Organs-on-Chips in Drug Development: The Importance of Involving Stakeholders in Early Health Technology Assessment

Organs-on-chips are three-dimensional, microfluidic cell culture systems that simulate the function of tissues and organ subunits. Organ-on-chip systems are expected to contribute to drug candidate screening and the reduction of animal tests in preclinical drug development and may increase efficiency of these processes. To maximize the future impact of the technology on drug development, it is important to make informed decisions regarding the attributes and features of organs-on-chips even though the technology is still in a stage of early development. It is likely that different stakeholders in organ-on-chip development, such as engineers, biologists, regulatory scientists, and pharmaceutical researchers, will have different perspectives on how to maximize the future impact of the technology. Various aspects of organ-on-chip development, such as cost, materials, features, cell source, read-out technology, types of data, and compatibility with existing technology, will likely be judged differently by different stakeholders. Early health technology assessment (HTA) is needed in order to facilitate the essential integration of such potentially conflicting views in the process of technology development. In this critical review we discuss the potential impact of organs-on-chips on the drug development process, and we use a pilot study to give examples of how different stakeholders have different perspectives on attributes of organ-on-chip technology. As a future tool in early HTA of organs-on-chips, we suggest the use of multicriteria decision analysis (MCDA), which is a formal method to deal with multiple and conflicting criteria in technology development. We argue that it is essential to design and perform a comprehensive MCDA for organ-on-chip development, and so the future impact of this technology in the pharmaceutical industry can be maximized

Integrated 3D Acid Fracturing Model for Carbonate Reservoir Stimulation

Acid fracturing is one of the stimulation methods used in carbonate formations and has been proved effective and economical. Because of the stochastic nature of acidizing in carbonate formation, designing and optimizing acid fracture treatment today still remain challenging. In the past, a simple acid fracture conductivity correlation was usually considered sufficient to estimate the overall average fracture conductivity in the formation, leading to the computation of the productivity index for fractured well performance. However, the nature of heterogeneity could not be included in the modeling. Understanding the important role of heterogeneity to stimulation performance becomes a crucial step in design and optimization of acid fracture jobs. In order to study the effect of this stochastic nature on acid fracturing, a fully 3D acid reaction model was developed based on the geostatistical parameters of the formation. It is possible to describe local conductivity distribution related to acid transport and reaction process. In this study, we have developed a new interactive workflow allowing the model of the fracture propagation process, the acid etching process and the well production interactively. This thesis presents the novel approach in integrating fracture propagation, acid transport and dissolution, and well performance models in a seamless fashion for acid fracturing design. In this new approach, the fracture geometry data of a hydraulic fracture is first obtained from commercial models of hydraulic fracture propagation, and then the 3D acid fracture model simulates acid etching and transport from the fracture propagation model using the width distribution as the initial condition. We then calculate the fracture conductivity distribution along the created fracture considering the geostatistical parameters such as permeability correlation length and standard deviation in permeability of the formation. The final step of the approach is to predict well performance after stimulation with a reservoir flow simulator. The significant improvements of the new approach are two folds: (1) capturing the geostatistical effect of the formation; and (2) modeling the acid etching and transport more accurately. The thesis explains the methodology and illustrates the application of the approach with examples. The results from this study show that the new model can successfully design and optimize acid fracturing treatments

Evaluation of the toxin-to-protein binding rates during hemodialysis using sorbent-loaded mixed-matrix membranes

The transport and reaction phenomena that take place in multi-layered mixed-matrix membranes with activated carbon (AC) sorbents that are expected to improve extra-corporeal blood purification, are studied at the macroscopic scale. A model was developed that aims at the description of the removal efficiency of harmful uremic toxins from the blood in the presence of carbon-adsorptive particles and produces results that are aligned with the experimental data. The importance of the generally unknown kinetic rate constants of the association of toxins to albumin is investigated through sensitivity analysis. Matching with further experimental data allowed the extraction of vital kinetic rate constants for key uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Moreover, the effects of the plasma composition, as well as of the membrane loading with activated carbon, on the total removal of the protein-bound toxins are quantified and discussed