Physicians

Figure 1. Medical team at the Division of Internal Medicine of the University Medical Centre Ljubljana, Slovenia. From the left: Petra Zupan, a registered nurse, Miran Brvar, MD, PhD, Assist. Prof., a specialist in internal medicine, Hikmer Badnjević, a nurse.

Figure 2. Meeting with Prof. Dragica Smrke (first from the right) at the Department of Traumatology of the University Medical Centre Ljubljana.

The discussion panel with Prof. Dragica Smrke took place at the Department of Traumatology at the University Medical Centre Ljubljana on the 15th of July 2012. The panel consisted of student team members, advisers and Prof. Dragica Smrke, who is the head of the Department of Surgical Infections at the University Medical Centre Ljubljana (Figure 2). She specialises in treating chronic skin wounds and bone fractures that are not healing properly.

We presented the basic idea of our project and were interested if she thought that it was applicable to her area of specialty. There were two possible cases where we imagined it could be used, one is in the therapy of bone fractures that are not healing properly and the other is chronic skin wound healing. For the purpose of bone healing, microcapsules with therapeutic cells could be delivered at the site of the fracture and could support the formation of new bone tissue. The medical students in our team proposed to use bone morphogenetic protein factors (BMPs), of which she was sceptical. She informed us that although these biological drugs are effective they are not in general use in clinical medicine, mainly because of their extremely high price. If our delivery system solved this problem this could represent a therapeutic application with great potential in the future. Prof. Smrke thought we could put our system to a much better use in the healing of chronic skin wounds which are extremely common in her everyday medical practice. An advantage to this approach is the ease of applying the microcapsules to the wounded tissue and a proposed collaboration on in vivo testing. The conclusion of our meeting was that this application could be a good way to improve chronic wound healing.

Figure 3. Meeting with Prof. Mojca Matičič (first from the left) at the Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana.

The meeting with Prof. Mojca Matičič, head of the Department for Viral Hepatitis, took place in the conference room at the Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana on the 17th of July 2012. The panel consisted of student team members, advisers and Prof. Mojca Matičič (Figure 3). She is a specialist in infectious diseases and internal medicine and her main area of expertise is clinical management of patients with chronic hepatitis B or C.

We introduced the idea of our project to Prof. Matičič and wanted to know if it could be applicable for the treatment of chronic hepatitis C. We proposed the idea of treating this disease with a combination of the standard therapeutic interferon-alpha and hepatocyte growth factor that would potentially reverse the long term effects of infection on progression to life threatening conditions such as liver cirrhosis and liver cancer that happen in up to 40% of untreated patients or patients unsuccessfully treated with the currently recommended standard of care medications. Her consideration was that something like this has never been done before and so it would be a complete novelty in treating hepatitis C and in her opinion it holds much promise for the future. She also wanted to know about the route of administration of the microcapsules. We considered two possibilities. The first would be a direct application to the liver. She told us this might be possible and that she could organize a meeting with an intervention radiologist, specialising in liver procedures, with whom we made arrangements to discuss this matter further. The other possibility which we considered for administration was to inject the microcapsules into the peritoneal cavity, which could accommodate a larger volume of microcapsules as a mimic of an artificial organ. It turns out intraperitoneal application might be suboptimal because the concentration of therapeutic in the liver would probably be lower.

Since we were interested in the perception of this type of therapy by patients, we composed a questionnaire on our project which she reviewed and distributed among her patients during her outpatient clinic duties.

Figure 4. Meeting with Prof. Zlatko Fras (second from the right) at the Division of internal medicine, University Medical Centre Ljubljana.

The meeting with Prof. Zlatko Fras took place in the seminar room at the Division of Internal Medicine at the University Medical Centre Ljubljana on the 10th of September 2012 (Figure 4). The panel consisted of student team members, advisers and Prof. Zlatko Fras, who is a cardiologist and head of the Division of internal medicine of the University Medical Centre Ljubljana. He specializes in treating ischemic heart disease, peripheral arterial disease and various other cardiovascular diseases.

We were interested in the application of our idea to the field of expertise of Prof. Fras. Treating cardiac ischemia was first on our list of possible applications. Prof. Fras suggested it could be especially effective in treating patients after myocardial infarction in whom the narrow time window of opportunity was missed. This includes patients who did not receive the proper treatment in less than 90 minutes after the myocardial infarction. Microcapsules could be applied simultaneously with percutaneous coronary intervention via the catheter applied into the coronary artery, thus minimizing the need for any additional procedures. Another possibility of administration of microcapsules in the myocardial muscle would be through pericardiocentesis. Prof. Fras also suggested another way of using our therapeutic system. He daily encounters patients with peripheral arterial obstructive disease in his clinical practice. The prevalence of this disease in the adult population is 3% (20.000-30.000 patients with this disease are treated per year in the University Medical Centre Ljubljana). He considered that it would be possible to deliver microcapsules to the occluded vessel where they would produce antiinflammatory and revascularizing therapeutics. The route of administration is much easier in the limb than in the heart.

During the course of our project we often asked ourselves what the best way to introduce microcapsules with engineered synthetic devices into the body would be. The ideal type of administration would have to be:

1. as minimally invasive as possible,
2. deliver the capsules throughout the whole affected tissue and
3. ensure that the capsules will remain in this location.

Figure 5. Peter Popovič, MD, from the Institute of Radiology, University Medical Centre Ljubljana.

With respect to the treatment of hepatitis C we thought of three approaches: percutaneus application of capsules into the liver parenchyma, delivery into the peritoneal cavity or delivery via the interventional radiology approach through the portal vein or hepatic artery, a procedure which we discussed with radiologist Peter Popovič, MD, Msc, teaching assistant. Mr. Popovič is the head of the Department for abdominal radiology (Figure 5) at the Institute of Radiology and specializes in hepatic interventional radiology. We discussed the following approach: a radiologist introduces a catheter into the femoral artery and proceeds via the thoracic artery to the hepatic artery where he injects the suspension of our cells into the blood. The capsules then travel through the arterial tree, getting stuck inside arterioles and capillaries of the liver, remaining there and producing our drug of choice. We got very excited as he went on to say that injecting capsules into the hepatic artery would most likely be possible. He explained that his team carries out these procedures on a daily basis, injecting microspheres (approximately the same size as our capsules) with attached chemoterapeutics into the hepatic artery to target malignant tumours located in the liver parenchyma. To our fear that the capsules would block the blood flow to a significant portion of the liver parenchyma he responded with the fact that the liver gets the majority (80%) of nutrients and oxygen via the portal vein. He added that with the appropriate number of capsules a very small number of vessels would be blocked therefore all of the tissue would be perfused because of collaterals. This led us to our next question about the delivery to an ishemic muscle or the myocardium for the treatment of ishemic heart disease or peripheral arterial disease. Again he responded that an interventional radiology approach may be feasible. Mr. Popovič also mentioned that this approach could be tested on pigs, as mice are too small. He invited us to stay in touch for potential testing of this type of delivery with our microcapsules. Before the meeting we were concerned about not being able to deliver the capsules to the appropriate sites with ease, this meeting, however, filled us with renewed excitement.

In summary, all physicians we contacted thought that the proposed approach offers many advantages and that it would definitely be worthwhile to test it in vivo.