Drug Screening Devices Research Articles

A high-throughput system for drug screening based on the movement analysis of zebrafish

Zebrafish is a highly advantageous model animal for drug screening and toxicity evaluation thanks to its amenability to optical imaging (i.e., transparency), possession of organ structures similar to humans, and the ease with which disease models can be established. However, current zebrafish drug screening technologies and devices suffer from limitations such as low level of automation and throughput, and low accuracy caused by the heterogeneity among individual zebrafish specimens. To address these issues, we herein develop a high-throughput zebrafish drug screening system. This system is capable of maintaining optimal culturing conditions and simultaneously monitoring and analyzing the movement of 288 zebrafish larvae under various external conditions, such as drug combinations. Moreover, to eliminate the effect of heterogeneity, locomotion of participating zebrafish is assessed and grouped before experiments. It is demonstrated that in contrast to the experimental results without pre-selection, which shows ∼20 % damaged motor function (i.e., degree of attenuation), the drug-induced variations among zebrafish with equivalent mobility reaches ∼80 %. Overall, our high-throughput zebrafish drug screening system overcomes current limitations by improving automation, throughput, and accuracy, resulting in enhanced detection of drug-induced variations in zebrafish motor function.

Recent Advances in Organ-on-Chips Integrated with Bioprinting Technologies for Drug Screening.

Currently, the demand for more reliable drug screening devices has made scientists and researchers develop novel potential approaches to offer an alternative to animal studies. Organ-on-chips are newly emerged platforms for drug screening and disease metabolism investigation. These microfluidic devices attempt to recapitulate the physiological and biological properties of different organs and tissues using human-derived cells. Recently, the synergistic combination of additive manufacturing and microfluidics has shown a promising impact on improving a wide array of biological models. In this review, different methods are classified using bioprinting to achieve the relevant biomimetic models in organ-on-chips, boosting the efficiency of these devices to produce more reliable data for drug investigations. In addition to the tissue models, the influence of additive manufacturing on microfluidic chip fabrication is discussed, and their biomedical applications are reviewed.

Organ-on-a-Chip for Drug Screening: A Bright Future for Sustainability? A Critical Review.

Globalization has raised concerns about spreading diseases and emphasized the need for quick and efficient methods for drug screening. Established drug efficacy and toxicity approaches have proven obsolete, with a high failure rate in clinical trials. Organ-on-a-chip has emerged as an essential alternative to outdated techniques, precisely simulating important characteristics of organs and predicting drug pharmacokinetics more ethically and efficiently. Although promising, most organ-on-a-chip devices are still manufactured using principles and materials from the micromachining industry. The abusive use of plastic for traditional drug screening methods and device production should be considered when substituting technologies so that the compensation for the generation of plastic waste can be projected. This critical review outlines recent advances for organ-on-a-chip in the industry and estimates the possibility of scaling up its production. Moreover, it analyzes trends in organ-on-a-chip publications and provides suggestions for a more sustainable future for organ-on-a-chip research and production.

Fabrication and Evaluation of Tubule-on-a-Chip with RPTEC/HUVEC Co-Culture Using Injection-Molded Polycarbonate Chips.

To simulate the ADME process such as absorption, distribution, metabolism, and excretion in the human body after drug administration and to confirm the applicability of the mass production process, a microfluidic chip injection molded with polycarbonate (injection-molded chip (I-M chip)) was fabricated. Polycarbonate materials were selected to minimize drug absorption. As a first step to evaluate the I-M chip, RPTEC (Human Renal Proximal Tubule Epithelial Cells) and HUVEC (Human Umbilical Vein Endothelial Cells) were co-cultured, and live and dead staining, TEER (trans-epithelial electrical resistance), glucose reabsorption, and permeability were compared using different membrane pore sizes of 0.4 μm and 3 μm. Drug excretion was confirmed through a pharmacokinetic test with metformin and cimetidine, and the gene expression of drug transporters was confirmed. As a result, it was confirmed that the cell viability was higher in the 3 μm pore size than in the 0.4 μm, the cell culture performed better, and the drug secretion was enhanced when the pore size was large. The injection-molded polycarbonate microfluidic chip is anticipated to be commercially viable for drug screening devices, particularly ADME tests.

Evaluation of five drug screening devices for testing of amphetamines and methamphetamines

Evaluation of five drug screening devices for testing of amphetamines and methamphetamines

An Ammonia-Induced Calcium Phosphate Nanostructure: A Potential Assay for Studying Osteoporosis and Bone Metastasis.

Osteoclastic resorption of bones plays a central role in both osteoporosis and bone metastasis. A reliable in vitro assay that simulates osteoclastic resorption in vivo would significantly speed up the process of developing effective therapeutic solutions for those diseases. Here, we reported the development of a novel and robust nanostructured calcium phosphate coating with unique functions on the track-etched porous membrane by using an ammonia-induced mineralization (AiM) technique. The calcium phosphate coating uniformly covers one side of the PET membrane, enabling testing for osteoclastic resorption. The track-etched pores in the PET membrane allow calcium phosphate mineral pins to grow inside, which, on the one hand, enhances coating integration with a membrane substrate and, on the other hand, provides diffusion channels for delivering drugs from the lower chamber of a double-chamber cell culture system. The applications of the processed calcium phosphate coating were first demonstrated as a drug screening device by using alendronate, a widely used drug for osteoporosis. It was confirmed that the delivery of alendronate significantly decreased both the number of monocyte-differentiated osteoclasts and coating resorption. To demonstrate the application in studying bone metastasis, we delivered a PC3 prostate cancer-conditioned medium and confirmed that both the differentiation of monocytes into osteoclasts and the osteoclastic resorption of the calcium phosphate coating were significantly enhanced. This novel assay thus provides a new platform for studying osteoclastic activities and assessing drug efficacy in vitro.

Microfluidic based Platform for drug screening-A review

There is a lot of requirement to develop a preclinical rapid drug screening devices to treat the throat cancerous patients in effective manner. Very High cost models like animal based, 2d and 3d type models are static drug screening models and they are unable to mimic the human body dynamic condition. So microfluidic platform based drug screening devices will give predetermined and prominent result in rapid drug screening by mimic dynamic body conditions. Now it is required to review what are the developments from last five years in screening the drug for cancer. Recently research is going on microfluidic platforms to screen the efficacy of mixed drugs, drug tolerance, and drug susceptibility. So this study presents the review on what are the advancements in microfluidic platforms for rapid drug screening and for different cancer patients. This study also presents what are the different sensing methodologies of microfluidic devices exists to screen the drug for various cancerous tissues

Inexpensive and Versatile Paper-Based Platform for 3D Culture of Liver Cells and Related Bioassays.

The present study delineates the fabrication of paper-based devices for culturing liver cells and developing related bioassays. The devices were prepared by conventional lab-based LaserJet printing technology and employed for 3D cell culture. Our results demonstrated that the devices efficiently supported the growth of multiple cell types incuding HepG2, HUVEC, fibroblasts, and MSCs. We further showed that the device specifications (grade of paper or design parameters) greatly impacted the functional phenotype of the HepG2 cells. We also explored the application of the developed devices for routine cell culture, drug screening, coculture, and transwell migration assays. The cellular responses observed on the paper under different culture configurations were similar to those obtained in the case of tissue culture plate (TCP). Moreover, we showed that the paper-based devices were compatible with the immunocytochemistry and ELISA procedures (no indication of nonspecific matrix-antibody interaction). Considering the simplicity, experimental flexibility, cost-effectiveness, and multiplexibility of the paper-based liver models, it is deemed to be ideal for developing cell-based bioassays, especially in resource-limited settings.

Grafting of 3D Bioprinting to In Vitro Drug Screening: A Review.

The inadequacy of conventional cell-monolayer planar cultures and animal experiments in predicting the toxicity and clinical efficacy of drug candidates has led to an imminent need for in vitro methods with the ability to better represent in vivo conditions and facilitate the systematic investigation of drug candidates. Recent advances in 3D bioprinting have prompted the precise manipulation of cells and biomaterials, rendering it a promising technology for the construction of in vitro tissue/organ models and drug screening devices. This review presents state-of-the-art in vitro methods used for preclinical drug screening and discusses the limitations of these methods. In particular, the significance of constructing 3D in vitro tissue/organ models and microfluidic analysis devices for drug screening is emphasized, and a focus is placed on the grafting process of 3D bioprinting technology to the construction of such models and devices. The in vitro methods for drug screening are generalized into three types: mini-tissue, organ-on-a-chip, and tissue/organ construct. The revolutionary process of the in vitro methods is demonstrated in detail, and relevant studies are listed as examples. Specifically, the tumor model is adopted as a precedent to illustrate the possible grafting of 3D bioprinting to antitumor drug screening.

Integration of Graphene Electrodes with 3D Skeletal Muscle Tissue Models.

Integration of conductive electrodes with 3D tissue models can have great potential for applications in bioelectronics, drug screening, and implantable devices. As conventional electrodes cannot be easily integrated on 3D, polymeric, and biocompatible substrates, alternatives are highly desirable. Graphene offers significant advantages over conventional electrodes due to its mechanical flexibility and robustness, biocompatibility, and electrical properties. However, the transfer of chemical vapor deposition graphene onto millimeter scale 3D structures is challenging using conventional wet graphene transfer methods with a rigid poly (methyl methacrylate) (PMMA) supportive layer. Here, a biocompatible 3D graphene transfer method onto 3D printed structure using a soft poly ethylene glycol diacrylate (PEGDA) supportive layer to integrate the graphene layer with a 3D engineered ring of skeletal muscle tissue is reported. The use of softer PEGDA supportive layer, with a 105 times lower Young's modulus compared to PMMA, results in conformal integration of the graphene with 3D printed pillars and allows electrical stimulation and actuation of the muscle ring with various applied voltages and frequencies. The graphene integration method can be applied to many 3D tissue models and be used as a platform for electrical interfaces to 3D biological tissue system.

A one-step tannic acid coating to improve cell adhesion and proliferation on polydimethylsiloxane

A green and straightforward tannic acid functionalization can enhance cell adhesion and proliferation on PDMS, and thus, can be potentially used for microfluidic cell assay devices for cellular physiological study or drug screening.

Nanoscale Substrate Roughness Hinders Domain Formation in Supported Lipid Bilayers.

Supported lipid bilayers are model membranes formed at solid substrate surfaces. This architecture renders the membrane experimentally accessible to surface-sensitive techniques used to study their properties, including atomic force microscopy, optical fluorescence microscopy, quartz crystal microbalance, and X-ray/neutron reflectometry, and allows integration with technology for potential biotechnological applications such as drug screening devices. The experimental technique often dictates substrate choice or treatment, and it is anecdotally recognized that certain substrates are suitable for a particular experiment, but the exact influence of the substrate has not been comprehensively investigated. Here, we study the behavior of a simple model bilayer, phase-separating on a variety of commonly used substrates, including glass, mica, silicon, and quartz, with drastically different results. The distinct micron-scale domains observed on mica, identical to those seen in free-floating giant unilamellar vesicles, are reduced to nanometer-scale domains on glass and quartz. The mechanism for the arrest of domain formation is investigated, and the most likely candidate is nanoscale surface roughness, acting as a drag on the hydrodynamic motion of small domains during phase separation. Evidence was found that the physicochemical properties of the surface have a mediating effect, most likely because of the changes in the lubricating interstitial water layer between the surface and bilayer.

Design of an Automatic Light Intensity Control System and Image Processing Algorithm for the Development of an Assistive Drug Screening Device

Drug abuse, also called substance abuse is a disorder that is characterized by a destructive pattern that leads to problems and distress. It continues to be a significant problem in the world, with millions of adolescents and adults use illicit drugs, including the Philippines. To identify if the person is drug user, methods like urine testing, blood testing, hair and sweat testing has been used in different drug testing centres. Errors and faults may easily alter the interpretation of test result depending on the process of collecting a sample. One can cause false positive result if there is contamination and adulteration. However, testing’s requires time to comprehend the result. Therefore, study was made to provide alternative drug testing methodology with the main capability is to develop a light illuminating system that regulates the amount of light entering to the pupil, the image processing method to identify pupil size with an accuracy of not less than 95%, and also giving a result within less than 5 minutes. The objective of the project is to develop a device that can determine if a person is impaired by drugs or not. A total of 20 positive drug patients that are newly admitted at Camp Bagong Diwa Rehabilitation Center Philippines and 10 people who didn’t took drug were sampled. Based on the testing conducted, 20 positive drug patient was identified to be True by the device while the 10 patients who didn’t took drug at all was identified to have 1 patient only to be positive & resulted as error. After thorough testing and evaluation by the client, the device yielded to 96.67% accuracy and the requests of the client being small and portable is achieved. The accuracy of the device proved that the objectives were met based on the needs of the client.

Thread as a Low-Cost Material for Microfluidic Assays on Intact Tumor Slices.

In this paper we describe the use of thread as a low-cost material for a microfluidic chemosensitivity assay that uses intact tumor tissue ex vivo. Today, the need for new and effective cancer treatments is greater than ever, but unfortunately, the cost of developing new chemotherapy drugs has never been higher. Implementation of low-cost microfluidic techniques into drug screening devices could potentially mitigate some of the immense cost of drug development. Thread is an ideal material for use in drug screening as it is inexpensive, widely available, and can transport liquid without external pumping hardware, i.e., via capillary action. We have developed an inexpensive microfluidic delivery prototype that uses silk threads to selectively deliver fluids onto subregions of living xenograft tumor slices. Our device can be fabricated completely for less than $0.25 in materials and requires no external equipment to operate. We found that by varying thread materials, we could optimize device characteristics, such as flow rate; we specifically explored the behavior of silk, nylon, cotton, and polyester. The incremental cost of our device is insignificant compared to the tissue culture supplies. The use of thread as a microfluidic material has the potential to produce inexpensive, accessible, and user-friendly devices for drug testing that are especially suited for low-resource settings.

Membrane bioreactor for investigation of neurodegeneration.

To gain a better understanding of neurodegeneration mechanisms and for preclinical evaluation of new therapeutics more accurate models of neuronal tissue are required. Our strategy was based on the implementation of advanced engineered system, like membrane bioreactor, in which neurons were cultured in the extracapillary space of poly(l-lactic acid) (PLLA) microtube array (MTA) membranes within a dynamic device designed to recapitulate specific microenvironment of living neuronal tissue. The high membrane permeability and the optimized fluid dynamic conditions created by PLLA-MTA membrane bioreactor provide a 3D low-shear stress environment fully controlled at molecular level with enhanced diffusion of nutrients and waste removal that successfully develops neuronal-like tissue. This neuronal membrane bioreactor was employed as in vitro model of β-amyloid -induced toxicity associated to Alzheimer's disease, to test for the first time the potential neuroprotective effect of the isoflavone glycitein. Glycitein protected neurons from the events induced by β-amyloid aggregation, such as the production of ROS, the activation of apoptotic markers and ensuring the viability and maintenance of cellular metabolic activity. PLLA-MTA membrane bioreactor has great potential as investigational tool in preclinical research, contributing to expand the available in vitro devices for drug screening.

Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications.

Neurodegenerative disorders are related to the progressive functional loss of the brain, often connected to emotional and physical disability and, ultimately, to death. These disorders, strongly connected to the aging process, are becoming increasingly more relevant due to the increase of life expectancy. Current pharmaceutical treatments poorly tackle these diseases, mainly acting only on their symptomology. One of the main reasons of this is the current drug development process, which is not only expensive and time-consuming but, also, still strongly relies on animal models at the preclinical stage. Organ-on-a-chip platforms have the potential to strongly impact and improve the drug screening process by recreating in vitro the functionality of human organs. Patient-derived neurons from different regions of the brain can be directly grown and differentiated on a brain-on-a-chip device where the disease development, progression and pharmacological treatments can be studied and monitored in real time. The model reliability is strongly improved by using human-derived cells, more relevant than animal models for pharmacological screening and disease monitoring. The selected cells will be then capable of proliferating and organizing themselves in the in vivo environment thanks to the device architecture, materials selection and bio-chemical functionalization. In this review, we start by presenting the fundamental strategies adopted for brain-on-a-chip devices fabrication including e.g., photolithography, micromachining and 3D printing technology. Then, we discuss the state-of-theart of brain-on-a-chip platforms including their role in the study of the functional architecture of the brain e.g., blood-brain barrier, or of the most diffuse neurodegenerative diseases like Alzheimer's and Parkinson's. At last, the current limitations and future perspectives of this approach for the development of new drugs and neurodegenerative diseases modeling will be discussed.

Transmembrane Electric Conductivity Modulation in PCBM Doped Free-Standing Lipid Bilayers By Visible Light Irradiation

A cell membrane has a thickness of several nanometer and function as an insulating film having a resistance of more than 100 GΩ in a biological body. The cell membrane has a structure in which phospholipid molecules are aligned as a bilayer. Researches have been conducted to artificially construct cell membranes in vivo and to apply them as highly sensitive biosensors and drug screening devices by embedding biological membrane proteins in cell membranes. On the other hand, photovoltaic properties of lipid bilayer membranes have been reported by introducing fullerene (C60) in the lipid bilayer membrane. Although this technique suggests the function of the cell membrane as a photosensor, the mechanism has not been discussed yet. If we modulated the trans-electrical-conduction with external energies of electric filed or light irradiation, we could expect to control of carrier and/or ion incorporation at the cell membrane, that would be used a biosensing and bio-ion-incorporation devices. In this work, we investigated that modulation of transmembrane electric conductivity in Phenyl-C61-Butyric-Acid-Methyl Ester (PC60BM) doped free-standing lipid bilayers by the visible light irradiation.

Microfluidic-based screening of resveratrol and drug-loading PLA/Gelatine nano-scaffold for the repair of cartilage defect

Cartilage defect is common in clinical but notoriously difficult to treat for low regenerative and migratory capacity of chondrocytes. Biodegradable tissue engineering nano-scaffold with a lot of advantages has been the direction of material to repair cartilage defect in recent years. The objective of our study is to establish a biodegradable drug-loading synthetic polymer (PLA) and biopolymer (Gelatine) composite 3D nano-scaffold to support the treatment of cartilage defect. We designed a microfluidic chip-based drug-screening device to select the optimum concentration of resveratrol, which has strong protective capability for chondrocyte. Then biodegradable resveratrol-loading PLA/Gelatine 3D nano-scaffolds were fabricated and used to repair the cartilage defects. As a result, we successfully cultured primary chondrocytes and screened the appropriate concentrations of resveratrol by the microfluidic device. We also smoothly obtained superior biodegradable resveratrol-loading PLA/Gelatine 3D nano-scaffolds and compared the properties and therapeutic effects of cartilage defect in rats. In summary, our microfluidic device is a simple but efficient platform for drug screening and resveratrol-loading PLA/Gelatine 3D nano-scaffolds could greatly promote the cartilage formation. It would be possible for materials and medical researchers to explore individualized pharmacotherapy and drug-loading synthetic polymer and biopolymer composite tissue engineering scaffolds for the repair of cartilage defect in future.

Microfluidic Devices for Drug Delivery Systems and Drug Screening.

Microfluidic devices present unique advantages for the development of efficient drug carrier particles, cell-free protein synthesis systems, and rapid techniques for direct drug screening. Compared to bulk methods, by efficiently controlling the geometries of the fabricated chip and the flow rates of multiphase fluids, microfluidic technology enables the generation of highly stable, uniform, monodispersed particles with higher encapsulation efficiency. Since the existing preclinical models are inefficient drug screens for predicting clinical outcomes, microfluidic platforms might offer a more rapid and cost-effective alternative. Compared to 2D cell culture systems and in vivo animal models, microfluidic 3D platforms mimic the in vivo cell systems in a simple, inexpensive manner, which allows high throughput and multiplexed drug screening at the cell, organ, and whole-body levels. In this review, the generation of appropriate drug or gene carriers including different particle types using different configurations of microfluidic devices is highlighted. Additionally, this paper discusses the emergence of fabricated microfluidic cell-free protein synthesis systems for potential use at point of care as well as cell-, organ-, and human-on-a-chip models as smart, sensitive, and reproducible platforms, allowing the investigation of the effects of drugs under conditions imitating the biological system.

Meet the First Authors.

Meet the First Authors.