AN IN VITRO HUMAN-ORGAN-SPECIFIC SYSTEM FOR TESTING GENOTOXIC AGENTS

Cancer research has considerably progressed with the improvement of in vitro study models, helping to understand the key role of the tumor microenvironment in cancer development and progression. Over the last few years, complex 3D human cell culture systems have gained much popularity over in vivo models, as they accurately mimic the tumor microenvironment and allow high-throughput drug screening. Of particular interest, in vitrohuman 3D tissue constructs, produced by the self-assembly method of tissue engineering, have been successfully used to model the tumor microenvironment and now represent a very promising approach to further develop diverse cancer models. In this review, we describe the importance of the tumor microenvironment and present the existing in vitro cancer models generated through the self-assembly method of tissue engineering. Lastly, we highlight the relevance of this approach to mimic various and complex tumors, including basal cell carcinoma, cutaneous neurofibroma, skin melanoma, bladder cancer, and uveal melanoma.

Download Full-text

Latest Trends in Biosensing for Microphysiological Organs-on-a-Chip and Body-on-a-Chip Systems

Biosensors ◽

10.3390/bios9030110 ◽

2019 ◽

Vol 9 (3) ◽

pp. 110 ◽

Cited By ~ 10

Author(s):

Sebastian Kratz ◽

Gregor Höll ◽

Patrick Schuller ◽

Peter Ertl ◽

Mario Rothbauer

Keyword(s):

Animal Testing ◽

Human Organ ◽

Organ Specific ◽

Vitro Model ◽

Induced Pluripotent ◽

Organ Models ◽

Specific Reactions ◽

Analysis Platform

Organs-on-chips are considered next generation in vitro tools capable of recreating in vivo like, physiological-relevant microenvironments needed to cultivate 3D tissue-engineered constructs (e.g., hydrogel-based organoids and spheroids) as well as tissue barriers. These microphysiological systems are ideally suited to (a) reduce animal testing by generating human organ models, (b) facilitate drug development and (c) perform personalized medicine by integrating patient-derived cells and patient-derived induced pluripotent stem cells (iPSCs) into microfluidic devices. An important aspect of any diagnostic device and cell analysis platform, however, is the integration and application of a variety of sensing strategies to provide reliable, high-content information on the health status of the in vitro model of choice. To overcome the analytical limitations of organs-on-a-chip systems a variety of biosensors have been integrated to provide continuous data on organ-specific reactions and dynamic tissue responses. Here, we review the latest trends in biosensors fit for monitoring human physiology in organs-on-a-chip systems including optical and electrochemical biosensors.

Download Full-text

Human Microphysiological Models of Airway and Alveolar Epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00103.2021 ◽

2021 ◽

Author(s):

Dave Anuj Lagowala ◽

Seoyoung Kwon ◽

Venkataramana K. Sidhaye ◽

Deok-Ho Kim

Keyword(s):

Respiratory Disease ◽

Cell Biology ◽

Disease Modeling ◽

Alveolar Epithelium ◽

Animal Testing ◽

Future Directions ◽

Human Organ ◽

Organ Specific

Human organ-on-a-chip models are powerful tools for pre-clinical research that can be used to study the mechanisms of disease and evaluate new targets for therapeutic intervention. Lung-on-a-chip models have been one of the most well-characterized designs in this field, and can be altered to evaluate various types of respiratory disease and to assess treatment candidates prior to clinical testing. These systems are capable of overcoming the flaws of conventional 2D cell culture and in vivo animal testing due to their ability to accurately recapitulate the in vivo microenvironment of human tissue with tunable material properties, microfluidic integration, delivery of precise mechanical and biochemical cues, and designs with organ-specific architecture. In this review, we first describe an overview of currently available lung-on-a-chip designs. We then present how recent innovations in human stem cell biology, tissue engineering, and microfabrication can be used to create more predictive human lung-on-a-chip models for studying respiratory disease. Finally, we discuss the current challenges and future directions of lung-on-a-chip designs for in vitro disease modeling with particular focus on immune and multi-organ interactions.

Download Full-text

SARS-CoV-2 causes human BBB injury and neuroinflammation indirectly in a linked organ chip platform

10.1101/2021.10.05.463205 ◽

2021 ◽

Author(s):

Peng Wang ◽

Lin Jin ◽

Min Zhang ◽

Yunsong Wu ◽

Zilei Duan ◽

...

Keyword(s):

Cell Activation ◽

In Vitro Models ◽

Human Organ ◽

System Disease ◽

Host Interaction ◽

Glial Cell Activation ◽

New Findings ◽

New Strategy ◽

Organ Specific

COVID-19 is a multi-system disease affecting many organs outside of the lungs, and patients generally develop varying degrees of neurological symptoms. Whereas, the pathogenesis underlying these neurological manifestations remains elusive. Although in vitro models and animal models are widely used in studies of SARS-CoV-2 infection, human organ models that can reflect the pathological alterations in a multi-organ context are still lacking. In this study, we propose a new strategy to probe the effects of SARS-CoV-2 on human brains in a linked alveolus-BBB organ chip platform. The new multi-organ platform allows to recapitulate the essential features of human alveolar-capillary barrier and blood-brain barrier in a microfluidic condition by co-culturing the organ-specific cells. The results reveal direct SARS-CoV-2 exposure has no obvious effects on BBB chip alone. While, infusion of endothelial medium from infected alveolus chips can cause BBB dysfunction and neuroinflammation on the linked chip platform, including brain endothelium disruption, glial cell activation and inflammatory cytokines release. These new findings suggest that SARS-CoV-2 could induce neuropathological alterations, which might not result from direct viral infection through hematogenous route, but rather likely from systemic inflammation following lung infection. This work provides a new strategy to study the virus-host interaction and neuropathology at an organ-organ context, which is not easily obtained by other in vitro models. This will facilitate to understand the neurological pathogenesis in SARS-CoV-2 and accelerate the development of new therapeutics.

Download Full-text

Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice

Scientific Reports ◽

10.1038/s41598-020-80940-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maki Murakoshi ◽

Tomohito Gohda ◽

Eri Adachi ◽

Saki Ichikawa ◽

Shinji Hagiwara ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Kidney Injury ◽

Proximal Tubules ◽

Tubular Damage ◽

Standard Diet ◽

Mrna Levels ◽

High Fat ◽

Organ Specific

AbstractProgranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.

Download Full-text

Using the Microwell-mesh to culture microtissues in vitro and as a carrier to implant microtissues in vivo into mice

Scientific Reports ◽

10.1038/s41598-021-84154-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Melissa E. Monterosso ◽

Kathryn Futrega ◽

William B. Lott ◽

Ian Vela ◽

Elizabeth D. Williams ◽

...

Keyword(s):

Hair Follicles ◽

Live Animal ◽

Nsg Mice ◽

Animal Imaging ◽

Organ Specific ◽

Bioluminescence Signal ◽

Serial Transplantation ◽

Live Animal Imaging

AbstractProstate cancer (PCa) patient-derived xenografts (PDXs) are commonly propagated by serial transplantation of “pieces” of tumour in mice, but the cellular composition of pieces is not standardised. Herein, we optimised a microwell platform, the Microwell-mesh, to aggregate precise numbers of cells into arrays of microtissues, and then implanted the Microwell-mesh into NOD-scid IL2γ−/− (NSG) mice to study microtissue growth. First, mesh pore size was optimised using microtissues assembled from bone marrow-derived stromal cells, with mesh opening dimensions of 100×100 μm achieving superior microtissue vascularisation relative to mesh with 36×36 μm mesh openings. The optimised Microwell-mesh was used to assemble and implant PCa cell microtissue arrays (hereafter microtissues formed from cancer cells are referred to as microtumours) into mice. PCa cells were enriched from three different PDX lines, LuCaP35, LuCaP141, and BM18. 3D microtumours showed greater in vitro viability than 2D cultures, but neither proliferated. Microtumours were successfully established in mice 81% (57 of 70), 67% (4 of 6), 76% (19 of 25) for LuCaP35, LuCaP141, and BM18 PCa cells, respectively. Microtumour growth was tracked using live animal imaging for size or bioluminescence signal. If augmented with further imaging advances and cell bar coding, this microtumour model could enable greater resolution of PCa PDX drug response, and lead to the more efficient use of animals. The concept of microtissue assembly in the Microwell-mesh, and implantation in vivo may also have utility in implantation of islets, hair follicles or other organ-specific cells that self-assemble into 3D structures, providing an important bridge between in vitro assembly of mini-organs and in vivo implantation.

Download Full-text

Mechanical Strain-Enabled Reconstitution of Dynamic Environment in Organ-on-a-Chip Platforms: A Review

Micromachines ◽

10.3390/mi12070765 ◽

2021 ◽

Vol 12 (7) ◽

pp. 765

Author(s):

Qianbin Zhao ◽

Tim Cole ◽

Yuxin Zhang ◽

Shi-Yang Tang

Keyword(s):

Cell Culture ◽

Shear Stress ◽

Cultured Cells ◽

Mechanical Strain ◽

3D Cell Culture ◽

Small Scale ◽

Mechanical Stimuli ◽

Human Organ ◽

Organ On A Chip

Organ-on-a-chip (OOC) uses the microfluidic 3D cell culture principle to reproduce organ- or tissue-level functionality at a small scale instead of replicating the entire human organ. This provides an alternative to animal models for drug development and environmental toxicology screening. In addition to the biomimetic 3D microarchitecture and cell–cell interactions, it has been demonstrated that mechanical stimuli such as shear stress and mechanical strain significantly influence cell behavior and their response to pharmaceuticals. Microfluidics is capable of precisely manipulating the fluid of a microenvironment within a 3D cell culture platform. As a result, many OOC prototypes leverage microfluidic technology to reproduce the mechanically dynamic microenvironment on-chip and achieve enhanced in vitro functional organ models. Unlike shear stress that can be readily generated and precisely controlled using commercial pumping systems, dynamic systems for generating proper levels of mechanical strains are more complicated, and often require miniaturization and specialized designs. As such, this review proposes to summarize innovative microfluidic OOC platforms utilizing mechanical actuators that induce deflection of cultured cells/tissues for replicating the dynamic microenvironment of human organs.

Download Full-text

Human Organ Specific Autoimmunity: Personal Memories

Autoimmunity ◽

10.3109/08916938808997171 ◽

1988 ◽

Vol 1 (1) ◽

pp. 11-13 ◽

Cited By ~ 6

Author(s):

Deborah Moniach ◽

Ivan M. Roitt

Keyword(s):

Human Organ ◽

Organ Specific

Download Full-text

Organ-Specific Phytochemical Profiling and Antioxidant Analysis of Parthenium hysterophorus L.

BioMed Research International ◽

10.1155/2018/9535232 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Javed Ahmad ◽

Rita Bagheri ◽

Humayra Bashir ◽

M. Affan Baig ◽

Asma Al-Huqail ◽

...

Keyword(s):

Antioxidant Potential ◽

Parthenium Hysterophorus ◽

High Threshold ◽

Hexadecanoic Acid ◽

Biotic And Abiotic Stresses ◽

Organ Specific ◽

Global Concern ◽

Phytochemical Profile ◽

Stem Leaf

Parthenium hysterophorus is a weed of global concern with high threshold of tolerance against most of biotic and abiotic stresses. Phytochemical profile and in vitro antioxidant analysis may help in understanding its tolerance to stresses. Root, stem, leaf, phyllary, and receptacle (including disc and ray florets) were chemotyped employing GC tof-MS and assessed for antioxidant activity by DPPH, FRAP, HRSA, and TAC assays. Phytochemicals identified were terpenes, fatty acids, hydrocarbons, phytosterols, and compounds of miscellaneous chemical nature. Organ-specific maximum concentration of metabolite was β-vatirenene (root), hexadecanoic acid methylester (stem), aristolene epoxide (leaf), hexadecanoic acid methylester (phyllary), and hexadecanoic acid methylester (receptacle). Identified metabolites could be associated with stress tolerance mechanisms, basic metabolism, and allelopathy, etc. Root extracts showed highest antioxidant potential followed by receptacle. It can be concluded that diverse and unique phytochemical profile and great antioxidant potential make P. hysterophorus stress-tolerant, hence a weed of global habitat.

Download Full-text