Three-Dimensional Advantages

An ageing population and high expectations for a better quality of life in western European society have led to calls for more efficient and affordable healthcare. However, the development of new drugs and therapies has decelerated, despite the application of combinatorial chemistry and new therapeutic strategies, such as nanoparticle-based drug delivery systems (nanomedicine) (1). Although the numbers of newly developed compounds have steadily increased, regulatory approval rates are declining while attrition rates during Phase II and III clinical trials are on the rise. In other words, despite initial successful animal testing, drug failure remains high, thus putting a huge cost and time burden on pharmaceutical companies (2).

Some of the general problems associated with animal testing include those of reproducible animal growth, health status, weight, diet and method of drug administration. Additional limitations of animal testing are based on intrinsic genetic differences between rodents and humans, leading to the development of improper therapeutic strategies. As a result, efforts to develop new drugs based on data derived from animal models suffer from unreliable transition of preclinical rodent data to clinical application. However, due to the lack of alternatives and regulatory requirements, animal testing has become the model of choice for a number of medical research areas, despite its limitations.

CELL-BASED ASSAYS

One alternative to animal testing is cell-based assays. These are generally considered to be more reliable because cellular responses provide a better understanding of both the physiology of the drug target, as well as the pharmacological interaction. However, classical cell-based assays, particularly in combination with prevailing screening technologies, continue to employ cell phenotypes that differ markedly from those found in human pathology. Many studies have demonstrated that cellular phenotypes are controlled by the complex interaction between genome, proteome and the external environment. Cells regularly change by altering their output of matter and energy which, depending on its genetic makeup and environmental context, can lead to either a pathological (disease) or a normal phenotype. Furthermore, it is important to note that cells exist in vivo within three-dimensional cell communities that form tissue. These communities, or biological niches, consist of various cell types coexisting in close proximity to each other. Biological niches are influenced by various parameters, such as nutrient supply, waste removal and constant temperature. Finding the proper balance between these parameters provides a minimal stress environment, thus allowing cells to display their natural phenotypes (3). In contrast, current in vitro cell-based assays do not take into consideration the natural spacing between cells, and do not adequately control temperature and fluid stress (4).