The interview with project manager of 3D-printing of bionic pancreas, dr Michał Wszoła

Paweł Łepkowski: This year, the American company Medtrononic began selling Minimed 670 GE in the United States, which, due to the cooperation of an intelligent sensor monitoring glycemia with an insulin pump, was called a hybrid artificial pancreas. Another American company, Beta Bionics, introduced a device called “iLet”, which has already been hailed as the first bionic pancreas because it creates an intelligent, algorithm-controlled closed loop of insulin and glucagon inflow to the body. The founder of this device, Prof. Damiano from the University of Massachusetts, describes this device as a bridge to the invention of a cure for diabetes type I. Diabetologists are hoping for a breakthrough in the treatment of type I diabetes, but in fact it is only your project that radically solves this problem.

Dr Michal Wszola: The devices you are mentioning will certainly make it much easier to treat diabetes, but I agree with the statement that this is a bridging treatment. Both devices are de facto artificial pancreas. Of course, this is verbal semantics. It doesn’t matter how we call it: artificial or bionic. The point is that it is a mechanical device. I do not under any circumstances depreciate their value, I even support their producers. However, it is important to realise that these devices have their limitations. In fact, they don’t test blood sugar, they only test sugar in interstitial fluid.  The difference in glycaemia between blood and interstitial fluid may be about 25 minutes. So if the level of glucose in the bloodstream drops, it will take almost half an hour before the tissue fluid “observes” it. All algorithms are supposed to predict trends of decreasing or increasing glycemia. Maybe in the future algorithms will teach and improve the profile of action for a given patient. However, this is still a worrying and dangerous half an hour’s delay. This is the first difference compared to the proposed bionic pancreas. The second difference is that Minimed injects only insulin using a very advanced algorithm – no glucagon supply – i. e. the risk of underestimation still exists – this device will certainly improve the control of high sugars, but not low ones. iLET is additionally a pump adapted to various CGM (continous glucose monitoring) systems, so it is dependent on the glycemic measurement system – continuous measurement in most devices is performed every 5 minutes. That is why we cannot talk about a complete cure for diabetes, but about enabling people with diabetes to function well. This is not yet clear, but it is likely to reduce diabetic complications. I say “likely” because none of us really knows how much these pumps and all these devices will be able to improve and reduce the risk of complications. These are undoubtedly very good devices, much better than what has been so far, but still not offering such a supply of insulin that is suitable for what is really needed by our body. In a critical situation, this can be of paramount importance. For example, when someone drives a car. In addition, I believe that defining such devices as “bionic” is unjustified, because “bionic” means – created with the help of engineering, but also related to a biological element. Unfortunately, there is no biological element there, although the engineering part is very developed. And the project we’re working on is to create a truly bionic pancreas using 3D printing, advanced bioengineering elements, using stem cells and pancreatic islets to create a truly functional organ that will produce insulin and glucagon from cells – that’s just what can be called a real bionic pancreas.

: In a word, will it be a fully functional biological organ?

MW: That is what we have plans for. There will be no pump, no accumulator that has to supply hormones, but living cells of the patient, which will naturally produce insulin and glucagon. We will take the stem cells from the patient and transform them into pancreatic islets, i. e. into a group of alpha and beta cells producing glucagon and insulin. Our islets will be arranged with the help of a 3D printer around the vessels printed with the same printer (we will connect them surgically with the patient’s vessels). From our islets through the vessels insulin and glucagon will reach the patient’s body. This hormonal production will be exactly the same as in every healthy person. Our project in no way tries to compete with the production of mechanical equipment. Bionic pancreas, as well as hybrid devices work on two opposite wings of the fight against diabetes. If we look at who qualifies for clinical trials of these very advanced devices, these are mainly people with well-controlled diabetes – young, healthy people, without complications, who do not have severe diabetes mellitus. This is because any disruption in the administration of insulin in these algorithms can have fatal consequences for patients.

: Therefore, even the most perfect pump is only used to maintain normoglycemia, under certain conditions and with a healthy lifestyle. We can therefore say that there is only support for certain processes.

MW: Of course, this is a very important support, because now it is believed that it is no longer important to measure glycemia only on a unit basis, but only as long as a constant range of normal glycemia is maintained. Certainly, these devices, combined with a fixed glycemic measuring system, help to provide a much better supply of insulin than was previously the case of pens, injections or even with the use of ordinary insulin pumps. And it is known that the longer someone is in the range of correct glycemic norms, the smaller is the chance for the development of complications. The bionic pancreas is at the other end of the approach to diabetes. I am a transplant surgeon and the entire idea for the creation of a bionic pancreas originated from the fact that for many years I was involved in the transplantation of pancreas and pancreatic islets to patients with diabetes, in whom very serious complications already took place, such as e. g. kidney failure. Such a patient is transplanted with the pancreas and kidney, or pancreatic islets with the kidney. Another group are patients with severe diabetes, i. e. patients who have large drops in blood glucose levels but do not feel them. Such a patient may have a glucose level of 30 mg/dL (the norm should be in the range of 70-120) and will not feel it. And yet the human brain feeds only on glucose. So it works well until the bloodstream is at the right level of sugar. When it falls below a certain limit, it can simply turn itself off, i. e. the patient loses consciousness. Immunosuppressions are the most dangerous for a group of patients who already have a damaged nervous system and do not show signs of undernourishment, such as trembling, dizziness or excessive sweating. Generally, about half of diabetics have undiabetics, but most are able to observe their coming. When low sugar comes, we have the symptoms I mentioned. These are the symptoms of hypoglycaemia associated with the activation of the nervous system, which gives us a signal that something needs to be done about it – if there is no such signal – there may be a loss of consciousness.

: A healthy pancreas contains about a million cells called islets of Langerhans. The cells that make up the islets – alpha, beta and delta cells – are mainly responsible for the production of glucagon and insulin. Will the bionic pancreas that your research team is working on contain the same number of cells as the healthy pancreas? Will there not be a danger that it will only play the role of an insulin hormone producer, such as the previously mentioned minimed?

MW: No, it is not an option at all. This is the most important aspect of this project. The pancreatic islets, as you said, consist of several cell types. Our goal is to create pancreatic islets that will have: firstly, insulin-producing cells; secondly, glucagon-producing cells. Only from these cells we will create pancreatic islets during 3D breeding. Then the islets grown in this way will be put into a bio-printer and printed together with our bioink and blood vessels. In the course of my professional work I saw so many complications, so many problems that I started to think about how to solve them – this is how the idea for the project came into being. If everything succeeds, the first patients who will be qualified for this type of treatment will be people with various complications of diabetes. If it turns out that all this works perfectly, eliminates complications, is lightweight, cheap to use and transferable on a large scale, then, of course, the group of potential people who could benefit from it will certainly be much larger.

: Who will be the potential donor of the cells from which the bionic pancreas will be printed?

MW: We will take cells from the bloodstream or from the adipose tissue of patients who we will qualify for transplantation. The first step will be to collect the stem cells, then modify them so that the immune system of the patient does not later recognize them as enemies. After the modification they will be multiplied in large quantities. If we have a sufficient number of stem cells, only then we will begin to transform them into alpha and beta cells, i. e. producing glucagon and insulin. When we have the right amount of these cells we will create pancreatic islets from them, and only then we will put them into one cardridge in a 3D printer with a special bioink dedicated to pancreatic islets. In the next cardridge there will be elements that will build the vascular system – the smallest vessels that we are able to print are those that have a diameter of about 1 mm. We hope that the remaining tiny capillaries of the capillary vessel will develop by themselves under the influence of certain factors, which will also be added to our bio ink. Our task is to stimulate angiogenesis and create new vessels, so that the organ, which we implant to the patient, will additionally rebuild itself in the patient’s body. With the design of this vessel, the 3D printer will create: first the support layers on which it will apply the pancreatic islands, and around it will expand the vessels. And so, layer by layer, it will create a bionic organ. This organ will then be placed in a special chamber, a bio-reactor, where the flow will be connected and the culture will be carried out over the next few days to assess how functional what we have printed is. Only after these tests, we will notify the patient that we have an organ ready for him or her and invite him or her for a mini-invasive organ implantation procedure.

: This is great news. It follows that the organ will come from the cells of the patient, who will not have to wait for the donor to be transplanted.

MW: That is our hope. Additionally, we modify the cells in such a way that they are not recognized by the immune system, because we should remember that type I diabetes is an autoimmune disease, so if we produced exactly the same pancreatic islets as the patient had before, his immune system would destroy them very quickly. Therefore, we produce slightly different ones, which will have different markers on their surface, so that they will not be noticeable to the immune system. The use of the recipient’s own cells, apart from the obvious aspect of not having to wait for the donor, thanks to our modifications, will most likely avoid immunosuppression.

: I counted three stages, which you mentioned. Which of these stages, from the moment we take the cells to the moment when the transplant is ready, causes you the biggest problems?

MW: Each of these stages has its own very difficult moments. Firstly, in order to be clear, we are not yet able to change the stem cells at this stage in such a way that the immune system of a person with diabetes does not recognise the produced pancreatic islets. So this is a true terra incognita, which we have to move around. The second point is stem cell proliferation. It looks different in the laboratory phase to cure the mouse, and completely different when we have to multiply the stem cells to several tens of billions of cells with exactly the same identity. During multiplication, they cannot start to transform into any other cells. The third problem is the transformation of stem cells into insulin and glucagon-producing ones. Currently, the effectiveness of transformation in laboratories around the world is around 40 percent. Another matter – nobody described the conditions under which pancreatic islets should be printed, can they be printed? Using what bioink? How to print vessels? We don’t know yet how the bionic pancreas will look like. We have already found answers to a number of questions on this particular issue. We also have a model of the bionic pancreas, but will it work and will it function properly, or such a system of vessels as we planned it is the right one? Or maybe we should change it a little – all this will only be shown to us by further research. We have spent the last 1.5 on creating a bioink that will be suitable for use with pancreatic islets, fine-tuning the conditions of bioprinting of pancreatic islets and starting to print vessels, so let’s say that one important stage is over.

: Will the transplant procedure that you envisage have side effects on the patient’s health?

MW: The procedure of bionic pancreas implantation is supposed to be a minimally invasive procedure. Nevertheless, we will have to implant an organ, i. e. we will have to come to the vessels, make a vascular anastomosis, i. e. sew the artery to the artery and the vein to the vein, but comparing to a very burdensome pancreatic transplant with a very high risk of perioperative complications, it will really be a very little invasive procedure.

: The pancreas is located in the upper part of the abdomen rim. Do you plan to place a bionic pancreas there?

MW: We will not get close to the patient’s own pancreas at all, because we do not need it in any way. The pancreas is normally transplanted to the hip plate and I think that we will use a similar model for the transplantation of our bionic organ – but in a less invasive way – I think of the extraperitoneal space, i. e. the placement of the pancreas outside the abdominal cavity. In addition, we will use slightly smaller vessels than the hip ones, which will allow the patient to go home faster, quicker rehabilitation, minor pain and hopefully – a small number of surgical complications.

: And now perhaps the most important question: when will the transplanted bionic pancreas work?

MW: Assuming that the organ will work as I presented it, the patient will not have to take insulin at all, although it may turn out that for a short transitional period this bionic pancreas will be subject to some changes already in the human body. However, the patient will gradually decrease the insulin dose within a few days by observing his or her glycemic values.

: Thus hyper and hypoglycemic states are not going to threaten him anymore?

MW: No, because he will already have his own beta cells that produce insulin and alpha cells that produce glucagon.

: We have the last quarter of 2018. When, with very conservative estimates, do you expect the first patient to leave the hospital with a bionic pancreas?

MW: As we have already talked about, this is a very complicated program with many question marks. Several entities forming the Bionic Consortium – the Foundation of Research Science Development as the leader of the whole project with me and the scientific team, additionally Warsaw Medical University with the team of Prof. Artur Kaminski, Nencki Institute with Prof. Agnieszka Dobrzyn, Warsaw University of Technology with Prof. Wojciech Święszkowski and the Clinical Hospital of the Child Jesus and MediSpace Ltd. as a business and technological partner are involved in the whole project. We have received funding from the National Centre for Research and Development under the Strategmed programme, which runs until the end of 2019 – but this is the end of pre-clinical research. The clinical phase, assuming that everything goes well, will be in 4-5 years at the earliest.

: Your project means a complete cure for type one diabetes. After years of hard fight against this disease, you are proposing an unprecedented breakthrough in the discovery of penicillin or the insulin hormone itself. This is great news for the whole world. I wish you good luck.

MW: Thank you for your warm words, but the breakthrough is still a long way to go – for now there is a vision of hard work ahead of us and if we don’t do our homework – the whole breakthrough will be just a few articles in the press… Which I hope will not happen. I firmly believe that Poles will once again show that they are able to create breakthrough medical therapies. I also invite everyone to visit the Foundation’s website www.fundacjabirn.pl where you can learn more about our activities – for example, we are planning to auction images created from microscopic images taken during work on the bionic pancreas – it sometimes really looks cosmic. I also encourage everyone to follow our actions on social media.

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