scholarly journals Three-Dimensional Liver Culture Systems to Maintain Primary Hepatic Properties for Toxicological Analysis In Vitro

2021 ◽  
Vol 22 (19) ◽  
pp. 10214
Author(s):  
Sarah Kammerer
Keyword(s):  
Drug Development ◽  
Three Dimensional ◽  
3D Culture ◽  
Cell Types ◽  
Culture Techniques ◽  
Toxicological Analysis ◽  
Culture Systems ◽  
Toxicity Studies

Drug-induced liver injury (DILI) is the major reason for failures in drug development and withdrawal of approved drugs from the market. Two-dimensional cultures of hepatocytes often fail to reliably predict DILI: hepatoma cell lines such as HepG2 do not reflect important primary-like hepatic properties and primary human hepatocytes (pHHs) dedifferentiate quickly in vitro and are, therefore, not suitable for long-term toxicity studies. More predictive liver in vitro models are urgently required in drug development and compound safety evaluation. This review discusses available human hepatic cell types for in vitro toxicology analysis and their usage in established and emerging three-dimensional (3D) culture systems. Generally, 3D cultures maintain or improve primary hepatic functions (including expression of drug-metabolizing enzymes) of different liver cells for several weeks of culture, thus allowing long-term and repeated-dose toxicity studies. Spheroid cultures of pHHs have been comprehensively tested, but also other cell types such as HepaRG benefit from 3D culture systems. Emerging 3D culture techniques include usage of induced pluripotent stem-cell-derived hepatocytes and primary-like upcyte cells, as well as advanced culture techniques such as microfluidic liver-on-a-chip models. In-depth characterization of existing and emerging 3D hepatocyte technologies is indispensable for successful implementation of such systems in toxicological analysis.

scholarly journals Adipose and Muscle Cell Co-Culture System: A Novel In Vitro Tool to Mimic the In Vivo Cellular Environment

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 6
Author(s):  
Palaniselvam Kuppusamy ◽  
Dahye Kim ◽  
Ilavenil Soundharrajan ◽  
Inho Hwang ◽  
Ki Choon Choi
Keyword(s):  
Drug Development ◽  
Culture System ◽  
Cell Types ◽  
Culture Cell ◽  
In Vitro Techniques ◽  
Culture Systems ◽  
Complex Interactions ◽  
Cellular Environment

A co-culture system allows researchers to investigate the complex interactions between two cell types under various environments, such as those that promote differentiation and growth as well as those that mimic healthy and diseased states, in vitro. In this paper, we review the most common co-culture systems for myocytes and adipocytes. The in vitro techniques mimic the in vivo environment and are used to investigate the causal relationships between different cell lines. Here, we briefly discuss mono-culture and co-culture cell systems and their applicability to the study of communication between two or more cell types, including adipocytes and myocytes. Also, we provide details about the different types of co-culture systems and their applicability to the study of metabolic disease, drug development, and the role of secretory factors in cell signaling cascades. Therefore, this review provides details about the co-culture systems used to study the complex interactions between adipose and muscle cells in various environments, such as those that promote cell differentiation and growth and those used for drug development.

A rhabdomyosarcoma hydrogel model to unveil cell-extracellular matrix interactions

2021 ◽  
Author(s):  
Mattia Saggioro ◽  
Stefania D'Agostino ◽  
Anna Gallo ◽  
Sara Crotti ◽  
Sara D'Aronco ◽  
...  
Keyword(s):  
Cell Culture ◽  
Extracellular Matrix ◽  
Three Dimensional ◽  
3D Culture ◽  
3D Cell Culture ◽  
Culture Systems ◽  
Matrix Interactions ◽  
In Vitro Systems ◽  
Extracellular Matrix Interactions

Three-dimensional (3D) culture systems are progressively getting attention given their potential in overcoming limitations of the classical 2D in vitro systems. Among different supports for 3D cell culture, hydrogels (HGs)...

scholarly journals Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1186
Author(s):  
Bárbara Pinto ◽  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Hassan Bousbaa
Keyword(s):  
Cancer Research ◽  
Low Cost ◽  
Three Dimensional ◽  
3D Culture ◽  
Comprehensive Overview ◽  
Culture Techniques ◽  
Drug Candidates ◽  
In Vivo Testing

Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying the discovery of successful therapeutics. This is because 2D culture lacks cell–cell contacts and natural tumor microenvironment, important in tumor signaling and drug response, thereby resulting in a reduced malignant phenotype compared to the real tumor. In this sense, three-dimensional (3D) cultures of cancer cells that better recapitulate in vivo cell environments emerged as scientifically accurate and low cost cancer models for preclinical screening and testing of new drug candidates before moving to expensive and time-consuming animal models. Here, we provide a comprehensive overview of 3D tumor systems and highlight the strategies for spheroid construction and evaluation tools of targeted therapies, focusing on their applicability in cancer research. Examples of the applicability of 3D culture for the evaluation of the therapeutic efficacy of nanomedicines are discussed.

scholarly journals 3D Culture as a Clinically Relevant Model for Personalized Medicine

2017 ◽  
Vol 22 (3) ◽  
pp. 245-253 ◽  
Author(s):  
Eliza Li Shan Fong ◽  
Tan Boon Toh ◽  
Hanry Yu ◽  
Edward Kai-Hua Chow
Keyword(s):  
Cancer Research ◽  
Drug Development ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Three Dimensional ◽  
3D Culture ◽  
Research Field ◽  
Cancer Drug ◽  
Specific Patient ◽  
Culture Systems

Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient. Three-dimensional (3D) culture systems paired with patient-derived xenografts or patient-derived organoids may provide a more clinically relevant system to address issues presented by personalized or precision medical approaches. In this review, we cover the current methods available for applying 3D culture systems toward personalized cancer research and drug development, as well as key challenges that must be addressed in order to fully realize the potential of 3D patient-derived culture systems for cancer drug development. Greater implementation of 3D patient-derived culture systems in the cancer research field should accelerate the development of truly personalized medical therapies for cancer patients.

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

2021 ◽  
Vol 9 ◽  
Author(s):  
Ana S. Serras ◽  
Joana S. Rodrigues ◽  
Madalena Cipriano ◽  
Armanda V. Rodrigues ◽  
Nuno G. Oliveira ◽  
...  
Keyword(s):  
Drug Development ◽  
Liver Toxicity ◽  
Three Dimensional ◽  
Cell Types ◽  
Cell Phenotype ◽  
Drug Induced ◽  
Characterization Methods ◽  
Clinical Phase ◽  
Post Marketing

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

scholarly journals Development of Injectable Thermosensitive Chitosan-Based Hydrogels for Cell Encapsulation

2020 ◽  
Vol 10 (18) ◽  
pp. 6550 ◽  
Author(s):  
Antonella Stanzione ◽  
Alessandro Polini ◽  
Velia La Pesa ◽  
Alessandro Romano ◽  
Angelo Quattrini ◽  
...  
Keyword(s):  
Three Dimensional ◽  
3D Culture ◽  
Cell Encapsulation ◽  
Mechanical Stiffness ◽  
Culture Systems ◽  
Beneficial Effects ◽  
Physico Chemical ◽  
Hydrogen Carbonate ◽  
Biological Tests

The three-dimensional complexity of the native extracellular matrix (ECM) suggests switching from 2D to 3D culture systems for providing the cells with an architecture more similar to the physiological environment. Reproducing the three-dimensionality in vitro can guarantee beneficial effects in terms of cell growth, adhesion, proliferation, and/or their differentiation. Hydrogels have the same tailorable physico-chemical and biological characteristics as ECM materials. In this study, we propose a thermoresponsive chitosan-based hydrogel that gels thanks to the addition of organic and inorganic salt solutions (beta-glycerolphosphate and sodium hydrogen carbonate) and is suitable for cell encapsulation allowing obtaining 3D culture systems. Physico-chemical analyses showed that the hydrogel formulations jellify at physiological conditions (37 °C, pH 7.4), are stable in vitro up to three weeks, have high swelling ratios and mechanical stiffness suitable for cellular encapsulation. Moreover, preliminary biological tests underlined the pronounced biocompatibility of the system. Therefore, these chitosan-based hydrogels are proposed as valid biomaterials for cell encapsulation.

scholarly journals Current Advances in 3D Tissue and Organ Reconstruction

2021 ◽  
Vol 22 (2) ◽  
pp. 830
Author(s):  
Georgia Pennarossa ◽  
Sharon Arcuri ◽  
Teresina De Iorio ◽  
Fulvio Gandolfi ◽  
Tiziana A. L. Brevini
Keyword(s):  
Cell Biology ◽  
Drug Testing ◽  
Three Dimensional ◽  
3D Culture ◽  
In Vitro Models ◽  
The Body ◽  
Cellular Functions ◽  
Culture Systems

Bi-dimensional culture systems have represented the most used method to study cell biology outside the body for over a century. Although they convey useful information, such systems may lose tissue-specific architecture, biomechanical effectors, and biochemical cues deriving from the native extracellular matrix, with significant alterations in several cellular functions and processes. Notably, the introduction of three-dimensional (3D) platforms that are able to re-create in vitro the structures of the native tissue, have overcome some of these issues, since they better mimic the in vivo milieu and reduce the gap between the cell culture ambient and the tissue environment. 3D culture systems are currently used in a broad range of studies, from cancer and stem cell biology, to drug testing and discovery. Here, we describe the mechanisms used by cells to perceive and respond to biomechanical cues and the main signaling pathways involved. We provide an overall perspective of the most recent 3D technologies. Given the breadth of the subject, we concentrate on the use of hydrogels, bioreactors, 3D printing and bioprinting, nanofiber-based scaffolds, and preparation of a decellularized bio-matrix. In addition, we report the possibility to combine the use of 3D cultures with functionalized nanoparticles to obtain highly predictive in vitro models for use in the nanomedicine field.

scholarly journals Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation

2017 ◽  
Vol 22 (5) ◽  
pp. 583-601 ◽  
Author(s):  
P. Marc D. Watson ◽  
Edel Kavanagh ◽  
Gary Allenby ◽  
Matthew Vassey
Keyword(s):  
Cell Culture ◽  
Drug Discovery ◽  
Glial Cell ◽  
Critical Role ◽  
3D Culture ◽  
Cell Types ◽  
Culture Systems ◽  
Cellular Environment

Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer’s and Parkinson’s disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures. Given the complexity of the environment from which cells originate, and their various cell–cell and cell–matrix interactions, it is important to develop models that can be controlled and reproducible for drug discovery. 3D cell models have now been developed for almost all CNS cell types, including neurons, astrocytes, microglia, and oligodendrocyte cells. This review will highlight a number of current and emerging techniques for the culture of astrocytes and microglia, glial cell types with a critical role in neurodegenerative and neuroinflammatory conditions. We describe recent advances in glial cell culture using electrospun polymers and hydrogel macromolecules, and highlight how these novel culture environments influence astrocyte and microglial phenotypes in vitro, as compared to traditional 2D systems. These models will be explored to illuminate current trends in the techniques used to create 3D environments for application in research and drug discovery focused on astrocytes and microglial cells.

scholarly journals Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3417
Author(s):  
Alessandro Poggi ◽  
Federico Villa ◽  
Jordi Leonardo Castrillo Fernadez ◽  
Delfina Costa ◽  
Maria Raffaella Zocchi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Tumor Cell ◽  
Nk Cells ◽  
Tumor Cells ◽  
Three Dimensional ◽  
3D Culture ◽  
Culture Systems ◽  
Advantages And Disadvantages

Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.

scholarly journals Application of lung microphysiological systems to COVID-19 modeling and drug discovery: a review

2021 ◽  
Author(s):  
Argus M. Sun ◽  
Tyler Hoffman ◽  
Bao Q. Luu ◽  
Nureddin Ashammakhi ◽  
Song Li
Keyword(s):  
Drug Development ◽  
High Throughput Screening ◽  
Current Model ◽  
3D Structure ◽  
Three Dimensional ◽  
Cell Types ◽  
Model Systems ◽  
Biological Interactions ◽  
Microphysiological Systems

AbstractThere is a pressing need for effective therapeutics for coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The process of drug development is a costly and meticulously paced process, where progress is often hindered by the failure of initially promising leads. To aid this challenge, in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening, thereby saving valuable time and resources during a pandemic crisis. The SARS-CoV-2 virus attacks the lung, an organ where the unique three-dimensional (3D) structure of its functional units is critical for proper respiratory function. The in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell types. Current model systems include Transwell, organoid and organ-on-a-chip or microphysiological systems (MPSs). We review models that have direct relevance toward modeling the pathology of COVID-19, including the processes of inflammation, edema, coagulation, as well as lung immune function. We also consider the practical issues that may influence the design and fabrication of MPS. The role of lung MPS is addressed in the context of multi-organ models, and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung MPS to accelerate drug development for COVID-19 and other infectious diseases.

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