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

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

Carbon Adsorbents With Dual Porosity for Efficient Removal of Uremic Toxins and Cytokines from Human Plasma

Abstract The number of patients with chronic kidney disease increases while the number of available donor organs stays at approximately the same level. Unavoidable accumulation of the uremic toxins and cytokines for these patients comes as the result of malfunctioning kidneys and their high levels in the blood result in high morbidity and mortality. Unfortunately, the existing methods, like hemodialysis and hemofiltration, provide only partial removal of uremic toxins and/or cytokines from patients’ blood. Consequently, there is an increasing need for the development of the extracorporeal treatments which will enable removal of broad spectrum of uremic toxins that are usually removed by healthy kidneys. Therefore, in this work we developed and tested ordered mesoporous carbons as new sorbents with dual porosity (micro/meso) that provide selective and efficient removal of a broad range of uremic toxins from human plasma. The new sorbents, CMK-3 are developed by nanocasting methods and have two distinct pore domains, i.e. micropores and mesopores, therefore show high adsorption capacity towards small water soluble toxins (creatinine), protein-bound molecules (indoxyl sulfate and hippuric acid), middle molecules (β-2-microglobulin) and cytokines of different size (IL-6 and IL-8). Our results show that small amounts of CMK-3 could provide selective and complete blood purification

Estudo da densidade de ligações Cruzadas em géis superabsorventes obtidos do acetato de celulose Study of the crosslinking density in superabsorbent gels obtained from cellulose acetate

Neste trabalho foram realizadas sínteses de géis derivados de acetato de celulose (AC) com grau de substituição (GS) 2,5 por intermédio de reações de reticulação via esterificação. Os grupos hidroxílicos livres do AC foram reagidos com o dianidrido do ácido 1, 2, 4, 5 benzenotetracarboxílico (PMDA) em meio homogêneo. As caracterizações foram realizadas por TGA (Análise termogravimétrica), espectroscopia na região do infravermelho (FTIR), retro titulação para determinar o grau de substituição do AC e microscopia de força atômica (AFM). Os géis foram sintetizados com as seguintes razões estequiométricas: [1:1], [1:2/3], [1:3] e [3:1] mol de PMDA/mol de OH livre respectivamente. A base da teoria de Flory-Rehner foi empregada para determinar ligações cruzadas nos géis. Os resultados de AFM mostram topografias distintas quando são comparados os géis entre si e quando os géis são comparados ao polímero de acetato de celulose. Este trabalho foi motivado pela importância tecnológica de polímeros de fontes renováveis como a celulose, em que um derivado de celulose foi usado para obter um polímero promissor para liberação controlada de medicamentos e adsorção de metais pesados em meio aquoso. Uma das vantagens deste polímero derivado do acetato de celulose é o emprego de poucas etapas na sua síntese.<br>This work reports the synthesis of gels derived from cellulose acetate (CA) with degree of substitution (DS) 2.5 through esterification and crosslinking reactions. The free hydroxyl groups were reacted by using dianhydride of acid 1,2,4,5 benzenotetracarboxylic (PMDA) as modifier in a homogeneous media. Characterization was performed with Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), retrotitration (known as back titration) to determine the degree of substitution of AC and atomic force microscopy (AFM). The gels were synthesized with the following stoichiometric ratios: [1:1], [1:2/3], [1:3] and [3:1] PMDA mol/mol of free OH, respectively. A gel was synthesized in excess of 200% of PMDA in relation to free OH groups of the AC. The basis of the Flory-Rehner theory was used for determining crosslinking in the gels. Briefly, the main results showed that the crosslinking density increased proportionally to the amount of PMDA added to the reaction medium. Distinct AFM topographies were obtained for distinct gels, which were also different from the polymer cellulose acetate. This work was motivated by the technological importance of polymers from renewable sources such as cellulose, in which a cellulose derivative was developed with promising application in drug delivery and in adsorption of heavy metals in aqueous systems. The advantage of this cellulose acetate derivative is the use of fewer steps in its synthesis

Bioengineering Organs for Blood Detoxification

For patients with severe kidney or liver failure the best solution is currently organ transplantation. However, not all patients are eligible for transplantation and due to limited organ availability, most patients are currently treated with therapies using artificial kidney and artificial liver devices. These therapies, despite their relative success in preserving the patients' life, have important limitations since they can only replace part of the natural kidney or liver functions. As blood detoxification (and other functions) in these highly perfused organs is achieved by specialized cells, it seems relevant to review the approaches leading to bioengineered organs fulfilling most of the native organ functions. There, the culture of cells of specific phenotypes on adapted scaffolds that can be perfused takes place. In this review paper, first the functions of kidney and liver organs are briefly described. Then artificial kidney/liver devices, bioartificial kidney devices, and bioartificial liver devices are focused on, as well as biohybrid constructs obtained by decellularization and recellularization of animal organs. For all organs, a thorough overview of the literature is given and the perspectives for their application in the clinic are discussed

Bioengineered kidney tubules efficiently excrete uremic toxins

The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs