next-generation tissue models that would allow in vitro experimentation within the context of tissue-level complexity.
Multi-cellular 3-D spheroids are used in a variety of applications beyond oncology and can be created by incubating cell suspensions on non-adherent surfaces or as hanging drops. Biomaterial scaffolds comprised of synthetic polymers, extracellular matrix proteins, or de-cellularized tissues can be combined with cells to create 3-D composite structures. With the advance of additive manufacturing strategies into the life sciences arena, it is now possible to use highly specialized 3-D printers (bioprinters) to reproducibly build compartmentalized 3-D tissues that mimic key aspects of native tissue architecture and function, with an extraordinary degree of user control in both tissue design and fabrication strategy. Although the field of 3-D bioprinting is young, the emerging capability to create new in vitro models that embrace the heterogeneity of native tissue is extremely compelling. We can expect a continuous flow of data over the next few years that reveals the benefits and predictive capabilities of these models.
Efforts have also been expended to build models that incorporate human context at the level of a whole organism. “Humanized” animals, predominantly rats and mice, are being generated that incorporate human cells or tissues to reconstitute some portion of the animal. Examples here include animals that bear human tumor xenografts, have been reconstituted with human bone marrow/immune systems, or contain “humanized” livers. These chimeras are providing new insights at the level of the whole organism, and it is exciting to think about the potential of combining complex tissue manufacturing strategies, like 3-D bioprinting, with this approach to enable these models to be more intricate and reproducible.
As with any new technology, success will create a host of additional challenges. Building systems that are reproducible, user-friendly, and provide true human correlation is key. To get the most out of these complex heterogeneous tissue models, we need to understand the tissue responses as well as the cellular, mechanistic responses. The development of analysis tools, in particular those that enable detailed temporal and spatial measurements at the cellular and molecular level without destructive testing, will be needed to maximize the value from experiments using 3-D tissue models.
The greatest challenge that lies ahead may be the drug discovery and development process, with a shift toward strategies that recognize and embrace the amazing complexity of human biology. If we are attempting to predict a human outcome, we should be asking the questions in models that approximate the complexity of a living human tissue, and deriving answers at the finest resolution achievable.
It is an exciting time to be working in predictive tissue modeling. Accelerating technologies, such as induced pluripotent stem cells and synthetic biology, are creating the opportunity to build even more sophisticated models that can be tailored to specific populations, disease states, or individuals. Advancements in engineering, cell biology, computing, and genomics will undoubtedly converge to create the kinds of integrated systems that our predecessors could only imagine.
