One concept I think is important to understand is the cellular density of these models. So obviously, tissue in most cases, has a very dense set of cells in it. So in figure (d) you see the 100% cellular matrix that’s going to represent most of your soft tissues. Interestingly, if you’re talking about cartilage or material like that, that actually looks a lot more like figure (c) with various biomaterials forming the basis of it, and then some living codocytes that helped to replenish it and repair it. But most tissues and certainly the stuff I work with is all more like (d). So highly dense tissues in terms of the cell positions, and how many cells there are in a volume.
And this is actually an area that’s very important to understand, because people use different techniques, and they don’t always work with the most dense cells. So sometimes people start with gel cell mixes that look almost like (b) – like 10% volume of cells in something. Things like organoids started with that in the early days, basically asking: Can we just grow cells in 3D culture, starting with the surrounding gel material and see what happens? Will the cells behave better just because they are in 3D? They did get some good results, and it showed that they can grow, take over and be 3D even if you start with that. And you can get interesting and good early results, so people still use them.
In the context of solving some deeper biology questions, nowadays you start as close to 100% cellular as you can, because in reality, in the soft tissue of interest, you want the cells to be interacting with one another. So you’re going from a 2D model where cells interact with plastic, and that dominates their shape and their behavior because that material interaction is very different and foreign to them, to a 100% cellular environment, where if you compare their native environment in the body with what they end up with in the dish, there are cells all the way around them. And that enables them to act the most normal because they’re getting the mechanical signals from those other cells that are correct, they’re getting the cell signaling, and the biochemical signaling is going to be very comparable.
And so you’re solving a different problem if you start to work that way. Historically, in terms of animals, we’re engineering a disease model in an animal. Now we ask: Well, how do we actually just find a way to replicate the conditions in the body, so the cells will act exactly as they do in the body? Where the biology will be inherent, versus a petri dish where they’re interacting with plastic and that alone strips them down a bad path for many cell types.