PORTFOLIO

Ziel des Impulsprogramms „Biomaterials“, das unter der koordinierten Ägide des SVMT steht, ist es den Biomaterialwissenschaften durch eine beispielhafte Durchführung von guten Pilotprojekten einen Anstoss zu geben. Die im Rahmen einer Ausschreibung geförderten anwendungsorientierten Projekte zeichnen sich durch eine hohe wissenschaftliche Qualität, Interdisziplinarität in Bezug auf Materialwissenschaften, Medizin, Pharmazie sowie Naturwissenschaften aus.

Mit dem interdisziplinären Programm Biomaterialien werden Projekte an Hochschulen gefördert, die eine Brückenfunktion zwischen Materialentwicklung und klinischer Anwendung aufweisen. Die Gebert Rüf Stiftung unterstützt das Programm in Sinne eines Impulsprojektes auf einem für die schweizerischen Hochschulen sowie für die schweizerische Industrie sehr wichtigen Gebiet.

Im Rahmen einer Ausschreibung konnten im Sommer 1999 drei hervorragende Projekte gefördert werden:

Tissue Engineering Heartvalue

Projektleiter: PD Dr. Gregor Zünd, Oberassistent, UniversitätsSpital Zürich, Departement Chirurgie, Klinik für Herz- und Gefässchirurgie, D-LAB-32, Rämistrasse 100, 8091 Zürich, eMail gregor.notexisting@nodomain.comzund@chi.notexisting@nodomain.comusz.notexisting@nodomain.comch

Abstract: Valvular heart disease is a significant cause of morbodity and mortality world wide. Valve replacement surgery is efficacious, and the state-of-the art valves used clinically include mechanical valves, glutaraldehyde fixed xenografts, and cryopreserved homografts. Because mechanical valves represents a foreign body, a live-long administration of anticoagulation therapy, which shows side-effects due to hemorrahigc complications has to be carried out. Xenograft valves have a lack of durability, most oft them have to be replaced after 10 – 15 years (difficult for young people). These limitations gave the motivation to use tissue engineering techniques to create a new autologous hart valve. Initial in-vitro and in-vivo experiments demonstrated the feasability of construction a tissue-engineered valve leaflet tissue in lambs. No stenosis or reguritation could be detected after implantation of valve leaflets at the pulmonary leaflet position. From the good results with animal cells, the research group at UniversitätsSpital Zürich decided to create heart valves also from human cells as well.

Results: About six month after starting the project a group of several medical and scientific researchers have created a team under the leadership of Dr. G. Zünd and Dr. Hoerstrup to develop a human heart valve. The concept is to transplant human aortic tissue onto a biodegradable scaffold (Collaboration with the Dept. of Materials Science, Prof. U. Suter at ETHZ), to grow and to condition the seeded cell-scaffold device in vitro and finally to implant the tissue-like construct into the patient. The donor cells are harvested e.g. from peripheral ateries and mixed vascular cell populations consisting of myofibroblasts and endothelial cells are obtained. Out of these pure viable cell lines can be easily obtained by cell sorters and the subsequent seeding onto the biodegradable scaffold is undertaken in two steps: First the myofibroblasts are seeded and grown in vitro followed by endothelial cell seeding leading to the formation of a native leaflet-analogous histological structure. The next step is to enhance the growth potential of the various cells, to get a tissue which is enough strong and to undergo infections which can occur by the donor cells.


Submucosal Urethral Bulking
Projektleiter: Prof. C. Iselin, Clinique d‘Urologie, Département de Chirurgie, Hôpital Cantonal, 1211 Genève 14, eMail Christophe.notexisting@nodomain.comIselin@hcuge.notexisting@nodomain.comch

Abstract: Urinary incontinence (UI) is a frequent problem that exerts a social and/or hygienic impact in 23% of woman 20 years old and over attending family physicians offices. This prevalence translates into significant health care costs, estimated to exeed 10 billion dollars per year in the United States. Pathophysiological mechanisms of UI include detrusor instability, vesicourethral hypermobility in females, and intrinsic sphincter deficiency (ISD). Last mentioned is a weakening of the bladder outlet closure mechanism due to damage or malfunction of the intrinsic sphincter unit. When incontinence is related to ISD, reduction and abolition of urine leakage may be achieved by increasing the proximal urethral resistance. Submucosal injections of bulking agents were shown to increase urethral coaptation, e.g. submucosal urethral collagen injections have become an increasing applied treatment, improving significantly 58 to 85 % of patients with follow-up currently limited for periods of 6 to36 months. Although collagen has proven to be a safe and valuable bulking agent, it is prone to resorption and local migration, therefore questioning the durability of its beneficial effect. Current research is focusing on biomaterials with increasing stability to lengthen the success rate of submucosal urethral bulking. It is therefore the aim of the project a) to develop non-degradable biomaterials and to refine the endoscopic technique of its minimally invasive implantation, b) to test non-degradable biomaterials which are currently used for other medical applications, c) to design and perform new test methods for submucosal urethral collagen injections to improve this minimal invasive tissue bulking, possibly also for other applications.

Results: In the last six month polymers were developed by the Pharmaceutic Department, University of Geneva. These polymers are in the last test phase and have been patented some weeks ago. Publications will follow. In addition in-vitro models for submucosal injections into bladders of pigs have been established, by which the different non resorbable polymers can be tested on their behaviour to form bulks susceptible to increase tissue coaptation. If the test polymers behave good, histological tests will follow. In the next step, pigs will be used as animal models. Their bladder behave like a human one, so that similar endoscopic instrumentation can be used. A part of the pigs will be sacrified after 3 month and a histology as well as pathologic investigations will be carried out on other organs to examine possible migration of polymer particles. This procedure will be carried out with another group of pigs after 6 and 9 month.


Microsphere Vaccines
Projektleiter: Dr. Pål Johansen, ETH Zürich, Galenical Pharmacy, Winterthurerstrasse 190, 8057 Zürich, Email johansen@pharma.notexisting@nodomain.comethz.notexisting@nodomain.comch

Abstract: Due to the partly inefficient immunisation coverage in the developing countries as well as high mortality and morbidity of related diseases which have been practically eradicated in the industrial world, the World Health Organisation (WHO) has supported research programmes aiming at improving and simplifying immunisation schemes and, thereby, improving the epidemiological health situation in the third world. Since 1990 a major effort of the research activities of the Galenic Pharmacy at ETHZ has been devoted to develop a single-injection vaccine delivery system based on injectable microspheres fabricated from biodegradable and biocompatible polyesters. Today WHO considers the ETHZ group to be one of very few research teams capable to prepare an efficacious single-injection vaccine. The overall goal of this project is to develop a single-injection vaccine containing several antigens. A pre-clinical screening in mice and guinea pigs of vaccines containing tetanus, diphteria, pertussis and synthetic malaria antigens is therfore performed.

Resultate: The results of the first part of this study on microsphere-based multivalent vaccines have shown interesting features both with regard to the fabrication of such vaccines and to their performance in vivo. We have obtained important information on the microencapsulation of antigens which previously have not been studied with polymeric microspheres but which will be essential in a multivalent vaccine (Haemophilus Influenza B and Pertussis) or as a single vaccine (malaria). The combination of tetanus and diphtheria toxoids did not cause unwanted interaction in vivo but generated strong and protective antibody responses which were dependent on the polymeric material utilised. Importantly, single populations of antigen loaded microspheres performed better than mixtures of microspheres. This very much should simplify the production technology and progress towards clinical testing.
Next, triple and quadruple vaccines will be tested. These will also be accompanied with challenge experiments in order to determine the protection efficacy of the vaccines. Furthermore, we will look closer to immediate immune responses and the influence of materials and technology on the onset and type of immune response stimulated.

Projekt Microsphere Vaccines
Johansen P, Gander B, Merkle HP, Sesardic D (2000) Ambiguities in pre-clinical assessment of microparticulate vaccines. Trends in Biotechnology 18, 203-211
Johansen P, Men Y, Merkle HP, Gander B (2000) Revisiting PLA/PLGA microspheres: an analysis of their potential in parenteral vaccination. European Journal of Pharmaceutics and Biopharmaceutics 50, 129-146
Johansen P, Merkle HP, Gander B (2000) Technological considerations related to the up-scaling of protein microencapsulation by spray-drying. European Journal of Pharmaceutics and Biopharmaceutics accepted
Johansen P, Estevez F, Zurbriggen R, Corradin G, Merkle HP, Glück R, Gander B (2000) Towards clinical testing of a single-administration tetanus vaccine based on PLA/PLGA microspheres. Vaccine Submitted.
Johansen P, Peyre MI, Gander B, Sesardic T (2000) Tetanus and diphtheria toxoid combined in biodegradable microspheres induce protective immunity in guinea pigs after a single-administration. Under preparation

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