Periodic Reporting for period 3 - HUMAN TEXTILES (Human, Woven, Tissue-Engineered Blood Vessels (TEBV) Exclusively from Cell-Assembled Extracellular Matrix (CAM).)
Reporting period: 2021-11-01 to 2023-04-30
With our current eating habits and more sedentary lifestyle, disease of the blood vessels (cardiovascular) is the most important cause morbidity and mortality in the richer countries. The need for hemodialysis, which linked to diabetes and hypertension, is also very important (about 2 million worldwide) and will likely increase at the population ages. Clearly, finding better blood vessel replacements would improve the life of millions.
Our approach is to produce biological vessels in the lab by using human cells in culture. This would avoid the use of synthetic materials that the body recognized as foreign while insuring an infinite supply of replacement vessels. We have previously shown that cells can lay down a sheet of material (called extracellular matrix) in the right culture conditions. We have previously shown that this cell-assembled matrix (CAM) can be used to produce vessel by rolling the sheets and that these vessels can perform well in humans. In this project, we want to create blood vessels by weaving yarn made from CAM because this will allow the production of vessels much more rapidly (so less expensively), reliably, and with better control over their properties. Our objectives are to 1) Create and characterize CAM yarn made in the lab with human and a large animal cells, 2) Test the biocompatibility (under the skin) of theses yarns in vivo (test human in an immunosuppressed rat model and the large animal yarn in the same selected large animal species), 3) Weave small diameter vessels with human and animal yarn, characterize them in vitro, and optimize their properties, and 4) Implant large animal woven vessels in the arterial circulation of the same species and evaluate their performance for up to 1 year.
We have developed a model of subcutaneous implantation of human yarn in nude rats (immunosuppressed rats). We have shown that these rats will not reject human CAM but will degrade extracellular matrix that has been denatured. With this model, we have shown that the CAM yarn is well tolerated and is still present and largely untouched after 6 months. Similarly, ovine yarn have been implanted in the subcutaneous space of sheep. In our first experiment, we recovered yarns at 1 month but we unable to confidently identify the yarn at 3 and 6 months. We will redo this experiment with a different implantation strategy to better localize the yarn after long-term implantation. Initial results show that yarns are also well tolerated. We have learned to make woven vessels with human yarn and with ovine yarn. Both vessel types have promising mechanical properties. We are in the process of understanding how production parameters influence the final vessel properties in order to be able to optimize the vessels. As a transitional model, and because this is the only way to test human vessels in vivo, we have implanted miniature human vessels in the aorta of nude rats to analyze their remodeling in the circulation. We have achieved 9 month implantations at this time. Finally, we are implanting a first series of ovine vessels (carotid implants) to establish this model and validate the basic woven vessel model before starting a series to evaluate long-term implantations and the performance of optimized vessels.