3D patterning of blood vessels: Creating a fertile landscape for engineered tissues

Author: Holly Wobma, 05/22/13
Nepalese terraces. Photo: strudelt via Flickr

Picture traveling back in time to an era before cell phones (*shudder*). Before radios. Before germ theory. In fact, try taking yourself back to when written language was first being developed around 6000 BC. It’s hard to imagine.

And yet while these societies may have lacked our freeways and our Facebook, they did have complex irrigation systems. Throughout the millennia, these water networks have brought life to three-dimensional space, from the aqueducts of Ancient Rome to the terraced hills of Nepal. Orderly arranged. Tightly controlled. It seems that from the very onset of civilization humans have been masters of fluid dynamics.

So with all of our modern technologies, can we live up to the ingenuity of our ancestors to tackle current problems in fluid flow? If we want to advance the field of tissue engineering, then we’ll have to. I’m, of course, referring to the challenge of vascularization.

If you’re up to speed on the status of tissue engineering, you’ll know that scientists have been able to engineer cellular patches of heart, bone, skin, liver … the list goes on. But for these tissues to actually be useful to a patient, they need to somehow be vascularized. Thus far, at least two broad strategies have been explored.

Strategy 1: You try to engineer pre-vascularized tissues. This means de novo engineering of both the blood vessel and the tissue together.

  • Pros: You could control the architecture of the vascular network and it would enable you to engineer larger tissues in the lab (since they would have oxygen delivery throughout).
  • Cons: You have to co-coordinate the development of both the tissue that you are trying to make with the growth of the blood vessel (not trivial).  The vessels you make must function physiologically, permit gas exchange, not clot or stenose, and be durable enough to suture into a patient.

Strategy 2: 
Implant your engineered tissue and let the body’s vasculature grow into it over time.

  • Pros: Body takes responsibility for making the vessel, which may be anatomically and physiologically similar to other vessels in the body.
  • Cons: Lack control of vessel architecture, and the ingrowth of host vessels can be very slow (implanted tissue may die).

While the strategies outlined above are not completely inclusive of everything being tried, you can start to appreciate that both have some very compelling advantages but also notable shortcomings. Wouldn’t it be nice to combine the advantages of both into an innovative new strategy?

That’s basically what Dr. Christopher Chen’s group has recently done at the University of Pennsylvania. In their approach, which was published in this month’s issue of PNAS, they made networks of tiny “cords” out of collagen and endothelial cells (the cells that line blood vessels). These cords are not substitute blood vessels, but when they are implanted into an animal model, the endothelial cells send signals to the body to replace the cords with capillaries.

The brilliance of this technique is that the patient’s body forms natural blood vessels, but in an accelerated fashion due to signals from the endothelial cells in the cords. Furthermore, you have some control over the 3D network of vessels that form, because the cords serve as template that gets replaced. This geometric control is important because many tissues in our bodies have a specific vascular architecture. In fact, the investigators go onto show that when they implant engineered liver tissue along with their cords, the liver becomes more functional (based on an enzyme assay) than if it were implanted alongside random cell seeding. Overall the technique is creative, inspiring, and a useful step forward for vascular engineering.

I think it’s curious to reflect that our ancestors were able to sustain life by using hydraulic networks to bring water to their fields, and now we are learning how to engineer vessels to sustain life through regenerative medicine. I can only conclude that while our technologies and interests change over time, human ingenuity remains the same.

Research cited:
Baranski J.D., Chaturvedi R.R., Stevens K.R., Eyckmans J., Carvalho B., Solorzano R.D., Yang M.T., Miller J.S., Bhatia S.N. & Chen C.S. & (2013). Geometric control of vascular networks to enhance engineered tissue integration and function., Proceedings of the National Academy of Sciences of the United States of America, PMID:

Vunjak-Novakovic G., Tandon N., Godier A., Maidhof R., Marsano A., Martens T.P. & Radisic M. Challenges in cardiac tissue engineering., Tissue engineering. Part B, Reviews, PMID:

Marolt D., Knezevic M. & Novakovic G.V. (2010). Bone tissue engineering with human stem cells., Stem cell research & therapy, PMID:

Metcalfe A.D. & Ferguson M.W.J. (2007). Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration, Journal of The Royal Society Interface, 4 (14) 413-437. DOI:

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Holly Wobma

Holly Wobma

MD/PhD student at Columbia University
Holly is an MD-PhD student at Columbia University in New York. She recently (2011) completed a Bachelor of Health Sciences Honours Degree from the University of Calgary, where she pursued research related to nanotechnology and regenerative medicine. In addition to research, she enjoys participating in science outreach roles. Previously, she contributed to an award-winning Nanoscience animation produced by the Science Alberta Foundation (“Do You Know What Nano Means?”), and served on the board of directors for the Canadian Institute for Photonic Innovations Student Network.
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