The present invention relates to a method for driving an array of temperature controlled cells and to an array of temperature controlled cells.
An array of temperature controlled cells, also referred to as a temperature-processing array, is in general applied in devices in which the temperature of multiple cells is to be controlled independently from the temperature of other cells. An exemplary application is application in a bio-chip. Such a bio-chip may, for example, be suited to perform a chemical reaction. The cells may then represent a reaction chamber, whereby the cells may comprise a sealed or seal-able compartment, and the array may be employed for heating, and controlling the temperature, of each reaction chamber on the bio-chip. Alternatively, the cells may represent different regions in a larger compartment which need to be individually temperature controlled. Fluid may flow across or between the compartments.
An exemplary application is the use of a temperature-processing array for the thermal cycling during DNA amplification, such as Polymerase Chain Reaction (PCR). This is a temperature controlled and enzyme-mediated amplification technique for nucleic acid molecules, usually comprising a periodical repetition of three reaction steps: a denaturing step at about 92-96° C., an annealing step at about 37-65° C. and an extending step at about 72° C. The basic requirement for an efficient amplification is rapid heat transfer, which makes temperature control an important feature of a micro-PCR system.
US 2002/0048765 discloses an integrated micro-array device having a number of temperature controlled reaction wells. Each well may be provided with a temperature control chip. Each chip is individually driven through two addressing wires, resulting in a complex and thereby expensive design.
It is desirable to provide a simple and low-cost array of temperature controlled cells.
In a first aspect the present invention provides a method of driving an array of temperature controlled cells, each cell comprising a heat control means comprising a heating element, a switch element, and a temperature sensor, and the array further comprising a driver circuit, the method comprising:
supplying an address signal for controlling a switch element of a cell in order to connect the heat control means of the cell to the driver circuit;
determining an actual temperature using the temperature sensor; supplying a data signal from the driver circuit to the heat control means; and
supplying energy corresponding to the data signal.
Each cell is provided with a number of elements. A heating element is provided to perform heating. The heating element may be any suitable heating element, such as a resistive heating element, a peltier element, an infrared heater, and the like. In addition, the cell may comprise a plurality of heating elements. The heating element may further incorporate a cooling element, such as a peltier element. In an embodiment, a cell may comprise a heating element and a cooling element, possibly separately controllable.
A temperature sensor is provided to determine an actual temperature representative of the temperature of the cell at the moment of measurement. The temperature sensor may be any suitable temperature sensor. Further for performing the above method, a switch element is provided in each cell. The function of the switch element is explained in detail below.
The array of temperature controlled cells further comprises at least one driver circuit. The driver circuit is suited to drive at least one temperature controlled cell, i.e. to control the heating element, possibly in response to the actual temperature as determined by the temperature sensor.
In the above method the cell is supplied with a control signal. The control signal controls the switch element of the cell. Due to the control signal, the switch element switches and thereby connects the heat control means of the cell to the driver circuit of the array.
The temperature sensor determines the actual temperature in the temperature-controlled cell. The determination may be performed after the switch element has connected the heat control means to the driver circuit. However, it may as well be a continuous action or may be performed at any other suitable moment during the method. The temperature sensor may output an actual temperature signal. In an embodiment, the actual temperature signal is supplied to the data driver circuit and the data driver circuit determines the data signal corresponding to the actual temperature signal.
The driver circuit is configured to supply a data signal to the heat control means. The data signal represents a setting determined by the driver circuit. The setting may be a heating period indicating a period during which the heating element is to heat the cell; the setting may be a heating power indicating a power with which power the heating element is to heat the cell. Other kind of settings may be suitable as well. In particular, the setting may comprise a set temperature, i.e. a temperature that is to be obtained or maintained in the respective cell. The setting may be stored in a memory element as is described below.
In an embodiment the temperature-controlled cells in an array are arranged in rows and columns. The rows and columns may be substantially perpendicularly arranged, but may as well be arranged otherwise, for example hexagonal or circular arrangements. The cells may be rectangularly shaped corresponding to substantially perpendicularly arranged rows and columns of cells, or the cells may have a different shape such as a hexagonal or circular shape.
In an embodiment, the heat control means comprise a memory element. The memory element may store a setting supplied by the driver circuit. When the setting is stored in the memory element, the control signal may be ended and the memory element may be disconnected from the driver circuit at which point the data signal may be ended. Then, energy may be supplied to the heating element. The amount of energy and/or a period of supply corresponds to the setting stored in the memory element.
Simultaneously, while the heating element is driven corresponding to the setting, the temperature-controlled cells of at least one other row of the array may be supplied with the control signal and with a data signal. Thus, the temperature controlled cells of the array are driven such that they are controlled during short periods of time, while being enabled to supply heat to the cell almost continuously.
The above method enables to use a simple array of temperature controlled cells in which a complex driver circuit is not necessarily comprised in a cell, but may be positioned near a side of the array.
In an embodiment, each cell comprises a first switch element and a second switch element and the method comprises:
supplying a first control signal to the first switch element in order to connect the memory element of the cell to the driver circuit;
supplying a second control signal to the second switch element in order to connect the temperature sensor of the cell to the driver circuit for supplying an actual temperature signal to the driver circuit; and
determining by the driver circuit the data signal to be supplied to the memory element based on the actual temperature signal and a set temperature.
In this embodiment, the temperature sensor is connected to the driver circuit. The driver circuit is thus provided with the actual temperature in the respective temperature controlled cell. The driver circuit is further provided with a set temperature, i.e. a temperature to be obtained or maintained in the respective temperature controlled cell. Based on the actual temperature signal and the set temperature, a setting is determined by the driver circuit and supplied to the cell memory element. Then, the connection may be broken and a connection may be established with another cell.
In an embodiment, the heat control means comprise a control circuit and the method comprises connecting the temperature sensor of the cell to the control circuit for supplying an actual temperature signal to the control circuit. The control circuit may be supplied with the data signal from the data driver circuit and may control the heating element corresponding to the data signal and the actual temperature signal. The data signal may as well be provided to a memory element and the heating element is controlled by the control circuit and by the memory element corresponding to the actual temperature signal and the data signal, respectively.
Further, an array of temperature controlled cells is provided. The cells may be arranged in rows and columns. Each cell has a set of control signal terminals for supplying a control signal to the cell and each cell has a set of data signal terminals for supplying a data signal to the cell. Each cell comprises a heat control means comprising a heating element coupled to an energy source; a switch element coupled to the set of control signal terminals for coupling the heat control means to the data signal terminals in response to the control signal; and a temperature sensor for determining an actual temperature. The array further comprises a data driver circuit connectable to the cell.
In an embodiment the temperature sensor is connectable to the data signal terminals for supplying an actual temperature signal to the driver circuit. Thereto, the cell comprises a first switch for connecting the heat control means to the set of data signal terminals and a second switch for connecting the temperature sensor to the set of data signal terminals.
In an embodiment the heat control means comprise a control circuit, the control circuit being connected to the temperature sensor for supplying a temperature signal to the control circuit and the control circuit being connected to the heating element for controlling the heating element.
The cells of the array may be arranged in rows and columns. The reference to a row or a column is to be regarded as a reference to a line of elements in a first direction or in a second direction, respectively. Reference to a row or column does not explicitly or implicitly refer to any orientation of such a line of elements. A line of elements may be a straight line or may be a differently shaped line. Each cell is a member of one such row and is a member of one such column. Thus, each cell is addressable by addressing a respective row and a respective column.
In a preferred embodiment the array of temperature controlled cells is a biochip. In a more preferred embodiment, this biochip is suitable for performing a chemical reaction.
The array is preferably used for amplification of nucleic acid sequences such as in a PCR reaction.
In operation, a sample temperature TY is fed back to the control circuit CC. In response to the actual sample temperature TY and a set temperature TX the temperature control circuit CC adjusts the power dissipated in the heating element H, and thus the heat current W such that a difference between the actual temperature TY and the set temperature TX is as small as possible.
The stability and accuracy of the control method depends on the type of control. A number of feedback control types may be employed:
1) On-Off control—Heating is turned off when the sample temperature TY is above the set temperature TX and heating is turned on when the sample temperature TY is below the set temperature TX. This method is slow and has low accuracy and can have significant overshoot and undershoot.
2) Proportional control—Heating current W is applied proportional to the difference between the actual sample temperature TY and the set temperature TX. This removes the temperature cycling of “On-Off control” and gives moderate temperature control with a smoother action. Thus:
W=P(TX−TY)
where P is the proportional gain. If the sample temperature TY is higher than the set temperature TX, the heating is turned off.
3) Proportional Differential control—Differential control adds a damping factor which can be made critical to achieve the set temperature TX without overshoot and ringing, or undershoot and slow response. This method gives improved accuracy but is less noise tolerant and gives a steady state offset:
where D is a damping factor.
4) Proportional Integral Differential control—Compared to Proportional Differential Control, a further integral control is added to correct for a steady state offset. Heating is changed until a time averaged response goes to zero:
where I is an integral gain.
5) Phase control—Each of the above types of temperature control may be applied in a multiple phase approach of temperature control. In a multiple phase approach, the temperature control is divided in a number of phases. Various types of temperature control may be applied, and per phase the parameters {P,I,D} may be varied. For example, a 3-phase fast temperature control with high accuracy and negligible overshoot may consist of an ‘approach’ phase, a ‘hand-over’ phase and a ‘control’ phase. During the ‘approach’ phase the temperature TY is moved fastly (e.g. maximum ramp) towards the set temperature TX. To prohibit overshoot, the ‘hand-over’ phase is enabled as soon as the actual temperature TY is a predetermined temperature difference away from the set temperature TX. During the ‘hand-over’ phase the temperature is brought to the set temperature TX. Thereafter, the ‘control’ phase is enabled to stabilize the actual temperature TY at the set temperature TX.
The above-described temperature control methods may be employed to control the temperature of a cell of an array of cells. Such an array of temperature controlled cells are known in the art. Each cell may function as a chemical reaction chamber, for example for use in a so-called bio-chip.
The heating element HE may be any suitable heating element, such as a resistor, a peltier element, an infrared heater, and the like. The temperature sensor may be any suitable temperature sensor such as a reversed bias PN junction diode or transistor providing a leakage current or a band-gap temperature sensor as known in the art.
In operation, referring to
When addressed the temperature controlled cell TC is connected to the data driver circuit DDC. The data driver circuit DDC comprises the circuitry for temperature control. The actual cell temperature (
These method steps may be repeated for each row of cells TC and thus each cell TC of the array ATC may be temperature controlled using a control circuit (data driver circuit DDC) without requiring that each cell TC is provided with such a complex control circuit. The period required to control all rows is referred to hereinafter as a field period. Thus, in one field period, all rows are addressed and controlled once per field period. It is noted that the connection of the data driver circuit DDC and the address driver circuit ADC with respect to the columns and rows may be exchanged.
In both
When the corresponding address driver circuit ADC addresses the cell, the switch transistors ST1 and ST2 are switched conductive, connecting the temperature sensor TS and the memory element, i.e. capacitor C1 (
If the temperature control circuit as shown in
Alternatively, if power loss across the drive transistor DT is acceptable, the drive transistor DT may be driven as a current source and analogue data voltages controlling the current may be stored on the capacitor C1 over a field period. However, the voltage at the drain node of the drive transistor DT may not be well defined so the power, and hence heat produced and delivered, may not be well controlled. Methods such as current programming and threshold voltage measurement may be useful for producing more accurate power delivery enabling uniform power delivery across an array of cells.
The above-described embodiments operate in an intermittent manner, hence the temperature data and the memory data are updated once per field period. In another embodiment of the present invention, the temperature feedback may be performed within the temperature controlled cell. This may provide more accurate temperature control, since the temperature feedback is virtually continuous, while in the above-described embodiments, the feedback is only once per field period. The memory element may then store a set temperature that may be updated once per field period. The actual temperature control in response to the set temperature is performed within the cell.
In another embodiment as shown in
In the embodiment shown if
To increase the temperature, the data voltage representing the set temperature, i.e. the voltage on the second capacitor C2, is increased causing the duty period to initially increase thereby delivering more power to the heating element. As the temperature increases the temperature sensor TS starts to produce more current charging the second capacitor C2 to the threshold voltage of the control transistor CT at a higher rate. Thus, the duty period is shortened. Eventually, a stable steady-state at the desired set temperature is achieved. To reduce the temperature, the data voltage on the second capacitor C2 is reduced causing the duty period to shorten or become zero. As the temperature drops, the current in the temperature sensor TS reduces and the duty period starts to increase. A stable steady-state will eventually be reached at the desired lower temperature.
As described above, the heating element HE may be switched on during any period of time (duty period) required for heating the cell to the desired set temperature. Thus, a better accuracy may be achieved compared to the control method as described in relation to
At the address period, data, i.e. a voltage, is stored on capacitor C and the inverter is held at a mid-point in this period, so the capacitor C can be charged and any inverter offsets cancelled. The current to the heating element HE is also switched off in this period. After the address period (and assuming the set temperature is higher than the actual temperature) the capacitor C is switched to the temperature sensor voltage, which is low at that moment, and current then flows to the heating element HE so the temperature sensor voltage rises, thereby reducing the current to the heating element HE. Then, with an appropriately designed system, a stable temperature may be achieved.
The gain in the circuit of
More sophisticated systems such as systems with integration and differentiation as described above in relation to
In the above description of the drawings, reference is made to transistors in general. In practice, the temperature controlled cell-array is suited to be manufactured using Low Temperature Poly-Silicon (LTPS) Thin Film Transistors (TFT). Therefore, in an embodiment, the transistors referred to above may be TFT's. In particular, the array may be manufactured on a large area glass substrate using LTPS technology, since LTPS is particularly cost effective when used for large areas.
Further, although the present invention has been described with regard to low temperature poly-Si (LTPS) based active matrix device, amorphous-Si thin film transistor (TFT), microcrystalline or nano-crystalline Si, high temperature poly SiTFT, other anorganic TFTs based upon e.g. CdSe, SnO or organic TFTs may be used as well. Similarly, MIM, i.e. metal-insulator-metal devices or diode devices, for example using the double diode with reset (D2R) active matrix addressing methods, as known in the art, may be used to develop the invention disclosed herein as well.
Number | Date | Country | Kind |
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05112373.5 | Dec 2005 | EP | regional |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/IB06/54893 | 12/15/2006 | WO | 00 | 6/17/2008 |