Integrating Biosensors in Organs-on-Chip Devices: A Perspective on Current Strategies to Monitor Microphysiological Systems

Organs-on-chip (OoC), often referred to as microphysiological systems (MPS), are advanced in vitro tools able to replicate essential functions of human organs. Owing to their unprecedented ability to recapitulate key features of the native cellular environments, they represent promising tools for tissue engineering and drug screening applications. The achievement of proper functionalities within OoC is crucial; to this purpose, several parameters (e.g., chemical, physical) need to be assessed. Currently, most approaches rely on off-chip analysis and imaging techniques. However, the urgent demand for continuous, noninvasive, and real-time monitoring of tissue constructs requires the direct integration of biosensors. In this review, we focus on recent strategies to miniaturize and embed biosensing systems into organs-on-chip platforms. Biosensors for monitoring biological models with metabolic activities, models with tissue barrier functions, as well as models with electromechanical properties will be described and critically evaluated. In addition, multisensor integration within multiorgan platforms will be further reviewed and discussed.

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Imaging Microphysiological Systems: A Review

AJP Cell Physiology ◽

10.1152/ajpcell.00186.2020 ◽

2020 ◽

Author(s):

Samantha Peel ◽

Mark Jackman

Keyword(s):

Drug Discovery ◽

Animal Studies ◽

Imaging Techniques ◽

Quantitative Information ◽

In Vitro Models ◽

Microscopy Imaging ◽

In Vivo Models ◽

Microphysiological Systems

Microphysiological Systems (MPS), often referred to as 'organ-on-chips' are microfluidic-based in vitro models that aim to recapitulate the dynamic chemical and mechanical microenvironment of living organs. MPS promise to bridge the gap between in vitro and in vivo models, and ultimately improve the translation from pre-clinical animal studies to clinical trials. However, despite the explosion of interest in recent years, and the obvious rewards for such models which could improve R&D efficiency and reduce drug attrition in the clinic, the pharmaceutical industry has been slow to fully adopt this technology. The ability to extract robust, quantitative information from MPS at scale is a key requirement if these models are to impact drug discovery and the subsequent drug development process. Microscopy imaging remains a core technology that enables the capture of information at the single cell level and with subcellular resolution. Furthermore, such imaging techniques can be automated, increasing throughput, enabling compound screening. In this review we discuss a range of imaging techniques that have been applied to MPS of varying focus, such as organoids and organ-chip-type models. We outline the opportunities these technologies can bring in terms of understanding mechanistic biology, but also how they could be used in higher-throughput screens, widening the scope of their impact in drug discovery. We discuss the associated challenges of imaging these complex models and the steps required to enable full exploitation. Finally, we discuss the requirements for MPS, if they are to be applied at a scale necessary to support drug discovery projects.

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Barrier-on-a-Chip with a Modular Architecture and Integrated Sensors for Real-Time Measurement of Biological Barrier Function

Micromachines ◽

10.3390/mi12070816 ◽

2021 ◽

Vol 12 (7) ◽

pp. 816

Author(s):

Patrícia Zoio ◽

Sara Lopes-Ventura ◽

Abel Oliva

Keyword(s):

Real Time ◽

Barrier Function ◽

Imaging Techniques ◽

Real Time Monitoring ◽

Modular Architecture ◽

Element Analysis ◽

Cell Culture Techniques ◽

Biological Barriers ◽

On Chip

Biological barriers are essential for the maintenance of organ homeostasis and their dysfunction is responsible for many prevalent diseases. Advanced in vitro models of biological barriers have been developed through the combination of 3D cell culture techniques and organ-on-chip (OoC) technology. However, real-time monitoring of tissue function inside the OoC devices has been challenging, with most approaches relying on off-chip analysis and imaging techniques. In this study, we designed and fabricated a low-cost barrier-on-chip (BoC) device with integrated electrodes for the development and real-time monitoring of biological barriers. The integrated electrodes were used to measure transepithelial electrical resistance (TEER) during tissue culture, thereby quantitatively evaluating tissue barrier function. A finite element analysis was performed to study the sensitivity of the integrated electrodes and to compare them with conventional systems. As proof-of-concept, a full-thickness human skin model (FTSm) was grown on the developed BoC, and TEER was measured on-chip during the culture. After 14 days of culture, the barrier tissue was challenged with a benchmark irritant and its impact was evaluated on-chip through TEER measurements. The developed BoC with an integrated sensing capability represents a promising tool for real-time assessment of barrier function in the context of drug testing and disease modelling.

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Beating organs-on-chip as technological platforms in drug screening: Advanced in vitro models of human physiology and pathology

Biomedical Science and Engineering ◽

10.4081/bse.2021.141 ◽

2021 ◽

Vol 4 (s1) ◽

Author(s):

Paola Occhetta ◽

Roberta Visone ◽

Stefano Piazza ◽

Ferran Lozano ◽

Marco Rasponi

Keyword(s):

Human Physiology ◽

Drug Screening ◽

In Vitro Models ◽

Human Organs ◽

On Chip ◽

Technological Platforms ◽

Mechanical Microenvironment

Taking advantages of uBeat® technology, 3D beating Organs-on-Chip integrates the native complexity of human mechanical microenvironment into clinically relevant in vitro models of human organs and diseases.

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Technological Advances in Tumor-On-Chip Technology: From Bench to Bedside

Cancers ◽

10.3390/cancers13164192 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4192

Author(s):

Santa Bērziņa ◽

Alexandra Harrison ◽

Valérie Taly ◽

Wenjin Xiao

Keyword(s):

Tumor Model ◽

Cancer Therapies ◽

Analysis Tools ◽

Chip Technology ◽

Technological Advances ◽

Anti Cancer ◽

On Chip ◽

Chip Analysis

Tumor-on-chip technology has cemented its importance as an in vitro tumor model for cancer research. Its ability to recapitulate different elements of the in vivo tumor microenvironment makes it promising for translational medicine, with potential application in enabling personalized anti-cancer therapies. Here, we provide an overview of the current technological advances for tumor-on-chip generation. To further elevate the functionalities of the technology, these approaches need to be coupled with effective analysis tools. This aspect of tumor-on-chip technology is often neglected in the current literature. We address this shortcoming by reviewing state-of-the-art on-chip analysis tools for microfluidic tumor models. Lastly, we focus on the current progress in tumor-on-chip devices using patient-derived samples and evaluate their potential for clinical research and personalized medicine applications.

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Detecting apoptosis as a clinical endpoint for proof of a clinical principle

Ophthalmologica ◽

10.1159/000513584 ◽

2020 ◽

Author(s):

Piero Zollet ◽

Timothy E.Yap ◽

M Francesca Cordeiro

Keyword(s):

Drug Development ◽

Therapeutic Response ◽

Imaging Techniques ◽

Brain Diseases ◽

Promising Strategy ◽

Sight Loss ◽

Apoptosis Detection ◽

Novel Therapeutic Strategies

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis, and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarize the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

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Optimization of X-ray Investigations in Dentistry Using Optical Coherence Tomography

Sensors ◽

10.3390/s21134554 ◽

2021 ◽

Vol 21 (13) ◽

pp. 4554

Author(s):

Ralph-Alexandru Erdelyi ◽

Virgil-Florin Duma ◽

Cosmin Sinescu ◽

George Mihai Dobre ◽

Adrian Bradu ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Radiation Dose ◽

Imaging Techniques ◽

Image Resolution ◽

Optical Coherence ◽

X Rays ◽

High Quality ◽

X Ray

The most common imaging technique for dental diagnoses and treatment monitoring is X-ray imaging, which evolved from the first intraoral radiographs to high-quality three-dimensional (3D) Cone Beam Computed Tomography (CBCT). Other imaging techniques have shown potential, such as Optical Coherence Tomography (OCT). We have recently reported on the boundaries of these two types of techniques, regarding. the dental fields where each one is more appropriate or where they should be both used. The aim of the present study is to explore the unique capabilities of the OCT technique to optimize X-ray units imaging (i.e., in terms of image resolution, radiation dose, or contrast). Two types of commercially available and widely used X-ray units are considered. To adjust their parameters, a protocol is developed to employ OCT images of dental conditions that are documented on high (i.e., less than 10 μm) resolution OCT images (both B-scans/cross sections and 3D reconstructions) but are hardly identified on the 200 to 75 μm resolution panoramic or CBCT radiographs. The optimized calibration of the X-ray unit includes choosing appropriate values for the anode voltage and current intensity of the X-ray tube, as well as the patient’s positioning, in order to reach the highest possible X-rays resolution at a radiation dose that is safe for the patient. The optimization protocol is developed in vitro on OCT images of extracted teeth and is further applied in vivo for each type of dental investigation. Optimized radiographic results are compared with un-optimized previously performed radiographs. Also, we show that OCT can permit a rigorous comparison between two (types of) X-ray units. In conclusion, high-quality dental images are possible using low radiation doses if an optimized protocol, developed using OCT, is applied for each type of dental investigation. Also, there are situations when the X-ray technology has drawbacks for dental diagnosis or treatment assessment. In such situations, OCT proves capable to provide qualitative images.

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Designing of an Advanced Compression Bioreactor with an Implementation of a Low-Cost Controlling System Connected to a Mobile Application

Processes ◽

10.3390/pr9060915 ◽

2021 ◽

Vol 9 (6) ◽

pp. 915

Author(s):

Gözde Dursun ◽

Muhammad Umer ◽

Bernd Markert ◽

Marcus Stoffel

Keyword(s):

Mobile Application ◽

Low Cost ◽

Experimental Information ◽

Raspberry Pi ◽

Tissue Constructs ◽

Cost Controlling ◽

Controlling System ◽

And Control ◽

Tissue Models

(1) Background: Bioreactors mimic the natural environment of cells and tissues by providing a controlled micro-environment. However, their design is often expensive and complex. Herein, we have introduced the development of a low-cost compression bioreactor which enables the application of different mechanical stimulation regimes to in vitro tissue models and provides the information of applied stress and strain in real-time. (2) Methods: The compression bioreactor is designed using a mini-computer called Raspberry Pi, which is programmed to apply compressive deformation at various strains and frequencies, as well as to measure the force applied to the tissue constructs. Besides this, we have developed a mobile application connected to the bioreactor software to monitor, command, and control experiments via mobile devices. (3) Results: Cell viability results indicate that the newly designed compression bioreactor supports cell cultivation in a sterile environment without any contamination. The developed bioreactor software plots the experimental data of dynamic mechanical loading in a long-term manner, as well as stores them for further data processing. Following in vitro uniaxial compression conditioning of 3D in vitro cartilage models, chondrocyte cell migration was altered positively compared to static cultures. (4) Conclusion: The developed compression bioreactor can support the in vitro tissue model cultivation and monitor the experimental information with a low-cost controlling system and via mobile application. The highly customizable mold inside the cultivation chamber is a significant approach to solve the limited customization capability of the traditional bioreactors. Most importantly, the compression bioreactor prevents operator- and system-dependent variability between experiments by enabling a dynamic culture in a large volume for multiple numbers of in vitro tissue constructs.

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Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia

Scientific Reports ◽

10.1038/s41598-021-82853-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kornphimol Kulthong ◽

Guido J. E. J. Hooiveld ◽

Loes Duivenvoorde ◽

Ignacio Miro Estruch ◽

Victor Marin ◽

...

Keyword(s):

Gene Expression ◽

Culture Conditions ◽

Gene Set Enrichment Analysis ◽

Shear Stresses ◽

Static Culture ◽

Dynamic Culture ◽

Intestinal Segments ◽

On Chip

AbstractGut-on-chip devices enable exposure of cells to a continuous flow of culture medium, inducing shear stresses and could thus better recapitulate the in vivo human intestinal environment in an in vitro epithelial model compared to static culture methods. We aimed to study if dynamic culture conditions affect the gene expression of Caco-2 cells cultured statically or dynamically in a gut-on-chip device and how these gene expression patterns compared to that of intestinal segments in vivo. For this we applied whole genome transcriptomics. Dynamic culture conditions led to a total of 5927 differentially expressed genes (3280 upregulated and 2647 downregulated genes) compared to static culture conditions. Gene set enrichment analysis revealed upregulated pathways associated with the immune system, signal transduction and cell growth and death, and downregulated pathways associated with drug metabolism, compound digestion and absorption under dynamic culture conditions. Comparison of the in vitro gene expression data with transcriptome profiles of human in vivo duodenum, jejunum, ileum and colon tissue samples showed similarities in gene expression profiles with intestinal segments. It is concluded that both the static and the dynamic gut-on-chip model are suitable to study human intestinal epithelial responses as an alternative for animal models.

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Microphysiological systems: What it takes for community adoption

Experimental Biology and Medicine ◽

10.1177/15353702211008872 ◽

2021 ◽

pp. 153537022110088

Author(s):

Passley Hargrove-Grimes ◽

Lucie A Low ◽

Danilo A Tagle

Keyword(s):

Rare Diseases ◽

Development Process ◽

Emerging Technology ◽

National Institutes Of Health ◽

Drug Development Process ◽

Microphysiological Systems ◽

Pediatric Populations ◽

Neural Disorders ◽

Future Path

Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools.

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The Antibacterial Effects of Resin-Based Dental Sealants: A Systematic Review of In Vitro Studies

Materials ◽

10.3390/ma14020413 ◽

2021 ◽

Vol 14 (2) ◽

pp. 413

Author(s):

Saad Saeed AlShahrani ◽

Mana’a Saleh AlAbbas ◽

Isadora Martini Garcia ◽

Maha Ibrahim AlGhannam ◽

Muath Abdulrahman AlRuwaili ◽

...

Keyword(s):

Antibacterial Agents ◽

Data Extraction ◽

Risk Of Bias ◽

Dental Sealants ◽

Medium Risk ◽

Metabolic Activities ◽

High Degree ◽

Phosphate Buffered Saline ◽

Full Text Screening

This review aimed to assess the antimicrobial effects of different antibacterial agents/compounds incorporated in resin-based dental sealants. Four databases (PubMed, MEDLINE, Web of Science and Scopus) were searched. From the 8052 records retrieved, 275 records were considered eligible for full-text screening. Nineteen studies met the inclusion criteria. Data extraction and quality assessment was performed by two independent reviewers. Six of the nineteen included studies were judged to have low risk of bias, and the rest had medium risk of bias. Compounds and particles such as zinc, tin, Selenium, chitosan, chlorhexidine, fluoride and methyl methacrylate were found to be effective in reducing the colony-forming unit counts, producing inhibition zones, reducing the optical density, reducing the metabolic activities, reducing the lactic acid and polysaccharide production and neutralizing the pH when they are added to the resin-based dental sealants. In addition, some studies showed that the antibacterial effect was not significantly different after 2 weeks, 2 months and 6 months aging in distilled water or phosphate-buffered saline. In conclusion, studies have confirmed the effectiveness of adding antibacterial agents/compounds to dental sealants. However, we should consider that these results are based on laboratory studies with a high degree of heterogeneity.

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