3D-Bioprinted bionic pancreas – ATMP: A disruptive innovation in transplantology.
Michal Wszola1,2,3, Marta Klak 1,2, Andrzej Berman 1,2,3, Sylwester Domanski 2, Tomasz Dobrzanski2, Katarzyna Wozniak 2, Oliwia Janowska2, Przemyslaw Wrochna 2, Dominika Ujazdowska2, Agnieszka Gornik2, Anna Papierniak-Wygladala2, Dominika Piatek3,4,5, Jaroslaw Wejman6, Dominika Szkopek7, Katarzyna Roszkowicz-Ostrowska7, Kacper Nowak8, Robert Paslawski8, Urszula Paslawska8,9, Lukasz Kownacki10, Piotr Cywoniuk14, Jaroslaw Wolinski7, Agnieszka Dobrzyn11, Artur Kaminski12, Wojciech Swieszkowski13.
1Foundation of Research and Science Development, Warsaw, Poland; 2Polbionica S.A., Warsaw, Poland; 3Medispace Medical Centre, Warsaw, Poland; 4I-st Department of Clinical Radiology, Medical University of Warsaw, Warsaw, Poland; 5Department of Dental and Maxillofacial Radiology, Medical University of Warsaw, Warsaw, Poland; 6Center for Pathomorphological Diagnostics Ltd, Warsaw, Poland; 7Institute of Animal Physiology and Nutrition Jan Kielanowski of the Polish Academy of Sciences, Jablonna, Poland; 8Department of Internal Diseases with Clinic for Horses, Dogs and Cats, Faculty of Veterinary Medicin, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland; 9Veterinary Institute, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Torun, Poland; 10Department of Radiology, European Health Center, Otwock, Poland; 11Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland; 12Department of Transplantology and Central Tissue Bank, Medical University of Warsaw, Warsaw, Poland; 13Faculty of Materials Engineering, Warsaw University of Technology, Warsaw, Poland; 14NanoBiomedical Center, Adam Mickiewicz University, Poznan, Poland
The WHO states that only 10% of the global organ transplant demand is met. 3D bioprinting offers a potential solution for chronic diseases like pancreatitis and type 1 diabetes but faces challenges, with obtains: 1. The bioprinting of a vascular system to form a dense network within the organ. 2. Ensuring that bioprinted organs can withstand pressures exceeding 300 mmHg. 3. Developing storage devices that allow for flow culture to maintain and assess organ functionality. Regulatory hurdles also hinder clinical translation. Our studies confirmed biomaterial biocompatibility in vitro(1) and in small animals(2). Mouse models showed stable insulin production after pancreatic patch transplantation(3), leading to a pig study where 3D-bioprinted pancreases maintained stable blood flow without pancreatic islets(4).The aim of this study presents the results of the transplantation of a fully functional 3D-bioprinted Bionic Pancreas (BP-ATMP) in a large animal.
Material & Methods: 20 pigs (55±6kg) were studied for 2 months in 4 groups:Healthy Control(n=5), Diab Group (pancreatectomy;n=5), Portal Group (pancreatectomy&islet transplantation into the portal vein; n=5),BP Group (pancreatectomy&3D-bioprinted BP-ATMP transplantation; n=5).BP-ATMP used dECM-derived bioinks, endothelial cells, fibroblasts, and pancreatic islets. After bioprinting, constructs were maintained at 36.6°C for flow assessment and GSIS tests. Transplants occurred within 24h via aortic and vena cava anastomosis. Glucose was monitored 5 times daily, with insulin given as needed. Fasting C-peptide was checked weekly.CT scans were done in the BP group. After the study, animals were sacrificed for histopathological analysis.
Results: CT scans in the BP group revealed stable graft function and blood flow throughout the observation period. As of the study's conclusion, mean c-peptide levels in the BP group were 0.4±0.15, significantly higher than the undetectable levels in the Diab group and 0.1±0.01 in the Portal group (p=0.0001). Insulin requirements in the BP group were 0.085±0.17 IU/kg/day compared to 0.16±0.035 IU/kg/day in the Diab group (p=0.0001), reflecting a 53% reduction in insulin use (p<0.001). Histopathological analysis of explanted BP-ATMPs revealed new microvasculature and positive staining for both insulin and glucagon in all specimens.
Conclusion: These findings demonstrate that BP-ATMP is a viable candidate for regulatory review and preparation for first-in-human clinical trial.
This research was funded by The National Centre for Research and Development: - TECHMATSTRATEG-III/0027/2019-00/ - STRATEGMED3/305813/2/NCBR/2017.
[1] 3D bioprinting
[2] Pancreas
[3] type 1 diabetes
[4] beta cells
[5] bionic organs