Study Of Measurement And Control Technology Of Sensorless PCR Chip Array

This study is limited in the cross-areas of the control theory and control engineering, micro-electromechanical systems (MEMS) and life science. A new style of equipment that is widely used in life science is researched and developed. The technology developed in the study may be extended to other relative fields.Polymerase chain reaction (PCR) is an enzymatic method to amplify DNA by repeating a series of thermally controlled reaction steps. It has become one of the most widely used techniques in molecular biology, forensic analysis, evolutionary biology, and medical diagnostics. In this paper a new style of PCR equipment in which PCR chips based on MEMS technology are used to contain the reaction liquid is studied. Because the volumes and qualities of PCR chips are very small and the relative surfaces of PCR chips are very big, they are of many advantages contrast to the traditional desk PCR machines. So the PCR equipment is a new, advanced and practical equipment contrast to the existing equipments.The goal of this study is how to reduce the cost of the micro-reactor PCR chip, improve the reliability of the chip and make a hundred of chips working together at the same time. Several kinds of integrated micro-reactor PCR chips made by MEMS technology have been reported by other researchers, within which there are micro-sensors and micro-heaters. But in this paper a kind of PCR chip that no micro-sensor and micro-heater is studied. This is a concrete way to reduce the cost of the chip and improve the reliability of it. And this kind of chip is called the sensorless PCR chip or the low cost PCR chip. To the integrated micro-reactor PCR chips, the focus is their design, simulation and process related to MEMS. But to the sensorless PCR chips, the main difficulty is how to measure and control them. And this can play the advantage of automatic control specialty and avoid the disadvantage of the specialty in the MEMS processing. In fact the capability and level of the micro-processing are insufficient in Chinese enterprises now. It may be accepted easily by Chinese enterprises to produce PCR chips avoiding the complicated MEMS processing. So the study results obtained in laboratories enter the market easily.Similar to the design, simulation and process of microstructure, the modeling, measuring and control are also basic and important technology to MEMS. The measurement and control device of the sensorless PCR chips developed can be also used to study the measurement and control of some other MEMS and some methods obtained in this paper can be also used in other MEMS.Two kinds of low-cost PCR chips are designed and their test elements are made and the serial design of the PCR chip is proposed and studied. Multi-unit and multi-sensitivity lumped thermal parameter analysis is used to simulate the low-cost PCR chips and a new, creative measurement and control scheme to the low-cost PCR chips is designed and simulated. Combined the unitized macroscopic control and distributed microcosmic control, the system is able to do the temperature cycling control to the chip array which made up of many chips at the same time.The measurement and control scheme to the sensorless PCR chips is the most creative thing in this paper and it is described as the following. The sensorless PCR chips are set in the upper-surface of a fast heat exchanger. The temperature that the PCR chips required is controlled approximately by the unitized macroscopic subsystem in which water as the thermal medium is pumped through the heat exchanger. Using the principle that the copper-foil resistance has a certain relation with its temperature, the array of the micro-heaters and micro-sensors corresponding to the array of the PCR chips is designed and manufactured on a flexible printed circuit board (PCB), which provides temperature compensation to each PCR chip in the chip array. The surface of the heat exchanger is divided into many small zones according to its temperature uniformity, and each zone called as an isothermal zone in which the temperature is thought same. In each isothermal zone one chip is selected as the model chip based on the theory of fuzzy optimum selection for multiobjective decision. A temperature micro-sensor is set in the micro-reactor of the model chip where the distilled water is filled with. There are no temperature sensors in other chips that are not the model chips. In the model chips the PCR liquid does not exist and the PCR takes place in the other chips. In an isothermal zone, the control output gained from the feedback signal of the model chip is applied to all the chips in same isothermal zone at the same time. So the temperatures of all PCR chips in the isothermal zone can be considered same. The model chips are regard as an inherent configuration of the measurement and control system and it can be calibrated precisely. The method to use the model chips can not only measure the temperature of the sensorless PCR chip indirectly but also decrease the amount of the temperature sensors and temperature control loops and simply the hardware configuration of the control system.For above scheme, the hardware is designed based on industrial control computer (IPC). Especially, a highly efficient, special-purpose heat exchanger is designed and manufactured.There are no sensors in the PCR chips in which the PCR takes place, so it is a key how to measure the liquid temperature within the chip. So the measurement technology about the chip is studied in-depth and the following creative works are done:(1) The loading effect that the temperature sensor on the temperature field and its compensation method is studied in considerable detail. For MEMS elements, because they are very small, the loading effect of the sensor to them is often a universal and inevitable problem. A method called "subtracting one from two" is proposed and it is also suitable for other occasions where the loading effect of the sensor should be considered.(2) The dynamic characteristics, dynamic repeatability and dynamic measurement errors of the thermocouples in the model chips are studied fully, and an intelligent compensation method to the dynamic measurement errors is put in practice. Now there is no standard definition of the dynamic repeatability of the sensor. To take the static repeatability of the sensor as a model, a definition of the dynamic repeatability of the first-order sensor is given.(3) The temperature measurement error to the liquid within the model chip was analyzed and synthesized, and the uncertainty of the indirect measurement to the temperature of the PCR liquid has been assessed. According to the root-sum-square formula about uncertainty synthesis, the uncertainty of the indirect measurement to the temperature of the PCR liquid is 0.52℃.Control strategy is the soul of the control system. This system is a temperature servo-system. Some important and creative research works are done as following: (1) The dynamic models of two kinds of low-cost PCR chips are obtained using multi-unit and multi-sensitivity lumped thermal parameter analysis. Cascade control strategy is applied to further improve the performance of the control loops. As the step amount of the T networks increasing, the model will be of the similar characteristics as the distributed parameter object. The finite element method is often used in the study of the distributed parameter object but it isn't suited for the design of control system. The method for the modeling of the PCR chip that using multi-unit and multi-sensitivity lumped thermal parameter analysis may be used to get the dynamic control models of MEMS.(2) If the difference between the contact thermal resistance of each PCR chip and that of its model chip is too big, the performance of control system would decline seriously and the amplification would fail. But it is very difficult to measure the contact thermal resistance in real-time. So the statistical process control (SPC) method is used to monitor the uniformity of the contact thermal resistances of the chips indirectly through measuring the temperature of the upper-surface of each chip.(3) Generally, complex and expensive instruments are often needed to plot isothermal zones. In order to decrease the cost of study, the elements of the measurement and control system are used to plot the upper-surface of the heat exchanger into isothermal zones. And the theory of the fuzzy optimum selection for multi-objective decision is applied to select the locations of the model chips.(4) A correction algorithm is designed for non-standard thermal resistance sensors that are made of copper-foil on the PCB board. By means of this correction algorithm the signal conditioning circuits for standard thermal resistances can be used in the signal conditioning of non-standard thermal resistance sensors. The signal conditioning circuits for standard thermal resistances have been matured and standardized. So the hardware of the control system is simplified and its reliability and stability are improved correspondingly. The idea about signal conditioning is practical for other intelligent sensor systems, especially for some multi-type and few-batch measurement and control systems. And a method that uses the hardware to compensate the dispersivity of the thermal resistance on PCB is implemented.(5) A systematic and scientific performance index to assess the performance of temperature cycling control of the PCR chip system is established. It is a key to make the PCR chip system go out of the laboratory and enter the market. The performance index is applied to assess the control system in the laboratory. To make reference to the performance of MW-1 DRI-PLATE PCR device in temperature cycling control, the system developed in this paper meets the requirements of PCR. The performance of the system in temperature cycling control is better than that of the traditional PCR devices but the cost of it is not more. The cost of the system is much lower than the integrated PCR chips but the performance of it is almost equal to the integrated PCR chips. So the system is of many advantages whether compared to the traditional PCR devices or to the integrated PCR chips. The technology developed in the study such as the compensation method to loading effect of sensor, the multi-unit and multi-sensitivity lumped thermal parameter analysis, the signal conditioning method of non-standard sensor may be extended to other relative fields.