How can we more efficiently treat cardiovascular diseases for a long-lasting therapy in affected patients in terms of better survival and quality of life?
The research group of Cardiovascular Regenerative Medicine aims at creating innovative, viable and functional solutions as advanced treatments for cardiac diseases. The main objective is to translate newly formulated classic and transcatheter heart valve replacements, arterial substitutes, as well as a novel total artificial heart and a total bioengineered heart into potential therapies for patients with valve pathologies, heart ischemia or heart failure.
The research team aims also to provide more suitable sterilization and preservation techniques for these novel cardiovascular replacements.
Cardiovascular diseases are the leading cause of death and affect millions of people worldwide.
Ischemic cardiac disease and valvulopathies are only few of the clinical conditions possibly evolving to end-stage heart failure. Current therapeutic solutions foresee the surgical implantation of mechanical and bioprosthetic devices, as heart valve replacements, left ventricle assist devices or total artificial hearts. Such cardiosurgical therapies ameliorate the history of cardiovascular diseases, but are related to many drawbacks, as the lack of tissue viability, self-repair and remodel in function to somatic ingrowth. Thus, they represent temporary solutions with short durability and need replacement in re-do procedures, particularly disadvantageous for growing paediatric patients and generally associated to high mortality risks.
Our research aims to conceive and develop novel viable and functional cardiovascular replacements by application of regenerative medicine technologies. Through medical, biotechnological and bioengineering multidisciplinary approaches, we pursue the translation of bench-developed biodevices into safe and effective applications in the clinical arena.
Next-generation heart valve replacements
Current valve prostheses are either mechanical or biological, i.e. derived from human donors or glutaraldehyde-treated animal tissues: life-long anticoagulation or bioprosthetic valve degeneration adversely affect implanted patients. Responsible for degeneration in heart valve biological prostheses is calcification, primed by many triggers, as mechanical stress, extracellular release of cell debris released after glutaraldehyde-induced cytotoxicity, and chiefly, immunological responses to incompletely glutaraldehyde-shielded xenoantigens, as alpha-gal. Alpha-gal is an oligosaccharide composing glyco- and lipoproteins and expressed at the surface of endothelial and stromal valve cells. Not metabolized by humans and non-human primates for evolutionary gene silencing, it induces hyperacute rejection in xenotransplantation challenges.
Heart valve tissue engineering intends to overcome these limits by generating novel biocompatible substitutes combining cardiovascular scaffolds and stem or differentiated cells. In order to obtain an optimal scaffold for heart valve regeneration, we developed an innovative decellularization method, i.e. TriCol. Based on osmotic shock, sodium cholate and Triton X-100 detergents and endonucleases, this methodology renders cardiovascular tissues completely decellularized and freed from any pro-inflammatory and pro-calcific stimuli, as DNA, RNA or cell membrane lipids. Moreover, TriCol-treated native animal tissues are alpha-gal-free certified, as verified with patented, ad hoc developed biochemical tests.
TriCol heart valve scaffolds demonstrate full biocompatibility and bioactivity in experiments of in vitro tissue engineering with valve interstitial cells and bone marrow mesenchymal stems cells. In addition, they were evaluated in vivo with an exceptional tissue engineering modality, i.e. tissue guided regeneration. Applied for the reconstruction of the right ventricle outflow tract in a long-term follow-up in allogeneic model, non-preconditioned, TriCol aortic valves demonstrated adequate haemodynamic profile and self-regeneration abilities, as verified by the adaptive annulus enlargement and tissue repopulation. In fact, the original scaffolding, fully preserved by TriCol decellularization, guides recipient cells to their engraftment and opportune differentiation in valvular cytotypes able to secrete novel extracellular matrix, participate to neovascularization and neoinnervation, typical hallmarks of a viable and functional valve. Clinical studies with TriCol allogeneic heart valves are now ongoing.
Novel heart valve replacements with equal self-regeneration abilities, but minimal invasive implantation are in development. With the goal to treat high-risk patients, we are manufacturing transcatheter heart valve substitutes, composed of a proprietary expandable stent and decellularized animal pericardium (Marie Curie ITN network TECAS).
Advanced arterial replacements
Shortage of allogeneic arteries and thrombotic events on synthetic conduits, especially of small diameter, have increased the interest in the development of more biocompatible replacements to be applied in coronary artery bypass surgery or peripheral arterial disease.
Medium and small diameter acellular arterial vessels are now generated through decellularization of natural conduits by applying newly formulated, timesaving decellularization techniques.
Novel methodologies to preserve and sterilize cardiovascular grafts
Cardiovascular scaffolds or constructs, fruit of tissue engineering or tissue guided regeneration technologies, must be distributed as off-the shelf-solutions, in order to offer a more valid therapeutic alternative to a larger patient population.
So far, available preservation and sterilization techniques are not compatible with the maintenance of tissue viability and/or bioactivity in so-obtained grafts.
New preservation and sterilization techniques are currently investigated to ensure the reset of bioburden potentially associated to human or animal donor derivation and allow optimal conservation of these biodevices for a prospective patient implantation (Marie Curie ITN network TECAS).
Ground-breaking technologies for the therapeutic treatment of end-stage heart failure
Heart transplantation is the ideal treatment for an insufficient cardiac function, but organ availability is limited by the increasing shortage of donations. Current donor age is rising to 50 years, period in which heart pathophysiological alterations are frequently observed as consequence of hypertension and/or hypercholesterolemia. In addition, transplanted patients are submitted to life-long immune regimens to prevent organ rejection.
Left-ventricle assist devices and total artificial hearts have been proposed as life-saving mechanical supports with temporary or permanent application for the failing heart patients. Such clinical devices are not viable and are associated to thrombogenic risks, battery load-dependence, steric hindrance and/or high noisiness, all conditions limiting patients’ eligibility for treatment, as well as life quality and expectancy.
Our projects expect to tackle end-stage heart failure through two modalities:
– In a view of short-term applicability, we are manufacturing a new concept of total artificial heart with biocompatible inner blood surfaces and lower size for suitability in all-gender and -age patients.
- We are also developing a completely natural cardiac replacement i.e. the autologous-like total bioengineered heart, by applying ad hoc developed perfusion-based decellularization on whole organ and induced pluripotent stem cell technologies.
Eleonora Dal Sasso
Sabra Zouhair (TECAS Marie Curie ITN)
Andrea Mario Rossi
- Iop L, Dal Sasso E, Menabò R, Di Lisa F, Gerosa G. The Rapidly Evolving Concept of Whole Heart Engineering. Stem Cells Int. 2017;2017:8920940
- Fidalgo C, Iop L, Sciro M, Harder M, Mavrilas D, Korossis S, Bagno A, Palù G, Aguiari P, Gerosa G. A sterilization method for decellularized xenogeneic cardiovascular scaffolds. Acta Biomater. 2017 Dec 2. pii: S1742-7061(17)30719-5
- Gallo M, Bonetti A, Poser H, Naso F, Bottio T, Bianco R, Paolin A, Franci P, Busetto R, Frigo AC, Buratto E, Spina M, Marchini M, Ortolani F, Iop L, Gerosa G. Decellularized aortic conduits: could their cryopreservation affect post-implantation outcomes? A morpho-functional study on porcine homografts. Heart Vessels. 2016 Nov;31(11):1862-1873
- Iop L, Paolin A, Aguiari P, Trojan D, Cogliati E, Gerosa G. Decellularized Cryopreserved Allografts as Off-the-Shelf Allogeneic Alternative for Heart Valve Replacement: In Vitro Assessment Before Clinical Translation. J Cardiovasc Transl Res. 2017 Apr;10(2):93-103.
- Gerosa G, Scuri S, Iop L, Torregrossa G. Present and future perspectives on total artificial hearts. Ann Cardiothorac Surg. 2014 Nov;3(6):595-602.
- Iop L, Bonetti A, Naso F, Rizzo S, Cagnin S, Bianco R, Dal Lin C, Martini P, Poser H, Franci P, Lanfranchi G, Busetto R, Spina M, Basso C, Marchini M, Gandaglia A, Ortolani F, Gerosa G. Decellularized allogeneic heart valves demonstrate self-regeneration potential after a long-term preclinical evaluation. PLoS One. 2014 Jun 18;9(6):e99593
- Naso F, Gandaglia A, Bottio T, Tarzia V, Nottle MB, d’Apice AJ, Cowan PJ, Cozzi E, Galli C, Lagutina I, Lazzari G, Iop L, Spina M, Gerosa G. First quantification of alpha-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses. Xenotransplantation. 2013 Jul-Aug;20(4):252-61.
- Naso F, Gandaglia A, Iop L, Spina M, Gerosa G. First quantitative assay of alpha-Gal in soft tissues: presence and distribution of the epitope before and after cell removal from xenogeneic heart valves. Acta Biomater. 2011 Apr;7(4):1728-34.
- Iop L, Renier V, Naso F, Piccoli M, Bonetti A, Gandaglia A, Pozzobon M, Paolin A, Ortolani F, Marchini M, Spina M, De Coppi P, Sartore S, Gerosa G. The influence of heart valve leaflet matrix characteristics on the interaction between human mesenchymal stem cells and decellularized scaffolds. Biomaterials. 2009 Sep;30(25):4104-16.
- Iop L, Chiavegato A, Callegari A, Bollini S, Piccoli M, Pozzobon M, Rossi CA, Calamelli S, Chiavegato D, Gerosa G, De Coppi P, Sartore S. Different cardiovascular potential of adult- and fetal-type mesenchymal stem cells in a rat model of heart cryoinjury. Cell Transplant. 2008;17(6):679-94.
- MD, University of Verona Medical School, Verona, Italy (1983)
- Specialization in Cardiac surgery, University of Verona Medical School, Verona, Italy (1988)
- Visiting Surgeon, University Hospital, London, Ontario, Canada (1991)
- Visiting Surgeon, Texas Heart Institute, Houston, USA (1995)
- Associate Professor Cardiac Surgery, University of Padua Medical School (2000-2012)
- Chief Cardiac Surgery Unit, Padua University Hospital, Italy (2003–present)
- Director Heart Transplant and VAD program, Padua University Hospital, Italy (2003–present)
- Full Professor of Cardiac Surgery, Department of Cardiac Thoracic Vascular Sciences, University of Padua Medical School, Italy (2012–present)
- Group leader, Cardiovascular Regenerative Medicine, VIMM (2014–present)
- 2018-2020 – Presidente Eletto Società Italiana di Cardiochirurgia
- 2018 – Socio Non Residente ATENEO VENETO
- 2017 – Accademico Olimpico Onorario ACCADEMIA OLIMPICA
- 2013 – Lifetime Achievement Award in Valve Surgery – Heart Valve Society of America
- 2013 – Trentino Citizen of the year Award
- 2012 – Excellent Padova Citizens Award
- 2012-2014 – President Society for Heart Valve Disease
- 1999-2001 – Chairman Working Group on Tissue Engineering – Society for Heart Valve Disease
- 1998-2000 – President Ross Surgical Society
- 1993 – Alexis Carrel Award