Fight Aging!

Today I'll point out a good example of a new and improved methodology in tissue engineering: model arteries created in hours rather than the previous standard of weeks. There is a lot going in in this field, and the ability to create tissues from the starting point of cells and raw biomaterials is improving in leaps and bounds from year to year. From the point of view of speeding up research, many of the most important advances in the life sciences relate to logistics, and thus go largely unheralded because they have no direct connection to clinical translation of research into therapies. Yet any new technique that dramatically reduces time or cost in materials means that all of the research groups using it can get more done at a given level of funding. Moreover, reductions in cost usually also mean that researchers who were previously stuck on the sidelines can now get involved, adding their efforts to moving the state of the art that much faster. At the large scale, and over the long term, science is built on a foundation of ever-better infrastructure, not leaps of ideation.

At the present time a lot of the most important advances in tissue engineering are logistical, somewhat distant from clinical applications. The first engineered tissues very similar to those in living individuals are not destined for therapies, but rather to be used to speed up testing and research. Living tissue sections can replace a lot of the use of animal models, and at a much lower cost. At some stages small amounts of engineered human tissue can be far better tools for research than animal models, especially where tissue can be produced from the cells of patients with specific diseases or genetic conditions.

Another reason for this focus on small tissue sections for research is that generating blood vessel networks sufficient to support larger solid tissue masses, such as whole organs, is not yet a robustly solved problem. Researchers are definitely making progress, especially with the use of bioprinters capable of generating scaffolds incorporating small-scale structures, but the practical upper size limit on engineered tissue is still too small to be building organs in their entirety. This is one of the reasons why a great deal of effort is going into decellulization as a transitional technology, the use of donor organs cleared of cells to create a scaffold with blood vessels already in place that can be repopulated with a recipient's cells.

Looking at the results linked below, I think you'll agree that this is an impressive piece of work, though still removed a way from the desired end goals of firstly producing patient-matched replacement blood vessels to order for transplantation, and secondly finding a way to create blood vessel networks to order inside engineered tissue as it grows.

Rapidly Building Arteries that Produce Biochemical Signals

Arterial walls have multiple layers of cells, including the endothelium and media. The endothelium is the innermost lining of all blood vessels that interacts with circulating blood. The media is made mostly of smooth muscle cells that help control the flow and pressure of the blood within. These two layers communicate through a suite of chemical signals that control how the vascular system reacts to stimuli such as drugs and exercise. In a new study, biomedical engineers successfully engineered artificial arteries containing both layers and demonstrated their ability to communicate and function normally. The blood vessels are also miniaturized to enable 3D microscale artificial organ platforms to test drugs for efficacy and side effects. The new technique may also enable researchers to conduct experiments on arterial replacements in record time.

"We wanted to focus on arteries because that's where most of the damage is caused in coronary diseases. Most previous studies had focused on the media cells but hadn't spent much time on the endothelial cells, and nobody had shown how the two would interact. Many of the techniques for creating artificial tissue also were rather lengthy, which was frustrating." The frustration came from the six-to-eight weeks it took to grow arteries in the laboratory. Turning to the literature, researchers found a paper detailing a much faster technique used to create a trachea. The method works by putting cells of the desired tissue inside collagen and compressing for a few minutes. This both squeezes out excess water and increases the mechanical strength of the resulting tissue. For the next six months, researchers worked to convert the technique so they could create arteries. And not just any arteries - arteries scaled down to one tenth the size of a typical human's, which made the translation even trickier. "With a smaller diameter, we could make a lot of these artificial vessels in a short amount of time. We can make these vessels and use them in only a few hours. To me that was the biggest advance, because spending several weeks on each set was driving me crazy. While our arteries are small and intended for testing, they're just as mechanically strong as those intended to be put inside of the body. So the technique could be beneficial to researchers trying to create artificial arteries to replace damaged ones in patients as well."

Human Vascular Microphysiological System for in vitro Drug Screening

In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs were made by embedding human neonatal dermal fibroblasts (hNDFs) or human bone marrow-derived mesenchymal stem cells (hMSCs) in dense collagen gel. The TEBVs developed in this study had several novel features. They could be prepared with inner diameters of 500-800 μm and perfused in less than three hours. In contrast, other approaches to prepare TEBVs require 6-8 weeks in vitro culture before the mechanical strength is sufficient to enable perfusion.

After 1 week of perfusion, medial hNDFs or hMSCs expressed contractile proteins α-smooth muscle actin and calponin, indicating a switch to a contractile phenotype. TEBVs also produced the extracellular matrix proteins laminin, collagen IV, and fibronectin and exhibited burst pressures similar to human saphenous veins. Quantifiable and physiologically relevant reactions to vasoactive stimuli occurred after only 1 week. TEBVs released nitric oxide, elicited endothelium-independent vasoconstriction to phenylephrine and endothelium-dependent vasodilation in response to acetylcholine, and maintained these responses during 5 weeks of in vitro perfusion culture.