Project

Discipline

implantable biochip; continuous monitoring sensors; biomarkers and drugs; personalized therapy; gut inflammation; Carbon Nanotubes; P450 cytochromes; Drugs monitoring; pharmacokinetics; in-vivo experiments; inflammatory diseases

Lead
Lay summary
A fully mature biochip system capable of continuous monitoring drugs and biomarkers in blood, or in sub-cutaneous districts would constitute a major breakthrough in molecular medicine for personalizing therapy of complex diseases. To this end the following project aims will be pursued:(i) development of innovative sensors towards array drugs detection, including nanotechnology to improve sensor's sensitivity and system level integration to improve sensor's specificity, (ii) implementation of micro-electronic technology to decrease chip size for implantation in experimental animals (mice) as well as for convenient chip remote powering and data transmission, (iii) testing on an experimental model for a specific medical situation in which drugs toxicity and development of new therapies would benefit from the chip application,(iv) investigation of biochemical enzymes-substrates pharmacokinetics to identify the best P450 isoforms over more than 3.000 possible to be integrated onto the biochip to assure the detection of those exogenous and endogenous compounds which are relevant for the considered medical application.The project requires a strong convergence between micro-nano-bio-medical technologies. To address at best all these multidisciplinary demands, the project partnership includes experts on:(i) nano-sensing with special focus on P450 biosensors (S.Carrara/EPFL - Engineering), (ii) chip fabrication with focus on implantable systems (Dehollain's /EPFL- Engineering), (iii) pathophysiology of T-cells for therapy of autoimmune diseases (Grassi's group/IRB- biomedical), (iv) Pharmakokinetics and drugs side effects (von Mandach's goup/Univ. Hospital of Zurich - biomedical)The motivation for this project stems from pharmacological treatments with high risk side effects, e.g. toxicity of commonly used drugs, where direct monitoring of the patient's drug metabolism could dramatically influence pharmacological choices since high variability on a patient-by-patient basis characterizes metabolic pathways , as demonstrated in the literature by the case of nortriptyline. The social relevance of the project is on a better and more reliable diagnostics implantable system to be used also for personalized therapy and for new research in molecular medicine. The Economical Relevance of the project is in the pharmaceutical market. Our fully-electronics implantable biochip will provide a unique tool for industrial advancement in the field of drugs discovery and personalized therapy in Switzerland.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Self-organised

Title	Year

Number	Title	Start	Funding scheme

Currently, there are no fully mature biochip systems to monitor drugs amount in blood, in serum, or in sub-cutaneous districts. The aim of the present project is to develop an implantable biochip system to investigate the complexity of drugs/biomarkers relationships for molecular medicine investigations and personalized therapy. The outlines of the project will play a crucial role to advance the state-of-the-art for implantable devices. To reach the goal a multidisciplinary approach is required as because the system development requires addressing the following items:(i) Innovative sensor towards array drugs detection, including nanotechnology to improve sensor’s sensitivity and system level integration to improve sensor’s specificity, (ii) New micro-electronics technology to decrease chip size for implantation in animals (mice) as well as a convenient chip remote powering and data transmission, (iii) Identification of a real application and tests on animals for a specific medical field where drugs toxicity and drugs development is relevant for the chip application,(iv) biochemical enzymes-substrates pharmaco-kinetics investigations in order to identify the best P450 isoforms over more than 3.000 possible ones to be integrated onto the biochip in order to assure the detection of those exogenous and endogenous compounds which are relevant for the considered medical application. Thus, the project highly requires a convergence between micro-nano-bio-&-medical technologies. To address at best all these multidisciplinary demands, the project partnership includes experts on:(i) nano-sensing with special focus on P450 biosensors (S.Carrara/EPFL - Engineering), (ii) chip fabrication with focus on implantable systems (De Hollain’s /EPFL- Engineering), (iii) biomarkers variations and new drugs development (Grassi’s group/IRB- biomedical), (iv) Pharmakokinetics and drugs therapy side effects (Von Mandach’s goup/Univ. Hospital of Zurich - biomedical)Deep motivation of the project is that personalization and individualization of therapies require accurate and frequent monitoring of metabolic responses by living organisms during drug treatments. On the other hand, molecular medicine requires continuous in-vivo monitoring of bio-markers. In both the cases, this is true for endogenous molecules used as disease markers as well as for the exogenous compounds used as therapeutic drugs. For example, in case of high risk side effects, e.g. high toxicity drugs commonly used in pharmacological therapies, direct monitoring of the patient’s drug metabolism is essential as the metabolic pathways efficacy is highly variable on a patient-by-patient basis, as demonstrated by literature in the case of nortriptyline. The reason relies on the patient’s genetic polymorphism. Genetic polymorphism affects protein expression and, thus, induces polymorphism in key proteins of human metabolism. For example, polymorphism in cytochrome P450 2D6 phenotype (a central enzyme in human metabolism) causes overdosing in “poor metabolizers” and under-dosing in “ultrafast metabolizers”. This explains why still most effective drug therapies for major diseases provide benefit only to a fraction of patients, typically in the 20 to 50% range [1], and why approximately 7% of hospitalized patients have serious adverse drug reactions [1]. Other effects affecting the drugs cure efficacy and efficiency are the difference between the genetic predisposition and the actual metabolism of the patients under pharmacological therapy, metabolisms which can vary on the day basis, and the difference between the amount of the supplied compounds and the amount actually reaching the disease site. Thus, low-costs monitoring biochips are highly required for a real-time, continuous, close to disease site monitoring.Social RelevanceThe main social relevance of the project will be a better and more reliable diagnostics implantable system to be used also for personalized therapy and new research in molecular medicine. The developed platform and the research outcomes will be useful to further develop the individualization of therapies and prevention in patients. In case of therapy, despite increased expenditure for drug development, sophisticated high-throughput techniques and the apparently infinite chances brought about by the exploding knowledge in genetics, still most effective drug therapies of major diseases provide benefit only to a fraction of patients. Any improvement of this situation is highly desirable. It is being recognized increasingly that any drug therapy needs to be selected and modified according to the individual patient (“individualization” or “personalization”). (Turner ST et al. Hypertension. 2007;50:1-5; Daly AK. Curr Opin Drug Discov Devel. 2007;10:29-36). Therapeutic monitoring, i.e. diseases molecular markers monitoring after drug administration is highly important to see whether the supplied pharmacological therapy has been effective with the patients. The biochip developed by the present project will also provide a very powerful platform to investigate the possibility for personalization of therapy to be used in chronic patients.Economical RelevanceA relevant part of the whole Swiss economy is driven by the pharmaceutical industry. Even in 2008, a year of financial and economical crisis and the Down Jones index that lost close to 40% of its initial value, Novartis close the year with a gain of 9%. This means not only that Pharmaceutics is one of the key markets of Switzerland, but event that is one of the most important in a crisis era.The development of a new chemical entity as a drug is a costly and time consuming process, requiring a mean amount of roughly 700 M€ and typically between 7 an 11 years, while drug patents expire after 15 years. Any technique which accelerates the process is highly required; if the drug to be developed is highly successful (a “block buster”), a single day of bringing a drug earlier to market may increase the benefit for millions of patients and also increase the benefit for the manufactures by more than 1 M€. Early identification of drug candidates as P450 substrates or inhibitors is an important step for the selection of the appropriate lead structure from a group of compounds with a very similar chemical structure and the same mechanism of action. Substances metabolized primarily by enzymes with relevant genetic polymorphisms (e.g. CYP2D6) or exerting a pronounced inhibitory effect on P450s are avoided for further development. The multi-panel biochip like that here proposed will accelerate this process by days or even weeks and will cut down the costs considerably. Pharmacokinetic studies in animals and humans are an essential part of drug development. Obtaining the results of such trials by standard quantification methods (e.g., LC-MS/MS) after completion of the clinical part today typically takes 1-2 months. The multi-panel biochip like that proposed in the present study may provide such results at the very day of the end of the study. Because some of the studies conducted are sequential, an optimal use of the biochip may accelerate drug development by several months, and it will save costs for analytics by an order of magnitude of 1 M€. In summary, the potential socio-economical relevance of the biochip systems here proposed is huge for the worldwide society in order to improve the quality of life of the patients, in order to decrease the medical care costs, in order to shorten the time-to-market for drug producers, and in order to increase enormously the diagnostic market. However, this study has clearly outlined which bottleneck and drawbacks a development like that will meet and has to overcome. A fully-electronics implantable biochip for continuous drugs detection will provide a unique toll for industrial advancement in the field of drugs discovery and personalization of therapy in Swiss.