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Published Online: 29 May 2013

Scaffold-Based Delivery of a Clinically Relevant Anti-Angiogenic Drug Promotes the Formation of In Vivo Stable Cartilage

Publication: Tissue Engineering Part A
Volume 19, Issue Number 17-18

Abstract

Standard cartilage tissue engineering approaches, for example, matrix-induced autologous chondrocyte implantation (MACI), consist of the implantation of cell-based constructs whose survival and further development first depend on the degree of graft maturity at the time of surgery (e.g., matrix production) and, subsequently, on initial host reaction. Indeed, blood vessel ingrowth and macrophage migration within the implant may endanger graft stability of immature constructs; so, control of angiogenesis was proposed as an adjuvant of cellular therapy for the treatment of cartilage defects. In this study, we hypothesized that engineered constructs with no in vitro precultivation, but functionalized to block angiogenesis right on implantation, might result in better survival, as well as superior long-term cartilaginous quality. Here, we propose a clinically compatible fibrin/hyaluronan scaffold seeded with nasal chondrocytes (NC) and functionalized with an FDA-approved anti-angiogenic drug (bevacizumab; Avastin®), which sequestrates vascular endothelial growth factor from the surrounding environment. Our results show that the sustained bevacizumab release from NC-loaded scaffolds after subcutaneous implantation in nude mice efficiently blocked host vessels ingrowth (five times lower CD31+ cells infiltration vs. control group, at 3 weeks after implant), and enhanced constructs survival rate (75% vs. 18% for the control, at 6 weeks after implant). In vitro assays, developed to elucidate the role of specific construct components in the in vivo remodeling, allowed to determine that fibrin degradation products enhanced the in vitro endothelial cell proliferation, as well as the macrophage migration; whereas the presence of bevacizumab was capable of counteracting these effects. The proposed pharmacological control of angiogenesis by a therapeutic drug released from a scaffold might enhance cartilage regeneration by MACI approaches, possibly allowing it to bypass the complex and costly phase of graft preculture to gain increased functionality.

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cover image Tissue Engineering Part A
Tissue Engineering Part A
Volume 19Issue Number 17-18September 2013
Pages: 1960 - 1971
PubMed: 23611597

History

Published in print: September 2013
Published ahead of print: 30 May 2013
Published online: 29 May 2013
Published ahead of production: 24 April 2013
Accepted: 26 March 2013
Received: 26 July 2012

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Matteo Centola
Tissue Engineering Laboratory, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Departments of Surgery and of Biomedicine, University Hospital Basel, Basel, Switzerland.
Franca Abbruzzese
Tissue Engineering Laboratory, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Celeste Scotti
Departments of Surgery and of Biomedicine, University Hospital Basel, Basel, Switzerland.
Andrea Barbero
Departments of Surgery and of Biomedicine, University Hospital Basel, Basel, Switzerland.
Gianluca Vadalà
Area of Orthopedics and Trauma Surgery, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Vincenzo Denaro
Area of Orthopedics and Trauma Surgery, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Ivan Martin
Departments of Surgery and of Biomedicine, University Hospital Basel, Basel, Switzerland.
Marcella Trombetta
Tissue Engineering Laboratory, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Alberto Rainer
Tissue Engineering Laboratory, Center for Integrated Research, Università Campus Bio-Medico di Roma, Rome, Italy.
Anna Marsano
Departments of Surgery and of Biomedicine, University Hospital Basel, Basel, Switzerland.

Notes

Address correspondence to:Alberto Rainer, PhDTissue Engineering LaboratoryCenter for Integrated ResearchUniversità Campus Bio-Medico di Romavia Álvaro del Portillo 21Rome 00128Italy
E-mail: [email protected]

Disclosure Statement

There are no conflicts of interest to declare. The writing of this article was the sole responsibility of the authors.

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