title: The proangiogenic potential of a novel calcium releasing composite biomaterial: Orthotopic in vivo evaluation.
abstract: Insufficient angiogenesis remains a major hurdle in current bone tissue engineering strategies. An extensive body of work has focused on the use of angiogenic factors or endothelial progenitor cells. However, these approaches are inherently complex, in terms of regulatory and methodologic implementation, and present a high cost. We have recently demonstrate the potential of electrospun poly(lactic acid) (PLA) fiber-based membranes, containing calcium phosphate (CaP) ormoglass particles, to elicit angiogenesis in vivo, in a subcutaneous model in mice. Here we have devised an injectable composite, containing CaP glass-ceramic particles, dispersed within a (Hydroxypropyl)methyl cellulose (HPMC) matrix, with the capacity to release calcium in a more sustained fashion. We show that by tuning the release of calcium in vivo, in a rat bone defect model, we could improve both bone formation and increase angiogenesis. The bone regeneration kinetics was dependent on the Ca2+release rate, with the faster Ca2+release composite gel showing improved bone repair at 3weeks, in relation to control. In the same line, improved angiogenesis could be observed for the same gel formulation at 6weeks post implantation. This methodology allows to integrate two fundamental processes for bone tissue regeneration while using a simple, cost effective, and safe approach.
  
  
  
  In current bone tissue engineering approaches the achievement of sufficient angiogenesis, during tissue regeneration, is a major limitation in order to attain full tissue functionality. Recently, we have shown that calcium ions, released by the degradation of calcium phosphate ormoglasses (CaP), are effective angiogenic promoters, in both in vitro and in a subcutaneous implantation model. Here, we devised an injectable composite, containing CaP glass-ceramic particles, dispersed within a HPMC matrix, enabling the release of calcium in a more sustained fashion. We show that by tuning the release of calcium in vivo, in a rat bone defect model, we could improve both bone formation and increase angiogenesis. This simple and cost effective approach holds great promise to translate to the clinics.
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France. Electronic address: hugo.de-oliveira@inserm.fr.
authors.forename: Hugo
authors.initials: H
authors.lastname: Oliveira
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; CHU Bordeaux, Services d'Odontologie et de Santé Buccale, F-33076 Bordeaux, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Catros
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain; Materials Science and Physical Chemistry, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Castano
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rey
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Siadous
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain.
authors.forename: Douglas
authors.initials: D
authors.lastname: Clift
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Marti-Munoz
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Batista
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France.
authors.forename: Reine
authors.initials: R
authors.lastname: Bareille
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain; Materials Science and Physical Chemistry, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Planell
authors.affiliation: Biomaterials for Regenerative Therapies, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, 50018 Zaragoza, Spain; Materials Science and Metallurgical Engineering, Universitat Politècnica de Catalunya, Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Engel
authors.affiliation: University of Bordeaux, Tissue Bioengineering, U1026, F-33076 Bordeaux, France; Inserm, Tissue Bioengineering, U1026, F-33076 Bordeaux, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Amédée
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D064593:Heterografts; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003692:Delayed-Action Preparations; D011091:Polyesters; C033616:poly(lactide); D002118:Calcium
keywords: Angiogenesis; Bone regeneration; Calcium phosphate ormoglasses