Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> This paper presents the development of a disposable plastic biochip incorporating smart passive microfluidics with embedded on-chip power sources and integrated biosensor array for applications in clinical diagnostics and point-of-care testing. The fully integrated disposable biochip is capable of precise volume control with smart microfluidic manipulation without costly on-chip microfluidic components. The biochip has a unique power source using on-chip pressurized air reservoirs, for microfluidic manipulation, avoiding the need for complex microfluidic pumps. In addition, the disposable plastic biochip has successfully been tested for the measurements of partial oxygen concentration, glucose, and lactate level in human blood using an integrated biosensor array. This paper presents details of the smart passive microfluidic system, the on-chip power source, and the biosensor array together with a detailed discussion of the plastic micromachining techniques used for chip fabrication. A handheld analyzer capable of multiparameter detection of clinically relevant parameters has also been developed to detect the signals from the cartridge type disposable biochip. The handheld analyzer developed in this work is currently the smallest analyzer capable of multiparameter detection for point-of-care testing. <s> BIB001 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> A rapidly emerging field in lab-on-a-chip (LOC) research is the development of devices to improve the health of people in developing countries. In this review, we identify diseases that are most in need of new health technologies, discuss special design criteria for LOC devices to be deployed in a variety of resource-poor settings, and review past research into LOC devices for global health. We focus mainly on diagnostics, the nearest-term application in this field. <s> BIB002 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> Two important challenges of the rapid development of microfluidic chip systems are addressed in this paper: 1) new polymer materials and technologies for chip preparation and 2) a label-free method for analyte detection in microchannels. One of the general pacemakers in lab-on-a-chip concepts, capillary electrophoresis (CE) in chip format, was used as workhorse for demonstration. CE chips were fabricated and characterized using polymers such as PMMA, polystyrene and polycarbonate, cycloolefine copolymer, and for the first time, the outstanding high-performance polymer polyether ether ketone (PEEK). Especially for one of the most critical steps in microchannel preparation, bonding of the cover layer to the microstructured substrate, an advanced plasma preconditioning process has been developed. An electrical detection method, capacitively coupled contactless conductivity measurement (CCD), was transferred to the chip level. A high signal-to-noise ratio was obtained by using sputtered thin-film electrodes. It was additionally improved by the very thin channel cover layer thickness, which could be easily obtained by polymer technology. CCD was used for analyte detection near the outlet of the CE separation channel. Further, to demonstrate generally the benefit of CCD for microfluidic flow control, measurement electrodes were positioned at the CE chip injection cross to monitor the reliability of the sophisticated injection processes. A completely miniaturized CE device (ldquoMinCErdquo), was developed for low cost application. Potential applications were demonstrated on selected typical examples: for in situ food analysis, the determination of saccharides in beverages, for medical point-of-care diagnostics, the quantitative determination of antidepressant lithium in blood serum, and for bio analytics, the detection of proteinogenic amino acids. Biological macro molecules-in particular, for life sciences fundamental DNA-have not been in focus of contactless conductivity measurements until now. However, it was possible for the first time to detect DNA highly sensitive by conductivity measurement. The extremely low detection limits achieved are competitive with laser induced fluorescence (LIF) in commercial CE-chip-devices and could provide a highly cost-efficient alternative. <s> BIB003 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> Microfluidics holds great promise to revolutionize various areas of biological engineering, such as single cell analysis, environmental monitoring, regenerative medicine, and point-of-care diagnostics. Despite the fact that intensive efforts have been devoted into the field in the past decades, microfluidics has not yet been adopted widely. It is increasingly realized that an effective system integration strategy that is low cost and broadly applicable to various biological engineering situations is required to fully realize the potential of microfluidics. In this article, we review several promising system integration approaches for microfluidics and discuss their advantages, limitations, and applications. Future advancements of these microfluidic strategies will lead toward translational lab-on-a-chip systems for a wide spectrum of biological engineering applications. <s> BIB004 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> Advances in microsystems integration are enabling the development of new biological and medical devices. Beyond the multifunctional integration on a single chip of sensors, actuators, signal processing and wireless communications; microfluidic implementation to microelectronics opens the door to the elaboration of innovative and complex Lab-On-a-Chip. Various applications are targeted to allow personalized medicine with early diagnostic and therapeutic applications, as well as the monitoring of the living. CMOS and microfluidic platforms convergence will then successfully make the transition to hand-held portable, low-cost point-of-care devices. <s> BIB005 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> Rapid development of microelectronic technology in past four decade is closely related to remarkable progress of technological tools. These new tools may be used for fabrication of MEMS (Micro-ElectroMechanical-System) which integrate microelectronic and micromechanical structures in one system enabling interdisciplinary application. Although MEMS have grown from microelectronics, they are different in technological approach. Using MEMS approach, called microfluidic, small volume of fluid down to less than pico liters can be handled. The scaling of single or multiple lab process down to chip-format known as Lab-on-a-Chip (LOC). Micro and nanoparticles handling can be done using LOC which combines several laboratory functions on a single chip that is only a few millimeters to a few square centimeters in size. MEMS is used to perform chemical analysis by combining laboratory processes on a single chip. The basis for most LOC fabrication processes is photolithography directly derived from microelectronic fabrication. For specific optical characteristics, bio or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, deposition and bonding, PDMS process or soft lithography, as well as fast replication methods via electroplating, injection molding and embossing. This talk also discusses several research activities related to the development of LOC conducted at IMEN, UKM Malaysia to handle biological process for medical applications. <s> BIB006 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Design Constraints and Advantages of Lab-on-Chip Technology <s> Two different types of nanosensors recently developed in our group are presented in this article. Silicon nanowire (Si-NW) field effect sensors have been developed and recent measurements demonstrating pH sensors with Nernstian sensitivity as well as real-time DNA hybridization measurements with binding affinity assessment are presented. Metal nanostructured surfaces are presented with periodically self-aligned nanopyramid and nanowire structures with precisely defined pitch and nanogap dimensions spanning large areas that form high-density arrays of hot-spot scattering sites ideally suited for surface-enhanced Raman scattering (SERS) and Raman spectroscopy. <s> BIB007
A LoC is a device which is capable of scaling the single or multiple laboratory functions down to chip-format [4] . The size of this chip ranges from millimetres to few square centimetres. Extremely small fluid volumes of less than pico litres can be handled by LoC. High throughput screening and automation also becomes possible by the introduction of LoC technology. LoC devices are often indicated by "μTAS" (Micro Total Analysis Systems) and are a subset of MEMS (Micro -electromechanical systems) devices. LoC technology is closely related to the microfluidics which is primarily the combination of physics, the study and manipulation of small quantities of fluids. The major difference between LoC and μTAS is that μTAS generally indicates the integration of the total sequence of lab processes in order to perform chemical analysis whereas LoC is dedicated to the integration of one or several of the lab processes onto a single chip. The applications of LoC in the medical field such as to diagnose HIV infections and in the field of plant sciences have been explored. The paper BIB006 presents the on-going research activities in LoC technology and recent advancements in the handling of various biological processes medical applications. The progress and success of available technological tools leads to the fabrication of MicroElectro-Mechanical-System (MEMS) that integrate micromechanical and microelectronic structures in one system leading to interdisciplinary applications. MEMS and microelectronics differ in technological approaches inspite of the fact the MEMS have grown from microelectronics. The MEMS approach known as microflidics helps in the handling of small fluid volumes even less than picolitres. The scaling of one or several of the lab processes onto a single chip-format is known as LoC which has the capability of handling micro and nano particles by combining several laboratory functions on one chip. To perform chemical analysis, MEMS is used. Photolithography which is directly derived from microelectronic fabrication is the the basis for most LoC fabrication processes and is discussed in this paper. A review BIB004 on various promising system integration techniques for microfluidics has been presented along with their merits, challenges and applications. The emerging microfluidic strategies in order to perform the effective integration of multiple microfluidic components leading to fully automated lab-on-a-chip systems are: (i) Multilayer Soft Lithography; (ii) Capillary Driven and Paper-based Microfluidics; (iii) EWOD Driven Droplet Microfluidics; (iv) Multiphase Microfluidics; (v) Centrifugal Microfluidics; (vi) Electrokinetics, and (vii) Hybrid Microfluidics. Due to on-going research in this area, fully automated microfactories can now be thought of that will have the capability of performing various biochemical analyses at a much low cost for a wide spectrum of biomedical and biological engineering applications. The obstacle in the designing of LoC or microfluidic devices for biomedical applications is that most of these applications need sensitive detection modules like thermal cyclers for PCR reactions, mass spectrometers for sample analyses, microscopes for cells, fluorescence visualization and bacteria. The two major challenges that come in the way for the rapid development of microfluidic Lab-on-Chip systems have been addressed in BIB003 . The first challenge is to investigate the technologies and new polymer materials for chip preparation and the second challenge is to choose the best label-free method for the detection of analytes in microchannels. For the demonstration purposes, a general Lab-on-Chip concept i.e. CE (capillary electrophoresis) in chip format is used. The CE chips are then fabricated and characterized using different polymers such as cycloolefine copolymer, PMMA etc. and the polyether ether ketone (PEEK) come out to be the best polymer having the outstanding performance. Capacitively coupled contactless conductivity measurement (CCD), an electrical detection method is used for analyte detection. Thus, a completely miniaturized and low-cost CE chip is developed known as "MinCE" and different applications are demonstrated such as in medical area, for the quantitative determination and measurement of lithium (an antidepressant) in blood serum suitable for point of care diagnostics. Other applications that are demonstrated include proteinogenic amino acids detection for bio analytics and in beverages, saccharides determination for in situ food analysis. Finally, CCD application is extended for the highly sensitive detection of biologically relevant macromolecules particularly DNA. One of the limitations of this chip system is that in order to get high performance and accurate results, it is essential to individually optimize the different process parameters. Different stages involved in the construction and development of a lab on-a-chip (LOC) system has been discussed in  . For miniaturizing the conventional and current laboratory devices and apparatus, this state-of-art technology use different polymer materials. First, the independent unit components of this microfluidic system are introduced and then for realizing a Lab-on-Chip system, the functional integration of each component into one monolithic system is demonstrated. Specifically, a microscale PCR unit, a microscale injection component and a technique for assembling the device under mild environment conditions are demonstrated. Fabrication of all the unit components is done by the use of a PDMS elastomer and pressure is used for the actuation of a sample flow. By this technique, it is possible to replace the expensive and bulky peripheral components such as heaters and pumps. This also solves the issues of contamination and degradation of sample and extends the application of LoC at the molecular level in case of urodynamic studies. In BIB007 , recently developed nanosensors are presented. These nanosensors are required to improve the efficiency of LoC systems in biological and chemical applications and they have the capability of measuring the biomolecular binding directly. The two sensors presented in this paper are Si-NW (Silicon Nanowire) sensors based on field effect and the platform of second sensor is based on metal nanostructured surfaces. Almost all electrical sensors as Si-NW biosensor have advantages since they have the capability of direct integration with the conventional circuits necessary for miniaturized and compact sensing systems. Si-NW sensors can be demonstrated as pH sensors having Nernstian sensitivity and it becomes possible to have the real-time measurements of DNA hybridization. Nanostructured metal surface based sensor platform defines nanogaps precisely suitable for Raman spectroscopy and SERS (surface-enhanced Raman scattering) application. An overview of the various possibilities that microfluidics can offer for biomedical applications has been provided in BIB005 . The integration of multifunction on a single chip such as actuators, sensors, wireless communication and signal processing; and the implementation of microfluidic to microelectronics has led to the possibility of a novel, innovative and complex LoC. The applications of CMOS and microfluidic co-integration are presented in this paper. This paper also explains the actual trend needed to achieve higher frequencies such as millimeter and microwave ranges. Then the numerous applications are targeted for better life monitoring and to permit personalized medicine with therapeutic and early diagnostic applications. From this, we can conclude that the convergence of microfluidic and CMOS platforms will successfully lead to the portable, handheld, low-cost point-of-care devices. The limitation is that it becomes necessary to face the high challenges and even surpass them like heterogeneous integration and the challenge of fluid handling at the packaging and system level also and not only at the circuit level for reaction, sensing and manipulations. In BIB001 , the requirements for the development of a disposable and smart plastic biochip used in clinical diagnostics applications and for Point-of-Care Testing (POCT) are presented. This paper gives a comprehensive overview of the development of smart passive LoC system, incorporating microfluidic system with on-chip power source embedded on it and the integration of biosensor array. The advantages of this fully integrated system include the control of volume precisely with the help of manipulations of microfluids and all this is done with the low cost on-chip components. The applications demonstrated with this chip include the biochemical detection of various parameters such as the measurement of lactate level and glucose in human blood and gas concentration like partial oxygen measurement in blood. Finally, a handheld analyzer is developed used for the multi parameter measurement and detection applications required for POCT systems. The capability of Lab-on-Chip technology in the field of life science is investigated in  . Microfluidic or Lab-on-Chip technology enables the several sequential experimental steps to be integrated into one single automated process and thus leads to downscaling. With the help of this technology, many enormous tasks such as deciphering of human genome, automated analysis of biomolecules and development of novel targeted therapeutics now become possible in a much faster manner. Conventional techniques such as capillary electrophoresis or gel electrophoresis used commonly for the analysis of RNA, DNA, proteins and for the quantization of nucleic acids are very laborious and time consuming. LoC technology offers several advantages to overcome the limitations of conventional techniques such as ease-of-use, rapid analysis, minimal sample requirement, reduced waste generation and minimized exposure to hazardous materials. In BIB002 , many diseases such as TB, HIV, and malaria are identified that need immediate attention and require new health technologies for their prevention, on-time diagnosis and therapeutics. One such promising solution can now be thought of because of the recent advances in the LoC technology. On-going research in this technology leads to the rapid emergence of such devices that can prove to be very useful for improving the health of people especially in developing countries. Special design criteria for these LoC devices to be deployed in developing countries are also discussed. The main focus of this review is to explore the role of LoC devices in the field of diagnostics. The other applications of LoC technology identified and discussed are efficient and automated drug delivery, environmental sensing and monitoring.