Article ; Online: Effects of locally applied adipose tissue-derived microvascular fragments by thermoresponsive hydrogel on bone healing.
2018 Volume 77, Page(s) 201–211
Abstract: Insufficient vascularization is a major cause for the development of non-unions. To overcome this problem, adipose tissue-derived microvascular fragments (MVF) may serve as vascularization units. However, their application into bone defects needs a ... ...
| Abstract | Insufficient vascularization is a major cause for the development of non-unions. To overcome this problem, adipose tissue-derived microvascular fragments (MVF) may serve as vascularization units. However, their application into bone defects needs a carrier system. Herein, we analyzed whether this is achieved by a thermoresponsive hydrogel (TRH). MVF were isolated from CD-1 mice and cultivated after incorporation into TRH, while non-incorporated MVF served as controls. Viability of MVF was assessed immunohistochemically over a 7-day period. Moreover, osteotomies were induced in femurs of CD-1 mice. The osteotomy gaps were filled with MVF-loaded TRH (TRH + MVF), unloaded TRH (TRH) or no material (control). Bone healing was evaluated 14 and 35 days postoperatively. MVF incorporated into TRH exhibited less apoptotic cells and showed a stable vessel morphology compared to controls. Micro-computed tomography revealed a reduced bone volume in TRH + MVF femurs. Histomorphometry showed less bone and more fibrous tissue after 35 days in TRH + MVF femurs compared to controls. Accordingly, TRH + MVF femurs exhibited a lower osseous bridging score and a reduced bending stiffness. Histology and Western blot analysis revealed an increased vascularization and CD31 expression, whereas vascular endothelial growth factor (VEGF) expression was reduced in TRH + MVF femurs. Furthermore, the callus of TRH + MVF femurs showed increased receptor activator of NF-κB ligand expression and higher numbers of osteoclasts. These findings indicate that TRH is an appropriate carrier system for MVF. Application of TRH + MVF increases the vascularization of bone defects. However, this impairs bone healing, most likely due to lower VEGF expression during the early course of bone healing. Statement of significance: In the present study we analyzed for the first time the in vivo performance of a thermoresponsive hydrogel (TRH) as a delivery system for bioactive microvascular fragments (MVF). We found that TRH represents an appropriate carrier for MVF as vascularization units and maintains their viability. Application of MVF-loaded TRH impaired bone formation in an established murine model of bone healing, although vascularization was improved. This unexpected outcome was most likely due to a reduced VEGF expression in the early phase bone healing. |
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| MeSH term(s) | Adipose Tissue/cytology ; Animals ; Bone Regeneration ; Bony Callus/pathology ; Elasticity ; Femur/pathology ; Fracture Healing ; Hydrogels/chemistry ; Male ; Mice ; Microcirculation ; Microvessels/growth & development ; Neovascularization, Physiologic ; Osteoclasts/metabolism ; Osteotomy ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Shear Strength ; Vascular Endothelial Growth Factor A/metabolism ; Viscosity ; X-Ray Microtomography |
| Chemical Substances | Hydrogels ; Platelet Endothelial Cell Adhesion Molecule-1 ; Vascular Endothelial Growth Factor A |
| Language | English |
| Publishing date | 2018-07-17 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2173841-5 |
| ISSN | 1878-7568 ; 1742-7061 |
| ISSN (online) | 1878-7568 |
| ISSN | 1742-7061 |
| DOI | 10.1016/j.actbio.2018.07.029 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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