Adipose tissue is vitally important to various normal processes of the human body, and it has also many implications for human disease states. Obesity is a common health problem and is considered as a major risk factor for non insulin-dependent diabetes mellitus, cardiovascular diseases and hypertension. Obesity is a well-known risk factor of breast cancer in post-menopausal women that also correlates with a diminished therapeutic response.

The biological significance of 3D cell culture in understanding cellular behavior and function is highlighted by studies with various cell types. Therefore, 3D adipocyte cultures have been developed to better understand the role of adipocytes in adipogenesis and the treatment of obesity or preclinical formulation screening for cosmetic application. BIOMIMESYS® biofunctionalized with collagen type I and VI, represents the only model based on Hyaluronic Acid and a physiological mixture of undenatured collagen I and VI, which is ready-to-use for 3D adipocyte culture. The mechanical properties and the highly porous nature of the matrix allows the rapid uptake of nutrients into the cells, and makes the model compatible with all downstream analyses on 3D adipocyte cultures.

 

With low success rates in clinical trials, drug discovery remains a slow and costly business. Currently, more than half of all drugs fail in Phase II and Phase III clinical trials due to a lack of efficacy and about another third of drugs fail due to safety issues including an insufficient therapeutic index. The importance of the extracellular matrix (ECM) in cell behavior, it is now well-accepted that culturing cells in three-dimensional (3D) systems that mimic key factors of tissue is much more representative of the in vivo environment than simple two-dimensional (2D) monolayers.

“Currently, the majority of cell-based HTS is being carried out on cultured cells propagated in two-dimensions (2D) on plastic surfaces optimized for tissue culture. At the same time, compelling evidence suggests that cells cultured in these non-physiological conditions are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to be a significant contributor to the high failure rate in drug discovery, where only a low percentage of drugs investigated ever make it through the gamut of testing and approval to the market. Thus, three-dimensional (3D) cell culture technologies that more closely resemble in vivo cell environments are now being pursued with intensity as they are expected to accommodate better precision in drug discovery.”

In this review, Sigrid A Langhans provides an overview on the most common 3D cell culture techniques, address the opportunities they provide for both drug repurposing and the discovery of new drugs, and discuss the challenges in moving those techniques into mainstream drug discovery.

Source : https://doi.org/10.3389/fphar.2018.00006

Increasing evidence suggests that the 3D character of the microenvironment is required for development of many critical cell responses observed in vivo, kindle innovation in the development of functional and Biomimetic Materials for engineering the 3D cell microenvironment.

In this review, authors examine emerging and exciting based biomaterials technologies for 3D cell culture. Biomimetic Materials made of a large variety of materials with different composition (ECM compounds), porosities, and mechanical characteristics designed to mimic the microenvironment of specific tissues.

Future directions and technical challenges still remain to produce matrix with in vivo–like complexity for 3D cells-based HTS and HCS for drug discovery.

Source : http://pubs.acs.org/doi/abs/10.1021/acs.chemrev.7b00094

For ethical and cost-related reasons, use of animals for the assessment of mode of action, metabolism and/or toxicity of new drug candidates has been increasingly scrutinized in research and industrial applications. Physiologically based pharmacokinetic (PBPK2) modeling is the most potent in silico tool used for extrapolation of pharmacokinetic parameters to animal or  human models from results obtained in vitro. Two dimensional (2D) cell cultures have been a part of drug development for many years.

Nowadays, their role is decreasing in favor of three-dimensional (3D) cell cultures and co-cultures. 3D cultures exhibit protein expression patterns and intercellular junctions that are closer to in vivo states in comparison to classical monolayer cultures. In vitro absorption, distribution, metabolism, and excretion assessment, as well as drug-drug interaction (DDI), are usually performed with the use of various cell culture based assays. Progress in in silico and in vitro methods can lead to better in vitro-in vivo extrapolation (IVIVE) outcomes and have a potential to contribute towards a significant reduction in the number of laboratory animals needed for drug research. As such, concentrated efforts need to be spent towards the development of an HTS in vitro platform with satisfactory IVIVE features.

Source : https://www.ncbi.nlm.nih.gov/pubmed/28811111


Advances in bioprinting are fast and exciting: As you can read in this paper, it’s now possible to use living bacteria in ink. It allows the creation of complex actives material very useful in healthcare, for exemple, but also in 3D cell co-cultures. Article presents us the enormous potential of this technology in many other domains.

In HCS Pharma we are very interested by this evolution and we are working on our biomimetic hydrogel scaffold BIOMIMESYS® to propose a great product in few months.BIOMIMESYS®!

A group of ETH researchers led by Professor André Studart, Head of the Laboratory for Complex Materials, has now introduced a new 3D printing platform that works using living matter. The researchers developed a bacteria-containing ink that makes it possible to print mini biochemical factories with certain properties, depending on which species of bacteria the scientists put in the ink.

Source: 3D-printed minifactories | ETH Zurich

We were present at the last HCS conference in Boston and, during these two days of intensive discussions, lots of topics were addressed in HCS and HCA. I summarize below what seems really important for me.

A lot of molecules fail in the process of drug development in a very late stage (more than 50% in pre-clinical step and phase I for safety reasons, and 80 % for efficacy in phase II). Furthermore, there is more and more data showing that there is a huge transitional problem between animal and human studies. During this event, the pharmaceutical industry and academic groups have shown the importance to use phenotypic screening to found new drugs, but with improved relevance of the in vitro models and data analysis as explain, for exemple, by Christophe Antczak from Novartis. They have published a review on this topic : “How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice“. Kristin Fabre from AstraZeneca and Matt Wagoner from Takeda Pharmaceuticals have also highlighted the need for better human models for drug research, in order to improve efficacy and safety of molecules during the early steps of drug research. Another review was presented by Kristin Fabre from AstraZeneca, explaining why we need better human models : “Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework.

To improve relevance of the in vitro models, many presentations during this event were about 3D culture and the involvement of the micro-environment with modification of the extracellular matrix (ECM). As explained by Sophie Lelièvre from Purdue University for cancer research, during the tumoral progression, the ECM is modified with an increase of its density due to collagen production from cancer cells. The density of the extracellular matrix is a hallmark of tumor aggressiveness. During this tumor progression, there is an increase in the heterogeneity of the cells in the different grades, inducing resistance to chemotherapy. To mimic the tumor progression in in vitro models, it is necessary to reproduce this cellular heterogeneity with the modification of the extracellular matrix in 3D culture.

To improve the relevance of cellular models, microfluidics are also more and more used to generate dynamic models and to better mimic in vivo situation. Different presentations about “organ-on-a-chip” systems during this event have shown that this technology is getting more and more advanced. Jonathan Himmelfarb, from the University of Washington, has shown that 3D model including microfluidic devices to mimic human kidney proximal tubule, express higher transporters and metabolic enzymes compared to 2D model on Transwell filters. Finally, this technology has been already transferred from academic labs to the pharmaceutical industry as shown by Kriten Fabre from AstraZeneca. For example, they use microfluidic systems to check the potential inflammation of lipid nanoparticles.

This event was really of great interest to show that all new technologies like 3D culture, bioprinting, microfluidics for cell culture – and deep learning/machine learning and AI for data analysis – are increasingly used and synergistically help to get predictive human models.

Review from Novartis : http://online.liebertpub.com/doi/10.1089/adt.2017.796

Review from AstraZeneca : http://dx.doi.org/10.1038/nrd4309

We will be in Strasbourg on Tuesday and Wednesday next Week for Biofit 2017 event. We will have a booth on Eurasante space.

We will present our new robotic platform, HAPIx, dedicated to HCS and our new assays, especially on genotoxicity analysis (mutiparametric assay with micronucleus, gH2AX and PHH3 analysis in a same experiment).

We will present also our collaborative R&D programs on iPS, 3D culture and innovative 3D cellular models for phenotypic screening!

We will be really happy to discuss with you on our booth. Contact us now if you want to book a meeting. See you next week in Strasbourg!

I will be present at the High content Analysis and 3D Screening Conference in Boston from Monday (November 7)  to Wednesday (November 9).

“Now in its fifteenth year, Cambridge Healthtech Institute’s High-Content Analysis & 3D Screening Conference will deliver the most recent developments in high-content and phenotypic screening. Leading pharma and academic researchers will focus on advancements in HCA technologies and applications, including screening of 3D and physiologically-relevant cellular models, data analysis techniques, and case studies and strategies for successful drug discovery. The expanded 3-day coverage on 3D cellular models and 3D screening will present the latest in spheroid, organoid and organotypic cell culture, and organ-on-a-chip technologies for drug screening, toxicity testing, and disease modeling.”

In this conference, I will present a poster on our collaborative work with Dr Karim Si-Tayeb, researcher from Institut du Thorax (CHOPIN project) on differentiation of iPS in hepatocytes in 3D culture for metabolic diseases screening.

If you want to know more on this project, don’t hesitate to come and discuss with me or contact us.

Last day at Eurotox 2017 ! I was very impressed by the enthousiasm of the community these past 2 days. A lot of tremending studies were presented, conforting our will to pursue our toxicology assay development. Last workshop will talk about advanced liver model integration for chemical safety assesment, and I am impatient to attend it !

This was a pleasure to be present at Advances in Cell Based Screening 2017 #ELRIGCBS17 congress in Gothenburg. Presentations during those two days were interesting showing new progress in technologies as in 3D cell culture and patients derived culture iPS cell. Phenotypic screening and machine learning are becoming the standard in the industry and will allow personalized medicine in a near future.

As an example Professor Neil Carragher from Edinburgh University has explained their phenotypic screen on glioma using patient derived culture, cell painting as described by Anne Carpenter from the Broad Institute of MIT as read-outs and machine learning for image and data analysis. Another topic of interest was from Vilja Pietiäinen (Institute for Molecular Medicine Finland – FIMM) showing their proof of concept for personalized medicine in oncology, on leukemia and solid tumors. They used genomic and phenotypic screening on patients derived cells on 2D and 3D culture with machine learning to choose the drugs which are the most effective for the patient. We were also very interested by topics about advances in 3D culture, especially for human hepatocytes as presented by Volker Laushke. Indeed, 3D culture of PHH and human derived PHH are part of two subjects from our R&D project InnovCell 3D, and Chopin.

Other talks from pharmaceutical industries as Astrazeneca and GSK showed also the interest of all these new technologies to be more efficient in drug research and development. We remember the presentation from Sinead Knight from AstraZeneca depicting the High-Throughput phenotypic screen to identify modulators of human pancreatic β-Cell proliferation for Type II Diabetes.

Discussions around our HCS Pharma ‘s booth (located close to the poster) were intense and have lead to new ideas and collaborations. Thanks of all of you visiting us! We hope to meet you all again at the next conference.

As shown by AstraZeneca in nature reviews*, one third of safety failures along the drug discovery process is linked to CNS toxicity uncovered in clinical trials. To avoid this attrition, the potential neurotoxicity of any drug going through the blood brain barrier (BBB) needs to be assessed in the very early stages of new chemical entities (NCE) research. Neurotoxicity assays can be performed on the SH-SY5Y human cell line by using High-Content Screening (HCS) technologies. The present study was performed using classical 2D and 3D culture protocols. In this poster, 2D results and preliminary 3D culture results on multiple reference compounds are depicted.

View and download on Slideshare (low quality) : https://www.slideshare.net/hcspharma/in-vitro-dermocosmetology-high-content-analysis-approach-using-human-primary-keratinocytes-and-fibroblasts

Ask for high quality link  by putting your email below

We will be present at « High-Content and Phenotypic Screening » conference in Cambridge (25 – 26 April 2017) to talk about advantages of 3D culture in phenotypic screening, during the user meeting of Molecular Devices.

Cellular assays in 3D culture have shown many advantages to better mimic the in vivo situation. A few examples in oncology, CNS and metabolic diseases, will be presented during this talk. High-Content Screening (HCS) devices, such as the ImageXpress Micro confocal from Molecular Devices, are now fast enough and sensitive enough to allow image acquisition in 3D cellular models. Nevertheless, to go further, perceptions and processes need to be changed. We will discuss cutting-edge new technologies, including virtual and augmented realities, deep learning and machine learning, and explain how these new technologies can be of benefit to phenotypic screening.

If you want to talk with our CEO or our CIO, feel free to send a message with our contact form !

Méryl Roudaut* will present a poster on the work of Institut du Thorax (Nantes, France) during the meeting “advances in cell engineering, imaging and screening conference”. This conference will be held on 17-18 november 2016, in Louvain (Belgium). It will focus on novel technologies through presentations in several sessions:

  • New imaging and microscopy tools
  • Super-resolution Imaging
  • IPS and cell reprogramming
  • 3D cell culture and organoids
  • Cell manipulation
  • In vivo cell-based assays
  • Cytometry
  • High Content Screening.

If you want more informations about the CHOPIN program and the work presented on the poster, don’t hesitate to discuss with Méryl* during this event!

*Méryl is our PhD student working in collaboration with Pr Bertrand Cariou and Dr Karim Si-Tayeb within the CHOPIN RHU program.

According to a report issued by the Tufts Center for the Study of Drug Development, the costs associated with bringing a novel drug to market exceed $2.5 billion per successful compound. Drug developers search for other innovation systems which are more relevant with physiological and clinical predictability. They deplore the Gap between Conventional 2D Cell Cultures and In Vivo Animal Models. New technologies, as 3D culture including micro-environnement as proposed by Celenys company, our partner for 3D culture, or to go further as bioprinting or as organ-on-a-chip with microfluidic system are really nice technologies to fill the gap between both systems or to replace 2D culture experiments.

“Historically, drug discovery research has relied on two-dimensional in vitro assays (that is, cell monolayers cultured on plastic substrata) and in vivo animal models. Although these systems still predominate, drug developers are beginning to doubt whether the familiar assays and animal models are adequate with respect to physiological relevance and clinical predictability. And drug developers are losing patience with persistently dismal rates of translation.”

Source: 3D Cell Culture Draws Drug Developers’ Interest | GEN Magazine Articles | GEN

Development of a ECM

Whether for preclinical research or clinical use, research teams are developing ever finer templates to democratize the use of tissue engineered models. In this publication, the focus is on the development of matrices, guided thanks to a biosynthetic skeleton optimized for cells and tissues aimed to compose it.

Good reading.

Source : Extracellular Matrix Revisited: Roles in Tissue Engineering
Youhwan Kim & al.

 

We are really pleased to announce that we have received the award of innovative poster for our Parkinson model and first results in 3D culture. This award recognizes our collaboration with two other startups to implement new innovative assays. These two other partnairs are CELENYS, which develops new plate for 3D culture which mimics the extracellular matrix, and QuantaCell, which develops new IT tools for image and results/statistics analysis (eg for 3D analysis and/or timelapse). With these two partnairs, HCS Pharma will seek to develop new assays in 3D culture by integrating extracelullar matrix to mimic as close to a healthy organ vs diseased organ. We hope to present new 3D validated assays during the next ELRIG session.

 

 

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