The McDevitt laboratory is now involved in six clinical trials involving the programmable bio-nano-chip for major diseases in the areas of cardiac heart disease, oral cancer, ovarian cancer, prostate cancer and drugs of abuse. These translational activities are unique and place this approach in a position to make transformative changes to the US and global healthcare. John T. McDevitt has recently established the "Texas Cancer Diagnostics Pipeline" and serves at the Director for the newly formed "Early Disease Detection Gulf Coast Consortium Cluster" thereby creating a network of over 100 clinical researchers devoted to next generation of affordable diagnostics. Collectively these activities are helping to move swiftly these medical microdevices from the bench to the bedside. Read more about these bench to the bedside translational activities.
|Study||Sponsor||Study Period||Disease Area||# of Participants||Clinical Sites||Number of Biomarkers|
|Development of a Lab-on-a-Chip System for Saliva-Based Diagnostics||NIDCR-U01||9/1/06 - 2/28/11||Cardiac Disease||1000 patients||15 proteins|
|Monitoring of Oral Cancer Patients Using Novel Lab-on-a-Chip Ensembles||NIDCR-Grand Opportunity||9/25/09 - 8/31/11||Oral Cancer||950 patients||7 celluar markers|
|Texas Cancer Diagnostics Pipeline Consortium: Oral Cancer||CPRIT||9/1/10 - 8/31/13||Oral Cancer||2200 patients||7 celluar markers|
|Texas Cancer Diagnostics Pipeline Consortium: Ovarian Cancer||CPRIT||9/1/10 - 8/31/13||Ovarian Cancer||1250 patients||4 proteins + >10 auto-antibodies|
|Texas Cancer Diagnostics Pipeline Consortium: Prostate Cancer||CPRIT||9/1/10 - 8/13/13||Prostate Cancer||400 patients||3 proteins|
|Advanced Bio-nano-chips for Saliva Based Drug Tests at the Point of Arrest||UK: Home Office||9/1/09 - 3/31/11||Drugs of Abuse||240 participants||4 drugs|
In the US, there are more than 8 million visits to emergency departments (EDs) annually for chest pain or other symptoms consistent with acute coronary syndrome (ACS) that includes acute myocardial infarction (AMI) or heart attack.
The challenge to clinicians is rapid identification of those who require admission for urgent management and those with a benign cause who can be discharged directly from the ED. Likewise, ACS outcomes depend strongly on time-dependent intervention and therapies; indeed, time is muscle for the ACS patient and the attending ED physician. Recent guidelines by the American College of Cardiology and the American Heart Association for the diagnosis and treatment of ACS recommend that cardiac markers should be evaluated within 30-60 minutes from the time of ED presentation. Many EDs and central laboratories do not meet this recommendation, as processing of samples in these environments includes transport of blood from the ED to the lab, extraction of serum (via clotting), centrifugation and long assay times (at best 20 minutes if an automated immunoassay analyzer is used).
Point of care (POC) devices, as developed in the McDevitt lab, address this demand for accelerated diagnostic information and reduction in result turn-around-times (TATs). POC tests are attractive because they can be performed simply, outside the laboratory without the requirement for highly trained personnel and quickly, offering swift TAT of results. POC tests provide a means for reducing hospital stay and complications, as well as help accelerate the application of life-saving treatments. Further, POC tests can be performed in the ED setting negating the need of sample transportation to a central laboratory and, thereby, reducing the risk for sample degradation, thus allowing for a more accurate diagnosis.
Cardiovascular disease (CVD), a diagnostic class that includes several separate diseases of the heart and the circulatory system, including coronary heart disease (CHD) and cerebrovascular disease, is the leading cause of death in the United States (US), as well as on a global basis. Despite recent remarkable and continuing declines in the mortality rates, CVD statistics are still staggering. In 1997 alone, nearly 1 million people died of CVD in the US alone, constituting about 40 percent of all deaths for that year. In 1998, in the US 460,390 people died of CHD and 158,060 of stroke. In 2000, it was estimated that the direct heath expenditure cost due to CVD was $186 billion in the US, with additional indirect costs of $190 billion. In 2006, CHD caused approximately 1 of every 6 deaths in the US. In 2010, it was estimated that 785,000 Americans would have a new coronary attack, and approximately 470,000 will suffer a recurrent attack. It is estimated that an additional 195,000 silent first myocardial infarctions occur each year. Approximately every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one. The estimated direct and indirect cost of CVD for 2010 is a staggering $503.2 billion, making CVD a continuing major contributor to the escalating price tag of health care in the US.
Development of A Lab-on-a-Chip System for Saliva-Based Diagnostics
1000 patients (over 4 clinical sites)
Cardiac heart disease is the number one killer in the world as well as in the United States. Building on the biomarker discoveries made for the heart attack test and the momentum gathered from the parent U-01 program sponsored by the NIH, the clinical study tasked here aims to validate a multiplexed salivary biomarker panel for the screening of AMI in the emergency room setting. The proposed research activities is beingcarried out by an interdisciplinary, multi-institutional team that leverages the strengths of a bioengineering group (at Rice) with expertise in biosensor development and a leading cardiology group at Baylor College of Medicine with an established record in cardiac research and clinical study infrastructure. The program is conducted according to NIH/NIDCR guidelines on human subject safety benefiting from the guidance, monitoring and recommendations of the Clinical Study Oversight Committee (CSOC). The clinical program also utilizes the services of NIDCR’s contractor Rho that provides critical clinical operations and management support. The program’s objectives are being met through the completion of a clinical study that involves 588 chest pain patients recruited upon their admission to the emergency room. Whole blood and saliva samples are collected from these patients at 0, 1, 3 and 6 hours from their time of presentation. Gold standard methodologies, such as serum testing and electrocardiogram (ECG), are used to determine the subjects’ AMI status, while salivary biomarkers of myocardial injury aremeasured using LUMINEX, ELISA and bio-nano-chip (BNC) technology pioneered in the McDevitt laboratory. The clinical accuracy of the BNC tests and biomarker concentration thresholds for the diagnosis of AMI for the salivary panel are determined. Completion of the proposed activities for this biomarker validation program will promote the translation of the saliva- based AMI tests by concurrently validating the biomarkers discovered in a pilot study, as well as the BNC technology used for their measurement. These studies will pave the way to future clinical trials that will help fulfill regulatory requirements for FDA approval of the BNC tests, which may ultimately be used to improve the speed and accuracy of diagnosis of AMI chest pain, allowing triage to specialist care and improving the outcome for patients with AMI using saliva as the diagnostic fluid.
The current procedures for oral cancer diagnosis are Biopsy and histopathological examination, Vital staining, Biomarkers, DNA ploidy, brush biopsy and optical techniques.
Biopsy and histopathological examination is the current golden standard of oral cancer diagnosis where a large piece of tissue from the suspected lesion and area surrounding it is taken and is analyzed for dysplasia and cancer. However the process is very painful and takes several days for diagnosis.
Vital staining is a technique used to stain living cells in order to highlight probable dysplastic areas before a biopsy is done. Vital tissue staining via topical application of toluidine blue (tolonium chloride), a metachromatic dye that preferentially stains cells with elevated DNA content, has been utilized for decades to assist in identifying oral cancer sites and/or delineating margins for excisional biopsy. Although toluidine blue staining yields high sensitivity in detecting SCC malignancies, its usefulness may be limited in characterizing mild-moderate epithelial dysplasia found in oral pre-malignant lesions.
Recent advances in molecular techniques has helped examining for abnormal protein expression to unravel complex cellular mechanisms associated with tumorigenesis revealing a number of molecular markers, or biomarkers, related to oral cancer initiation and progression. Biomarkers have been utilized in a range of clinical settings including screening, diagnosis, staging, prediction of treatment response, and monitoring of treatment and recurrence.
DNA ploidy is the measurement of nuclear DNA content. This may provide a surrogate measure of gross genetic damage and this could act as a surrogate for individual molecular markers. DNA ploidy can be measured fairly simply with automated image cytometry of nuclei obtained from routinely processed tissue samples.
The brush biopsy uses a small nylon brush to gather cytology samples then sent for computer scanning and analysis (Oral CDx) to identify and display individual cells. If suspect cells are identified, a pathologist then examines them to determine the final diagnosis and, in samples judged to be cancerous, a printout of the abnormal cells from the computer display and a written pathologist's report are returned to the clinician with the recommendation that a positive result be followed with a conventional incisional biopsy. The technique has proved rather controversial, with concern largely related to the question of false negative results.
NIH-ARRA-Grand Opportunity Grant
Monitoring of Oral Cancer Patients Using Novel Lab-on-a-Chip Ensembles
950 patients (over 3 clinical sites)
Oral cancer, largely oral squamous cell carcinoma (OSCC), is a global health problem afflicting close to 300,000 people each year. Despite significant advances in surgical procedures and treatment, the long-term prognosis for patients with OSCC remains poor, with a 5-year survival rate at approximately 50% that is among the lowest for all major cancers. High mortality associated with OSCC is often attributed to the advanced disease stage of many OSCCs upon initial identification and surgical biopsy, underscoring the need for new diagnostic methods targeting early tumor progression and malignant transformations. We propose here a broad, innovative, high impact and cross-cutting translational research program that targets development, testing and validation of powerful new microchip sensor systems for the diagnosis, prognosis and monitoring of potentially malignant lesions (PML) and malignant lesions of the oral cavity. This effort pairs the leading group involved in development programmable bio-nano-chip systems (p-BNC)with leading clinicians in pathology and oral cancer research.
To support the testing and validation of the new microchip sensor systems, subjects will be recruited that are diagnosed clinically with a suspicious, potentially malignant (provisional clinical diagnosis of leukoplakia or erythroplakia) or oral squamous cell carcinoma, where a conventional biopsy is indicated. The p-BNC to be developed through this program will allow for the analysis of cellular samples obtained from a minimally invasive brush biopsy sample. The cell suspensions collected in this manner will allow for the simultaneous quantification of cell morphometric data and expression of molecular biomarkers of malignant potential in an automated manner using refined image analysis algorithms based on pattern recognition techniques and advanced statistical methods. This novel p-BNC approach, which will turn around biopsy results in a matter of minutes as compared to days for traditional pathology methods, has already demonstrated its ability to distinguish between normal mucosa and oral cancer lesions. We propose here to adapt this chip-based platform to include a panel of biomarkers indicative of dysplasia as derived from cytomorphometric and molecular data as well as to assess the capabilities of this approach to function in point of care settings using noninvasive brush biopsy samples. The PNBC approach will be compared to the current standard of care based on biopsy and histopathological assessment of the lesions. The multi-institution, multi-disciplinary team assembled with members from Rice University, the Universities of Texas Health Science Centers in Houston and San Antonio, and the University of Sheffield, offers unique patient based case/control resources, biomarker and pathology proficiency combined with the expertise in integrated microchip sensors that will allow the team to develop new diagnostic aids for oral cancer patients that are desperately needed.
In 2010, approximately 21,880 women will be diagnosed with ovarian cancer in the United States and 13,850 women will succumb to this disease. Although 90% of ovarian cancers can be treated at stage I with the currently existing surgical and chemotherapeutic regimens, only 25% of ovarian cancers are detected at this treatable stage due to the non-specific ‘silent’ symptoms and the lack of effective screening procedures. Given the low prevalence of ovarian cancer (1 in 2500 post menopausal women), an extremely high specificity (99.6%) and sensitivity (> 75%) are required to achieve a minimum PPV of 10% (10 laparotomies per case of ovarian cancer detected). No single screening test exists currently for recommended use in the general population, underscoring the need for novel early detection and screening methods.
For suspected pelvic masses, diagnosis of ovarian cancer is realized by pelvic examination, transvaginal sonography (TVS) and serum CA125 leading to exploratory or diagnostic laparoscopy. TVS provides a precise image of the ovary and while PPVs in the most promising studies have been reported to be close to 10%, prohibitively high costs for implementation have precluded its utility as a first line screen. Serum CA125 has been extensively utilized in advanced stage disease management and has been FDA approved for recurrent disease detection and monitoring chemotherapy response. However, CA125 is elevated in only 50-60% of early stage cancers with false positives for a variety of non-malignant gynecological and physiological conditions.
Texas Cancer Diagnostics Pipeline Consortium: Ovarian Cancer
275 Patients (over 2 clinical sites)
Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies. This year in the US approximately 21,650 women will be diagnosed with OC and 15,520 will die from this disease. Despite advances in the management of OC, about 70-75% of women with OC are diagnosed with advanced stage disease where the cure rate is less than 20%. When OC is diagnosed in stage I, up to 90% of patients can be cured with conventional surgery and chemotherapy. Consequently, the rate of cure and overall survival might be significantly improved by detection of ovarian cancer at an early stage in a larger fraction of patients.
Across the clinical sites for this disease 3327 patients will be recruited. Blood will be drawn from control and case patients and shipped to Rice University for the testing of a bio-nano-chip. Controls would be drawn from our screening trial and would include postmenopausal women age 50-74 able to give informed consent and exclude women with two or more relatives with breast or ovarian cancer, previous cancer or previous oophorectomy. The ovarian cancer patients would include women age 50-74 who were about to undergo surgery for a potentially malignant pelvic mass and be able to give informed consent. We would exclude patients with a previous history of cancer or previous oophorectomy.
Prostate cancer is the most common cancer in American men, with an estimated 217,730 cases diagnosed in 2010. Following lung cancer, it is the second most common cause of cancer-related mortality in the United States resulting in 32,050 deaths in 2010. Despite its prevalence, prostate cancer has little to no early symptoms and is typically diagnosed by a prostate gland biopsy following abnormal results during regular screening by digital rectal examinations (DRE) and testing serum levels of prostate specific antigen (PSA). Although the efficacy of testing remains unclear, PSA is the only currently available marker for prostate cancer and the recommendation for use of PSA for early screening remains controversial while both DRE and PSA methods may not detect all prostate tumors, including those that are highly aggressive. These issues in current screening methodologies highlight the need for new biomarkers to accurately detect prostate cancer.
As part of the Cancer Prevention and Research Institute of Texas (CPRIT) and University in collaboration with Genitourinary (GU) Oncology expert Dr. Ian Thompson from the Department of Urology at the University of Texas Health Science Center at San Antonio, the McDevitt Lab at Rice University is currently evaluating strategies to utilize the Lab-on-a-chip based sensor for effective screening of prostate cancer. These strategies include the creation of a multi-marker panel prostate cancer bio-nano-chip to function as in vitro diagnostic device (IVD) intended to simultaneously quantitate the levels of a panel of prostate cancer to yield a multi-marker signature. This device is compatible with the use a finger-stick blood sample obtained from apparently healthy men (typically 50 years and above) and would be available as a point-of-care test with immediate results for clinicians. This screening will be used in conjunction with other known risk factors for prostate cancer, such as age, race, and the presence of a family history of prostate cancer to help clinicians determine which patients require urologic consultation and prostate biopsy. The development of a minimally invasive sample collection approach combined with a highly-sensitive integrated approach that uses significantly smaller reagent and sample volumes than conventional methods, on a unique portable instrument platform that provides results in minutes vs. hours or days, has the potential to impact significantly patient care and clinical practice. An early detection strategy is more effective in improving treatment options and outcomes, and reducing overall healthcare costs than the reaction to symptoms of advanced disease.
Texas Cancer Diagnostics Pipeline Consortium: Prostate Cancer
400 Patients (over one clinical site)
Prostate cancer is the most common non-skin cancer in American men. The current methods of screening for prostate cancer, which include digital rectal examinations (DREs) and serum levels of prostate specific antigen (PSA), do not detect many prostate tumors including some of which that are high grade and aggressive.
In this CPRIT program we address the need for rapid assays for a more efficient screening of Prostate Cancer (PC) at the POC.
The specific translational tasks of the proposal for prostate cancer are:
An estimated 12.8 million Americans, about 6 percent of the household population aged twelve and older, use illegal drugs on a current basis.
The social and health costs to society of illicit drug use are staggering. Drug-related illness, death, and crime cost the nation approximately $66.9 billion.
Every man, woman, and child in America pays nearly $1,000 annually to cover the expense of unnecessary health care, extra law enforcement, auto accidents, crime, and lost productivity resulting from substance abuse.
Illicit drug use hurts families, businesses, and neighborhoods; impedes education; and chokes criminal justice, health, and social service systems.
UK: Home Office- Contract
Advanced Nano-Bio-Chips for Saliva Based Drug Tests at the Point of Arrest
240 participants (over one clinical site)
Drugs of Abuse
Over the past decade, the McDevitt laboratory has pioneered the development of a series of powerful nano-bio-chip sensor (NBC) systems that are suitable for a wide range of chemical, biological and cellular assays. Developed initially as “electronic taste chips”, these mini-sensors systems are fashioned with the same micro-fabrication methods used by the microelectronics industry. These devices are created in such a manner so they can be reprogrammed for new applications in an efficient manner while at the same time yielding sensors with strong analytical performance characteristics. Our laboratory has published several peer-reviewed papers documenting the formation of sensor systems, including one dedicated to the measurement of C- reactive protein. This saliva-based test exhibits 1000-fold decreases in the limit of detection relative to the 13 existing commercial products. More recently, the NBC approach was selected as part of Science Coalition’s Best Scientific Advances for Year and for the 2008 Popular Science’s “Best of What's New Award” in the Medical Device category for a new saliva-based heart attack diagnosis test system. Here, all aspects of saliva sample collection, processing, reagent manipulation, analyte isolation and detection are handled within these integrated ensembles. Leveraging these past successful activities, these proven mini-sensor systems will be adapted in this new program. Roadside NBC drug tests to be developed with this Home Office Scientific Development Branch (HOSDB) program promise to serve as important tools for police officers to prosecute drugged driving. The NBC roadside drug tests are projected to save time and simplify the enforcement procedure by avoiding the need to take the suspected drugged drives to a police station, or health care facility, for testing. Completion of the proposed work promises a more convenient, cost-effective and comprehensive drug screening approach that may be applied for roadside testing of drivers at the point of arrest (POA).
More than 30 million people in developing countries are living with HIV infection with almost 3 million new infections each year. The global burden of this disease is not equitable. For instance, in North America the incidence rate is 0.5% while in Africa it is 4.7%, with some countries having incidence rates of over 20% (WHO). Of the 33 million people living with HIV/AIDS, 22 million of them reside in sub-Saharan Africa; making low cost, portable care a necessity. An enormous global effort is now underway to bring antiretroviral treatment to those in low to middle income countries; resulting in a recent 17% decrease in incidence(WHO). Moreover, 20% less people died in sub-Saharan Africa in 2009 versus 2004, largely due to this effort. While drug prices have dropped considerably, the cost and technical complexity of laboratory tests essential for the management of HIV disease, such as CD4 cell counts, remain prohibitive. New, simple, and affordable methods for measuring CD4 cells that can be implemented in resource-scarce settings are urgently needed.
We have developed a prototype for a simple, rapid, and affordable method for counting CD4 lymphocytes. Microliter volumes of blood without further sample preparation are stained with fluorescent antibodies, captured on a membrane within a miniaturized flow cell and imaged through a fluorescent misroscope with attached CCD. An associated computer algorithm, utilizing ImageJ (NIH) converts the raw digital image into absolute CD4 counts and CD4 percentages in real time. The accuracy of this prototype system was validated through testing in the United States and Botswana, and showed close agreement with standard flow cytometry (r = 0.95) over a range of absolute CD4 counts, and the ability to discriminate clinically relevant CD4 count thresholds with high sensitivity and specificity.
Rodriguez et al., “A Microchip CD4 Counting Method for HIV Monitoring in Resource-Poor Settings”, PLoS Medicine, 2005.
Jokerst et al., “Integration of semiconductor quantum dots into nano-bio-chip systems for enumeration of CD4+ T cell counts at the point-of-need”, Lab on a Chip, 2008.
The McDevitt group is currently in the third year of a vital leadership role within a NIH/NIDCR funded U01 program specifically targeting the development and application of next-generation LOC systems for saliva-based cardiac diagnostics. Through this important program, the Texas Bio-nano-chip (NBC) sensor system has been adapted successfully to a number of important salivary diagnostic tests exhibiting the following characteristics:
Although the saliva research program has demonstrated capacity for a number of different diseases, our most important results are in the cardiac health arena. This funding program is making excellent progress in defining the relevant salivary biomarker targets and their time-course for AMI diagnosis, as well as in developing advanced micro-fluidic structures and the associated analyzer. Further work, seeks a better understanding of the contribution of oral disease to the measurements of salivary biomarkers of AMI. This same barrier exists for other systemic diseases that are to be measured with oral fluid tests and, as such, the information here gathered will serve to open the door for a series of other important salivary tests. This supplement program will benefit from the fore-mentioned advances and will also leverage clinical samples collected from orally healthy and periodontal disease patients, as well as of samples from an ongoing AMI ambulance study to accelerate progress in this important area. This high-profile program was recently selected as part of Science Coalition’s Best Scientific Advances for Year, as well as for the 2008 Popular Science’s “Best of What's New Award” in the Medical Device category for a new saliva heart attack test system and builds on the previous successes detailed below.
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Scope: The McDevitt group’s role for this joint program that spans five research groups is to develop new methods for measurement of saliva-based analytes using microfluidic devices.
Grant number: 1U01 DE017793-01 Development of a Lab-on-a-Chip System for Saliva Based Diagnostics
Scope: Building on the biomarker discoveries made for the heart attack test and the momentum gathered from the parent U-01 program, the clinical study tasked here aims to validate a multiplexed salivary biomarker panel for the screening of AMI in the emergency room setting.
Grant number: 3 U01 DE017793-05S1
Scope: The development of a minimally-invasive brush biopsy test for oral cancer diagnosis (no scalpel biopsy would be required) that when combined with a novel microchip can be performed in clinics or dentist’s offices with results that are available in a matter of minutes (within visit).
Grant number: 1 RC2 DE020785-01
Scope: Through this novel program, efforts are directed toward the development of a platform that can be used to accelerate the release of new cancer diagnostic tests and screening devices in the state of Texas. Through the unique partnerships here assembled an infrastructure will be developed that serves to span the essential areas of biomarker discovery, biomarker validation and clinical implementation with the goal of achieving technological innovation, reduced health care costs and improved healthcare outcomes. These efforts are unique in scope in terms of their capacity to combine nano science and engineering, state-of-the-art imaging methods, microfluidics concepts for sample processing and multiplexed biomarker panel analysis for the development of integrated test ensembles suitable for screening and diagnostic testing for oral, prostate and ovarian cancers.
Scope: RoadsideBNC drug tests to be developed with this Home Office Scientific Development Branch (HOSDB) program promise to serve as important tools for police officers to prosecute drugged driving. The BNC roadside drug tests are projected to save time and simplify the enforcement procedure by avoiding the need to take the suspected drugged drives to a police station, or health care facility, for testing. Completion of the proposed work promises a more convenient, cost-effective and comprehensive drug screening approach that may be applied for roadside testing of drivers at the point of arrest (POA).
Scope: The McDevitt group’s role for this joint program that spans two research groups is to develop new methods for measurement of acute trauma biomarkers in urine samples.
Dates: 9/1/09 – 8/31/11
PI: John Holcombe
Scope: This program served to expand upon the successful demonstration of the highly promising chip-based CD4 counting technology developed by the University of Texas at Austin and Harvard Medical School. With this accelerated effort, the already established and productive collaborative program between the Harvard Medical School Division of AIDS and the Chemistry/Biochemistry Department at the University of Texas at Austin was expanded to target the short-term development and deployment of important CD4 diagnostic instrumentation that is suitable for immediate use in resource-scarce settings.