traditional 2-dimensional cell cultures grown in petri dishes have the drawback of being largely distinct from the in vivo situation of tissues and organs. In order to get closer to the in vivo state, 3-dimensional cell cultures have been developed. In these 3-dimensional cultures, cells can grow in all directions and create a microenvironment that includes cell-cell and cell-matrix interactions closely resembling those of real organs. In order to create even more realistic models, the mechanical and chemical stresses and inputs also have to be taken into account. Tissues such as the heart or lungs are clear examples of organs that can only fulfill their purpose when in motion. This tissue motion results in shear forces on the cells and the extracellular matrix. In OOC lung cultures, for example, vacuum technology can be used to create movement patterns that closely resemble those of an in vivo lung. By combining several tissue types, it is even possible to create whole human-on-a-chip models, allowing for accurate simulation and evaluation of the metabolic and physiological effects of therapies. The use of OOC thus not only advances the field of personalized medicine, it also allows for a reduction in the need for animal tests in research and development.
High precision through sensing
The combination of these technologies and applications has immense potential. The possibilities seem endless. But all of the above applications struggle with similar hurdles. Paradoxically, these partly arise from their common strength – their high precision. In order to guarantee reliable and therefore effective results for patients, all internal processes and parameters must be precisely defined, monitored and controlled. These high requirements regarding precision and the sometimes miniscule sample volumes require advanced sensor technologies to monitor and control processes.
Such sensor technology can be found in Sensirion’s product portfolio. Sensirion is a leading supplier of environmental and flow sensing solutions. In addition to CO2, PM2.5 and humidity and temperature sensors, differential pressure and liquid and gas flow sensors complete the product portfolio. One example of such a sensor solution is the liquid flow sensor LPG10. With a footprint of just 10 x 10 mm2, it is easily integrated into even the smallest of medical devices such as so-called point of care devices. Apart from the excellent biocompatibility – glass is the only wetted material – the microthermal measurement principle with its high precision and speed at even the lowest flow rates makes the LPG10 a perfect solution for the above applications.
CMOSens® Technology integrates an extremely fast, miniaturized thermal sensor together with the complete high-precision evaluation circuitry on a single CMOS microchip. A heating element on the microchip applies a minimal amount of heat to the medium for a thermal flow measurement. Two temperature sensors, positioned symmetrically up and downstream of the heat source, detect minute temperature differences with extreme sensitivity and thus provide the fundamental information on heat dispersion, which is directly correlated to the flow rate. Integrating the technology on a single chip ensures that the sensitive, analog sensor signals are amplified, digitized and further processed without interference and with the highest precision, enabling the chip to provide the user with a calibrated and linearized signal via a digital interface.