Book Presentation Biomedical Membranes and (Bio) Artificial Organs

This book focusses on the development of biomedical membranes and their application for (bio)artificial organs. It covers the state of art and main challenges for applying synthetic membranes in these organs and it highlights the importance of accomplishing an integration of engineering with biology and medicine to understand and manage the scientific, industrial, clinical and ethical aspects of these organs. The book consists of the following 11 chapters

Transport and reaction phenomena in multilayer membranes functioning as bioartificial kidney devices

Classic hemodialysis only provides a limited removal of protein bound uremic toxins (PBUT) in patients with chronic kidney disease. A bioartificial kidney device, BAK, composed of a living cell monolayer of conditionally immortalized proximal tubule epithelial kidney cells (ciPTEC) cultured of hollow fiber polymeric membrane can remove protein bound uremic toxins from the blood in combination with classic hemodialysis. The development and clinical implementation of the BAK requires lots of optimization. This investigation is expensive and time consuming therefore modeling studies could help to optimize experiments and improve its design. In this work, a 3D mathematical model of the BAK is developed. The transport and reaction mechanisms associated with the removal of PBUT indoxyl sulfate are considered and various conditions are simulated. The model describes a single hollow fiber membrane and considers different domains for the blood flow, the membrane, the cell monolayer, and the dialysate region. A mathematical description of the relevant transport and/or reaction mechanisms is provided in each domain, and the corresponding differential equations are solved numerically. Since not all the modeling constants are experimentally available, a parametric study is performed for their quantification, including the active transport kinetics of the toxins through the cell monolayer, in comparison to the passive transport rates by diffusion. The parametric study also provides a background for the extraction of usually unknown quantities, including notably the Organic Anion Transporter (OAT) concentrations, with the support of experimental data. Satisfactory reproduction of experimental findings is achieved, and the role of systemic variables that affect significantly the uremic toxin removal is identified

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

REMOVED: Novel Concept for Artificial Kidney: Mixed Matrix Membranes Combining Diffusion and Adsorption in One Step

This article has been removed: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been removed at the request of the Executive Publisher.This article has been removed because it was published without the permission of the author(s)

Aliphatic isocyanurates and polyisocyanurate networks

The production, processing, and application of aliphatic isocyanate (NCO)-based thermosets such as polyurethane coatings and adhesives are generally limited by the surprisingly high viscosity of tri-functionality and higherfunctionality isocyanurates. These compounds are essential crosslinking additives for network formation. However, the mechanism by which these high viscosities are caused is not yet understood. In this work, model aliphatic isocyanurates were synthesized and isolated in high purity (>99%), and their viscosities were accurately determined. It was shown that the presence of the NCO group has a strong influence on the viscosity of the system. From density functional theory calculations, a novel and significant bimolecular binding potential of À8.7 kJ/mol was identified between NCO groups and isocyanurate rings, confirming the important role of the NCO group. This NCO-to-ring interaction was proposed to be the root cause for the high viscosities observed for NCO-functional isocyanurate systems. Molecular dynamics simulations carried out to further confirm this influence also suggest that the NCO-toring interaction causes a significant additional contribution to viscosity. Finally, model functional isocyanurates were further reacted into densely crosslinked polyisocyanurate networks which showed interesting material properties

Development of porous and flexible ptmc membranes for in vitro organ models fabricated by evaporation-induced phase separation

Polymeric membranes are widely applied in biomedical applications, including in vitro organ models. In such models, they are mostly used as supports on which cells are cultured to create functional tissue units of the desired organ. To this end, the membrane properties, e.g., morphology and porosity, should match the tissue properties. Organ models of dynamic (barrier) tissues, e.g., lung, require flexible, elastic and porous membranes. Thus, membranes based on poly (dimethyl siloxane) (PDMS) are often applied, which are flexible and elastic. However, PDMS has low cell adhesive properties and displays small molecule ad- and absorption. Furthermore, the introduction of porosity in these membranes requires elaborate methods. In this work, we aim to develop porous membranes for organ models based on poly(trimethylene carbonate) (PTMC): a flexible polymer with good cell adhesive properties which has been used for tissue engineering scaffolds, but not in in vitro organ models. For developing these membranes, we applied evaporation-induced phase separation (EIPS), a new method in this field based on solvent evaporation initiating phase separation, followed by membrane photo-crosslinking. We optimised various processing variables for obtaining form-stable PTMC membranes with average pore sizes between 5 to 8 µm and water permeance in the microfiltration range (17,000–41,000 L/m2 /h/bar). Importantly, the membranes are flexible and are suitable for implementation in in vitro organ models

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