A huge proportion of drugs (over 80%) that enter clinical trials fail because of problems with toxicity or because they are not shown to be effective. Pre-clinical studies in animals are useful but do not always accurately predict toxicities in humans. Microphysiological systems (MPS), small scale models of human tissues or organs, may act as a bridge between two-dimensional cell culture studies and in vivo animal studies, in order to better predict toxicity issues earlier in the drug development process.
A particular problem known as drug induced vascular injury (DIVI) is evident in pre-clinical animal studies as inflammation and changes in the level of blood vessel constriction, and can prevent on-going development of drug candidates. A human tissue-engineered blood vessel that is able to respond to stimuli would therefore be a useful model system in which to analyse toxicity and efficacy of potential drug candidates.
Biomedical engineers at Duke University have succeeded in developing a new technique in which to produce artificial arteries that do just that. These miniaturised blood vessels contain both the endothelial layer, which is the internal lining of the vessels and a media layer containing smooth muscle cells helping to control the diameter of the blood vessels.
One of the advances has been that the lab have reduced the time it takes to produce these blood vessels from six to eight weeks to just a few hours. They based their method on published techniques used to create trachea. In this case, human neonatal dermal fibroblasts (hNDFs) were suspended in collagen and then compressed to reduce the water volume and increase the collagen fibre density.
A suspension of hNDFs in collagen is poured into the mold containing an 810-μm diameter mandrel and allowed to gel for 30 minutes (a). Collagen fiber density increases through plastic compression and removal of water (b). Compressed TEBVs are immediately mounted in custom chambers (c). CAD EPCs are seeded into the lumen of the TEBV (d) and the chamber is rotated at 10 rph for 30 minutes (e). After endothelialization, TEBVs are mounted into the perfusion circuit and cultured for at least 1 week at a flow rate of 2 mL/min (f). TEBVs before (g) and after compression (h). Live-dead assay performed 24 hours after compression (i). H&E cross-section of TEBV after 1 week of perfusion culture (j). Scale bars indicate 200 μm unless otherwise noted.
The blood vessels were shown to respond normally to stimuli such as treatment with drugs to induce vasodilation or vasoconstriction. The blood vessels also responded to drugs that are known to cause drug-induced vascular injury, confirming that this is a suitable model for the study of this effect in vitro.
Fernandez, C. E. et al. Human Vascular Microphysiological System for in vitro Drug Screening. Sci. Rep. 6, 21579; doi: 10.1038/srep21579 (2016)
Duke University. “Rapidly building arteries that produce biochemical signals: New technique speeds tissue engineering of functional arteries.” ScienceDaily. ScienceDaily, 18 February 2016.
Blog written by Sarah Walker