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Heat integration in micro-fluidic devices
16th European Symposium on Computer Aided Process Engineering and 9th International Symposium on Process Systems Engineering W. Marquardt, C. Pantelides (Editors) © 2006 Published by Elsevier B.V.
1863
Heat Integration in Micro-Fluidic Devices Toshko Zhelev", Olaf Strelow^ ^Stokes Research Institute, U niversity of Limerick, Ireland ^University of Giessen-Frieberg, Germany Abstract Presented paper addresses some problems of energy consumption minimisation in portable micro-total-analysis systems (|i-TAS) and more precisely in micro-polymerase chain reaction systems (MPCRS) used for on spot DNA analysis. Applied methodology takes on board two well-established heat integration concepts such as earlier developed deterministic method and the conceptual design approach, adapts them and applies them in the challenging area of micro-reactors. The focus of presented procedures is on a range of designs, proven as promising by earlier researchers. It considers three heating/cooling options: (a) a classical resistor heating and cooling case; (b) a three fluids case, when the sample droplets moving in a carrier fluid are being heated and pumped by a third fluid, and (c) a new proposed design claiming to overcome major drawbacks of mincrofluidic devices. The main optimisation objectives are the energy conservation and the minimisation of the time for DNA amplification. Additional design requirements are the high throughput and flexibility (versatility) improvement. The major control parameters are the cycle time, the ramp rate and the number of cycles. Advanced steps towards development of a computer code for temperature distribution simulation using deterministic heat transfer model are also reported. Future steps towards more precise problem formulation including the consideration of an enzyme-catalysed bio-chemical reaction and its impact on the fluidic properties are discussed. Keywords: bio chips, heat integration, micro systems, PCR 1. Introduction Today's chemical industry is constantly searching for controllable, high throughput, and environmentally friendly methods of products generation characterised by high degree of chemical selectivity. For both synthesis and analysis, integrated chemical microdevices are now attracting great interest from many research groups. Novel microdesigns are made to perform many standard operations opening up new ways of carrying out chemical transformations. Since transport phenomena are scale-dependent, micro reaction systems, as a new type of reaction systems, possess some unique characteristics. Heat transfer coefficients exceed those of conventional heat exchangers by an order of magnitude. Micro-mixers can reduce mixing time to milli- or nano- seconds. The increased surface to volume ratio in micro reaction systems has implications for multi-phase surface-catalysed reactions (Ehrfeld et al., 2000). The benefit - ability to maintain high level of control and selectivity; elimination of problems associated with the conventional scaling up procedure, high throughput, rapid reaction, improved conversion and many others. Busy with the competitive game of cheap manufacturing, smaller sizes, challenges with surface phenomena and contamination, the researchers still battle with the separate components of the micro-systems and do not pay serious attention to grass-root
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r. Zhelev and O. Strelow
optimization. Our touch with the intensive activities in the area of micro-medical devices design, exercised by the members of Stokes Research Institute - Ireland (www.stokes.ie), helped to identify some optimization objectives that have important impact on the design and efficient operation of micro-reactor systems for DNA analysis, that will be revealed after a short introduction of the process.
2. The Process (PCR) PCR is an enzyme-catalyzed amplification technique, which allows any nucleic acid sequence to be generated in vitro (McPherson et al., 2001). Since its introduction in 1983, PCR has been playing a central role in the field of molecular biology. It is the most powerful technique, by which a DNA segment may be amplified exponentially, for applications like DNA fingerprinting, genomic cloning, genotyping for disease diagnosis, etc. PCR typically requires thermo-cycling with three-temperature steps to sequentially subject template DNA to denaturation (spliting the DNA molecule) at approximately 95°C, primer annealing at 50-60°C and extension at 72 to 75°C. A typical PCR reaction thus goes through 20-40 cycles so as to prepare sufficient DNA material for analysis by hybridization. The number of molecules or copies of segmented molecules varies from 10^ - for cancer detection, to 10^ fingerprinting and genetic disorder predisposition. 3. The Micro-System A micro polymerase chain reactor system (MPCRS) is generally defined as a series of interconnected micro-channels in the range of 10 to 300 microns in diameter etched into a solid substrate. The channel network is connected to a series of reservoirs containing chemical reagents, products and/or waste to form the complete device with overall dimensions of a few centimetres. PCR reactor (cycler) is usually silicon, glass, siliconglass, quartz or plastic device. The MPCRS in general case consists of three main components - (a) sample preparation subsystem; (b) polymerisation reactor; (c) product separation; (d) detection subsystem. In general the MPCR system comprises of integrated micro-unit operations such as channels and fluidic connections (piping), pumps, dosing and injection devices, reactors, mixers, valves, filters, heaters, coolers, physical and chemical sensors, separation and extraction units, detectors, centrofuges, feedback and control loops, etc. As one can see, the MPCRS appears to be in its character very similar to a typical large-scale processing technology and therefore its optimal design and operation would be expected to be very similar to the major chemical production processes. The current ability to design highly efficient, controllable and reliable industrial processes is mainly based on modem achievements of chemical and process engineering. The major approaches assisting the design process of such complex systems are the process modelling, process simulation and process optimisation. They intensify the design process providing ability to screen large number of options avoiding the danger of safety character, environmental hazards and waste of materials, time and money. Interesting enough, the application of current advances of process modeling, simulation, design and integration in the area of micro reactor systems are far from satisfactory.
4. Design Implications The system design (the architecture), is perhaps the most important feature of a microbio-chip as it defines the function and sequence of processes taking place in the device. Miniaturisation of the PCR system provides significantly improved thermal energy
Heat Integration in Micro-Fluidic Devices
1865
transfer compared to macro-scale systems, thus enabling an increased speed of thermal cycling. The design implications are quite different compare to the macro scale. For instance, the reserves (over-design, design margins) accounting for possible deviations from the nominal operation condition, can not be used as flexibility compensation in the case of micro reactors, because any over-sizing can substantially affect the function of the device. As stated by Hasebe (2003), the shape factor plays much bigger role in the design of micro devices compare to conventional unit operations. Terms such as perfect mixing, overall heat transfer coefficient, plug-flow, steady state operation, etc. as usual assumption in micro-systems are not applicable in micro-scale. The shape of the device has a large degree of freedom and needs to be constrained. New types constraints are to be introduced in the design problem formulation, such as average residence time; residence time distribution and temperature distribution. 4.1. Design Optimisation At present the design of PCR systems is based on intuition and trial-and-error approach. Lots of knowledge is palled in the area of fluidics (hydrodynamics of samples movement in small channels), heat transfer and samples preparation. The optimisation criterion targeting increased PCR efficiency is, according to Gad-elHak (1999), the cycle time minimisation, leading further to ramp-rate optimisation. As suggested by Walsh and Davies (2004), this consequently leads to minimisation of sample fluid volumes (in order to minimise the lumped heat capacity and transition times between temperature zones allowing for controllable residency times in each of the stages of the cycle and user controlled temperatures in each of the zones of the device). In summary, the following factors influence the efficiency of MPCRS: (a) temperature of denaturing, annealing and elongation; (b) duration of these thermal processes (heating and cooling); (c) ramp rate (trajectory) of heating and cooling; (d) cycle number to generate reliable amount of product. Some additional efficiency related factors should be considered, such as (e) transfer rate from a zone to zone (related to the design specifics), catalyst nature (enzyme), primer length, reaction buffer, preparation conditions (temperature), etc. It is interesting to note that most of the efficiency related factors are time-dependent. 5. Integration Nguyen (2002) refers to the density of component, concluding that the degree of integration in micro devices follows Moore's law, doubling integration density every 18 months. This growth currently is limited by the photolithography technology, slowing the forecast and doubling integration density every 24 months. The new paradigm for process-systems on chip has analogy with the Systems on chip announced by Benini (2003). It brings the problems of micro-network synthesis, micronetwork integration and resources management onto the domain of optimal process design and optimal process operation. 5.1. Architecture of Micro-system (structure, topology) As it can be expected, the architecture of micro-system plays substantial role in the total efficiency consideration. The production rate can be improved by increasing the number of micro-units operating working in parallel. The structure varies from aggregated micro devices, through a combination of conventional and micro devices, to a hybrid system. The production rate can be changed by changing the number of parallel reactor units. Following these principle we recognise the needs of a new design combining the qualities of traditional and micro-devices {paragraph 6.4.).
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T. Zhelev and O. Strelow
5.2. "Horizontal" and "Vertical" Integration The development of systems featuring "horizontal" integration by building parallel lanes for high throughput applications, and "vertical" integration by implementing several functions on a single device is the most exciting trend in the microchip world. Often the major push towards integration is the portability and decreased reliance on external infi'astructure. This brings the problems of heat integration, energy recovery and conservation higher in the agenda.
6. Heat integration We support the predictions for emerging market of portable DNA analysis devices. Decreasing the risk of contamination, sample mismanagement, rapid diagnostic and quick treatment support the concept of "on spot analysis". In this case energy conservation problems are to be of important concern together with the systems flexibility (ability to tackle different diseases). Let us analyse the possibility for energy conservation and energy recovery in some of the known designs. Due to different geometric design parameters, the contribution of heat conduction within the channel wall is significantly different from that of macroscopic devices. As reported by Punch et al (2003), the Biot number (the ratio of conductive to convective thermal resistance) is a key parameter in the thermal analysis of micro-PCR device. It was found that the velocities changes within 0.1 - 1.0 mm/s have little effect on the temperature profile along the micro-channels. 6.1. Classical meander-type PCR The design solution for controlling the temperature and the cycle-number in the three PCR's temperature zones is through solid resistors fixed under the meanders of channels. The following obvious sequence of heating/cooling zones assists the efficient energy management: The sample after being heated to 93''C passes bypassing meanders trough 72°-zone, assisting the beginning of the cooling and is ftirther cooled in the meanders of the 58° zone. Next, passing quickly through the 72° zone the sample is preheated helping to reach the required temperature in the adjacent 93° zone, and so on. The length of the channel in each zone/the wide of the heater, the volumetric flowrate/pumping abilities and the minimum size of the channel are in strong relation, where the pressure drop and contamination in parallel with the rigid control options are of major concerns. Temperature and cycle number control is possible through manipulating the number of heating sections or the meanders; 6.2, Liquid-liquid heating and pumping Due to the demands of highly-efficient handling of large groups of samples, methods of high-throughput PCR are considered. Serial processing of many samples in small time intervals is nowadays the most popular strategy used in laboratories, and therefore the generation of a continuous flow is a crucial factor. Since in microchannels extreme velocity gradients exist over the cross-section of streaming fluids and chemical guttering of templates and enzymes by reaction concentrates at the wall surfaces, the cross-talk leading to contamination between samples in serially working devices is a ftmdamentally important issue. Therefore, microheterogenous phase systems are applied in micro PCR systems, where a carrying fluid can insulate the reacting liquid volumes from other reacting samples. An example of such a system is the rotational device of Walsh & Davies, (2004). It arranges the droplets of sample fluid to float in a carrier immiscible fluid to prevent contamination. A third fluid comes in direct contact with the carrier fluid performing two fimctions - pumping and heating/cooling and leaving the channel in particular point. The control is much more flexible and easy, but the system
Heat Integration in Micro-Fluidic Devices
1867
stability is a bit of a problem. The task of heat exchanger network synthesis has here its specifics. It is required to find network structure which ensures minimum heating and cooling requirements adjusting the supply and target temperatures of one service stream (utility) having two functions (heating and cooling). The minimum temperature approach was 0.2°C; As pointed out earlier, the heat exchanger units are of parallel flow type because the heating/cooling fluid is in direct contact with the carrier fluid and has to perform pumping service as well. The mass flow rate in this case is restricted and supports the slow motion of the carrier fluid (in the range of 0.1-1.0 mm/s). The temperature difference at the "hot end" of the exchanger can be used to control the ramp rate. The optimal energy management structure was found using the Pinch concept. Because the cost is not of a concern and the maximum energy recovery is a goal driving us closer to portable device, the minimisation of Zir^/„ would be the only option and the trade-off in the tendency to allow for very small AT^nm would be offset by the quality/efficiency of DNA amplification related to the time to produce the require minimum of amplified DNA segments. The suggested energy recovery option requires more than twice less external energy supply (exactly 53.6%) and twice less cooling compared to the case when no energy recovery is considered. 6.3. Transferring Knowledge from Deterministic Plate Heat Exchanger Systems Design As it is well-known, the biggest advantage of plate heat exchangers is their flexibility. Strelow, (2000), proposed a generalised deterministic calculation method that can be utilised for the case of micro heat exchanger systems. The method considers the complexity of streams' flow patterns in plate heat exchangers. It accounts for parallel, serial and subdivided stream passages; covers the heat transfer between two and more process streams, spiral passages and other deviations from the classical counter-flow fluids pattern. The proposed method allows exact and iteration fi-ee determination of steady-state temperature profiles in all variations listed above and provides easy calculation of heat flow along the plates' walls and temperature distribution in plate passages. Iterations are unavoidable only in cases of phase changes and consideration of nonlinear temperature dependent fluid properties. Presented model allows adequate simulation of heat exchanger network operation based on generalised operating conditions. It is an approximation of the exact solutions of the precise system of differential equations describing accurately the system. In our case it permits the consideration of viscosity change and heat capacity change related to polymerisation process. The universal deterministic model of a heat exchanger system of an arbitrary structure/topology (as proposed by Strelow, 1997), consists of five matrices (input /, output O, structure 5, matches of thermal passages K and heat resistance L) and two vectors (of temperature T and heat capacities C). The matrix form of the plate heat exchanger model is: 7^ = ^f, or
(1)
T° =[OiE-Y[@,SrY{e,J]T' i-n
where
(2)
i=n
^-[(E±S'r'
0,,. = 2 ^ {
O'OjE ± Sy IC]K,LKf ^
}
The presented approach was used to model and predict the temperature distribution in a range of classical micro-fluidic devices - the meander type PCRs. A prototype of
1868
T. Zhelev and O. Strelow
software for interactive simulation of the heat integration was developed by Professor Strelow. 6.4. Revolving type cycler (new design) The reason to propose a new type of reactor was the desire to overcome the difficulties and inherited drawbacks of recent microfluidic devices. The biggest advantage of the micro-fluidic bio-chips is the size of the micro-channels and the continuous process allowing for rapid heating and cooling at a high throughput tackling large number of samples. The challenge in this case is the contamination, which has to be ignored at 100%. The second challenge is the flexibility and controllability of MPCRS. All known devices suffer drawbacks in these areas because of their rigid design. The new design is based on batch principles and has a revolving principle of operation and design. The samples are injected in a circular disposable cartridge, when the core (internal) of the system contains a revolving cylinder divided in three heating/cooling sections. The controllable speed of rotation allows for time controlled cycling; number of rotations will control the number of cycles and dynamic temperature control of heating/cooling zones control the ramp-rate. The samples are rejected to the separation and analysis section after efficiency test in vitro, the revolver is decoupled from the preparation section and the micro-channel cartridge is disposed. The process of manufacturing of disposable cartridges is still under design, but gives potential for increasing the number of micro channels (samples throughput), minimisation of wall thickness and decreasing the production cost. 7. Conclusions Putting together the results of this study we realise that we just started to scratch the surface of the problems of the optimal design and operation of efficient, high throughput micro polymerise chain reaction systems. We realise that the results are not fully conclusive and the main reason is the large variety of designs under constant and rapid development at present. When attempting structure synthesis and regimes optimisation, the process engineering practice usually steps on standard processes and unit operations. Here, in the micro reactor systems, the principles of design are still not settled. It will take quite some time to establish well proven efficient reactors, separators and heat transfer unit operations. This should be followed by reliable and adequate mathematical models helping simulation predictions and sensitivity analysis. This process should be guided by principles of process systems engineering, process integration and optimisation. Our work in this direction continues. 8. References J. Punch, B.Rogers, D.Newport & M.Davies, 2003, IMECE-41884, Washington, 1. L. Benini, G.De-Micheli, 2003, Networks on Chip: A New Paradigm for Systems on Chips Design, http://akebono.stanford.edu/users/nanni/research/net/papers/date02.pdf. M. Gad-el-Hak, 1999, The Fluid Mechanics of Microdevices, J.Fluid Engng., 121, 5. M.J. McPherson and S.G. Moller, 2001, The Basics PCR, BIOS Sci. PubHshers Ltd. N-T. Nguyen, 2002, Fundamentals & Application of Microfluidics, Artech House. O. Strelow, 1997, Eine Allgemeine Berechnungsmethode fiier Warmeubertragerschaltungen, Forsch Ingenieurwes, 63, 255-261. & 2000, Int.J.Therm.Sci., 39, 645-658. P. Walsh, and M. Davies, 2004, 7^ Annual Sir Bernard Crossland Symposium, 1. S. Hasebe, 2003, Process Systems Engineering, Elsevier Science, 89. W. Ehrfeld, W., V. Hessel, and H. Lowe, 2000 Microreactors. 1 ed., Wiley-VCH. 288.
1863
Heat Integration in Micro-Fluidic Devices Toshko Zhelev", Olaf Strelow^ ^Stokes Research Institute, U niversity of Limerick, Ireland ^University of Giessen-Frieberg, Germany Abstract Presented paper addresses some problems of energy consumption minimisation in portable micro-total-analysis systems (|i-TAS) and more precisely in micro-polymerase chain reaction systems (MPCRS) used for on spot DNA analysis. Applied methodology takes on board two well-established heat integration concepts such as earlier developed deterministic method and the conceptual design approach, adapts them and applies them in the challenging area of micro-reactors. The focus of presented procedures is on a range of designs, proven as promising by earlier researchers. It considers three heating/cooling options: (a) a classical resistor heating and cooling case; (b) a three fluids case, when the sample droplets moving in a carrier fluid are being heated and pumped by a third fluid, and (c) a new proposed design claiming to overcome major drawbacks of mincrofluidic devices. The main optimisation objectives are the energy conservation and the minimisation of the time for DNA amplification. Additional design requirements are the high throughput and flexibility (versatility) improvement. The major control parameters are the cycle time, the ramp rate and the number of cycles. Advanced steps towards development of a computer code for temperature distribution simulation using deterministic heat transfer model are also reported. Future steps towards more precise problem formulation including the consideration of an enzyme-catalysed bio-chemical reaction and its impact on the fluidic properties are discussed. Keywords: bio chips, heat integration, micro systems, PCR 1. Introduction Today's chemical industry is constantly searching for controllable, high throughput, and environmentally friendly methods of products generation characterised by high degree of chemical selectivity. For both synthesis and analysis, integrated chemical microdevices are now attracting great interest from many research groups. Novel microdesigns are made to perform many standard operations opening up new ways of carrying out chemical transformations. Since transport phenomena are scale-dependent, micro reaction systems, as a new type of reaction systems, possess some unique characteristics. Heat transfer coefficients exceed those of conventional heat exchangers by an order of magnitude. Micro-mixers can reduce mixing time to milli- or nano- seconds. The increased surface to volume ratio in micro reaction systems has implications for multi-phase surface-catalysed reactions (Ehrfeld et al., 2000). The benefit - ability to maintain high level of control and selectivity; elimination of problems associated with the conventional scaling up procedure, high throughput, rapid reaction, improved conversion and many others. Busy with the competitive game of cheap manufacturing, smaller sizes, challenges with surface phenomena and contamination, the researchers still battle with the separate components of the micro-systems and do not pay serious attention to grass-root
1864
r. Zhelev and O. Strelow
optimization. Our touch with the intensive activities in the area of micro-medical devices design, exercised by the members of Stokes Research Institute - Ireland (www.stokes.ie), helped to identify some optimization objectives that have important impact on the design and efficient operation of micro-reactor systems for DNA analysis, that will be revealed after a short introduction of the process.
2. The Process (PCR) PCR is an enzyme-catalyzed amplification technique, which allows any nucleic acid sequence to be generated in vitro (McPherson et al., 2001). Since its introduction in 1983, PCR has been playing a central role in the field of molecular biology. It is the most powerful technique, by which a DNA segment may be amplified exponentially, for applications like DNA fingerprinting, genomic cloning, genotyping for disease diagnosis, etc. PCR typically requires thermo-cycling with three-temperature steps to sequentially subject template DNA to denaturation (spliting the DNA molecule) at approximately 95°C, primer annealing at 50-60°C and extension at 72 to 75°C. A typical PCR reaction thus goes through 20-40 cycles so as to prepare sufficient DNA material for analysis by hybridization. The number of molecules or copies of segmented molecules varies from 10^ - for cancer detection, to 10^ fingerprinting and genetic disorder predisposition. 3. The Micro-System A micro polymerase chain reactor system (MPCRS) is generally defined as a series of interconnected micro-channels in the range of 10 to 300 microns in diameter etched into a solid substrate. The channel network is connected to a series of reservoirs containing chemical reagents, products and/or waste to form the complete device with overall dimensions of a few centimetres. PCR reactor (cycler) is usually silicon, glass, siliconglass, quartz or plastic device. The MPCRS in general case consists of three main components - (a) sample preparation subsystem; (b) polymerisation reactor; (c) product separation; (d) detection subsystem. In general the MPCR system comprises of integrated micro-unit operations such as channels and fluidic connections (piping), pumps, dosing and injection devices, reactors, mixers, valves, filters, heaters, coolers, physical and chemical sensors, separation and extraction units, detectors, centrofuges, feedback and control loops, etc. As one can see, the MPCRS appears to be in its character very similar to a typical large-scale processing technology and therefore its optimal design and operation would be expected to be very similar to the major chemical production processes. The current ability to design highly efficient, controllable and reliable industrial processes is mainly based on modem achievements of chemical and process engineering. The major approaches assisting the design process of such complex systems are the process modelling, process simulation and process optimisation. They intensify the design process providing ability to screen large number of options avoiding the danger of safety character, environmental hazards and waste of materials, time and money. Interesting enough, the application of current advances of process modeling, simulation, design and integration in the area of micro reactor systems are far from satisfactory.
4. Design Implications The system design (the architecture), is perhaps the most important feature of a microbio-chip as it defines the function and sequence of processes taking place in the device. Miniaturisation of the PCR system provides significantly improved thermal energy
Heat Integration in Micro-Fluidic Devices
1865
transfer compared to macro-scale systems, thus enabling an increased speed of thermal cycling. The design implications are quite different compare to the macro scale. For instance, the reserves (over-design, design margins) accounting for possible deviations from the nominal operation condition, can not be used as flexibility compensation in the case of micro reactors, because any over-sizing can substantially affect the function of the device. As stated by Hasebe (2003), the shape factor plays much bigger role in the design of micro devices compare to conventional unit operations. Terms such as perfect mixing, overall heat transfer coefficient, plug-flow, steady state operation, etc. as usual assumption in micro-systems are not applicable in micro-scale. The shape of the device has a large degree of freedom and needs to be constrained. New types constraints are to be introduced in the design problem formulation, such as average residence time; residence time distribution and temperature distribution. 4.1. Design Optimisation At present the design of PCR systems is based on intuition and trial-and-error approach. Lots of knowledge is palled in the area of fluidics (hydrodynamics of samples movement in small channels), heat transfer and samples preparation. The optimisation criterion targeting increased PCR efficiency is, according to Gad-elHak (1999), the cycle time minimisation, leading further to ramp-rate optimisation. As suggested by Walsh and Davies (2004), this consequently leads to minimisation of sample fluid volumes (in order to minimise the lumped heat capacity and transition times between temperature zones allowing for controllable residency times in each of the stages of the cycle and user controlled temperatures in each of the zones of the device). In summary, the following factors influence the efficiency of MPCRS: (a) temperature of denaturing, annealing and elongation; (b) duration of these thermal processes (heating and cooling); (c) ramp rate (trajectory) of heating and cooling; (d) cycle number to generate reliable amount of product. Some additional efficiency related factors should be considered, such as (e) transfer rate from a zone to zone (related to the design specifics), catalyst nature (enzyme), primer length, reaction buffer, preparation conditions (temperature), etc. It is interesting to note that most of the efficiency related factors are time-dependent. 5. Integration Nguyen (2002) refers to the density of component, concluding that the degree of integration in micro devices follows Moore's law, doubling integration density every 18 months. This growth currently is limited by the photolithography technology, slowing the forecast and doubling integration density every 24 months. The new paradigm for process-systems on chip has analogy with the Systems on chip announced by Benini (2003). It brings the problems of micro-network synthesis, micronetwork integration and resources management onto the domain of optimal process design and optimal process operation. 5.1. Architecture of Micro-system (structure, topology) As it can be expected, the architecture of micro-system plays substantial role in the total efficiency consideration. The production rate can be improved by increasing the number of micro-units operating working in parallel. The structure varies from aggregated micro devices, through a combination of conventional and micro devices, to a hybrid system. The production rate can be changed by changing the number of parallel reactor units. Following these principle we recognise the needs of a new design combining the qualities of traditional and micro-devices {paragraph 6.4.).
1866
T. Zhelev and O. Strelow
5.2. "Horizontal" and "Vertical" Integration The development of systems featuring "horizontal" integration by building parallel lanes for high throughput applications, and "vertical" integration by implementing several functions on a single device is the most exciting trend in the microchip world. Often the major push towards integration is the portability and decreased reliance on external infi'astructure. This brings the problems of heat integration, energy recovery and conservation higher in the agenda.
6. Heat integration We support the predictions for emerging market of portable DNA analysis devices. Decreasing the risk of contamination, sample mismanagement, rapid diagnostic and quick treatment support the concept of "on spot analysis". In this case energy conservation problems are to be of important concern together with the systems flexibility (ability to tackle different diseases). Let us analyse the possibility for energy conservation and energy recovery in some of the known designs. Due to different geometric design parameters, the contribution of heat conduction within the channel wall is significantly different from that of macroscopic devices. As reported by Punch et al (2003), the Biot number (the ratio of conductive to convective thermal resistance) is a key parameter in the thermal analysis of micro-PCR device. It was found that the velocities changes within 0.1 - 1.0 mm/s have little effect on the temperature profile along the micro-channels. 6.1. Classical meander-type PCR The design solution for controlling the temperature and the cycle-number in the three PCR's temperature zones is through solid resistors fixed under the meanders of channels. The following obvious sequence of heating/cooling zones assists the efficient energy management: The sample after being heated to 93''C passes bypassing meanders trough 72°-zone, assisting the beginning of the cooling and is ftirther cooled in the meanders of the 58° zone. Next, passing quickly through the 72° zone the sample is preheated helping to reach the required temperature in the adjacent 93° zone, and so on. The length of the channel in each zone/the wide of the heater, the volumetric flowrate/pumping abilities and the minimum size of the channel are in strong relation, where the pressure drop and contamination in parallel with the rigid control options are of major concerns. Temperature and cycle number control is possible through manipulating the number of heating sections or the meanders; 6.2, Liquid-liquid heating and pumping Due to the demands of highly-efficient handling of large groups of samples, methods of high-throughput PCR are considered. Serial processing of many samples in small time intervals is nowadays the most popular strategy used in laboratories, and therefore the generation of a continuous flow is a crucial factor. Since in microchannels extreme velocity gradients exist over the cross-section of streaming fluids and chemical guttering of templates and enzymes by reaction concentrates at the wall surfaces, the cross-talk leading to contamination between samples in serially working devices is a ftmdamentally important issue. Therefore, microheterogenous phase systems are applied in micro PCR systems, where a carrying fluid can insulate the reacting liquid volumes from other reacting samples. An example of such a system is the rotational device of Walsh & Davies, (2004). It arranges the droplets of sample fluid to float in a carrier immiscible fluid to prevent contamination. A third fluid comes in direct contact with the carrier fluid performing two fimctions - pumping and heating/cooling and leaving the channel in particular point. The control is much more flexible and easy, but the system
Heat Integration in Micro-Fluidic Devices
1867
stability is a bit of a problem. The task of heat exchanger network synthesis has here its specifics. It is required to find network structure which ensures minimum heating and cooling requirements adjusting the supply and target temperatures of one service stream (utility) having two functions (heating and cooling). The minimum temperature approach was 0.2°C; As pointed out earlier, the heat exchanger units are of parallel flow type because the heating/cooling fluid is in direct contact with the carrier fluid and has to perform pumping service as well. The mass flow rate in this case is restricted and supports the slow motion of the carrier fluid (in the range of 0.1-1.0 mm/s). The temperature difference at the "hot end" of the exchanger can be used to control the ramp rate. The optimal energy management structure was found using the Pinch concept. Because the cost is not of a concern and the maximum energy recovery is a goal driving us closer to portable device, the minimisation of Zir^/„ would be the only option and the trade-off in the tendency to allow for very small AT^nm would be offset by the quality/efficiency of DNA amplification related to the time to produce the require minimum of amplified DNA segments. The suggested energy recovery option requires more than twice less external energy supply (exactly 53.6%) and twice less cooling compared to the case when no energy recovery is considered. 6.3. Transferring Knowledge from Deterministic Plate Heat Exchanger Systems Design As it is well-known, the biggest advantage of plate heat exchangers is their flexibility. Strelow, (2000), proposed a generalised deterministic calculation method that can be utilised for the case of micro heat exchanger systems. The method considers the complexity of streams' flow patterns in plate heat exchangers. It accounts for parallel, serial and subdivided stream passages; covers the heat transfer between two and more process streams, spiral passages and other deviations from the classical counter-flow fluids pattern. The proposed method allows exact and iteration fi-ee determination of steady-state temperature profiles in all variations listed above and provides easy calculation of heat flow along the plates' walls and temperature distribution in plate passages. Iterations are unavoidable only in cases of phase changes and consideration of nonlinear temperature dependent fluid properties. Presented model allows adequate simulation of heat exchanger network operation based on generalised operating conditions. It is an approximation of the exact solutions of the precise system of differential equations describing accurately the system. In our case it permits the consideration of viscosity change and heat capacity change related to polymerisation process. The universal deterministic model of a heat exchanger system of an arbitrary structure/topology (as proposed by Strelow, 1997), consists of five matrices (input /, output O, structure 5, matches of thermal passages K and heat resistance L) and two vectors (of temperature T and heat capacities C). The matrix form of the plate heat exchanger model is: 7^ = ^f, or
(1)
T° =[OiE-Y[@,SrY{e,J]T' i-n
where
(2)
i=n
^-[(E±S'r'
0,,. = 2 ^ {
O'OjE ± Sy IC]K,LKf ^
}
The presented approach was used to model and predict the temperature distribution in a range of classical micro-fluidic devices - the meander type PCRs. A prototype of
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T. Zhelev and O. Strelow
software for interactive simulation of the heat integration was developed by Professor Strelow. 6.4. Revolving type cycler (new design) The reason to propose a new type of reactor was the desire to overcome the difficulties and inherited drawbacks of recent microfluidic devices. The biggest advantage of the micro-fluidic bio-chips is the size of the micro-channels and the continuous process allowing for rapid heating and cooling at a high throughput tackling large number of samples. The challenge in this case is the contamination, which has to be ignored at 100%. The second challenge is the flexibility and controllability of MPCRS. All known devices suffer drawbacks in these areas because of their rigid design. The new design is based on batch principles and has a revolving principle of operation and design. The samples are injected in a circular disposable cartridge, when the core (internal) of the system contains a revolving cylinder divided in three heating/cooling sections. The controllable speed of rotation allows for time controlled cycling; number of rotations will control the number of cycles and dynamic temperature control of heating/cooling zones control the ramp-rate. The samples are rejected to the separation and analysis section after efficiency test in vitro, the revolver is decoupled from the preparation section and the micro-channel cartridge is disposed. The process of manufacturing of disposable cartridges is still under design, but gives potential for increasing the number of micro channels (samples throughput), minimisation of wall thickness and decreasing the production cost. 7. Conclusions Putting together the results of this study we realise that we just started to scratch the surface of the problems of the optimal design and operation of efficient, high throughput micro polymerise chain reaction systems. We realise that the results are not fully conclusive and the main reason is the large variety of designs under constant and rapid development at present. When attempting structure synthesis and regimes optimisation, the process engineering practice usually steps on standard processes and unit operations. Here, in the micro reactor systems, the principles of design are still not settled. It will take quite some time to establish well proven efficient reactors, separators and heat transfer unit operations. This should be followed by reliable and adequate mathematical models helping simulation predictions and sensitivity analysis. This process should be guided by principles of process systems engineering, process integration and optimisation. Our work in this direction continues. 8. References J. Punch, B.Rogers, D.Newport & M.Davies, 2003, IMECE-41884, Washington, 1. L. Benini, G.De-Micheli, 2003, Networks on Chip: A New Paradigm for Systems on Chips Design, http://akebono.stanford.edu/users/nanni/research/net/papers/date02.pdf. M. Gad-el-Hak, 1999, The Fluid Mechanics of Microdevices, J.Fluid Engng., 121, 5. M.J. McPherson and S.G. Moller, 2001, The Basics PCR, BIOS Sci. PubHshers Ltd. N-T. Nguyen, 2002, Fundamentals & Application of Microfluidics, Artech House. O. Strelow, 1997, Eine Allgemeine Berechnungsmethode fiier Warmeubertragerschaltungen, Forsch Ingenieurwes, 63, 255-261. & 2000, Int.J.Therm.Sci., 39, 645-658. P. Walsh, and M. Davies, 2004, 7^ Annual Sir Bernard Crossland Symposium, 1. S. Hasebe, 2003, Process Systems Engineering, Elsevier Science, 89. W. Ehrfeld, W., V. Hessel, and H. Lowe, 2000 Microreactors. 1 ed., Wiley-VCH. 288.