Inspired by this vision and the realization that existing animal-based development programs are inadequate to confront the needs for accelerated development of drug countermeasures in a biothreat situation, the Defense Advanced Research Projects Agency (DARPA) requested grant applications in 2012 with a seemingly impossible challenge: develop 10 types of Organ Chips that recapitulate the complex functionalities of 10 different human organs, engineer an automated instrument to fluidically link them to create a functional human Body-on-Chips platform, and leverage computational modeling in combination with experimental data generated using this platform to quantitatively predict human drug PK/PD behavior in vitro. Animals are also used to analyze drug “pharmacodynamics” (PD), the effects the drug produces on its target organs, which underlies its mechanism of action as well as its adverse effects.īecause the Wyss Institute’s Organ Chips contain an endothelium-lined vascular channel, Ingber proposed in 2011 that it might be possible to create a human “Body-on-Chips” by transferring fluids between the vascular channels of many different types of Organ Chips to mimic blood flow, and assessing drug PK/PD behaviors across the entire linked system. These responses involve interplay between many different organs linked by a vasculature containing flowing blood. One example where living animals must be used in preclinical testing is the characterization of a drug’s “pharmacokinetics” (PK) that involves the quantification of its absorption, distribution, metabolism, and excretion (ADME), which together determine drug levels in the blood. The porous membrane allows the two compartments to communicate with each other, and to exchange molecules like cytokines, growth factors, and drugs, as well as drug breakdown products generated by organ-specific metabolic activities. Organ-specific cells are cultured on one side of the membrane in one of the channels, and vascular endothelial cells recapitulating a blood vessel line the other, while each channel is independently perfused with cell type-specific medium. Organ Chips are microfluidic culture devices composed of a clear flexible polymer the size of a computer memory stick, which contains two parallel hollow channels that are separated by a porous membrane. To help address this bottleneck in drug development, Donald Ingber, M.D., Ph.D., and his team at Harvard’s Wyss Institute for Biologically Inspired Engineering, developed the first human “Organ-on-a-Chip” (Organ Chip) model of the lung that recapitulates human organ level physiology and pathophysiology with high fidelity, which was reported in Science in 2010. Credit: Wyss Institute at Harvard University The researchers used a computational scaling method to predict dynamic drug pharmacokinetic behaviors in humans by translating data obtained from drug experiments in the human Body-on-Chip to the organ dimensions of the real human body. In this graphic, the Wyss Institute’s human Body-on-Chip system is layered on top of Leonardo da Vinci’s ink drawing of the “Vitruvian Man”, which represents ideal human body proportions. As a result, there has been a world-wide search to find replacements for animal models. There are also increasing ethical concerns relating to the use of animal studies. According to current estimates, only 13.8% of all tested drugs demonstrate ultimate clinical success and obtain approval by the Food and Drug Administration (FDA). ![]() (BOSTON) - Drug development is an extremely arduous and costly process, and failure rates in clinical trials that test new drugs for their safety and efficacy in humans remain very high. Fluidically-linked systems of multiple human Organ Chips that quantitatively predict drug pharmacokinetics may offer alternatives to some animal tests
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |