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1.  Biosensor diagnosis of urinary tract infections: a path to better treatment? 
Urinary tract infection (UTI) is among the most common bacterial infections and poses a significant healthcare burden. The standard culture-based diagnosis of UTI has a typical delay of two to three days. In the absence of definitive microbiological diagnosis at the point of care, physicians frequently initiate empirical broad-spectrum antibiotic treatment, which has contributed to the emergence of resistant pathogens. Biosensors are emerging as a powerful diagnostic platform for infectious diseases. Similar to how blood glucose sensors revolutionized the management of diabetes and pregnancy tests are now conducted at home, biosensors are poised to significantly improve UTI diagnosis. Biosensors are amenable to integration with microfluidic technology for point-of-care applications. This review focuses on promising biosensor technology for UTI diagnosis, including pathogen identification and antimicrobial susceptibility testing and hurdles in the translation of biosensor technology from bench to bedside.
doi:10.1016/j.tips.2011.03.001
PMCID: PMC3106133  PMID: 21458868
2.  Endoscopic imaging of Cerenkov luminescence 
Biomedical Optics Express  2012;3(6):1215-1225.
We demonstrate feasibility of endoscopic imaging of Cerenkov light originated when charged nuclear particles, emitted from radionuclides, travel through a biological tissue of living subjects at superluminal velocity. The endoscopy imaging system consists of conventional optical fiber bundle/ clinical endoscopes, an optical imaging lens system, and a sensitive low-noise charge coupled device (CCD) camera. Our systematic studies using phantom samples show that Cerenkov light from as low as 1 µCi of radioactivity emitted from 18F-Fluorodeoxyglucose (FDG) can be coupled and transmitted through conventional optical fibers and endoscopes. In vivo imaging experiments with tumor bearing mice, intravenously administered with 18F-FDG, further demonstrated that Cerenkov luminescence endoscopy is a promising new tool in the field of endoscopic molecular imaging.
doi:10.1364/BOE.3.001215
PMCID: PMC3370963  PMID: 22741069
(170.2150) Endoscopic imaging; (170.0110) Imaging systems; (170.4580) Optical diagnostics for medicine
3.  Seeing it through: translational validation of new medical imaging modalities 
Biomedical Optics Express  2012;3(4):764-776.
Medical imaging is an invaluable tool for diagnosis, surgical guidance, and assessment of treatment efficacy. The Network for Translational Research (NTR) for Optical Imaging consists of four research groups working to “bridge the gap” between lab discovery and clinical use of fluorescence- and photoacoustic-based imaging devices used with imaging biomarkers. While the groups are using different modalities, all the groups face similar challenges when attempting to validate these systems for FDA approval and, ultimately, clinical use. Validation steps taken, as well as future needs, are described here. The group hopes to provide translational validation guidance for itself, as well as other researchers.
doi:10.1364/BOE.3.000764
PMCID: PMC3345805  PMID: 22574264
(170.0110) Imaging systems; (170.3880) Medical and biological imaging
4.  Electrothermal Fluid Manipulation of High-Conductivity Samples for Laboratory Automation Applications 
JALA (Charlottesville, Va.)  2010;15(6):426-432.
Electrothermal flow is a promising technique in microfluidic manipulation toward laboratory automation applications, such as clinical diagnostics and high throughput drug screening. Despite the potential of electrothermal flow in biomedical applications, relative little is known about electrothermal manipulation of highly conductive samples, such as physiological fluids and buffer solutions. In this study, the characteristics and challenges of electrothermal manipulation of fluid samples with different conductivities were investigated systematically. Electrothermal flow was shown to create fluid motion for samples with a wide range of conductivity when the driving frequency was above 100 kHz. For samples with low conductivities (below 1 S/m), the characteristics of the electrothermal fluid motions were in quantitative agreement with the theory. For samples with high conductivities (above 1 S/m), the fluid motion appeared to deviate from the model as a result of potential electrochemical reactions and other electrothermal effects. These effects should be taken into consideration for electrothermal manipulation of biological samples with high conductivities. This study will provide insights in designing microfluidic devices for electrokinetic manipulation of biological samples toward laboratory automation applications in the future.
doi:10.1016/j.jala.2010.05.004
PMCID: PMC3003926  PMID: 21180401
5.  Clinical Validation of Integrated Nucleic Acid and Protein Detection on an Electrochemical Biosensor Array for Urinary Tract Infection Diagnosis 
PLoS ONE  2011;6(10):e26846.
Background
Urinary tract infection (UTI) is a common infection that poses a substantial healthcare burden, yet its definitive diagnosis can be challenging. There is a need for a rapid, sensitive and reliable analytical method that could allow early detection of UTI and reduce unnecessary antibiotics. Pathogen identification along with quantitative detection of lactoferrin, a measure of pyuria, may provide useful information towards the overall diagnosis of UTI. Here, we report an integrated biosensor platform capable of simultaneous pathogen identification and detection of urinary biomarker that could aid the effectiveness of the treatment and clinical management.
Methodology/Principal Findings
The integrated pathogen 16S rRNA and host lactoferrin detection using the biosensor array was performed on 113 clinical urine samples collected from patients at risk for complicated UTI. For pathogen detection, the biosensor used sandwich hybridization of capture and detector oligonucleotides to the target analyte, bacterial 16S rRNA. For detection of the protein biomarker, the biosensor used an analogous electrochemical sandwich assay based on capture and detector antibodies. For this assay, a set of oligonucleotide probes optimized for hybridization at 37°C to facilitate integration with the immunoassay was developed. This probe set targeted common uropathogens including E. coli, P. mirabilis, P. aeruginosa and Enterococcus spp. as well as less common uropathogens including Serratia, Providencia, Morganella and Staphylococcus spp. The biosensor assay for pathogen detection had a specificity of 97% and a sensitivity of 89%. A significant correlation was found between LTF concentration measured by the biosensor and WBC and leukocyte esterase (p<0.001 for both).
Conclusion/Significance
We successfully demonstrate simultaneous detection of nucleic acid and host immune marker on a single biosensor array in clinical samples. This platform can be used for multiplexed detection of nucleic acid and protein as the next generation of urinary tract infection diagnostics.
doi:10.1371/journal.pone.0026846
PMCID: PMC3204982  PMID: 22066011
6.  Electrochemical Immunosensor Detection of Urinary Lactoferrin in Clinical Samples for Urinary Tract Infection Diagnosis 
Biosensors & bioelectronics  2010;26(2):649-654.
Urine is the most abundant and easily accessible of all body fluids and provides an ideal route for non-invasive diagnosis of human diseases, particularly of the urinary tract. Electrochemical biosensors are well suited for urinary diagnostics due to their excellent sensitivity, low cost, and ability to detect a wide variety of target molecules including nucleic acids and protein biomarkers. We report the development of an electrochemical immunosensor for direct detection of the urinary tract infection (UTI) biomarker lactoferrin from infected clinical samples. An electrochemical biosensor array with alkanethiolate self-assembled monolayer (SAM) was used. Electrochemical impedance spectroscopy was used to characterize the mixed SAM, consisted of 11-mercaptoundecanoic acid and 6-mercapto-1-hexanol. A sandwich amperometric immunoassay was developed for detection of lactoferrin from urine, with a detection limit of 145 pg/ml. We validated lactoferrin as a biomarker of pyuria (presence of white blood cells in urine), an important hallmark of UTI, in 111 patient-derived urine samples. Finally, we demonstrated multiplex detection of urinary pathogens and lactoferrin through simultaneous detection of bacterial nucleic acid (16S rRNA) and host immune-response protein (lactoferrin) on a single sensor array. Our results represent first integrated sensor platform capable of quantitative pathogen identification and measurement of host immune response, potentially providing clinical diagnosis that is not only more expeditious but more informative than the current standard.
doi:10.1016/j.bios.2010.07.002
PMCID: PMC2946447  PMID: 20667707
Electrochemical biosensor; Amperometry; Urinary diagnostics; Urinary tract infections; Biomarkers
7.  Correction: Statistical Metamodeling for Revealing Synergistic Antimicrobial Interactions 
PLoS ONE  2011;6(7):10.1371/annotation/d598d976-2604-429b-a76f-14aeca628a8e.
doi:10.1371/annotation/d598d976-2604-429b-a76f-14aeca628a8e
PMCID: PMC3128627
8.  System Integration - A Major Step toward Lab on a Chip 
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.
doi:10.1186/1754-1611-5-6
PMCID: PMC3117764  PMID: 21612614
9.  Rapid Antimicrobial Susceptibility Testing Using High Surface-to-Volume Ratio Microchannels 
Analytical chemistry  2010;82(3):1012.
This study reports the use of microfluidics, which intrinsically has a large surface-to-volume ratio, toward rapid antimicrobial susceptibility testing at the point of care. By observing the growth of uropathogenic E. coli in gas permeable polymeric microchannels with different dimensions, we demonstrate that the large surface-to-volume ratio of microfluidic systems facilitates rapid growth of bacteria. For microchannels with 250 micrometer or less in depth, the effective oxygenation can sustain the growth of E. coli to over 109 cfu/ml without external agitation or oxygenation, which eliminates the requirement of bulky instrumentation and facilitates rapid bacterial growth for antimicrobial susceptibility testing at the point of care. The applicability of microfluidic rapid antimicrobial susceptibility testing is demonstrated in culture media and in urine with clinical bacterial isolates that have different antimicrobial resistance profiles. The antimicrobial resistance pattern can be determined as rapidly as 2 hours compared to days in standard clinical procedures facilitating diagnostics at the point of care.
doi:10.1021/ac9022764
PMCID: PMC2821038  PMID: 20055494
10.  A Microfluidic Cartridge System for Multiplexed Clinical Analysis 
JALA (Charlottesville, Va.)  2009;14(6):407-412.
Cartridge-based microfluidics is a promising technology for clinical diagnostics. By miniaturizing the fluid-handling processes required for genomic and proteomic analyses, reagent and specimen volume is minimized along with the size of the system. We demonstrate an automated microfluidic system capable of performing six multiplexed genomic and proteomic analyses simultaneously, by means of an integrated electrochemical sensor and embedded controls.
doi:10.1016/j.jala.2009.05.002
PMCID: PMC2808045  PMID: 20161584
microfluidics; electrochemical sensor; multiplexed assay; quantitative; molecular analysis; point of care; clinical diagnostics
11.  Statistical Metamodeling for Revealing Synergistic Antimicrobial Interactions 
PLoS ONE  2010;5(11):e15472.
Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO) scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future.
doi:10.1371/journal.pone.0015472
PMCID: PMC2988685  PMID: 21124958
12.  Laparoscopic Radical Nephrectomy in a Pelvic Ectopic Kidney: Keys to Success 
Preoperative imaging to delineate anomalous vascular anatomy is mandatory to perform laparoscopic radical nephrectomy for a pelvic ectopic kidney.
Background and Objectives:
Laparoscopic radical nephrectomy of a pelvic kidney for renal cell carcinoma is a procedure with little precedent, but one that offers the advantages of the minimally invasive approach. We present our experience with this unique procedure.
Methods:
A 64-year-old male with a history of end-stage renal disease was diagnosed with a 2.6-cm enhancing mass in a pelvic left kidney with 2 separate sources of blood supply. He was offered either an open radical nephrectomy or a laparoscopic radical nephrectomy and opted for the minimally invasive approach.
Results:
The procedure was performed successfully without complications and with minimal blood loss. The case was marked both by difficulty in mobilizing the sigmoid colon and the limited working space of the pelvis, which made localization of the numerous hilar vessels challenging.
Conclusions:
Laparoscopic radical nephrectomy for a pelvic ectopic kidney appears to be safe and efficacious. Success is dependent on familiarity with pelvic anatomy, optimal port placement, and preprocedure knowledge of the often-complicated vascular anatomy of the ectopic kidney. Preoperative imaging to delineate anomalous vascular anatomy is mandatory, and ureteral catheter placement is helpful for intraoperative identification purposes.
doi:10.4293/108680810X12674612765623
PMCID: PMC3021314  PMID: 20529537
Laparoscopy; Radical nephrectomy; Renal cell carcinoma; Ectopic kidney; Pelvic kidney
13.  Use of Electrochemical DNA Biosensors for Rapid Molecular Identification of Uropathogens in Clinical Urine Specimens 
Journal of Clinical Microbiology  2006;44(2):561-570.
We describe the first species-specific detection of bacterial pathogens in human clinical fluid samples using a microfabricated electrochemical sensor array. Each of the 16 sensors in the array consisted of three single-layer gold electrodes—working, reference, and auxiliary. Each of the working electrodes contained one representative from a library of capture probes, each specific for a clinically relevant bacterial urinary pathogen. The library included probes for Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterocococcus spp., and the Klebsiella-Enterobacter group. A bacterial 16S rRNA target derived from single-step bacterial lysis was hybridized both to the biotin-modified capture probe on the sensor surface and to a second, fluorescein-modified detector probe. Detection of the target-probe hybrids was achieved through binding of a horseradish peroxidase (HRP)-conjugated anti-fluorescein antibody to the detector probe. Amperometric measurement of the catalyzed HRP reaction was obtained at a fixed potential of −200 mV between the working and reference electrodes. Species-specific detection of as few as 2,600 uropathogenic bacteria in culture, inoculated urine, and clinical urine samples was achieved within 45 min from the beginning of sample processing. In a feasibility study of this amperometric detection system using blinded clinical urine specimens, the sensor array had 100% sensitivity for direct detection of gram-negative bacteria without nucleic acid purification or amplification. Identification was demonstrated for 98% of gram-negative bacteria for which species-specific probes were available. When combined with a microfluidics-based sample preparation module, the integrated system could serve as a point-of-care device for rapid diagnosis of urinary tract infections.
doi:10.1128/JCM.44.2.561-570.2006
PMCID: PMC1392664  PMID: 16455913

Results 1-13 (13)