macrophage; hydrogels; animal model; tissue engineering; endothelial; bone tissue formation; vascularization; hypertrophic cartilage; pericyte
Epple Christian, Haumer Alexander, Ismail Tarek, Lunger Alexander, Scherberich Arnaud, Schaefer Dirk Johannes, Martin Ivan (2019), Prefabrication of a large pedicled bone graft by engineering the germ for de novo vascularization and osteoinduction, in Biomaterials
, 192, 118-127.
Guerrero Julien, Pigeot Sebastien, Müller Judith, Schaefer Dirk J, Martin Ivan, Scherberich Arnaud (2018), Fractionated human adipose tissue as a native biomaterial for the generation of a bone organ by endochondral ossification, in Acta Biomaterialia
, 77, 142-154.
Rossi Eleonora, Guerrero Julien, Aprile Paola, Tocchio Alessandro, Kappos Elisabeth A., Gerges Irini, Lenardi Cristina, Martin Ivan, Scherberich Arnaud (2018), Decoration of RGD-mimetic porous scaffolds with engineered and devitalized extracellular matrix for adipose tissue regeneration, in Acta Biomaterialia
, 73, 154-166.
Blache Ulrich, Guerrero Julien, Güven Sinan, Klar Agnes Silvia, Scherberich Arnaud (2018), Microvascular Networks and Models, In vitro Formation, in Banfi Andrea, Kirkpatrick James, Holnthoner Wolfgang , Redl Heinz (ed.), Springer, Cham, Basel, 1.
Cerino Giulia, Gaudiello Emanuele, Muraro Manuele Giuseppe, Eckstein Friedrich, Martin Ivan, Scherberich Arnaud, Marsano Anna (2017), Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells, in Scientific Reports
, 7(1), 14252-14252.
Ismail Tarek, Osinga Rik, Todorov Atanas Jr., Haumer Alexander, Tchang Laurent A., Epple Christian, Allafi Nima, Menzi Nadia, Largo Rene D., Kaempfen Alexandre, Martin Ivan, Schaefer Dirk J., Scherberich Arnaud (2017), Engineered, axially-vascularized osteogenic grafts from human adipose-derived cells to treat avascular necrosis of bone in a rat model, in ACTA BIOMATERIALIA
, 63, 236-245.
Cerino Giulia, Gaudiello Emanuele, Muraro Manuele Giuseppe, Eckstein Friedrich, Martin Ivan, Scherberich Arnaud, Marsano Anna (2017), Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells., in Scientific reports
, 7(1), 14252-14252.
Saxer Franziska, Scherberich Arnaud, Todorov Atanas, Studer Patrick, Miot Sylvie, Schreiner Simone, Güven Sinan, Tchang Laurent A H, Haug Martin, Heberer Michael, Schaefer Dirk J, Rikli Daniel, Martin Ivan, Jakob Marcel (2017), Implantation of Stromal Vascular Fraction Progenitors at Bone Fracture Sites: From a Rat Model to a First-in-Man Study., in Stem cells (Dayton, Ohio)
, 34(12), 2956-2966.
Background. Promoting an efficient vascularization of tissue-engineered (TE) osteogenic constructs upon in vivo implantation remains a major challenge towards their clinical application for bone regeneration and repair. Though numerous studies based on pre-vascularization of TE grafts by using vascular cells demonstrated the validity of this approach, they so far failed to define precise parameters, such as the cellular composition (density of endothelial and pericytic cells and of macrophages) and the degree of maturation/ramification of the preformed vascular structures necessary to make such pre-vascular structures fully supportive of vascularization, engraftment and survival of cell inside the implant upon in vivo implantation. This is likely to ultimately regulate tissue formation in vivo.Working hypothesis.The degree of pre-vascularization and the density of macrophages in vitro regulate the vascularization, the engraftment and the bone formation capacity of TE osteogenic grafts in vivo.Specific aims.To address this question, 3 aims are defined: 1) Aim 1 will define if, and how, different in vitro maturation/ramification levels of vascular structures in vitro could affect the density (number of capillaries, branches and total capillary length) of the vascularization in those grafts upon in vivo implantation. 2) Aim 2 will investigate to which extent such different densities of vascularization reached in vivo could in turn affect the engraftment, as judged by cell survival in the graft and performance of the osteogenic grafts in terms of density and volume of bone formation. 3) Finally, aim 3 will examine how macrophages of different phenotypes, included in the grafts or recruited from the host, affect vascularization and bone formation, and how to better harness the power of macrophages to produce enhanced TE bone.Experimental design.The study will use a previously established cell culture and in vivo system using progenitor cells freshly isolated from human adipose tissue, typically referred to as stromal vascular fraction (SVF) cells, demonstrated not to only generate osteogenic grafts but also an intrinsic vasculogenic capacity in vivo. Pre-vascularization density in vitro will be modulated by varying the in vitro culture duration and the effect of this pre-vascularization density on the vascular density, survival of cells inside the implanted grafts and volume of bone formation in vivo. In the same model, the contribution of macrophages of different phenotypes to those processes will be evaluated by depletion of specific populations by using cell sorting or enrichment with peripheral-blood derived macrophages.Expected value of the proposed project. We propose a systematic approach to aim at defining release criteria and quality markers for the use of SVF cells-based grafts as clinical tools, such as i) percentage of specific vascular cells, ii) degrees of vascular cells organization/vascular structure density and iii) percentage and phenotype of macrophages. This is an essential step to initiate preclinical scaled-up models and to pave the way to a pilot clinical trial based on the use of SVF cells-based grafts.