Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery

The Annual Review of Pharmacology and Toxicology, Journal Year: 2017, Volume and Issue: 58(1), P. 65 - 82

Published: Oct. 14, 2017

Enhancing the early detection of new therapies that are likely to carry a safety liability in context intended patient population would provide major advance drug discovery. Microphysiological systems (MPS) technology offers an opportunity support enhanced preclinical clinical translation through generation higher-quality physiological data. In this review, we highlight technological by focusing on key target organs associated with and metabolism. By MPS models have been developed for these organs, alongside other relevant vitro models, review current state art challenges still need be overcome ensure application enhancing

Language: Английский

---

Toxicogenomics: A 2020 Vision

Trends in Pharmacological Sciences, Journal Year: 2018, Volume and Issue: 40(2), P. 92 - 103

Published: Dec. 26, 2018

HighlightsTogether with the promotion of non-animal testing, in vitro toxicogenomics (TGx) may play a vital role next-generation risk assessment paradigm.A strategic shift provides an unprecedented opportunity for repositioning TGx regulatory setting.As emerging technique continues to impact field, novel genomic features such as miRNAs, ncRNAs, and circular RNAs provide more resolution towards better understanding underlying mechanisms toxicological processes.Advances machine learning artificial intelligence are gaining ground their applicability biomedical fields. In near future, these advances be further applied field improve predictive power.AbstractToxicogenomics has contributed significantly toxicology now great potential support moves animal-free approaches decision making. Here, we discuss systems on assessment. We raise awareness rapid advancement genomics technologies, which generates essential enhanced specifically emphasize importance reproducibility utilizing setting. also highlight (particularly deep learning) developing TGx-based models. Lastly, touch topics how could facilitate adverse outcome pathways (AOP) development enhance read-across strategies application. Finally, summarize current efforts develop set out remaining challenges.

Language: Английский

---

3D culture of HepaRG cells in GelMa and its application to bioprinting of a multicellular hepatic model

Biomaterials, Journal Year: 2020, Volume and Issue: 269, P. 120611 - 120611

Published: Dec. 16, 2020

Language: Английский

---

In vitro and ex vivo models of adipocytes

AJP Cell Physiology, Journal Year: 2021, Volume and Issue: 320(5), P. C822 - C841

Published: Jan. 13, 2021

Adipocytes are specialized cells with pleiotropic roles in physiology and pathology. Several types of fat distinct metabolic properties coexist various anatomically defined depots mammals. White, beige, brown adipocytes differ their handling lipids thermogenic capacity, promoting differences size morphology. Moreover, release proteins paracrine endocrine functions. The intrinsic pose specific challenges culture. Mature float suspension culture due to high triacylglycerol content fragile. a fully differentiated state, notably acquirement the unilocular lipid droplet white adipocyte, has so far not been reached two-dimensional Cultures mouse human-differentiated preadipocyte cell lines primary have established mimic white, adipocytes. Here, we survey models mature adipocyte survival describing main characteristics, conditions, advantages, limitations. An important development is advent three-dimensional culture, adipose spheroids that recapitulate vivo function morphology depots. Challenges for future include isolation adipose-derived stem from different anatomic location animal humans differing sex, age, mass, pathophysiological conditions. Further understanding dysfunction will be achieved through genetic manipulation, CRISPR-mediated gene editing. Capturing heterogeneity at single-cell level within single depot key diversities cardiometabolic parameters among lean obese individuals.

Language: Английский

---

Today’s Challenges to De-Risk and Predict Drug Safety in Human “Mind-the-Gap”

Toxicological Sciences, Journal Year: 2018, Volume and Issue: 167(2), P. 307 - 321

Published: Oct. 26, 2018

Current gaps in drug safety sciences can result from the inability (1) to identify hazard across multiple target organs, (2) predict and risk assess with certainty against liabilities for major (3) optimally manage mitigate liabilities, (4) apply principles of governance on generation, integration, use experimental data. Translational assessment evaluate several target-organ toxicities only be partially achieved by current vitro vivo test systems. What remains tackled necessitates deployment vitro-human-relevant systems address human specific or selective forms toxicities. Nevertheless, such models may part some requirements today's armament biomedical tools essential improving discovery candidates. Refinement silico tools, Target Safety Assessment a greater understanding mechanistic insights might provide future opportunities better liabilities. The increasing diversity modalities present further challenges nonclinical clinical development requiring research develop suitable technologies. Our ability will come refinement margin estimates, provision human-relevant biomarkers, translation silico, vitro, studies human. An improvement frameworks standards at all levels within organizations, national, international, help facilitate programs.

Language: Английский

---

Coaxial extrusion bioprinted shell-core hydrogel microfibers mimic glioma microenvironment and enhance the drug resistance of cancer cells

Colloids and Surfaces B Biointerfaces, Journal Year: 2018, Volume and Issue: 171, P. 291 - 299

Published: July 20, 2018

Language: Английский

---

Detection of toxins involved in foodborne diseases caused by Gram‐positive bacteria

Comprehensive Reviews in Food Science and Food Safety, Journal Year: 2020, Volume and Issue: 19(4), P. 1605 - 1657

Published: June 11, 2020

Bacterial toxins are food safety hazards causing about 10% of all reported foodborne outbreaks in Europe. Pertinent to Gram-positive pathogens, the most relevant emetic toxin and diarrheal enterotoxins Bacillus cereus, neurotoxins Clostridium botulinum, enterotoxin perfringens, a family produced by Staphylococcus aureus some other staphylococci. These important virulence factors respective pathogens primary cause related diseases. They proteins or peptides that differ from each their size, structure, toxicity, toxicological end points, solubility, stability, types matrix which they mostly to. differences influence characteristics required detection methods. Therefore, these samples, production capacity bacterial isolate, remains one cornerstones microbial analysis an essential tool understanding properties toxins. Advanced research has led into new insights incidence toxins, mechanisms production, physicochemical properties, mode action dose-response profile. This review focuses on biological, immunological, mass spectrometry, molecular assays as commonly used quantification methods for B. C. S. aureus. Gathered analyzed information provides comprehensive blueprint existing knowledge principles assays, application safety, limits quantification, matrices applicable, type provide user.

Language: Английский

---

Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies

Cells, Journal Year: 2020, Volume and Issue: 9(2), P. 304 - 304

Published: Jan. 27, 2020

Organ and tissue shortage are known as a crucially important public health problem unfortunately small percentage of patients receive transplants. In the context emerging regenerative medicine, researchers trying to regenerate replace different organs tissues such liver, heart, skin, kidney. Liver engineering (TE) enables us reproduce restore liver functions, fully or partially, which could be used in treatment acute chronic disorders and/or generate an appropriate functional organ can transplanted employed extracorporeal device. this regard, variety techniques (e.g., fabrication technologies, cell-based microfluidic systems and, devices) applied medicine. Common TE based on allocating stem cell-derived hepatocyte-like cells primary hepatocytes within three-dimensional structure leads improvement their survival rate phenotype. Taken together, new findings indicated that developing engineering-based pave way for better liver-related disorders. Herein, we summarized novel technologies medicine future applications clinical settings.

Language: Английский

---

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Journal of Hepatology, Journal Year: 2021, Volume and Issue: 75(4), P. 935 - 959

Published: June 24, 2021

Drug-induced liver injury (DILI) is a major cause of acute failure (ALF) and one the leading indications for transplantation in Western societies. Given wide use both prescribed over counter drugs, DILI has become health issue which there pressing need to find novel effective therapies. Although significant progress been made understanding molecular mechanisms underlying DILI, our incomplete knowledge its pathogenesis inability predict largely due discordance between human animal preclinical drug development lack models that faithfully recapitulate complex pathophysiological features DILI. This exemplified by hepatotoxicity acetaminophen (APAP) overdose, ALF because extensive worldwide as an analgesic. Despite intensive efforts utilising current vitro models, involved APAP are still not fully understood. In this expert Consensus Statement, endorsed European Drug-Induced Liver Injury Network, we aim facilitate outline clinically impactful discoveries detailing requirements more realistic human-based systems assess guide future safety testing. We present insights discuss players pathophysiology, describe emerging vivo pre-clinical well advanced imaging silico technologies, may improve prediction clinical outcomes

Language: Английский

---

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Feb. 22, 2021

The poor predictability of human liver toxicity is still causing high attrition rates drug candidates in the pharmaceutical industry at non-clinical, clinical, and post-marketing authorization stages. This part caused by animal models that fail to predict various adverse reactions (ADRs), resulting undetected hepatotoxicity non-clinical phase development. In an effort increase prediction hepatotoxicity, different approaches enhance physiological relevance hepatic vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow better recapitulate hepatocyte organization cell-matrix contacts, include additional cell types, incorporate fluid flow create gradients oxygen nutrients, which have led improved differentiated phenotype functionality. comprehensive review addresses drug-induced mechanisms currently available 3D models, their characteristics, as well advantages limitations for assessment. addition, since toxic responses greatly dependent on culture model, a comparative analysis studies performed using two-dimensional (2D) strategies with recognized hepatotoxic compounds, such paracetamol, diclofenac, troglitazone performed, further highlighting need harmonization respective characterization methods. Finally, taking step forward, we propose roadmap assessment drugs based fully characterized fit-for-purpose advantage best each will ultimately contribute more informed decision-making development risk fields.

Language: Английский

---