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

Abstract

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.

An elastin-based vasculogenic scaffold promotes marginal islet mass engraftment and function at an extrahepatic site

“…Published data support that formation of mature new vascular networks requires initiation by a pro-angiogenic growth factor such as VEGF followed by vessel stabilization by PDGF [63,64]. VEGF and PDGF have been extensively used to enhance neovascularization of implants to improve their engraftment and overall tissue regeneration [64,65]. It has been demonstrated that co-release of both VEGF [66] and PDGF [64] in vivo allows for not only formation of new blood vessels, but also ensures an overall higher degree of vessel maturity [63,67].…”

Beyond Growth Factors: Macrophage-Centric Strategies for Angiogenesis

“…Similarly, Tengood et al showed that sequential delivery of bFGF followed by PDGF in a modified in vivo murine Matrigel plug assay with a hollow fiber delivery system produced better vascular integration versus non-sequential delivery of factors [52], the proposed mechanism of both being the initiation of endothelial sprouting with bFGF followed by vessel stabilization with PDGF at later time points. Interestingly, it is not just one specific sequence of factors, but many different combinations that have been tried that have shown promise with respect to enhanced vascularization [53][54][55].…”

Encapsulation of Biological Agents in Hydrogels for Therapeutic Applications

“…Many examples abound in the literature on the use of hydrogels for the encapsulation and controlled release of proteins for therapeutic applications. Among the possible proteins to be released from hydrogels, the delivery of growth factors has been widely reported as a strategy to improve wound healing [64,76,130,131,132,133,134,135,136,137,138,139,140,141], release of bone morphogenetic protein 2 (BMP-2) has been used for bone regeneration [142,143,144,145,146,147,148,149,150,151,152], encapsulation of insulin has been explored for oral delivery and/or triggered release under various conditions [153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172], encapsulation of different antigens in hydrogels has been explored in order to enhance the immune response for vaccine boosting effects and other immunotherapies [173,174,175,176,177,178,179,180], and encapsulation of antibodies has been use in localized delivery applications [181,182,183,184]. These are just a few of the many applications that have been explored involving the encapsulation of biomolecules, but they serve to exemplify why h...…”