3 D printed blood vessels

[mr friendly guy]

Saw this first on Chinese news, but it was a bit sparse in information, so I found this which gave more information

Dec 12, 2016 | By Benedict

Scientists in China have announced a breakthrough in stem cell biotechnology after their 3D bioprinted stem cell grafts implanted in monkeys were able to promote vascular tissue regeneration. Merging of the 3D printed blood vessels with the organic aorta took just seven days.

Hailed by many as one of the most exciting areas of biotechnology and medicine, 3D bioprinting could someday save countless lives. That’s because, unlike regular plastic and metal 3D printers, 3D bioprinters can be used to fabricate human tissue and organs from stem cells, and these 3D printed body parts—once perfected—could theoretically be transplanted into human bodies to replace defective livers, kidneys, and even hearts.

At present, most researchers in the field of 3D bioprinting have been realistic about the timescale required to 3D print transplantable human organs. Many appear well on the way to making such organs, but believe it could be decades before they are fully functional. Those hopeful of seeing 3D printed transplantable organs must also factor in the time it will take for the relevant authorities to eventually test, evaluate, and grant approval to 3D bioprinting procedures for medical use.

Because of the high-risk nature of transplanting organs, 3D printed tissue and organs are these days more likely to end up in pharmaceutical labs than the operating theater. Why? 3D bioprinted tissue and organs can be used to simulate the equivalent parts of the human body, and can therefore be used ex vivo to test the effects of drugs on the body. Despite their usefulness for drug screening, these fabricated body parts lack many of the attributes of natural human organs, and would therefore be unfit for human transplantation.

Given the fairly conservative timescales offered by many experts in the 3D bioprinting sphere regarding transplantation, and given that most bioprinting applications can be found in pharmaceutical industry, it has come as a major shock to hear that scientists in China have made a massive major breakthrough in stem cell biotechnology, as they witnessed vascular tissue regeneration from 3D bioprinted stem cell grafts implanted in a group of 30 monkeys. The announcement of the breakthrough was made by Dr. Y. James Kang, Chief Scientific Officer and Chief Executive Officer of Revotek, and Director of the Regenerative Medicine Research Center of West China Hospital at Sichuan University.

After overseeing the successful transplant of the 3D printed blood vessels in the large group of rhesus monkeys, Dr. Kang called a press conference to present his findings in detail. According to the biotechnology expert, a team of researchers used a Revotek-T 3D Blood Vessel Bioprinter to print biologically active blood vessels from a “Biosynsphere,” or stem cell bioink, which was prepared from the autologous adipose mesenchymal stem cells (ADSCs) of the monkeys. The 3D printed blood vessels were then used to replace a 2 cm segment of the monkeys’ abdominal aorta.

The researchers behind the groundbreaking 3D bioprinting technology have created a short animation (below) which shows the 3D printing process used to create the blood vessels. First, the temperature-sensitive hydrogel is printed to surround a metal tube. Next, a layer of the “Biosynsphere” is 3D printed on top of the hydrogel, forming a long, tubular structure made of the monkeys’ stem cells. Finally, a graft assemblage is placed over the Biosynsphere layer, after which the underlying layer of hydrogel is dissolved at 37°C, leaving only the aorta-shaped tube of stem cells and its protective graft assemblage. A few years ago, it would have been impressive just to 3D print the blood vessels in this way, but today the news is even more significant: the monkeys are using the blood vessels as if they were their own.

Dr. Kang reported that, five days after the surgery took place, the ADSCs sequentially differentiated into endothelial cells, smooth muscle cells, and other cell types of vascular tissue. Just two days later, the 3D bioprinted blood vessels began to merge with the rhesus monkeys’ own abdominal aorta, and this merging process was completed in just a single month. After closely monitoring the health of the monkeys over the course of several further months, the researchers determined that the 3D printed blood vessels behaved exactly the same as the monkeys’ original abdominal aorta. Moreover, the creatures required no further treatments besides anticoagulants during the first five days after surgery.

The breakthrough in China is huge news for the 3D bioprinting world, and presents an exciting prospect for the development of similar treatments for human subjects. With many people around the world suffering from various cardiovascular diseases, researchers may now be looking to adopt Dr. Kang’s methods to develop methods of 3D printing human blood vessels that are fit for transplantation. The Chinese researchers also believe that their work will also greatly affect stem cell research of all varieties.

The incredible story of monkeys receiving 3D printed blood vessels has already captured the attention of several television news reporters in China, which were granted access both to Dr. Kang’s press conference and the operating room where the implantation was carried out. See the short (Chinese language) reports in the videos below.

Long story short - numerous groups from around the world have been looking into using stem cells and 3 d printers to print blood vessels. There are several applications for this, to testing drugs and studying human physiology, to using blood vessels in transplants. This is not the first time 3d vessels have been printed, but AFAIK this is the first time they have been surgically implanted, although this was only done in resus monkeys. To be of use, it has to be doable in humans.

[Sea Skimmer]

This gives no useful information. Except that it tells us is a Chinese doctor claims he made an amazing breakthrough and went direct to the media about it. And he let TV cameras film his facility, amazing!

Maybe he did manage something, but the work is not even published. Which makes it non scientific bullshit spin 101 until that changes, passes peer review and the results are replicated by a different lab. As it the guy is acting exactly like the way we'd expect a bullshit spinner to act.

Need I point out that Italian doctor who got away with claiming success with 3D printed transplants for years, and it proved to just be a slow way to murder people?

[Broomstick]

Never heard about the Italian guy, can you point me to more info?

There have been some breakthroughs in constructing artificial organic human bits, but it's been slow as the systems are very complex. The only successes I've heard of before this are artificial bladders and a trachea, and I haven't heard about any follow up with those patients (the guy with the new trachea had cancer - he may well be dead of that by now regardless of the success of the transplant).

Or.... come to think of it, one of the guys involved in the artificial trachea was Italian, is that the guy you're referring to?

I find these sorts of medical things fascinating.

[Sea Skimmer]

Paolo Macchiarini and his trachea did not work. Several people lasted years with them, but it never really healed. Several more died rapidly. Then it came out that the guy was falsifying results, and managed to cover up reporting on two deaths early on.

His implants could be sewed up inside a living thing okay looking. But the living/fake boundary never attached, his entire method was in fact an attempt to solve that specific problem using stem cell seeding on the implant. So you got fluid pockets and swelling and infections endlessly.

This Chinese monkey experiment has the exact same damn problem to deal with, and that's where the extraordinary claim problem comes into play pretty damn hardcore. The run to the media approach is wrong by all measures and should be treated with scorn. I see nothing but parroting the official line from the original team.

[Broomstick]

Paolo Macchiarini and his trachea did not work. Several people lasted years with them, but it never really healed. Several more died rapidly. Then it came out that the guy was falsifying results, and managed to cover up reporting on two deaths early on.

His implants could be sewed up inside a living thing okay looking. But the living/fake boundary never attached, his entire method was in fact an attempt to solve that specific problem using stem cell seeding on the implant. So you got fluid pockets and swelling and infections endlessly.

Sounds like a lot of the same problems with artificial hearts - short term they'll work, but long term they won't and, again, there's a problem with natural/artificial interfaces. For people with either a very short life expectancy, or as a bridge to a more conventional transplant, they are arguably viable at this point but not for anyone else.

About the only non-biological thing the body seems to get along with is titanium, which bone bonds very nicely to, but while a titanium implant works for replacing a chunk of bone (in fact, my spouse has had a titanium rod do just that in his leg for 30+ years) that's a very limited role. You can't build a blood vessel out of titanium.

There are similar problems at least some of the time using cadaver tissues and products - they don't always heal up/fuse with the recipient.

It's one thing to say "we'll try this, it's experimental" and then not have it work out - falsifying results, though, is a Bad Thing.

The immune system has had at least a half billion years of evolution, likely more, it's pretty arrogant to think we'll best that in just a generation or two.

[mr friendly guy]

It's true that one requires extraordinary evidence, although given that people have at least printed blood vessels before, its less extraordinary compared to a few years ago. For example a quick search on pub med yields a few articles on previous teams who 3D printed blood vessels.

https://www.ncbi.nlm.nih.gov/pubmed/26951646

https://www.ncbi.nlm.nih.gov/pubmed/26732049

https://www.ncbi.nlm.nih.gov/pubmed/25421556

Since we had the capability of transplanting blood vessels for a long time (eg cardiac bypass surgery) but only 3D printing of vessels for a comparatively shorter time, I thought the latter was the more extraordinary part about it, and transplanting is merely the next step and more plausible. That being said, I would of course want this to be checked out and be repeatable like all science should.

[Simon_Jester]

Skimmer, do you think that the living/synthetic boundary layer problem is solvable, out of curiosity?

[Sea Skimmer]

I don't see why not, but it may require a much more advanced understanding of the physical flow structures of the human body and the process of stem cell differentiation then we have now. Even the hard tissues and bone in a human body allow fluid exchange for example, while most synthetic materials do not. This becomes one of several large problems to overcome.

People have been 3D printing and promising stuff for a long time, the reality is we may not have invented the proper material yet to implement our ideas.

About the only non-biological thing the body seems to get along with is titanium, which bone bonds very nicely to, but while a titanium implant works for replacing a chunk of bone (in fact, my spouse has had a titanium rod do just that in his leg for 30+ years) that's a very limited role. You can't build a blood vessel out of titanium.

My dad has a titanium heart valve. That's an old technology, and we've never gotten much past that. It will work because it's basically an isolated structure in the human body and can be somewhat rigid in placement. He also has one valve out of a pig. The valves work off pressure shifts so they involve no muscle actions. The problem with most tissue is it needs to flex in a more random way then an on/off valv. Which means you need a good bond with other flexible material or you'll get a cyst when a gap opens between them.

The immune system has had at least a half billion years of evolution, likely more, it's pretty arrogant to think we'll best that in just a generation or two.

Yeah that. The DNA code complexity matters is what we've learned, and it's long as hell and the body doesn't follow it perfectly either.

[Shroom Man 777]

I'm amazed at your grasp on everything from anti-ship missiles to tissue generation.

I guess scienticianists have to figure out the next step of tissue generation. That which lies beyond merely generating cells, but what happens when enough cells start working together, that boundary between merely "tissue" and "whole organ" or "larger body." Some kind of complexity emergence phase shift occurs there. Does this just happen when there's enough volume of cells? Or are there necessary feedback loop triggers that should be taken into consideration when one's growing things in Petri dishes (I think this is the case)?

[Broomstick]

Oh, wait - two more things that do seem to integrate into the human organism: cochlear implants, and the new experimental retina chips for blindness. But those are subject to much different stresses than, say, blood vessels. Also, if they fail you won't die from it.

I guess scienticianists have to figure out the next step of tissue generation. That which lies beyond merely generating cells, but what happens when enough cells start working together, that boundary between merely "tissue" and "whole organ" or "larger body." Some kind of complexity emergence phase shift occurs there. Does this just happen when there's enough volume of cells? Or are there necessary feedback loop triggers that should be taken into consideration when one's growing things in Petri dishes (I think this is the case)?

One of the mechanisms are signalling chemicals that exist in gradients from one end of an organism or organ or tissue. The concentration of the chemical signals the cells to differentiate. We can use this to create monsters - chickens with too many wings, frogs with too many legs, flies with legs and wings in the wrong places, etc. - but not new organs for people.

[Simon_Jester]

It would seem like one of the obvious things to experiment with (which may not be possible for ethics reasons) is growing small pieces of tissue that can be grafted and see how the graft progresses. Like, a few capillaries or something highly specific.

The problems with doing this are fairly obvious.

[Sea Skimmer]

I'm amazed at your grasp on everything from anti-ship missiles to tissue generation.

Can't say I know much else on it. But basically at a certain point technology and biology do merge on subjects like this, many of the super batteries and ultra carbon nantube structures we'd like to build and think are possible also require biological scale levels of materials control. The actual molecules the human body is made of can get pretty complicated. 3D printing can make a lot happen, but not if you don't know what to print or you need molecule by molecule changes.

Pure biotech can never be stronger then flesh basically, but bioinspired engineering is a whole different story. Nature has spent an enormous amount of time engaging in minimal strength-high stress engineering we are just starting to peel apart in detail. Ultimately though the problem with the article remains simply that it's a giant piece of venture capital investment bait propaganda, and not scientific at all. You don't need to know the subject to recognize it's trying to sell you something.

I guess scienticianists have to figure out the next step of tissue generation. That which lies beyond merely generating cells, but what happens when enough cells start working together, that boundary between merely "tissue" and "whole organ" or "larger body." Some kind of complexity emergence phase shift occurs there. Does this just happen when there's enough volume of cells? Or are there necessary feedback loop triggers that should be taken into consideration when one's growing things in Petri dishes (I think this is the case)?

Many feedback loops are at work within the organ and throughout the body, and understanding those signals is a major part of DNA's length. Some route through the brain, and some don't. Chemicals produced in the brain affect all organs in the body.

Replacing blood vessels is certainly more straightforward then growing a liver in a jar but you just can't judge anything off a random unpublished Chinese monkey lab. The method might work, might sorta work, or they might have a whole dumpster full of dead monkeys hidden in the back alley. We've got nothing to judge that on.

[Sea Skimmer]

It would seem like one of the obvious things to experiment with (which may not be possible for ethics reasons) is growing small pieces of tissue that can be grafted and see how the graft progresses. Like, a few capillaries or something highly specific.

The problems with doing this are fairly obvious.

That's what a skin graft basically is. Skin is kind of easy though because of how damn fast it grows and tough it is in general. That's also why skin cancer is so deadly.

The big practical problem though is regulating the growth environment to match the acceptable range of internal human body conditions. Right now our tech just can't do that all that well, it isn't precise enough and it's just not actually performing all required functions. Also a lot of our blood and chemical testing methods in general don't work in real time, a human body does, so we are batch monitoring processes meant to be constantly adjusted. Nanotechnology should eventually lead to some radical breakthroughs on that kind of testing. To a point it already is, but actually mass implementing some of this technology is not easy.

A big problem also remains that the same genes do different things in different contexts and organs. Makes any solution involving gene splicing realllly interesting.

[cosmicalstorm]

Printed blood vessels and functioning vasculature in general is far away still. Synthetic blood will hopefully arrive much sooner.

I keep tabs on Fightaging.org for serious no-nonsense and no hype news regarding the production of what will, hopefully, become our future rejuvenation medicine.

Engineering Vasculature in Decellularized Lungs
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Researchers here demonstrate the ability to regrow the blood vessel network in a decellularized lung, an important step in creating any sizable amount of engineered tissue. Decellularization is the process of stripping cells from donor tissue, leaving the intricate structure of the extracellular matrix and its chemical cues to guide cell growth. That matrix scaffold can be then be repopulated with a patient's cells to create an organ ready for transplant with minimal rejection risk. Since the scientific community still cannot recreate the full complexity of the extracellular matrix in artificial scaffolds, this remains the only way to create fully functional patient-matched organ tissue at the present time. Even so repopulation of decellularized organs has only been successfully carried out for a few organ and tissue types to date. It is a complicated process to deliver the right types of cells and coax them into recreating tissues correctly, especially when it comes to the all-important blood vessels that will supply the organ's cells:

Quote:
Bioengineered lungs produced from patient-derived cells may one day provide an alternative to donor lungs for transplantation therapy. Here we report the regeneration of functional pulmonary vasculature by repopulating the vascular compartment of decellularized rat and human lung scaffolds with human cells, including endothelial and perivascular cells derived from induced pluripotent stem cells. We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol.

Using these methods we achieved ~75% endothelial coverage in the rat lung scaffold relative to that of native lung. The regenerated endothelium showed reduced vascular resistance and improved barrier function over the course of in vitro culture and remained patent for 3 days after orthotopic transplantation in rats. Finally, we scaled our approach to the human lung lobe and achieved efficient cell delivery, maintenance of cell viability and establishment of perfusable vascular lumens.

Link: http://dx.doi.org/10.1038/nbt.3354