Drug development is a time-consuming and expensive process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation, and clinical trials, ending up in approval for clinical use. It is well known that 90 percent of drugs that reach clinical stage development never make it to FDA approval and commercialization. The cost of a failed drug is between $800m and £1.4bn. With this low success rate in clinical trials, drug discovery remains a slow and costly business. Hence, there is an urgent need for new technologies which can mitigate the risk of failures.
3D bioprinting is one of the most promising areas expected to improve the success rates in drug development. Whilst most people start to imagine printed human organs for transplanting into the patients when they hear the word bioprinting, in realitywe probably won’t see 3D printed, transplantable human organs for many years yet. Internal organs are more complex than simply printing layers of cells into the shape of a kidney or liver. They need to have nerves and blood vessels to function and survive, and bioprinting technology still has a way to go before reaching the required level of complexity.
The most realistic application of 3D Bioprinting in this decade will most likely be in drug discovery and development. In the pharma industry, the companies test drugs on animals before the drugs go to expensive clinical trials. However, the human physiology is very different from that of test animals, so what works in an animal, will not necessarily be effective in a person.
Bioprinting can be used to print a range of 3D culture systems and human tissue models to produce better in vitro testing by generating models with improved physiological relevance and high reproducibility. By applying bioprinting in drug discovery and development organisations can identify ineffective or harmful drugs earlier in the discovery process and shift their resources to more promising drug candidates. They can also reduce the cost of drug development caused by clinical trial failures.
We are delighted to tell you that we are attending the World Preclinical Congress in Lisbon, Portugal on 27-30 November. The conference provides a unique opportunity for academia and pharma/biotech companies to exchange knowledge in early drug discovery and development.
Unfortunately, the traditional drug development methods are still inefficient and expensive processes due to their high failure rate. There is evidence showing that species-specific differences limit the ability of animal models to predict human biological reactions. Thankfully, in the last few years, a new generation of 3D models have been developed as alternative in-vitro functional assays. Hereby, scientists can make progress towards predicting safety and efficacy screens that are more relatable to the clinic.
We look forward to meeting the key players of the preclinical world and learn the scientific and technical advancements related to better optimize drug candidates and accurately predict drug-related toxicity.
If you are visiting the event, please make sure to meet with us! Elia Lopez-Bernardo, PhD will be there for a chance to discuss our innovative technology and the applications of BiogelxTMproducts in preclinical drug discovery.
If you want to secure time to speak with Elia, please click here and arrange a meeting.
Three-Dimensional in Vitro Cell Culture Models in Drug Discovery
Drug development is a time-consuming and expensive process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation, and clinical trials, ending up in approval for clinical use. It is well known that 90 percent of drugs that reach clinical stage development never make it to FDA approval and commercialization. The cost of a failed drug is between $800m and £1.4bn. With this low success rate in clinical trials, drug discovery remains a slow and costly business. Hence, there is an urgent need for new technologies which can mitigate the risk of failures. Two of the most promising areas expected to improve the success rates in drug development are the development of novel biomarkers and the availability of new preclinical models that better imitate in vivo biology. It is now well-accepted that culturing cells in three-dimensional (3D) systems that can mimic key factors of tissue is much more representative of the in vivo environment.
Cell-based assays are simple, fast and cost-effective as well as versatile and easily reproducible compared to cost-intensive animal models. To date, the majority of cell cultures used in drug discovery are two-dimensional (2D). However, it has become clear that 2D cultures do not necessarily reflect the complex microenvironment cells encounter in a tissue.One of the biggest influences shaping our understanding of the limited physiological relevance of 2D cultures is the growing awareness of the interconnections between cells and the extracellular matrix (ECM) surrounding them. The ECM is characterized not only by its biochemical composition, but also its physical and mechanical properties, with tissue stiffness being importantfor the maintenance of homeostasis. The composition of the ECM along with its physical properties can influence a cell’s response to drugs by either enhancing drug efficacy, altering a drug’s mechanism of action (MOA) or by promoting drug resistance. Moreover, traditional 2D cell cultures are not amenable to studies of oxygen or nutrient gradients as all cells are homogeneously exposed to the tissue culture medium. In contrast, cells encapsulated into 3D matrices provide opportunities to understand oxygen, growth factor and nutrient-mediated mechanisms leading to changes in cell phenotype and alterations in drug response.
Most 3D culture techniques are categorized into non-scaffold, anchorage-independent and scaffold-based 3D culture systems as well as hybrid 3D culture models. In scaffold-based 3D cultures, cells are embedded into the matrix and the chemical and physical properties of the scaffold material will influence cell characteristics. Thus, when selecting a 3D cell culture scaffold for a certain application, one will need to consider properties of the material that define physical factors such as porosity, stiffness, and stability in culture as well as biological properties such as cell compatibility or adhesiveness.
Animal-derived versus Synthetic Hydrogel Scaffolds
Whilst hydrogels display solid-like material properties, they are comprised of over 95% water by volume, and thus can provide a cell-liquid interface. Hydrogels may come from natural sources or can be synthetic, with the possibility of mixing different hydrogel materials to obtain hybrid hydrogels possessing new physical and biological properties. Hydrogels from natural sources are biocompatible and facilitate cell attachment through integrin receptors which leads to the activation of cell signaling pathways. Therefore, they can control cell survival, growth, and differentiation and can modulate the response to therapeutic approaches, including chemotherapy, immunotherapy, and radiation. However, hydrogels processed from natural sources have batch-to-batch variability of the purified scaffold which may interfere with pharmacological studies of drug response. Often, in addition to their major constituents, they contain many other components and are therefore poorly chemically defined. In contrast to animal-derived, the synthetic hydrogels are chemically and physically well-defined and often have tunable mechanical properties to achieve a desired stiffness or porosity. Well-designed, synthetic hydrogels, such as BiogelxTMpeptide hydrogels, are ideal materials to use as 3D cell culture scaffolds as they can mimic biological properties of ECM, be functionalized with defined adhesive moieties, and encapsulate growth factors. They have the advantage of being comparatively inexpensive, have reproducible material properties that are usually easy to tune through synthesis or crosslinking, and are reproducible, thereby supporting the acquisition of consistent results.
Additional peptide hydrogels currently being used in 3D culture are the yeast-derived peptides EAK16 and RADA16, peptide amphiphiles Fmoc-FF (Fluorenylmethoxycarbonyl- diphenylalanine) and Fmoc-RGD (Fluorenylmethoxycarbonylarginine-glycine-aspartic acid), the peptide hydrogel h9e based on the fusion of functional domains from a silk protein and a human calcium channel, FEFK and FEFKEFK which form hydrogels in the presence of a metalloprotease, and the MAX1 peptide which gelates under physiological conditions, and like h9e, has shear-thinning properties.
Applications of 3D Cultures in Drug Discovery
In recent years, 3D cell culture systems that model the in vivo microenvironment, and are therefore expected to yield results with higher predictive value for clinical outcome, are becoming more prominent in drug discovery. In addition, 3D cell culture models using human cells can circumvent drawbacks of mouse models that, aside from the high cost and ethical considerations, are not always able to accurately recapitulate human diseases or capture side effects of drugs such as liver toxicity. 3D cell culture technology with primary patient-derived tumor cells, and molecular profiling data, may open the door for preclinical screening of a personalized panel of drug candidates to improve outcome and reduce side effects of cancer therapy.
Langhans SA (2018) Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. Front. Pharmacol. 9:6. doi: 10.3389/fphar.2018.00006
Many strategies are used to conduct cancer research and in the development of effective therapies, including analysis of clinical biopsies, in vivo animal models, and in vitro models. In vitro tumor models in three dimensions such as organoids have recently emerged as a promising tool which replicates many features of solid tumors in vivo. The ever-expanding use of organoids is evident by the fact that they were chosen as ‘Method of the Year’ by Nature in 2017.
Cancer organoids are miniature, three-dimensional cell culture models that allow culturing cancer cells in a spatially relevant manner. Biomimetic hydrogel scaffolds, like those provided by Biogelx, offer the biomechanical and biochemical cues that help to recapitulate the behavior of natural extracellular matrix (ECM) and are essential for regulating cancer cell behavior.
Extensive experimental evidence has shown that the rigidity of the matrix affects cancer cells growth and activity. Moreover, tissues stiffen during the pathological progression of cancer. However, most of the 3D scaffolds traditionally used, like collagen or Matrigel gels, have the major drawback of presenting very low rigidity, which does not mimic this naturally stiff cancer environment. Furthermore, alternative, newer scaffolds like PEG-based or other synthetic materials don’t have the capacity to mimic sufficiently rigid environments either, and can often only form scaffolds up to 2 kPa. This is not the case with Biogelx materials, which can be formed into gels of stiffness ranging from 0.5 to 100 kPa, hence offering a better option to mimic the stiff ECM of solid tumors. Indeed, such a broad range of stiffness, allows the researcher to model tumors at various stages of disease progression
Biogelx materials are peptide-based hydrogels which are biochemically tunable as well and provide biomimetic sequences to resemble the tumor matrix in a defined manner. Native ECM molecules (Fibronectins, Laminins, Collagens, etc) are replicated in the gels as functional peptide units that provide cell-to-cell and integrin-binding sites creating a suitable synthetic matrix for reproducible research in cancer biology and drug discovery.