SBIR-STTR Award

CMOS-Integrated Fluorescence Biochip Arrays Abstract Array technologies have been responsible for a multitude of discoveries in genomics and proteomics. However, they require sophisticated and highly accurate instrumentation. Today, the bulkiness, cost, and complexity of array readers have become barriers to their adoption in point-of-care (PoC) applications. There is thus a huge demand for rugged, portable, low cost, and ease-of-use systems that can be used outside of core facilities. In this proposal, we will develop a semiconductor-integrated solution for this problem: a CMOS-integrated fluorescence biochip. This system offers the "best of both worlds" by integrating the gold standard detection modality of biotechnology (fluorescence detection) with commercially available, conventional semiconductor manufacturing processes (complementary metal-oxide-semiconductor, CMOS). The active array substrates include not only the individual transducers required for sensing, but also the low-noise and high dynamic range sensor circuitry and electronic signal analysis blocks. Our preliminary results have demonstrated that by using CMOS, we will not only offer unprecedented detection dynamic range, but also make the cost of the integrated biochip arrays negligible. The latter is a truly unique criterion, as it justifies integration efforts by allowing the biochip array (effectively the reader) to be disposable. In this Phase I project, we plan to design and optimize a biochip system for the widely used DNA microarrays in molecular diagnostics applications with <1000 DNA capturing spots. The integrated biochip will be capable of high performance and multicolor fluorescence detection within the visible-range (¿=400nm to 800nm) with an array size of 1000 and a pixel pitch of 100 ¿m. The specific tasks in this project will be to (1) design and fabricate the electronics circuits that are required for such CMOS biochips, (2) integrate the emission filter, (3) optimize the surface functionalization protocols, and (4) create a microarray-compatible fluidics module for seamless experimentation. Our ultimate quantitative goal of this Phase I SBIR is to experimentally validate the whole system for DNA microarray applications and further develop and commercialize this technology in Phase II.

Public Health Relevance Statement:


Public Health Relevance:
Point-of-care (PoC) molecular diagnostic requires highly-integrated, robust, easy-to-use, low cost, and accurate detection platforms. Semiconductor integration can offer such characteristics for genomics and proteomics array-based screening technologies. In this project, we develop disposable CMOS-integrated fluorescence biochip arrays that can simultaneously screen 1000's of different DNA strands in real-time without requiring any bulky instrumentation or array reader whatsoever while offering unprecedented detection dynamic range.

NIH Spending Category:
Bioengineering; Biotechnology; Genetics; Human Genome

Project Terms:
Adopted; Adoption; base; biochip; Biological Assay; Biological Sciences; Biosensing Techniques; Biosensor; Biotechnology; Capital; Characteristics; Chemistry; Communicable Diseases; conditioning; Core Facility; cost; density; design; Detection; Diagnostic; digital; DNA; DNA Microarray Chip; DNA Sequence; Electronics; Equipment; Film; Fluorescence; Forensic Medicine; Genomics; Glass; Goals; Gold; Image; Individual; instrumentation; Kinetics; manufacturing process; Measurement; metal oxide; Methods; Modality; Modeling; Molecular; Nature; next generation; Noise; nucleic acid detection; Optics; Performance; Phase; point of care; Process; Protein Array; Proteins; Proteomics; Protocols documentation; public health relevance; Reader; Reagent; Research; Sampling; screening; Semiconductors; sensor; Signal Transduction; Small Business Innovation Research Grant; Solutions; Spottings; Surface; System; Technology; Time; Transducers; Validatio

Phase II project, submitted by InSilixa, Inc., a Silicon Valley start-up company, proposes to leverage Phase I accomplishments by developing a complementary metal-oxide- semiconductor (CMOS) biochip platform for the diagnosis of infectious diseases. This project addresses the growing global threat of antibiotic resistant bacteria whose emergence and dissemination now complicates antibiotic selection decisions, negatively affects prognosis, increases health care costs, and fuels increasing levels of resistance. To tackle this crisis, InSilixa will develop a highly multiplex platform that can simultaneously, rapidly and inexpensively detect an infectious agent in a clinical sample and identify the mutations that confer drug resistance. Specifically, the work proposed in this application will entail the design, implementation, and experimental validation of a nucleic acid amplification testing (NAAT) method that uses the proprietary HYDRA CMOS biochip detection platform. Aim 1 will develop a single-chamber, closed-tube, and highly multiplexed NAAT technology that quantifies, in real- time and in parallel, 10's of multiplex PCR reactions and identifies and characterizes the sequences of the generated amplicons by performing 100's of high-resolution melt curve analysis (MCA) experiments. Aim 2 will further develop the CMOS biochip detection platform (HYDRA-4K). And Aim 3 will develop a comprehensive NAAT assay based on combining the above technologies for detecting antimicrobial-resistance in M. tuberculosis. Though the initial clinical focus is tuberculosis, the design, development and manufacturing know-how gained during the course of this project will enable all other applications (and products) for the HYDRA platform. Included amongst these are attractive commercial opportunities including respiratory tract infections, drug resistant hospital acquired infections, outpatient urinary tract and pharyngeal infections and the identification, quantificatin and drug susceptibility genotyping of HIV in the blood of HIV/AIDS patients. The successful completion of this Phase II project will result in a fully characterized, working prototype of the InSilixa CMOS biochip platform that can simultaneously identify an infectious agent and the mutations that confer resistance to a large panel of antibiotics.

Public Health Relevance Statement:


Public Health Relevance:
This SBIR Phase II proposal will develop a new testing method for the diagnosis of infectious diseases. The technology is based on a novel platform developed by InSilixa, Inc., a Silicon Valley "start-up" company. The diagnostic assay resulting from this project will be an electronic "biochip" that can identify an infectious agent directly ina patient's clinical sample and determine its antibiotic resistance pattern. Such information will inform clinical decision making, improve patient outcome, reduce cost and preserve our precious antibiotic arsenal.

Project Terms:
Address; Adoption; Affect; AIDS/HIV problem; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Antiviral Agents; Applications Grants; Arts; Bacteria; base; biochip; Biological Assay; Blood; Characteristics; Clinical; clinical decision-making; communicable disease diagnosis; Communicable Diseases; Computer software; cost; data acquisition; design; Detection; Development; Development Plans; Devices; Diagnostic; DNA; Drug resistance; Electronics; Enterobacteriaceae; Extreme drug resistant tuberculosis; Fluorescence; Funding; Genomic DNA; Genotype; Goals; Health Care Costs; HIV; improved; In Vitro; indium arsenide; Infection; Infectious Agent; instrument; interest; Laboratories; melting; metal oxide; Methods; Microbe; Multi-Drug Resistance; Mutation; Mycobacterium tuberculosis; Nosocomial Infections; novel; Nucleic Acid Amplification Tests; nucleic acid detection; Organism; Outcome; outcome forecast; Outpatients; Patients; Pattern; performance tests; Pharmaceutical Preparations; Phase; point of care; Predisposition; Process; product development; prototype; public health relevance; Reaction; Reader; Recurrence; research study; Resistance; Resistance profile; Resolution; Resources; Respiratory Tract Infections; Sampling; Semiconductors; Silicon; Small Business Innovation Research Grant; Solutions; Specimen; Technology; Testing; Time; Tube; Tuberculosis; United States National Institutes of Health; Urinary tract; Urinary tract infection; Validation; Viral Load result; Work