Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Pancreatic cancer is the fourth leading cause of cancer death in the United States. Consequently, identification of clinically relevant biomarkers for the early detection of this cancer type is urgently needed. In recent years, proteomics profiling techniques combined with various data analysis methods have been successfully used to gain critical insights into processes and mechanisms underlying pathologic conditions, particularly as they relate to cancer. The LOCCANDIA (Lab-On-Chip based protein profiling for CANcer DIAgnosis) project is primarily concerned with validating the application of plasma protein profiling for early pancreatic cancer diagnosis by means of developing an innovative nano-technology based (lab-on-a-chip) platform integrated in a full proteomics analysis chain. This paper describes the integrated clinico-proteomic information management and analysis platform. In particular it focuses on discussing the underlying methodologies and technological aspects of key SW modules, i.e. the data preprocessing and profile reconstruction as well as the classification modules. <s> BIB001 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Oral squamous cell carcinoma (OSCC) is a disfiguring and deadly cancer. Despite advances in therapy, many patients continue to face a poor prognosis. Early detection is an important factor in determining the survival of patients with OSCC. No accurate, cost-efficient, and reproducible method exists to screen patients for OSCC. As a result, many patients are diagnosed at advanced stages of the disease. Early detection would identify patients, facilitating timely treatment and close monitoring. Mass screening requires a rapid oral cancer diagnostic test that can be used in a clinical setting. Current diagnostic techniques for OSCC require modern laboratory facilities, sophisticated equipment, and elaborate and lengthy processing by skilled personnel. The lab-on-chip technology holds the promise of replacing these techniques with miniaturized, integrated, automated, inexpensive diagnostic devices. This article describes lab-on-chip devices for biomarker-based identification of oral cancer. Similar methods can be employed for the screening of other types of cancers. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 <s> BIB002 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> The concern for “food safety” surely emerged very early in human history, contributing to the establishment of certain rules and customs. In today’s technologically developed countries, food safety is subject to strict laws that regulate the presence of undesired substances in food. In particular, in the milk industry, levels of residues of veterinary medicinal products, of which antibiotics represent a significant part, are regulated by European Council (EC) Regulation no. 2377/90. More precisely, a series of four antibiotic families are found to be of particular interest due to their routine use for treatment in bacterial infection and/or prophylactic purposes: fluoroquinolones, sulfonamides, β-lactams, and tetracyclines. Their excessive use in dairy diet in recent decades gave rise to stronger bacterial resistance, which consequently represents a serious problem in the efficiency of classic antibacterial treatment in humans [1]. In this context, there is a considerable need for developing sensing devices able to detect a series of antibiotic families simultaneously. A few dipstick format tests [1] commercially available that are cheap, fast, and reliable currently offer an interesting alternative to expensive conventional chromatographic techniques. However, those systems are not fully automated and are unable to detect more than two antibiotic families per single test. The present work reports the development of a lab-on-a-chip (LOC) test system for multiplexed detection of four antibiotic families in raw milk. A fabricated microfluidic cartridge is prefilled with the solutions necessary for immunoassays, and the whole detection sequence is operated automatically by external pump-and-valve combinations. The immunoassay principle is based on a competitive assay format, and the resulting refractive index changes at the sensor surface are probed using the wavelength interrogated optical sensing (WIOS) method. The multiplexed sensing system that was consequently developed was adapted for the simultaneous detection of sulfonamides, fluoroquinolones, β-lactams, and tetracyclines. The whole test procedure is fast (less than 10 min), easy to handle (automated actuation), and cost-effective due to the use of novel photosensitive materials in a “one-step” fabrication process. <s> BIB003 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> The research team is focused on lab-on-a-chip devices for clinical applications, with on-chip integration of electronic circuits, optical filters and (bio)sensors. An example of the work is a lab-on-a-chip where acoustic streaming technique is used to promote the mixing and the pumping of the fluids inside microchannels. The transducer that generates the acoustic streaming is based on a piezoelectric polymer, processed to be functionally graded for, in conjunction with the signal applied to the transducers, being able to control the movement and heating of the fluids. A highly selective optical interference filter co-integrated in CMOS allows the use of only a white light source when spectrophotometry is used as the detection technique, resulting in an actually portable device. <s> BIB004 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Microfluidics-based lab-on-chip (LOC) systems are an active research area that is revolutionising high-throughput sequencing for the fast, sensitive and accurate detection of a variety of pathogens. LOCs also serve as portable diagnostic tools. The devices provide optimum control of nanolitre volumes of fluids and integrate various bioassay operations that allow the devices to rapidly sense pathogenic threat agents for environmental monitoring. LOC systems, such as microfluidic biochips, offer advantages compared to conventional identification procedures that are tedious, expensive and time consuming. This paper aims to provide a broad overview of the need for devices that are easy to operate, sensitive, fast, portable and sufficiently reliable to be used as complementary tools for the control of pathogenic agents that damage the environment. <s> BIB005 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Effective pathogen detection is an essential prerequisite for the prevention and treatment of infectious diseases. Despite recent advances in biosensors, infectious diseases remain a major cause of illnesses and mortality throughout the world. For instance in developing countries, infectious diseases account for over half of the mortality rate. Pathogen detection platforms provide a fundamental tool in different fields including clinical diagnostics, pathology, drug discovery, clinical research, disease outbreaks, and food safety. Microfluidic lab-on-a-chip (LOC) devices offer many advantages for pathogen detection such as miniaturization, small sample volume, portability, rapid detection time and point-of-care diagnosis. This review paper outlines recent microfluidic based devices and LOC design strategies for pathogen detection with the main focus on the integration of different techniques that led to the development of sample-to-result devices. Several examples of recently developed devices are presented along with respective advantages and limitations of each design. Progresses made in biomarkers, sample preparation, amplification and fluid handling techniques using microfluidic platforms are also covered and strategies for multiplexing and high-throughput analysis, as well as point-of-care diagnosis, are discussed. <s> BIB006 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> The past two decades have seen a dramatic raise in the number of investigations leading to the development of Lab-on-a-Chip (LOC) devices for synthesis of nanomaterials. A majority of these investigations were focused on inorganic nanomaterials comprising of metals, metal oxides, nanocomposites and quantum dots. Herein, we provide an analysis of these findings, especially, considering the more recent developments in this new decade. We made an attempt to bring out the differences between chip-based as well as tubular continuous flow systems. We also cover, for the first time, various opportunities the tools from the field of computational fluid dynamics provide in designing LOC systems for synthesis inorganic nanomaterials. Particularly, we provide unique examples to demonstrate that there is a need for concerted effort to utilize LOC devices not only for synthesis of inorganic nanomaterials but also for carrying out superior in vitro studies thereby, paving the way for faster clinical translation. Even though LOC devices with the possibility to carry out multi-step syntheses have been designed, surprisingly, such systems have not been utilized for carrying out simultaneous synthesis and bio-functionalization of nanomaterials. While traditionally, LOC devices are primarily based on microfluidic systems, in this review article, we make a case for utilizing millifluidic systems for more efficient synthesis, bio-functionalization and in vitro studies of inorganic nanomaterials tailor-made for biomedical applications. Finally, recent advances in the field clearly point out the possibility for pushing the boundaries of current medical practices towards personalized health care with a vision to develop automated LOC-based instrumentation for carrying out simultaneous synthesis, bio-functionalization and in vitro evaluation of inorganic nanomaterials for biomedical applications. <s> BIB007 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Lab on Chip devices have a great potential for medical applications as illustrated in three examples. First, a disposable, prefilled capillary electrophoresis chip for monitoring lithium in blood of manic depressive patients is discussed. In a second example, we present a simple chip for counting sperm cells in semen is presented that is used to determine male fertility. Finally, we present the realization of a blood-brain barrier on chip that establishes a versatile platform for drug screening and has the potential to greatly reduce and replace animal testing. <s> BIB008 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers. <s> BIB009 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Background ::: Access to timely and accurate diagnostic tests has a significant impact in the management of diseases of global concern such as malaria. While molecular diagnostics satisfy this need effectively in developed countries, barriers in technology, reagent storage, cost and expertise have hampered the introduction of these methods in developing countries. In this study a simple, lab-on-chip PCR diagnostic was created for malaria that overcomes these challenges. <s> BIB010 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> Display Omitted Introduction on POCT diagnostic systems and their requirements in general.Review on demonstrated and commercially available POCT diagnostic systems.Discussion on current limitations and future prospects of POCT diagnostic systems. Point-of-care testing (POCT) is necessary to provide a rapid diagnostic result for a prompt on-site diagnosis and treatment. A quick analysis time and high sensitivity, with a sample-to-answer format, are the most important features for current POCT diagnostic systems. Microfluidic lab-on-a-chip technologies have been considered as one of the promising solutions that can meet the requirement of the POCT since they can miniaturize and integrate most of the functional modules used in central laboratories into a small chip. This review covers recent advances in POCT technologies with an emphasis on demonstrated and commercially available POCT diagnostic systems with laboratory quality using microfluidic lab-on-a-chip technologies. As working principles and required functional modules depend on target analytes, we categorize the applications of the POCT diagnostic systems according to the analyte types such as proteins, cells, nucleic acids, and metabolites. In each analyte category, detection methods, configuration of POCT lab-on-a-chip modules, and advantages and disadvantages of POCT systems are reviewed and discussed along with future prospects. <s> BIB011 </s> Lab-on-Chip Technology: A Review on Design Trends and Future Scope in Biomedical Applications <s> Application of Lab-on-Chip Technology <s> We evaluated the performance of the molecular lab-on-chip-based VerePLEX Biosystem for detection of multidrug-resistant tuberculosis (MDR-TB), obtaining a diagnostic accuracy of more than 97.8% compared to sequencing and MTBDRplus assay for Mycobacterium tuberculosis complex and rifampin and isoniazid resistance detection on clinical isolates and smear-positive specimens. The speed, user-friendly interface, and versatility make it suitable for routine laboratory use. <s> BIB012
The increased demand of LoC devices in many areas is due to the various technological advantages of LoC technology such as portability, automated sample handling, re-configurability etc. Immunoassay LoC for bacteria detection, Real time PCR detection chips, DNA chip, Gene Chip, Cellular Analysis chip, Flow Cytometer LoC (for HIV) etc. are some of the applications of LoC technology in the biomedical field.  The review BIB011 presents the characteristic of microfluidic LoC to be used for meeting the requirements and improving the efficiency of Point-of-Care diagnostic systems. Since the required functional modules and working principles generally depend on target analytes, so the applications of POCT systems are categorized according to the type of analyte such as cells, proteins, metabolites and nucleic acids. POCT systems have the ability to detect specific biomarkers from these analytes. These different biomarkers require different assays, diagnostic principles and operating systems. Thus in each category, configuration of modules, detection methods and advantages and disadvantages of Lab-on-Chip based POCT diagnostic systems are reviewed. The development of disposable and fully-integrated Lab-on-Chip devices for microfluidic and clinical applications especially in biological fluids for the point of care testing and monitoring of simultaneous parameters has been studied in BIB004 . This chip is fabricated by the integration of biosensors, optical filters and electronic circuits on a single chip. A Lab-on-Chip device is proposed that uses acoustic streaming technique for promoting the pumping and mixing of microfluids inside microchannels so as to improve the microfluidic device performance. To generate this acoustic streaming, a transducer is used which is based on a piezoelectric material like β-PVDF (polyvinylidene fluoride prepared in its β-phase). This polymer is processed to be functionally graded for being able to maintain the heating and to control the movement of fluids in conjunction with the input signal that is applies to the transducer. To facilitate the portability of LoC with less mixing time and to obtain high precision and reliability, it is proposed to use the white light source and spectrophotometry as the detection technique which can be made possible by the co-integration of highly selective optical interference filters on CMOS. The impact of LoC devices on biofunctionalization, synthesis, clinical translation and in-vitro and in-vivo evaluation of inorganic nanomaterials for biomedical applications is discussed in BIB007 . The LoC methods results in consumption of less energy and fast synthesis of quantum dots and inorganic nanomaterials such as metals, nanocomposites, and metal oxides etc. In this article, the comparison is made between tubular continuous and chip-based flow systems. This also shows the requirement of LoC devices for faster completion of clinical translations by carrying out superior in vitro studies. Because of the recent advances in the field of computational simulations, now it becomes possible to synthesize the inorganic nanomaterials-based nanomedicine in a single construct using LOC technology useful for theranostic applications. The recent advances in the Lab-on-Chip technology and design strategies that lead to the development of universal sample-to-result microfluidic devices useful for efficient pathogen detection with high specificity and sensitivity has been presented in BIB006 . The main focus is given on the development of accessory-free and totally integrated selfcontained microchips that will have many advantages such as point-of-care diagnosis, handling of small volumes of sample, rapid detection time, miniaturization and portability. This will help in reducing the mortality rate and in controlling the propagation of life-threatening diseases such as tuberculosis (TB), HIV and so on. The work in BIB003 presents the need for the development of LoC devices required for the multiplexed detection of various antibiotic families in raw milk. It is reported that four antibiotic families are excessively used in dairy diet leading to stronger bacterial resistance. This will pose a serious problem and threatens the efficient antibacterial treatment in humans. Precisely, the antibiotic families of sulfonamides, tetracyclines, βlactams, and fluoroquinolones are of interest. An automated, easy to use, fast and costeffective multiplexed sensing system was developed for detecting these antibiotic families. The proteomics profiling techniques integrated with the information management methodologies and analysis platform is described in BIB001 . The main objective of this is the identification of clinically relevant analytes and biomarkers for the detection of pancreatic cancer in the early phases. Since pancreas are LoCated deep in the abdomen, the ultrasonic and physical detection of pancreatic cancer becomes complex and cumbersome task and almost about 95% of all such cases are diagnosed in last stages; for e.g. in stage III or IV resulting in high mortality rate. In this, the LOCCANDIA project is discussed, shown in figure 3. This project is primarily concerned for the diagnosis of pancreatic cancer in early stage. This can be done by validating the plasma protein which is integrated with aprofiling application with the help of a Lab-on-Chip development i.e. a novel nanotechnology based platform a full proteomics analysis chain. The success of this project is based on the seamless combination of bio, nano and data processing and information management methodologies. Authors in BIB002 describe the emergence of LoC devices for the biomarker-based identification and early detection of oral cancer. Head and neck cancers constitute almost 40% of the oral cavity cancers. Other types of oral cavity cancers include squamous cell carcinomas of the lips, tongue, gums, buccal mucosa, hard and soft palate and floor of the mouth. OSCC (Oral squamous cell carcinoma) is a deadly cancer and results in high mortality, morbidity and disfigurement. Conventional diagnostic and screening methods for OSCC are not cost-efficient and are not highly accurate and require sophisticated equipments, modern laboratory and lengthy and elaborate processing by skilled personnel. The motive to overcome these issues leads to the need of a miniaturized, accurate, automated, integrated and inexpensive lab -on-chip. In order to screen the patients for OSCC, this microfluidic LoC will accept saliva as input sample, which is then processed by minimally trained personnel and thus provide the results on time. Within the chip, the identification of oral cancer and precancer(dysplastic) cells will be possible by means of membrane-associated cell proteins which are singularly expressed on dysplastic and cancer cells' membranes and have unique gene transcription profiles. The paper BIB005 addresses the need for microfluidics-based LoCs that can be used as complementary tools in controlling the effects of pathogenic agents so as to prevent the damage of environment. These LoC systems are easy to operate, fast, sensitive, sufficiently reliable and portable and thus offer several advantages as compared to conventional methods that are expensive, tedious and time consuming. The major application of LoC systems in pathogen detection includes DNA-based methods based on electrochemical techniques. The systems' fluid mechanics is discussed at the nanoscale level. The main limitation is that the use of mechanical pumps needed for fluid transmission requires attention and degrades the performance. The potential of LoCs in the medical area is illustrated in BIB008 . Three examples have been presented to illustrate the potential of LoC in the medical field. First, in the case of maniac patients for monitoring lithium in their blood, a prefilled, disposable chip which is based on capillary electrophoresis is discussed. Lithium in an oral manner is often used to treat the patients suffering from bipolar disorder. So, a glass chip based on capillary electrophoresis and vacuum-prefilled with buffer solution is fabricated and now commercialized by the company Medimate. This same chip also has the potential to determine magnesium and calcium in cow blood in order to detect milk fever. It is seen that sodium in urine can also be measured by this chip platform which is highly useful for kidney patients. In the second example, in order to determine male fertility, a simple chip used to count the sperm cells in semen is presented. Lastly, advanced in-vitro models used for drug development are presented. As an example of organ on chip, blood-brain barrier on chip is realized that is used to establish a versatile platform for the screening of drug and possesses the potential to greatly replace and reduce animal testing. The requirement for a simple, fast and on-time diagnosis and elimination of global concern diseases such as malaria led to the emergence of Lab-on-Chip PCR diagnostic method. In this study BIB010 , the LoC technology is described that has the potential to overcome the challenges of expensive, complex and conventional molecular diagnostics especially in developing countries. This technology has the capability to control the lifethreatening disease malaria in the following ways; as a diagnostic measure for acute malaria, can be used for surveillance in elimination settings and as a tool in clinical evaluations of new vaccines and drugs. This work presents a novel molecular technology that has the potential to make a remarkable contribution in the surveillance and diagnosis of various infectious diseases such as sexually transmitted infections (STI) and for detecting various infection causing pathogens and genetic markers. One of the most common and chronic diseases of today is Tuberculosis, causing high mortality rate due to the inefficient diagnosis and improper treatment. MDR-TB (Multidrug-resistant tuberculosis) is one of the stages of TB that require on time diagnosis and expensive treatment for a long period of time. The WHO (World Health Organization) has also endorsed the specific molecular diagnostic techniques so as to improve the fast diagnosis of MDR-TB BIB009 . The effectiveness of current methods is restricted by limited versatility, inappropriate interpretation of silent mutations and the geographical distribution and genotypic diversity of Mycobacterium tuberculosis complex (MTBC). To overcome all these challenges, STMicroelectronics (Geneva, Switzerland) has developed a Lab-on-Chip device known as VerePLEX Biosystem BIB012 . This molecular LoC based system has the potential to diagnose the MDR-TB considering time constraint and to rapidly detect the common Nontuberculous Mycobacteria (NTM) so as to reduce the mortality and morbidity rate. The user friendly interface; speedy and versatile performance of this system makes it suitable for routine laboratory use.