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Tissue Eng Part A. 2017 Dec;23(23-24):1382-1393. doi: 10.1089/ten.TEA.2017.0027. Epub 2017 Jun 27.

* Programmed Platelet-Derived Growth Factor-BB and Bone Morphogenetic Protein-2 Delivery from a Hybrid Calcium Phosphate/Alginate Scaffold.

Bayer EA1,2, Jordan J1, Roy A1,2, Gottardi R3,4,5, Fedorchak MV1,2,3,6, Kumta PN1,2,3,7,8, Little SR1,2,3,9.

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1 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania.
2 The McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.
3 Department of Chemical Engineering, University of Pittsburgh , Pittsburgh, Pennsylvania.
4 Department of Orthopedic Surgery, University of Pittsburgh , Pittsburgh, Pennsylvania.
5 Ri.MED Foundation , Palermo, Italy .
6 Department of Ophthalmology, University of Pittsburgh , Pittsburgh, Pennsylvania.
7 Department of Mechanical Engineering and Materials Science, University of Pittsburgh , Pittsburgh, Pennsylvania.
8 Department of Oral Biology, Center for Craniofacial Regeneration, University of Pittsburgh , Pittsburgh, Pennsylvania.
9 Department of Immunology, University of Pittsburgh , Pittsburgh, Pennsylvania.


Bone tissue engineering requires the upregulation of several regenerative stages, including a critical early phase of angiogenesis. Previous studies have suggested that a sequential delivery of platelet-derived growth factor (PDGF) to bone morphogenetic protein-2 (BMP-2) could promote angiogenic tubule formation when delivered to in vitro cocultures of human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs). However, it was previously unclear that this PDGF to BMP-2 delivery schedule will result in cell migration into the scaffolding system and affect the later expression of bone markers. Additionally, a controlled delivery system had not yet been engineered for programmed sequential presentation of this particular growth factor. By combining alginate matrices with calcium phosphate scaffolding, a programmed growth factor delivery schedule was achieved. Specifically, a combination of alginate microspheres, alginate hydrogels, and a novel blend of resorbable calcium phosphate-based cement (ReCaPP) was used. PDGF and BMP-2 were sequentially released from this hybrid calcium phosphate/alginate scaffold with the desired 3-day overlap in PDGF to BMP-2 delivery. Using a three-dimensional coculture model, we observed that this sequence of PDGF to BMP-2 delivery influenced both cellular infiltration and alkaline phosphatase (ALP) expression. It was found that the presence of early PDGF delivery increased the distance of cell infiltration into the calcium phosphate/alginate scaffolding in comparison to early BMP-2 delivery and simultaneous PDGF+BMP-2 delivery. It was also observed that hMSCs expressed a greater amount of ALP+ staining in response to scaffolds delivering the sequential PDGF to BMP-2 schedule, when compared with scaffolds delivering no growth factor, or PDGF alone. Importantly, hMSCs cultured with scaffolds releasing the PDGF to BMP-2 schedule showed similar amounts of ALP staining to hMSCs cultured with BMP-2 alone, suggesting that the sequential schedule of PDGF to BMP-2 presentation promotes differentiation of hMSCs toward an osteoblast phenotype while also increasing cellular infiltration of the scaffold.


3D coculture; angiogenesis; bone regeneration; controlled delivery; growth factors

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