Cell Culture
Figure 2 Higher order organ-on-a-chip solutions employ precisely- engineered microfluidics technology to connect different tissue types together in an in vitro system. This emerging technology will enable researchers to combine healthy and diseased 3D tissue models in a network that more closely simulates human tissue-tissue signalling interactions and responses through a controlled flow of media
These examples illustrate that culturing sub-
strates for 3D tissue models not only needs to be adapted to preserve optimally cellular and tissue functions, but also allow accessibility to gain unparalleled information. This includes access to the supernatant, the cells themselves for down- stream analysis and optical transparency for imag- ing. One need to consider scalability and compati- bility with standard assays.
Patient-focused disease modelling in 3D Central to drug discovery and development is the patient. When a patient has a condition that diverges from a pre-defined healthy state, the goal is to prevent further disease development or, even better, bring them back to the healthy state. Usually, some physiological
functions are
impaired, impacted or deficient in a way that sig- nificantly lessens quality of life. Thus, just having healthy, 3D tissues is of limited usefulness. One must also have the ability, knowledge and proto- cols for inducing specific disease states in 3D tis- sues within a reasonable window of time, to be able to rigorously test therapies for preventing or reversing disease states. It is important to stress that in vitro disease mod-
elling must be achieved in a reasonable time frame, as having to wait years to induce a disease is simply
Drug Discovery World Winter 2018/19
not acceptable. For example, it is thought that the average natural progression of each stage of non- alcoholic steatohepatitis (NASH) takes 7.7 years. Nobody wants to maintain their cell culture model over decades, so we need to accelerate this process significantly. Nevertheless, speeding the induction of disease states can be tied to compromises. A dis- eased 3D model needs to be carefully validated to ensure it sufficiently recapitulates key pathological aspects of the disease and, importantly, responds to disease treatments in this accelerated situation. One of the newest developments in the field of liver dis- ease is a screenable, in vitro 3D human liver disease model that faithfully recapitulates induction and progression of NASH. This model was bioengi- neered to include all primary liver cell types involved in NASH development. As in its in vivo counterpart, the progression of disease is induced over multiple steps, albeit condensed down to two weeks. Sufficient translational correspondence is based on clinical biomarkers such as cytokines or collagen fibrils deposition. Importantly, this model responds to treatments of anti-NASH candidate drugs in clinical development. This ‘fit for purpose’ proof of principle is important for any 3D model intended for drug development and testing. Thus, testing larger panels of compounds from clinical stages that were successful or failed is a crucial step in determining if a model is robust and ready to
49
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68
