An Approach to Solving the Blood Vessel Problem in the Tissue Engineering of Organs

Blood vessels are very important, and so it is always worth paying attention to progress such as that noted below, research that inches closer to the goal of being able to grow suitable blood vessel networks to supply large sections of engineered tissue. It is no great exaggeration to say that the shape and progress of the field of tissue engineering is determined by the thorny issue of building blood vessels - or rather the inability to build blood vessels. Cells must be continually supplied with nutrients and oxygen, and in anything larger than a thin slice of tissue this must be accomplished by an intricate web of tiny blood vessels, in turn joined to larger blood vessels, and which would be connected into the circulatory system if transplanted into a living individual.

Unfortunately it is still a little beyond the present state of the art to construct a blood vessel network that is up to the job of supplying a complete organ - though things are certainly moving closer to that goal in some labs. Larger individual blood vessels can be made in a variety of ways, such as by bioprinting a layered sheet and rolling it up, but building a spreading tree of hundreds or thousands of branching tiny vessels is still a problem in search of a robust solution. This is perhaps the biggest reason why the development of decellularization has seen such support among organ engineers: it bypasses the issue by using a donor organ with the cells stripped from it to provide the extracellular matrix scaffold complete with blood vessel structures. Its chemical cues can guide new, patient-matched cells to repopulate the organ and recreate all of its necessary blood vessels. Other applications of tissue engineering carried out so far have largely been limited to thin structures that can be nurtured without blood vessels, and which are quickly populated by new blood vessels when grafted.

Now that researchers are at the point of actually constructing complex, functional organ tissues from a small sample of patient-derived cells, it is becoming even more pressing to find a practical solution to the blood vessel network issue. If you have wondered why cutting edge tissue engineering has focused on the production of small tissue sections for use in research and testing, the creation of what are called organoids, accomplished for neural tissue, kidneys, livers, the thymus, and so forth, then let me tell you that the challenge of blood vessel network creation is a big part of the answer.

So here we have an interesting approach, which should probably be considered in the context that not all engineered organs don't actually have to look like their corresponding evolved organs. They just have to work. In some cases form follows function, so researchers are very constrained, but for chemical factories and filters like kidneys, livers, the pancreas, and so forth, the situation is different. If the engineered organ is a strange and unsightly collection of lumps assembled specifically to make the blood vessel problem more tractable, but still carries out its necessary jobs because it has all the right cells doing all the right things, then it is a viable candidate for transplantation.

Researchers create implant with network of blood vessels

Using sugar, silicone and a 3-D printer, a team of bioengineers and surgeons have created an implant with an intricate network of blood vessels that points toward a future of growing replacement tissues and organs for transplantation. The research may provide a method to overcome one of the biggest challenges in regenerative medicine: How to deliver oxygen and nutrients to all cells in an artificial organ or tissue implant that takes days or weeks to grow in the lab prior to surgery. The study showed that blood flowed normally through test constructs that were surgically connected to native blood vessels.

One of the hurdles of engineering large artificial tissues, such as livers or kidneys, is keeping the cells inside them alive. Tissue engineers have typically relied on the body's own ability to grow blood vessels - for example, by implanting engineered tissue scaffolds inside the body and waiting for blood vessels from nearby tissues to spread to the engineered constructs. That process can take weeks, and cells deep inside the constructs often starve or die from lack of oxygen before they're reached by the slow-approaching blood vessels.

Using an open-source 3-D printer that lays down individual filaments of sugar glass one layer at a time, the researchers printed a lattice of would-be blood vessels. Once the sugar hardened, they placed it in a mold and poured in silicone gel. After the gel cured, the team dissolved the sugar, leaving behind a network of small channels in the silicone. Collaborating surgeons connected the inlet and outlet of the engineered gel to a major artery in a small animal model. The team observed and measured blood flow through the construct and found that it withstood physiologic pressures and remained open and unobstructed for up to three hours. "This study provides a first step toward developing a transplant model for tissue engineering where the surgeon can directly connect arteries to an engineered tissue. In the future we aim to utilize a biodegradable material that also contains live cells next to these perfusable vessels for direct transplantation and monitoring long term."

In vivo anastomosis and perfusion of a 3D printed construct containing microchannel networks

The field of tissue engineering has advanced the development of increasingly biocompatible materials to mimic the extracellular matrix of vascularized tissue. However, a majority of studies instead rely on a multi-day inosculation between engineered vessels and host vasculature, rather than the direct connection of engineered microvascular networks with host vasculature. We have previously demonstrated that the rapid casting of 3D printed sacrificial carbohydrate glass is an expeditious and reliable method of creating scaffolds with 3D microvessel networks. Here, we describe a new surgical technique to directly connect host femoral arteries to patterned microvessel networks. Vessel networks were connected in vivo in a rat femoral artery graft model. We utilized laser Doppler imaging to monitor hind limb ischemia for several hours after implantation and thus measured the vascular patency of implants that were anastomosed to the femoral artery. This study may provide a method to overcome the challenge of rapid oxygen and nutrient delivery to engineered vascularized tissues implanted in vivo.
Comments

I prefer not to have silicon blood vessels in my organs.

Posted by: Martin S. at November 4th, 2015 12:11 AM

I'm not fond of the concept either (What if it gets ruptured?), but it beats being dead.

Posted by: Slicer at November 4th, 2015 1:50 PM

This is probably just my layman's lack of understanding, but this seems like a blindingly obvious thing to do. Any engineered/bioprinted tissue larger than a sheet is dying after implant due to lack of immediate blood supply, therefore print in some blood channels.

Can anyone tell me why it has taken so long to do this?

@Martin and Slicer - Haven't the scientists used silicone with a network of channels as a proof of concept that when implanted into an animal blood would flow through the channels? I get the impression from the articles (and the one below) that in the final product the silicone will be replaced with cells to carry out the function of the organ.

http://www.genengnews.com/gen-news-highlights/scientists-create-functional-tissue-implant-with-intricate-blood-vessel-network/81251932/

Posted by: Jim at November 4th, 2015 6:00 PM

@Jim: I did not know silicone was biodegradable. Or you did mean surgically replaced ?

Posted by: Martin S. at November 5th, 2015 12:05 AM

@Martin - my understanding from reading those articles is that silicone was used because it is easy to work with, and the experimenters were just testing if they could get blood flowing through the channels in the silicone successfully. The next step would to still creating the channels using disolvable sugar, but rather than silicone for the 'tissue use bioprinted cells.

Posted by: Jim at November 5th, 2015 1:27 AM

Indeed, tiny blood vessels are what's most important. Gas/nutrient exchange really happens at the capillary bed, in capillaries that are not much larger than individual cells. I hope they can get this worked out.

Posted by: KC at November 10th, 2015 11:48 AM

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