Drug Screening Technologies Research Articles

Examining the use of drug screening technologies in night-time entertainment districts

Examining the use of drug screening technologies in night-time entertainment districts

Predicting Clinical Outcomes of SARS-CoV-2 Drug Efficacy with a High-Throughput Human Airway Microphysiological System.

The average cost to bring a new drug from its initial discovery to a patient's bedside is estimated to surpass $2 billion and requires over a decade of research and development. There is a need for new drug screening technologies that can parse drug candidates with increased likelihood of clinical utility early in development in order to increase the cost-effectiveness of this pipeline. For example, during the COVID-19 pandemic, resources were rapidly mobilized to identify effective therapeutic treatments but many lead antiviral compounds failed to demonstrate efficacy when progressed to human trials. To address the lack of predictive preclinical drug screening tools, PREDICT96-ALI, a high-throughput (n = 96) microphysiological system (MPS) that recapitulates primary human tracheobronchial tissue,is adapted for the evaluation of differential antiviral efficacy of native SARS-CoV-2 variants of concern. Here, PREDICT96-ALI resolves both the differential viral kinetics between variants and the efficacy of antiviral compounds over a range of drug doses. PREDICT96-ALI is able to distinguish clinically efficacious antiviral therapies like remdesivir and nirmatrelvir from promising lead compounds that do not show clinical efficacy. Importantly, results from this proof-of-concept study track with known clinical outcomes, demonstrate the feasibility of this technology as a prognostic drug discovery tool.

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.

New epilepsy therapies in development.

Epilepsy is a common brain disorder, characterized by spontaneous recurrent seizures, with associated neuropsychiatric and cognitive comorbidities and increased mortality. Although people at risk can often be identified, interventions to prevent the development of the disorder are not available. Moreover, in at least 30% of patients, epilepsy cannot be controlled by current antiseizure medications (ASMs). As a result of considerable progress in epilepsy genetics and the development of novel disease models, drug screening technologies and innovative therapeutic modalities over the past 10 years, more than 200 novel epilepsy therapies are currently in the preclinical or clinical pipeline, including many treatments that act by new mechanisms. Assisted by diagnostic and predictive biomarkers, the treatment of epilepsy is undergoing paradigm shifts from symptom-only ASMs to disease prevention, and from broad trial-and-error treatments for seizures in general to mechanism-based treatments for specific epilepsy syndromes. In this Review, we assess recent progress in ASM development and outline future directions for the development of new therapies for the treatment and prevention of epilepsy.

RdRp activity test using CRISPR/Cas13a enzyme (RACE) for screening of SARS-CoV-2 inhibitors

The coronavirus disease 2019 pandemic has highlighted the need for efficient antiviral drug screening technologies, particularly for targeting RNA-dependent RNA polymerase (RdRp). Here, we present a novel RdRp activity assay using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 13a (Cas13a) enzyme (RACE) for screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibitors. This is the first application of the CRISPR/Cas complex for RdRp activity-based drug screening. The RACE system combines RdRp, RNA template, target inhibitor, CRISPR/Cas13a, and reporter probe, enabling accurate detection of the inhibitory effect on RdRp activity. This is demonstrated by the system's ability to provide half-maximal inhibitory concentration values of 7.5 ± 0.5 and 8.9 ± 0.6 μM for remdesivir triphosphate and C646, respectively. In addition, the RACE system requires a detection time of 5 min, making it more efficient than traditional endpoint assays. The real-time fluorometric output of the RACE system allows monitoring of reactions, providing insight into the kinetics of RdRp activity. Furthermore, the versatility of the RACE system extends to lateral flow assay formats, improving convenience. We anticipate that the RACE system has the potential to identify antiviral compounds that target RdRp, thereby accelerating the development of effective antiviral therapies.

Openable artificial intestinal tract device integrated with a permeable filter for evaluating drug permeation through cells

Organs-on-chips using cultured cells have been developed and applied for evaluating in vitro biological phenomena. We previously reported an openable artificial intestinal tract system, as an in vitro model of the small intestine, for in vitro drug screening. The intestinal tract device could be transformed using an integrated artificial muscle actuator. An initial flat state was suitable for cell culture, and the transformed tubular structure was used as a fluidic channel for perfusion tests. The previously developed intestinal tract system could be used to evaluate drug absorption by cells through perfusion testing. This study presents an improved artificial intestinal tract system for analysis of drug permeation, in addition to absorption. Permeable filters were integrated into the intestinal tract device. Integration of additional filters into the design of the existing artificial muscle actuator was accomplished by considering device performance and available filter locations. Filter permeability was evaluated by perfusion testing. MDCK-II cells were cultured on the device and visually and electrically evaluated. The openable device, equipped with new functions for further pharmacokinetic analysis, could perform and evaluate drug disposition using cultured cells. We anticipate that the improved, openable organ-on-a-chip device system will contribute to advances in in vitro drug screening technology.

A Perfluoropolyether Microfluidic Device for Cell-Based Drug Screening with Accurate Quantitative Analysis.

Microfluidic drug screening technologies have been extensively explored to evaluate the pharmacology and therapeutic implications of promising chemical compounds in multiplexed physiological microenvironments in vivo. However, conventional poly(dimethylsiloxane) microchips are susceptible to adsorption by hydrophobic molecules on channel surfaces and permeation in the matrix. These can significantly compromise the drug availability and accuracy of dose-dependent quantitative analyses. Here, we prepared a perfluorinated polyether (PFPE) microchip via digital light processing 3D printing as a quantitative drug screening platform for precise concentration-dependent pharmaceutical assays. Cells cultured on PFPE microchips exhibited excellent viability with a spread morphology as well as superior proliferative capability. Importantly, PFPE constructions with a low surface energy significantly prevented the nonspecific molecular adsorption into their surfaces or permeation into the matrix. In particular, the PFPE multibranched channel preserved the concentration of the pharmaceutical drug during the perfusion process and generated a linear concentration gradient, resulting in a dose-dependent chemotherapeutic effect. We suggest that the biocompatible and nonadsorbing PFPE microchannel can provide a cell-based drug screening platform for concentration-dependent quantitative analyses.

Establishment and Identification of Patient-Derived Xenograft Model for Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma is the most common head and neck malignancy with high morbidity and mortality. Currently, platinum-based chemotherapy is the conventional chemotherapy regimen for patients with oral squamous cell carcinoma. However, due to the heterogeneity of tumors and individual differences of patients, chemotherapy regimens lacking individualized evaluation of tumor patients are often less effective. Therefore, personalized tumor chemotherapy is one of the effective methods for the future treatment of malignant tumors. The patient-derived xenograft model is a relatively new tumor xenograft model that relies on immunodeficient mice. This model can better maintain various histological characteristics of primary tumor grafts, such as pathological structural features, molecular diversity, and gene expression profiles. Therefore, the patient-derived xenograft model combined with drug screening technology to explore new tumor chemotherapy is the critical research direction for future tumor treatment. This study successfully established the patient-derived xenograft model of oral squamous cell carcinoma. It was verified by hematoxylin-eosin staining and immunohistochemistry that the constructed patient-derived xenograft model retained the pathological and molecular biological characteristics of primary tumors. Our patient-derived xenograft model can be used further to study the oncological characteristics of oral squamous carcinoma and can also be applied to personalize the treatment of oral squamous carcinoma patients, providing a practical resource for screening chemotherapy drugs.

Affordable and effective optokinetic response methods to assess visual acuity and contrast sensitivity in larval to juvenile zebrafish.

The optokinetic response (OKR) is an effective behavioural assay to investigate functional vision in zebrafish. The rapid and widespread use of gene editing, drug screening and environmental modulation technologies has resulted in a broader need for visual neuroscience researchers to access affordable and more sensitive OKR, contrast sensitivity (CS) and visual acuity (VA) assays. Here, we demonstrate how 2D- and 3D-printed, striped patterns or drums coupled with a motorised base and microscope provide a simple, cost-effective but efficient means to assay OKR, CS and VA in larval-juvenile zebrafish. In wild-type, five days post-fertilisation (dpf) zebrafish, the 2D or 3D set-ups of 0.02 cycles per degree (cpd) (standard OKR stimulus) and 100% black-white contrast evoked equivalent responses of 24.2±3.9 or 21.8±3.9 saccades per minute, respectively. Furthermore, although the OKR number was significantly reduced compared to the 0.02 cpd drum (p<0.0001), 0.06 and 0.2 cpd drums elicited equivalent responses with both set-ups. Notably, standard OKRs varied with time of day; peak responses of 29.8±7 saccades per minute occurred in the early afternoon with significantly reduced responses occurring in the early morning or late afternoon (18.5±3 and 18.4±4.5 saccades per minute, respectively). A customised series of 2D printed drums enabled analysis of VA and CS in 5-21 dpf zebrafish. The saccadic frequency in VA assays was inversely proportional to age and spatial frequency and in CS assays was inversely proportional to age and directly proportional to contrast of the stimulus. OKR, VA and CS of zebrafish larvae can be efficiently measured using 2D- or 3D-printed striped drums. For data consistency the luminance of the OKR light source, the time of day when the analysis is performed, and the order of presentation of VA and CS drums must be considered. These simple methods allow effective and more sensitive analysis of functional vision in zebrafish.

Revisiting fetal hemoglobin inducers in beta-hemoglobinopathies: a review of natural products, conventional and combinatorial therapies.

Beta-hemoglobinopathies exhibit a heterogeneous clinical picture with varying degrees of clinical severity. Pertaining to the limited treatment options available, where blood transfusion still remains the commonest mode of treatment, pharmacological induction of fetal hemoglobin (HbF) has been a lucrative therapeutic intervention. Till now more than 70 different HbF inducers have been identified. The practical usage of many pharmacological drugs has been limited due to safety concerns. Natural compounds, like Resveratrol, Ripamycin and Bergaptene, with limited cytotoxicity and high efficacy have started capturing the attention of researchers. In this review, we have summarized pharmacological drugs and bioactive compounds isolated from natural sources that have been shown to increase HbF significantly. It primarily discusses recently identified synthetic and natural compounds, their mechanism of action, and their suitable screening platforms, including high throughput drug screening technology and biosensors. It also delves into the topic of combinatorial therapy and drug repurposing for HbF induction. Overall, we aim to provide insights into where we stand in HbF induction strategies for treating β-hemoglobinopathies.

Application of microfluidic chips in anticancer drug screening.

With the continuous development of drug screening technology, new screening methodologies and technologies are constantly emerging, driving drug screening into rapid, efficient and high-throughput development. Microfluidics is a rising star in the development of innovative approaches in drug discovery. In this article, we summarize the recent years’ progress of microfluidic chip technology in drug screening, including the developmental history, structural design, and applications in different aspects of microfluidic chips on drug screening. Herein, the existing microfluidic chip screening platforms are summarized from four aspects: chip structure design, sample injection and drive system, cell culture technology on a chip, and efficient remote detection technology. Furthermore, this review discusses the application and developmental prospects of using microfluidic chips in drug screening, particularly in screening natural product anticancer drugs based on chemical properties, pharmacological effects, and drug cytotoxicity.

Affordable and effective optokinetic response methods to assess visual acuity and contrast sensitivity in larval to juvenile zebrafish

The optokinetic response (OKR) is an effective behavioural assay to investigate functional vision in zebrafish. The rapid and widespread use of gene editing, drug screening and environmental modulation technologies has resulted in a broader need for visual neuroscience researchers to access affordable and more sensitive OKR, contrast sensitivity (CS) and visual acuity (VA) assays. Here, we demonstrate how 2D- and 3D-printed, striped patterns or drums coupled with a motorised base and microscope provide a simple, cost-effective but efficient means to assay OKR, CS and VA in larval-juvenile zebrafish. In wild-type, five days post-fertilisation (dpf) zebrafish, the 2D or 3D drums printed with the standard OKR stimulus of 0.02 cycles per degree (cpd), 100% black-white contrast evoked equivalent responses of 24.2 or 21.8 saccades per minute, respectively. Furthermore, although the OKR number was significantly reduced compared to the 0.02 cpd drum (p&lt;0.0001), the 2D and 3D drums evoked equivalent responses with the 0.06 and 0.2 cpd drums. Notably, standard OKRs varied with time of day; peak responses of 29.8 saccades per minute occurred in the early afternoon with significantly reduced responses occurring in the early morning or late afternoon (18.5 and 18.4 saccades per minute, respectively). A customised series of 2D printed drums enabled analysis of VA and CS in 5-21 dpf zebrafish. The saccadic frequency in VA and CS assays was inversely proportional to age, spatial frequency and contrast of the stimulus. OKR, VA and CS of zebrafish larvae can be efficiently measured using 2D- or 3D-printed striped drums. For data consistency the luminance of the OKR light source, the time of day when the analysis is performed, and the order of presentation of VA and CS drums must be considered. These simple methods allow effective and more sensitive analysis of functional vision in zebrafish.

Deep-Sea Coral Garden Invertebrates and Their Associated Fungi Are Genetic Resources for Chronic Disease Drug Discovery.

Chronic diseases characterized by bone and cartilage loss are associated with a reduced ability of progenitor cells to regenerate new tissues in an inflammatory environment. A promising strategy to treat such diseases is based on tissue repair mediated by human mesenchymal stem cells (hMSCs), but therapeutic outcomes are hindered by the absence of small molecules to efficiently modulate cell behaviour. Here, we applied a high-throughput drug screening technology to bioprospect a large library of extracts from Irish deep-sea organisms to induce hMSC differentiation toward musculoskeletal lineages and reduce inflammation of activated macrophages. The library included extracts from deep-sea corals, sponges and filamentous fungi representing a novel source of compounds for the targeted bioactivity. A validated hit rate of 3.4% was recorded from the invertebrate library, with cold water sea pens (octocoral order Pennatulacea), such as Kophobelemnon sp. and Anthoptilum sp., showing the most promising results in influencing stem cell differentiation toward osteogenic and chondrogenic lineages. Extracts obtained from deep-sea fungi showed no effects on stem cell differentiation, but a 6.8% hit rate in reducing the inflammation of activated macrophages. Our results demonstrate the potential of deep-sea organisms to synthetize pro-differentiation and immunomodulatory compounds that may represent potential drug development candidates to treat chronic musculoskeletal diseases.

Abstract 58: High throughput 3D tumor model drug screening technology

Abstract Two-dimensional (2D) cancer cell cultures, or monolayers, remain the standard for testing cancer drugs prior to animal studies due to their simplicity and compatibility with standard plates and commercially available robotic tools. However, monolayer cell assays often fail to predict the efficacy of cancer drug candidates resulting in 80% of cancer drugs failing in animal drug studies and contributing to the extremely high costs of cancer drug discovery. Unlike solid tumors, the standard 2D cell cultures allow cancer cells unrestricted access to nutrients and oxygen and lack intercellular communications that result in inaccurate drug efficacy data. Three-dimensional (3D) tumor models are biologically relevant cell cultures that reproduce key properties such as diffusion limitations and cellular network of solid tumors that influence cancer drug efficacy. To promote the use of 3D cancer cell cultures in oncology drug discovery, OncoSolutions has engineered a novel technology to generate biologically relevant 3D tumor models that uniquely meets the needs of the pharmaceutical industry. OncoSolutions’ technology is highly robust and reliable for drug screening and available in high throughput format (1536 microplate) to accommodate the large drug libraries of the pharmaceutical industry. Importantly, the technology utilizes standard microplates that are compatible with commercially available automated liquid handling and analysis tools to reduce associated costs and increase speed for formation and analyses. OncoSolutions’ groundbreaking 3D culture technology is based on the immiscibility of highly aqueous solutions of polyethylene glycol (PEG) and dextran (DEX) to form a stable two-phase system. Cancer cells are mixed with the denser aqueous DEX phase solution and robotically dispensed as a nanodrop into a well of a standard microwell plate containing the immersion aqueous PEG phase. Cells remain entrapped in the nanodrop to autonomously form a single, compact 3D culture per well of the microplate within 24 hours. Unlike existing techniques, our technology quickly and reliably forms highly reproducible 3D cancer cell cultures with a standard deviation of less than 10% of the average 3D culture diameter within microplates. OncoSolutions’ technology has been used for biologically relevant standard chemotherapeutic testing and displayed superior robustness through Z-factor measurement (a statistical robustness measurement). In addition to evaluating the viability response of 3D cancer cell cultures generated with OncoSolutions’ technology, an assay for determining the apoptotic effects on 3D cancer cell cultures following drug treatment was optimized. Importantly, tumor models grown with OncoSolutions’ technology have provided more predictive models of animal drug responses than standard monolayer cultures and can reduce the time and costs associated with the high failure rate of cancer drugs in animal studies. Citation Format: Stephanie L. Ham, Emily Mulvany, Hossein Tavana. High throughput 3D tumor model drug screening technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 58.

Patent Application Trends of Induced Pluripotent Stem Cell Technologies in the United States, Japanese, and European Applications

Patent application trends were investigated for induced pluripotent stem cell (iPSC) technologies, particularly disease-specific cell technologies related to iPSCs, in the U.S., Japanese, and European applications during 2017. The number of patent applications for iPSC technologies was 1516 in the United States, 895 in Japan, and 420 in Europe, with 5% of applications for disease-specific cell technologies. In contrast, the percentages of patent applications for iPSC preparation and differentiation technologies were 17% and 23%, respectively. Patent applications for disease-specific cell technologies were classified into four technical fields and 14 disorder groups. In the technical fields, patent applications for genetically engineered cell technologies were prominent, accounting for 63%, 50%, and 65% of the U.S., Japanese, and European applications for 11, 8, and 7 disorder groups, respectively. In the disorder groups, the percentages of patent applications for neurological disorders were 40%, 32%, and 40% of the U.S., Japanese, and European applications, respectively, which were filed in four technical fields in the U.S. and Japanese applications. The U.S. patent applications for disease-specific cell technologies were filed by applicants in the United States, Japan, France, Belgium, Italy, Korea, and Canada; however, patent applications filed by those in Belgium, Italy, and Canada were not found in the Japanese and European applications. The percentages of patent applications filed by the U.S. applicants were 72%, 55%, and 65% of the U.S., Japanese, and European applications, respectively. Most patent applications filed by the U.S. applicants were in the field of genetically engineered cells for 11 disorder groups, which mostly included neurological and blood disorders. Japanese applicants mainly filed patent applications for drug screening technologies; subjects included five disorder groups, particularly neurological and bone/articular disorders. French applicants filed patent applications for neurological disorders in the field of genetically engineered cells and drug screening technologies. Korean applicants filed patent applications for patient-derived cell technologies for neurological, metabolic, and chromosomal/genetic disorders. In conclusion, more than half of patent applications were for genetically engineered cells for 11 disorders, most of which were filed by U.S. applicants.

Fluorescent resonance energy transfer -based biosensor for detecting conformational changes of Pin1

Pin1, a peptidyl prolyl cis/trans isomerase (PPIase), regulates the activity and stability of various phosphorylated proteins. Pin1 consists of a PPIase domain and WW domain, both of which are required for the function of Pin1. However, how the behavior of these domains changes upon binding to phosphorylated proteins has not been analyzed. We created a Fluorescent Resonance Energy Transfer (FRET)-based biosensor “CPinY”, which is composed of Pin1 flanked by CFP and YFP, and analyzed the interaction between Pin1 and c-Myc. Our results indicated that the dual phosphorylation of c-Myc at Thr58 and Ser62 is essential for tight interaction with Pin1. Additionally, this interaction caused a significant conformational change in Pin1. Our CPinY biosensor also detected a novel type of inhibitor of Pin1 function. We believe that his biosensor will be a novel drug screening technology targeting Pin1.

Antifouling Stripes Prepared from Clickable Zwitterionic Copolymers.

In this study, we have fabricated robust patterned surfaces that contain biocompatible and antifouling stripes, which cause microorganisms to consolidate into bare silicon spaces. Copolymers of methacryloyloxyethyl phosphorylcholine (MPC) and a methacrylate-substituted dihydrolipoic acid (DHLA) were spin-coated onto silicon substrates. The MPC units contributed biocompatibility and antifouling properties, and the DHLA units enabled cross-linking and the formation of robust thin films. Photolithography enabled the formation of 200-μm-wide poly(MPC-DHLA) stripped patterns that were characterized using atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and rhodamine 6G staining. Regardless of the spacing between poly(MPC-DHLA) stripes (10, 50, or 100 μm), Escherichia coli rapidly adhered to the bare silicon gaps that lacked the copolymer, confirming the antifouling nature of MPC. Overall, this work provides a surface modification strategy for generating alternating biofouling and nonfouling surface structures that are potentially applicable for researchers studying cell biology, drug screening, and biosensor technology.

Fishing for Nature's Hits: Establishment of the Zebrafish as a Model for Screening Antidiabetic Natural Products.

Diabetes mellitus affects millions of people worldwide and significantly impacts their quality of life. Moreover, life threatening diseases, such as myocardial infarction, blindness, and renal disorders, increase the morbidity rate associated with diabetes. Various natural products from medicinal plants have shown potential as antidiabetes agents in cell-based screening systems. However, many of these potential “hits” fail in mammalian tests, due to issues such as poor pharmacokinetics and/or toxic side effects. To address this problem, the zebrafish (Danio rerio) model has been developed as a “bridge” to provide an experimentally convenient animal-based screening system to identify drug candidates that are active in vivo. In this review, we discuss the application of zebrafish to drug screening technologies for diabetes research. Specifically, the discovery of natural product-based antidiabetes compounds using zebrafish will be described. For example, it has recently been demonstrated that antidiabetic natural compounds can be identified in zebrafish using activity guided fractionation of crude plant extracts. Moreover, the development of fluorescent-tagged glucose bioprobes has allowed the screening of natural product-based modulators of glucose homeostasis in zebrafish. We hope that the discussion of these advances will illustrate the value and simplicity of establishing zebrafish-based assays for antidiabetic compounds in natural products-based laboratories.

Emerging biomaterials and strategies for medical applications: a review

The creation of new materials is one of the fundamental driving forces between research and industry and lays the foundation for new products to enhance health and well being for the future. Antibacterial materials are an active area of research but also an economic sector in full expansion that addresses many application domains. It is also a world priority in terms of reducing infection in humans for improved life and well being. Healthcare is one the largest and most rapidly expanding needs of modern society, and smart approaches and materials are required to extend the boundaries required to improve the field. In this paper, we systematically review a series of biomaterials and strategies that have emerged over the last decade. In particular, focus has been driven around the nanorealm. Some of the diverse arenas surrounding the nanodomain and applications include drug screening technologies, biocompatibility, emerging approaches and biomimetics. In a wider front, intelligent materials are where the next phases of research are driven, some of which are discussed herein.

A New Cells‐Compatible Microfluidic Device for Single Channel Recordings

AbstractWe report the fabrication of a microfluidic apparatus and the realization of a sensors based on PEDOT : PSS, a biocompatible semiconductor polymer used in substitution of standard electrodes for electrophysiological studies and for detection of nanopores in membrane. This gives the possibility to study the mechanisms of ions balance and molecular transport though cell membranes. In particular the apparatus is based on two chambers connected through an aperture in a PTFE sheet where lipid bilayer are formed using Montal‐Mueller method, and the pore‐forming proteins activity is detected by polymeric electrodes. This methodology could be applied to examine different membrane proteins for the purpose of biosensing, drug screening and nanopore technologies.