scholarly journals New Endeavors of (Micro)Tissue Engineering: Cells Tissues Organs on-Chip and Communication Thereof

2021 ◽  
pp. 1-15
Author(s):  
Haysam M.M.A.M. Ahmed ◽  
Liliana S. Moreira Teixeira
Keyword(s):  
Tissue Engineering ◽  
Food Additives ◽  
Market Potential ◽  
Model Systems ◽  
Human Model ◽  
Human Stem Cells ◽  
Animal Testing ◽  
Preclinical Research ◽  
On Chip

The development of new therapies is tremendously hampered by the insufficient availability of human model systems suitable for preclinical research on disease target identification, drug efficacy, and toxicity. Thus, drug failures in clinical trials are too common and too costly. Animal models or standard 2D in vitro tissue cultures, regardless of whether they are human based, are regularly not representative of specific human responses. Approaching near human tissues and organs test systems is the key goal of organs-on-chips (OoC) technology. This technology is currently showing its potential to reduce both drug development costs and time-to-market, while critically lessening animal testing. OoC are based on human (stem) cells, potentially derived from healthy or disease-affected patients, thereby amenable to personalized therapy development. It is noteworthy that the OoC market potential goes beyond pharma, with the possibility to test cosmetics, food additives, or environmental contaminants. This (micro)tissue engineering-based technology is highly multidisciplinary, combining fields such as (developmental) biology, (bio)materials, microfluidics, sensors, and imaging. The enormous potential of OoC is currently facing an exciting new challenge: emulating cross-communication between tissues and organs, to simulate more complex systemic responses, such as in cancer, or restricted to confined environments, as occurs in osteoarthritis. This review describes key examples of multiorgan/tissue-on-chip approaches, or linked organs/tissues-on-chip, focusing on challenges and promising new avenues of this advanced model system. Additionally, major emphasis is given to the translation of established tissue engineering approaches, bottom up and top down, towards the development of more complex, robust, and representative (multi)organ/tissue-on-chip approaches.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

scholarly journals EGFRAmplification and Glioblastoma Stem-Like Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Katrin Liffers ◽  
Katrin Lamszus ◽  
Alexander Schulte
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Model Systems ◽  
Preclinical Research ◽  
Epidermal Growth ◽  
Methodological Approaches ◽  
The Impact

Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintainedin vitrousing serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retainedEGFRamplification could overcome the limitations of currentin vitromodel systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with differentEGFRstatus in order to maintain EGFR-dependent intratumoral heterogeneityin vitro. Further, it will summarize the current knowledge about the impact ofEGFRamplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM.

scholarly journals Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3183
Author(s):  
Xingchi Chen ◽  
Chang Liu ◽  
Laureana Muok ◽  
Changchun Zeng ◽  
Yan Li
Keyword(s):  
Targeted Delivery ◽  
Neurological Diseases ◽  
In Vitro Models ◽  
Normal Function ◽  
Human Stem Cells ◽  
Design Development ◽  
High Throughput Drug Screening ◽  
The Central Nervous System ◽  
On Chip

The blood–brain barrier (BBB) is a vital structure for maintaining homeostasis between the blood and the brain in the central nervous system (CNS). Biomolecule exchange, ion balance, nutrition delivery, and toxic molecule prevention rely on the normal function of the BBB. The dysfunction and the dysregulation of the BBB leads to the progression of neurological disorders and neurodegeneration. Therefore, in vitro BBB models can facilitate the investigation for proper therapies. As the demand increases, it is urgent to develop a more efficient and more physiologically relevant BBB model. In this review, the development of the microfluidics platform for the applications in neuroscience is summarized. This article focuses on the characterizations of in vitro BBB models derived from human stem cells and discusses the development of various types of in vitro models. The microfluidics-based system and BBB-on-chip models should provide a better platform for high-throughput drug-screening and targeted delivery.

scholarly journals Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications

Materials ◽  
2019 ◽  
Vol 12 (11) ◽  
pp. 1824 ◽  
Author(s):  
Sandra Pina ◽  
Viviana P. Ribeiro ◽  
Catarina F. Marques ◽  
F. Raquel Maia ◽  
Tiago H. Silva ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Regenerative Medicine ◽  
Treatment Strategies ◽  
Biological Properties ◽  
Inorganic Materials ◽  
Bioactive Molecules ◽  
Cellular Interactions ◽  
Preclinical Research

During the past two decades, tissue engineering and the regenerative medicine field have invested in the regeneration and reconstruction of pathologically altered tissues, such as cartilage, bone, skin, heart valves, nerves and tendons, and many others. The 3D structured scaffolds and hydrogels alone or combined with bioactive molecules or genes and cells are able to guide the development of functional engineered tissues, and provide mechanical support during in vivo implantation. Naturally derived and synthetic polymers, bioresorbable inorganic materials, and respective hybrids, and decellularized tissue have been considered as scaffolding biomaterials, owing to their boosted structural, mechanical, and biological properties. A diversity of biomaterials, current treatment strategies, and emergent technologies used for 3D scaffolds and hydrogel processing, and the tissue-specific considerations for scaffolding for Tissue engineering (TE) purposes are herein highlighted and discussed in depth. The newest procedures focusing on the 3D behavior and multi-cellular interactions of native tissues for further use for in vitro model processing are also outlined. Completed and ongoing preclinical research trials for TE applications using scaffolds and hydrogels, challenges, and future prospects of research in the regenerative medicine field are also presented.

scholarly journals Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems

2020 ◽  
Vol 324 ◽  
pp. 113121 ◽  
Author(s):  
Nathan P. Staff ◽  
Jill C. Fehrenbacher ◽  
Martial Caillaud ◽  
M. Imad Damaj ◽  
Rosalind A. Segal ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Model Systems ◽  
Human Model ◽  
Current Review ◽  
A Current

scholarly journals Leveraging 3D Model Systems to Understand Viral Interactions with the Respiratory Mucosa

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1425
Author(s):  
Ethan Iverson ◽  
Logan Kaler ◽  
Eva L. Agostino ◽  
Daniel Song ◽  
Gregg A. Duncan ◽  
...  
Keyword(s):  
Basic Research ◽  
Respiratory Viruses ◽  
Model Systems ◽  
Emergent Properties ◽  
Airway Epithelial ◽  
Culture Techniques ◽  
Viral Interactions ◽  
Epithelial Cultures ◽  
On Chip

Respiratory viruses remain a significant cause of morbidity and mortality in the human population, underscoring the importance of ongoing basic research into virus–host interactions. However, many critical aspects of infection are difficult, if not impossible, to probe using standard cell lines, 2D culture formats, or even animal models. In vitro systems such as airway epithelial cultures at air–liquid interface, organoids, or ‘on-chip’ technologies allow interrogation in human cells and recapitulate emergent properties of the airway epithelium—the primary target for respiratory virus infection. While some of these models have been used for over thirty years, ongoing advancements in both culture techniques and analytical tools continue to provide new opportunities to investigate airway epithelial biology and viral infection phenotypes in both normal and diseased host backgrounds. Here we review these models and their application to studying respiratory viruses. Furthermore, given the ability of these systems to recapitulate the extracellular microenvironment, we evaluate their potential to serve as a platform for studies specifically addressing viral interactions at the mucosal surface and detail techniques that can be employed to expand our understanding.

Reproductive Toxicity Testing: Evaluating and Developing New Testing Systems

1985 ◽  
Vol 4 (2) ◽  
pp. 163-171 ◽  
Author(s):  
J. C. Lamb
Keyword(s):  
Environmental Protection Agency ◽  
Food Additives ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Reproductive Function ◽  
Test System ◽  
Toxic Substances ◽  
Animal Testing ◽  
In Vitro Techniques

Reproductive toxicity testing systems are used by national and international regulatory agencies. Protocols have not been standardized between agencies or even within certain agencies. Although there have been efforts at standardization, a certain amount of the differences between testing protocols is a reflection of the needs of the particular agency. New developments in in vitro techniques might lead to new test systems, but reproductive function is dependent upon the interaction of various cells and organs that cannot presently be copied in the test tube; this makes whole-animal testing systems a necessity. The present whole-animal models used by the Food and Drug Administration include the 3 segment reproduction studies used for testing drug safety and the multigeneration studies used for food additives. The Environmental Protection Agency has adopted 2 similar versions of a 2-generation study for the Office of Pesticide Programs and the Office of Toxic Substances. The National Toxicology Program, although not a regulatory agency, has taken a prominent role in reproductive toxicity testing, test system development, and test system evaluation. A new testing system, Fertility Assessment by Continuous Breeding (FACB), is currently being studied as a cost-effective and reliable alternative test system. The FACB protocol houses male and female mice as breeding pairs and removes offspring as soon as they are born during the first 14 weeks to allow continuous mating. Each breeding pair normally has up to 5 litters, and the last litter is saved to evaluate the second generation. The efficiency, reliability, and expense of the protocol are being compared to the existing testing systems.

scholarly journals Assessment of Ocriplasmin Effects on the Vitreoretinal Compartment in Porcine and Human Model Systems

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Bart Jonckx ◽  
Michael Porcu ◽  
Aurelie Candi ◽  
Isabelle Etienne ◽  
Philippe Barbeaux ◽  
...  
Keyword(s):  
Posterior Vitreous Detachment ◽  
Subretinal Fluid ◽  
Model Systems ◽  
Human Model ◽  
Blood Retinal Barrier ◽  
Barrier Permeability ◽  
Cell Type Specific ◽  
Insight Into

Ocriplasmin (Jetrea®) is a recombinant protease used to treat vitreomacular traction. To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed anin vivoporcine ocriplasmin-induced posterior vitreous detachment (PVD) model in which we investigated vitreoretinal tissues by optical coherence tomography, histology, and cytokine profiling. Eight weeks postinjection, ocriplasmin yielded PVD in 82% of eyes. Subretinal fluid (85%) and vitreous hyperreflective spots (45%) were resolved by week 3. Histological analysis of extracellular matrix (ECM) proteins such as laminin, fibronectin, and collagen IV indicated no retinal ocriplasmin-induced ECM distribution changes. Retinal morphology was unaffected in all eyes. Cytokine profiles of ocriplasmin-treated eyes were not different from vehicle. In cell-based electrical resistance assays, blood-retinal barrier permeability was altered by ocriplasmin concentrations of 6 μg/mL and higher, with all effects being nontoxic, cell-type specific, and reversible. Ocriplasmin was actively taken up by RPE and Müller cells, and our data suggest both lysosomal and transcellular clearance routes for ocriplasmin. In conclusion, transient hyperreflective spots and fluid in a porcine ocriplasmin-induced PVD model did not correlate with retinal ECM rearrangement nor inflammation. Reversiblein vitroeffects on blood-retinal barrier permeability provide grounds for a hypothesis on the mechanisms behind transient subretinal fluid observed in ocriplasmin-treated patients.

scholarly journals Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Proximity

2020 ◽  
Vol 21 (21) ◽  
pp. 7916 ◽  
Author(s):  
Alexandra Damerau ◽  
Timo Gaber
Keyword(s):  
Rheumatoid Arthritis ◽  
Current Model ◽  
Culture Conditions ◽  
In Vitro Models ◽  
Model Systems ◽  
Laboratory Animals ◽  
Systemic Autoimmune Disease ◽  
Preclinical Research ◽  
New Therapeutic Approaches

Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity in its clinical presentation, and is associated with autoantibodies directed against modified self-epitopes. Although many models already exist for RA for preclinical research, many current model systems of arthritis have limited predictive value because they are either based on animals of phylogenetically distant origin or suffer from overly simplified in vitro culture conditions. These limitations pose considerable challenges for preclinical research and therefore clinical translation. Thus, a sophisticated experimental human-based in vitro approach mimicking RA is essential to (i) investigate key mechanisms in the pathogenesis of human RA, (ii) identify targets for new therapeutic approaches, (iii) test these approaches, (iv) facilitate the clinical transferability of results, and (v) reduce the use of laboratory animals. Here, we summarize the most commonly used in vitro models of RA and discuss their experimental feasibility and physiological proximity to the pathophysiology of human RA to highlight new human-based avenues in RA research to increase our knowledge on human pathophysiology and develop effective targeted therapies.

scholarly journals Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids

2021 ◽  
Author(s):  
Dilara Sen ◽  
Alexis Voulgaropoulos ◽  
Albert J. Keung
Keyword(s):  
Stem Cell Differentiation ◽  
Cell Types ◽  
Brain Regions ◽  
Embryoid Bodies ◽  
Model Systems ◽  
Human Model ◽  
Spatial Factors ◽  
Neural Lineage

ABSTRACTBackgroundBiophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment. However, the complexity and experimental challenges capturing such early stages of development, and ethical concerns associated with human embryo and fetal research, limit our understanding of how these factors affect human brain organogenesis. Human cerebral organoids (hCO) are attractive models due to their ability to model important brain regions and transcriptomics of early in vivo brain development. Furthermore, they provide three-dimensional environments that better mimic the in vivo environment. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Establishing links between spatial factors and hCO development will require the development of new approaches.ResultsHere, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate generally towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular, we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions.ConclusionsThe findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding of in vivo development and differentiation, but also provide important handles with which to advance and improve control over human model systems for in vitro applications.

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