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Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation.

ABSTRACT: Large bone defects naturally regenerate via a highly vascularized tissue which progressively remodels into cartilage and bone. Current approaches in bone tissue engineering are restricted by delayed vascularization and fail to recapitulate this stepwise differentiation toward bone tissue. Here, we use the morphogen Sonic Hedgehog (Shh) to induce the in vitro organization of an endothelial capillary network in an artificial tissue. We show that endogenous Hedgehog activity regulates angiogenic genes and the formation of vascular lumens. Exogenous Shh further induces the in vitro development of the vasculature (vascular lumen formation, size, distribution). Upon implantation, the in vitro development of the vasculature improves the in vivo perfusion of the artificial tissue and is necessary to contribute to, and enhance, the formation of de novo mature bone tissue. Similar to the regenerating callus, the artificial tissue undergoes intramembranous and endochondral ossification and forms a trabecular-like bone organ including bone-marrow-like cavities. These findings open the door for new strategies to treat large bone defects by closely mimicking natural endochondral bone repair.

SUBMITTER: Rivron NC

PROVIDER: S-EPMC3311342 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation.

Rivron Nicolas C NC Raiss Christian C CC Liu Jun J Nandakumar Anandkumar A Sticht Carsten C Gretz Norbert N Truckenmüller Roman R Rouwkema Jeroen J van Blitterswijk Clemens A CA

Proceedings of the National Academy of Sciences of the United States of America 20120302 12

Large bone defects naturally regenerate via a highly vascularized tissue which progressively remodels into cartilage and bone. Current approaches in bone tissue engineering are restricted by delayed vascularization and fail to recapitulate this stepwise differentiation toward bone tissue. Here, we use the morphogen Sonic Hedgehog (Shh) to induce the in vitro organization of an endothelial capillary network in an artificial tissue. We show that endogenous Hedgehog activity regulates angiogenic ge ...[more]

PMID: 22388744

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Project description:ObjectiveSynthetic expanded polytetrafluoroethylene (ePTFE) grafts are known to be susceptible to bacterial infection. Results from preclinical and clinical studies of bioengineered human acellular vessels (HAVs) have shown relatively low rates of infection. This study evaluates the interactions of human neutrophils and bacteria with ePTFE and HAV vascular conduits to determine whether there is a correlation between neutrophil-conduit interactions and observed differences of their infectivity in vivo.MethodsA phase III comparative clinical study between investigational HAVs (n = 177) and commercial ePTFE grafts (n = 178) used for hemodialysis access (ClinicalTrials.gov Identifier: NCT02644941) was evaluated for conduit infection rates followed by histological analyses of HAV and ePTFE tissue explants. The clinical histopathology of HAV and ePTFE conduits reported to be infected was compared with immunohistochemistry of explanted materials from a preclinical model of bacterial contamination. Mechanistic in vitro studies were then conducted using isolated human neutrophils seeded directly onto HAV and ePTFE materials to analyze neutrophil viability, morphology, and function.ResultsClinical trial results showed that the HAV had a significantly lower (0.93%; P = .0413) infection rate than that of ePTFE (4.54%). Histological analysis of sections from infected grafts explanted approximately 1 year after implantation revealed gram-positive bacteria near cannulation sites. Immunohistochemistry of HAV and ePTFE implanted in a well-controlled rodent infection model suggested that the ePTFE matrix permitted bacterial infiltration and colonization but may be inaccessible to neutrophils. In the same model, the HAV showed host recellularization and lacked detectable bacteria at the 2-week explant. In vitro results demonstrated that the viability of human neutrophils decreased significantly upon exposure to ePTFE, which was associated with neutrophil elastase release in the absence of bacteria. In contrast, neutrophils exposed to the HAV material retained high viability and native morphology. Cocultures of neutrophils and Staphylococcus aureus on the conduit materials demonstrated that neutrophils were more effective at ensnaring and degrading bacteria on the HAV than on ePTFE.ConclusionsThe HAV material seems to demonstrate a resistance to bacterial infection. This infection resistance is likely due to the HAV's native-like material composition, which may be more biocompatible with host neutrophils than synthetic vascular graft material.

Dataset Information

Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation.

Publications

Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation.

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