Drug and bioactive molecule screening based on a bioelectrical impedance cell culture platform

Abstract

This review will present a brief discussion on the recent advancements of bioelectrical impedance cell-based biosensors, especially the electric cell-substrate impedance sensing (ECIS) system for screening of various bioactive molecules. The different technical integrations of various chip types, working principles, measurement systems, and applications for drug targeting of molecules in cells are highlighted in this paper. Screening of bioactive molecules based on electric cell-substrate impedance sensing is a trial-and-error process toward the development of therapeutically active agents for drug discovery and therapeutics. In general, bioactive molecule screening can be used to identify active molecular targets for various diseases and toxicity at the cellular level with nanoscale resolution. In the innovation and screening of new drugs or bioactive molecules, the activeness, the efficacy of the compound, and safety in biological systems are the main concerns on which determination of drug candidates is based. Further, drug discovery and screening of compounds are often performed in cell-based test systems in order to reduce costs and save time. Moreover, this system can provide more relevant results in in vivo studies, as well as high-throughput drug screening for various diseases during the early stages of drug discovery. Recently, MEMS technologies and integration with image detection techniques have been employed successfully. These new technologies and their possible ongoing transformations are addressed. Select reports are outlined, and not all the work that has been performed in the field of drug screening and development is covered.

Keywords: electric cell-substrate impedance sensing (ECIS); high-throughput screening; impedance-based cell study; real-time drug evaluation; screening of bioactive agents.

Figure 1

Schematic diagram of the ECIS method working principle. Notes: (A) Current flow before cell attachment. (B) After cell attachment, the current flows with cells from the surface of Au-sensing electrodes. Cells are grown to confluence on electrodes. The current flow between working electrodes and counter electrodes through cell culture medium, which acted as electrolyte. (C) Different types of ECIS electrode arrays for various applications. Abbreviations: ECIS, electric cell-substrate impedance sensing; W, well; E, electrode; idf, inter-digitated finger configuration; LE, linear electrode; F, flow array; E+, addition of more electrodes; LE, linear electrode; PC, polycarbonate substrate.

Figure 2

A typical electric cell-substrate impedance sensing (ECIS) measurement graph of normal HDFn cell growth response for 20 hours, showing various cellular morphological changes. Abbreviation: HDFn, human dermal fibroblasts, neonatal cells.

Figure 3

Schematic diagram showing various devices and microelectrode chip fabrication types for different studies using bioimpedance platform. Notes: (A) Real-time optical imaging and impedance measurements. The camera is located above the cell culture chip, which enables provision of real-time imaging. (B) Microfluidic based cell culture sensing system: interdigitated array of electrodes on glass for impedance sensing, a polydimethylsiloxane (PDMS) layer for gradient generation and cell culture, which can provide the concentration dependent cellular behavior. (C) Three-dimensional depiction of a hydrogel chamber of a diffusion cell culture chip integrated with electric cell-substrate impedance sensing (ECIS). (D) Qualitative and quantitative data acquisition using a computer interface with a data monitoring and storage system.

Figure 4

Applications of the ECIS system for analysis of cellular behaviors and activity for drug screening studies. Notes: (A) Barrier function analysis for paracellular pathway and permeability study. (B) Ion channel activity analysis for studying ion transport mechanisms and whether the compound is able to block the channel. (C) Cell signaling analysis for studying cell/extracellular matrix interaction or disruption of signaling pathways. (D) Cell metabolism analysis for studying the differences in growth and metabolic status of cells. (E) Cytotoxicity screening for studying analyte toxicity responses to the cells. (F) Cancer metastasis analysis for studying cancer cell behavior including the potentiality of drugs effects on cells. (G) Photoprotectivity analysis for studying photodamaging and photoprotective effects. (H) Drug resistance analysis for studying drug resistance capacity in various cells, including cancer cells, including cancer cells. Abbreviations: Acetyl CoA, acetyl coenzyme A; ATP, adenosine triphosphate; ECIS, electric cell-substrate impedance sensing; GPCR, G-protein-coupled receptor.

Figure 5

Concentration-response curves for 50% inhibition effects of cells, which is derived from the impedance profile at 12 hours after various analyte concentration administrations. Note: Basic graph for the half-inhibition (IC₅₀) concentration profile.