scholarly journals Circadian hormone control in a human-on-a-chip: In vitro biology’s ignored component?

2017 ◽  
Vol 242 (17) ◽  
pp. 1714-1731 ◽  
Author(s):  
Kevin J. Cyr ◽  
Omero M. Avaldi ◽  
John P. Wikswo
Keyword(s):  
Cell Culture ◽  
Circadian Rhythms ◽  
Hormonal Regulation ◽  
Reproductive Organs ◽  
Whole Body ◽  
Endocrine Regulation ◽  
Human Organ ◽  
Organ Systems ◽  
Endocrine Modulation

Organs-on-Chips (OoCs) are poised to reshape dramatically the study of biology by replicating in vivo the function of individual and coupled human organs. Such microphysiological systems (MPS) have already recreated complex physiological responses necessary to simulate human organ function not evident in two-dimensional in vitro biological experiments. OoC researchers hope to streamline pharmaceutical development, accelerate toxicology studies, limit animal testing, and provide new insights beyond the capability of current biological models. However, to develop a physiologically accurate Human-on-a-Chip, i.e., an MPS homunculus that functions as an interconnected, whole-body, model organ system, one must couple individual OoCs with proper fluidic and metabolic scaling. This will enable the study of the effects of organ-organ interactions on the metabolism of drugs and toxins. Critical to these efforts will be the recapitulation of the complex physiological signals that regulate the endocrine, metabolic, and digestive systems. To date, with the exception of research focused on reproductive organs on chips, most OoC research ignores homuncular endocrine regulation, in particular the circadian rhythms that modulate the function of all organ systems. We outline the importance of cyclic endocrine regulation and the role that it may play in the development of MPS homunculi for the pharmacology, toxicology, and systems biology communities. Moreover, we discuss the critical end-organ hormone interactions that are most relevant for a typical coupled-OoC system, and the possible research applications of a missing endocrine system MicroFormulator (MES-µF) that could impose biological rhythms on in vitro models. By linking OoCs together through chemical messenger systems, advanced physiological phenomena relevant to pharmacokinetics and pharmacodynamics studies can be replicated. The concept of a MES-µF could be applied to other standard cell-culture systems such as well plates, thereby extending the concept of circadian hormonal regulation to much of in vitro biology. Impact statement Historically, cyclic endocrine modulation has been largely ignored within in vitro cell culture, in part because cultured cells typically have their media changed every day or two, precluding hourly adjustment of hormone concentrations to simulate circadian rhythms. As the Organ-on-Chip (OoC) community strives for greater physiological realism, the contribution of hormonal oscillations toward regulation of organ systems has been examined only in the context of reproductive organs, and circadian variation of the breadth of other hormones on most organs remains unaddressed. We illustrate the importance of cyclic endocrine modulation and the role that it plays within individual organ systems. The study of cyclic endocrine modulation within OoC systems will help advance OoC research to the point where it can reliably replicate in vitro key regulatory components of human physiology. This will help translate OoC work into pharmaceutical applications and connect the OoC community with the greater pharmacology and physiology communities.

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

Micromachines ◽  
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.

scholarly journals The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock

2019 ◽  
Vol 20 (11) ◽  
pp. 2765 ◽  
Author(s):  
Jihwan Myung ◽  
Mei-Yi Wu ◽  
Chun-Ya Lee ◽  
Amalia Ridla Rahim ◽  
Vuong Hung Truong ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Sleep Disturbances ◽  
The Body ◽  
Circadian Clocks ◽  
Whole Body ◽  
The Hierarchical Structure ◽  
Body Level ◽  
The Brain ◽  
Master Clock

The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.

scholarly journals Tissue Engineering of Oral Mucosa and Salivary Gland: Disease Modeling and Clinical Applications

Micromachines ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1066
Author(s):  
Akram Abdo Almansoori ◽  
Bongju Kim ◽  
Jong-Ho Lee ◽  
Simon D. Tran
Keyword(s):  
Cell Culture ◽  
Salivary Gland ◽  
Oral Mucosa ◽  
Disease Modeling ◽  
Clinical Applications ◽  
New Drugs ◽  
Human Organ ◽  
Culture Models ◽  
Cell Culture Models

Oral mucosa and salivary gland are composed of complex and dynamic networks of extracellular matrix, multiple cell types, vasculature, and various biochemical agents. Two-dimensional (2D) cell culture is commonly used in testing new drugs and experimental therapies. However, 2D cell culture cannot fully replicate the architecture, physiological, and pathological microenvironment of living human oral mucosa and salivary glands. Recent microengineering techniques offer state of the science cell culture models that can recapitulate human organ structures and functions. This narrative review describes emerging in vitro models of oral and salivary gland tissue such as 3D cell culture models, spheroid and organoid models, tissue-on-a-chip, and functional decellularized scaffolds. Clinical applications of these models are also discussed in this review.

Production of soma and gonad in maturing female Illex argentinus (Mollusca: Cephalopoda)

1992 ◽  
Vol 72 (2) ◽  
pp. 281-291 ◽  
Author(s):  
E.M.C. Hatfield ◽  
P.G. Rodhouse ◽  
D.L. Barber
Keyword(s):  
Somatic Growth ◽  
Reproductive Organs ◽  
Reproductive Organ ◽  
Mantle Length ◽  
Whole Body ◽  
Relative Mass ◽  
Histological Structure ◽  
Organ Systems ◽  
Illex Argentinus ◽  
Nutrient Resources

Samples of female lllex argentinus were taken from the catch of a Japanese squid jigging vessel on the Patagonian Shelf during March 1986. Morphometrics of the somatic and reproductive organ systems and the histological structure of the mantle in relation to maturation were examined. The data suggest that growth and maturation occur simultaneously during most of the time that lllex argentinus females are on the feeding grounds. In a squid of a ‘standard’ mantle length the whole body mass increases relative to mantle length during maturation and growth of the reproductive organs. This is accompanied by a small but significant decrease in the relative mass of the mantle, head and viscera whilst the mass of the digestive gland remains constant. Although mantle mass of a ‘standard’ female squid decreases relative to mantle length with maturity this is not associated with degeneration of the mantle muscles. Energy and nutrient resources for maturation are apparently derived from the squid's food, not from reserves, and during the course of maturation there is an increasing shift of emphasis from somatic growth to production of gonad and accessory reproductive organs.

Production of soma and gonad in maturing male Illex argentinus (Mollusca: Cephalopoda)

1992 ◽  
Vol 72 (2) ◽  
pp. 293-300 ◽  
Author(s):  
P.G. Rodhouse ◽  
E.M.C. Hatfield
Keyword(s):  
Body Mass ◽  
Somatic Growth ◽  
Reproductive Organs ◽  
Reproductive Organ ◽  
Mantle Length ◽  
Whole Body ◽  
Patagonian Shelf ◽  
Organ Systems ◽  
Illex Argentinus ◽  
Nutrient Resources

Samples of male Illex argentinus were taken from the catch of a Japanese squid jigging vessel on the Patagonian Shelf during March 1986 and an analysis was carried out on the morphometrics of the somatic and reproductive organ systems in relation to maturation. The data show that growth and maturation occurred simultaneously during most of the time that Illex argentinus males were on the feeding grounds over the southern Patagonian Shelf. In a squid of a ‘standard’ mantle length the whole body mass increased relative to mantle length during maturation and this could be attributed to the increase in mass of the reproductive and accessory reproductive organs. During maturation the mantle and digestive gland mass showed no significant change relative to mantle length. The mass of the head increased and the mass of the viscera decreased relative to mantle length. In male Illex argentinus, as in the female, the energy and nutrient resources for maturation are derived from the squid's food and during the course of maturation there is an increasing shift of emphasis from somatic growth to production of gonad and accessory reproductive organs. The proportional investment of body mass in reproductive and accessory reproductive organs predicted for a fully mature male Illex argentinus was less than half that of the female.

scholarly journals Effects of Metalloporphyrins on Heme Oxygenase-1 Transcription: Correlative Cell Culture Assays Guide in Vivo Imaging

2003 ◽  
Vol 2 (3) ◽  
pp. 153535002003031
Author(s):  
Monica Hajdena-Dawson ◽  
Weisheng Zhang ◽  
Pamela R. Contag ◽  
Ronald J. Wong ◽  
Hendrik J. Vreman ◽  
...  
Keyword(s):  
Cell Culture ◽  
Heme Oxygenase ◽  
Liver Toxicity ◽  
Whole Body ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Live Animal ◽  
Cytotoxicity Studies

Heme oxygenase (HO) is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps), a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI) as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP) and zinc bis glycol porphyrin (ZnBG), were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.

scholarly journals Improving the physiological realism of experimental models

2016 ◽  
Vol 6 (2) ◽  
pp. 20150076 ◽  
Author(s):  
Kalyan C. Vinnakota ◽  
Chae Y. Cha ◽  
Patrik Rorsman ◽  
Robert S. Balaban ◽  
Andre La Gerche ◽  
...  
Keyword(s):  
Computational Models ◽  
Numerical Models ◽  
Experimental Models ◽  
Organ Function ◽  
Cell Organelles ◽  
Human Organ ◽  
Current State ◽  
Organ Systems

The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using examples from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease.

1120: Citrate and Vitamin E Blunt the SWL-Induced Free Radical Surge in an In-Vitro MDCK Cell Culture Model

2004 ◽  
Vol 171 (4S) ◽  
pp. 295-295
Author(s):  
Fernando C. Delvecchio ◽  
Ricardo M. Brizuela ◽  
Karen J. Byer ◽  
W. Patrick Springhart ◽  
Saeed R. Khan ◽  
...  
Keyword(s):  
Cell Culture ◽  
Free Radical ◽  
Vitamin E ◽  
Mdck Cell ◽  
Cell Culture Model ◽  
Culture Model

3D in vitro reconstruction of synthetic liver sinusoids in a microfluidic cell culture device

2013 ◽  
Vol 51 (01) ◽  
Author(s):  
J Böttger ◽  
J Schütte ◽  
K Benz ◽  
C Freudigmann ◽  
B Hagmeyer ◽  
...  
Keyword(s):  
Cell Culture ◽  
Liver Sinusoids ◽  
Microfluidic Cell Culture

Minimal contribution of cell-bound antibodies to the immunoscintigraphy of inflamed joints with 99mTc-anti-CD4 monoclonal antibodies

2002 ◽  
Vol 41 (03) ◽  
pp. 129-134 ◽  
Author(s):  
A. Wolski ◽  
E. Palombo-Kinne ◽  
F. Wolf ◽  
F. Emmrich ◽  
W. Becker ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Synovial Membrane ◽  
In Vitro Release ◽  
Peritoneal Macrophages ◽  
Lymphoid Organs ◽  
Whole Body ◽  
Free Form ◽  
Ankle Joints

Summary Aim: The cellular joint infiltrate in rheumatoid arthritis patients is rich in CD4-positive T-helper lymphocytes and macrophages, rendering anti-CD4 monoclonal antibodies (mAbs) suitable for specific immunoscintigraphy of human/ experimental arthritis. Following intravenous injection, however, mAbs are present both in the free form and bound to CD4-positive, circulating monocytes and T-cells. Thus, the present study aimed at analyzing the relative contribution of the free and the cell-bound component to the imaging of inflamed joints in experimental adjuvant arthritis (AA). Methods: AA rat peritoneal macrophages or lymph node T-cells were incubated in vitro with saturating amounts of 99mTc-anti-CD4 mAb (W3/25) and injected i.v. into rats with AA. Results: In vitro release of 99mTc-anti-CD4 mAb from the cells was limited (on average 1.57%/h for macrophages and 0.84%/h for T-cells). Following i.v. injection, whole body/joint scans and tissue measurements showed only negligible accumulation of radioactivity in inflamed ankle joints (tissue: 0.22 and 0.34% of the injected activity, respectively), whereas the radioactivity was concentrated in liver (tissue: 79% and 71%, respectively), kidney, and urinary bladder. Unlike macrophages, however, anti-CD4 mAb-coated T-cells significantly accumulated in lymphoid organs, the inflamed synovial membrane of the ankle joints, as well as in elbow and knee joints. Conclusion: While the overall contribution of cell-bound mAbs to the imaging of arthritic joints with anti-CD4 mAbs is minimal, differential accumulation of macrophages and T-cells in lymphoid organs and the inflamed synovial membrane indicates preferential migration patterns of these 2 cell populations in arthritic rats. Although only validated for 99mTc-anti-CD4 mAbs, extrapolation of the results to other anticellular mAbs with similar affinity for their antigen may be possible.

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