BMP-2

This work considers a glass polyalkenoate cement (GPC)-based carrier for the effective delivery of bone morphogenetic proteins (BMPs) at an implantation site. A 0.12 CaO-0.04 SrO-0.36 ZnO-0.48 SiO2 based glass and poly(acrylic acid) (PAA, Mw 213,000) were employed for the fabrication of the GPC. The media used for the water source in the GPC reaction was altered to produce a series of GPCs. The GPC liquid media was either 100 % distilled water with additions of albumin at 0, 2, 5 and 8 wt% of the glass content, 100 % formulation buffer (IFB), and 100 % BMP (150 mu g rhBMP-2/ml IFB). Rheological properties, compressive strength, ion release profiles and BMP release were evaluated. Working times (T-w) of the formulated GPCs significantly increased with the addition of 2 % albumin and remained constant with further increases in albumin content or IFB solutions. Setting time (T-s) experienced an increase with 2 and 5 % albumin content, but a decrease with 8 % albumin. Changing the liquid source to IFB containing 5 % albumin had no significant effect on T-s compared to the 8 % albumin-containing BT101. Replacing the albumin with IFB/BMP-2 did not significantly affect T-w. However, T-s increased for the BT101_BMP-2 containing GPCs, compared to all other samples. The compressive strength evaluated 1 day post cement mixing was not affected significantly by the incorporation of BMPs, but the ion release did increase from the cements, particularly for Zn and Sr. The GPCs released BMP after the first day, which decreased in content during the following 6 days. This study has proven that BMPs can be immobilized into GPCs and may result in novel materials for clinical applications.

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http://www.ncbi.nlm.nih.gov/pubmed/25773232
http://link.springer.com/article/10.1007/s10856-015-5494-3

Fabrication of an ideal scaffold having proper composition, physical structure and able to have sustained release of growth factors still is challenging for bone tissue engineering. Current study aimed to design an appropriate three-dimensional (3-D) scaffold with suitable physical characteristics, including proper compressive strength, degradation rate, porosity, and able to sustained release of bone morphogenetic protein-2 (BMP2), for bone tissue engineering. A highly porous 3-D β-tricalcium phosphate (β-TCP) scaffolds, inside of which two perpendicular canals were created, was fabricated using foam-casting technique. Then, scaffolds were coated with gelatin layer. Next, BMP2-loaded chitosan (CS) nanoparticles were dispersed into collagen hydrogel and filled into the scaffold canals. Physical characteristics of fabricated constructs were evaluated. Moreover, the capability of given construct for bone regeneration has been evaluated in vitro in interaction with human buccal fat pad-derived stem cells (hBFPSCs). The results showed that gelatin-coated TCP scaffold with rhBMP2 delivery system not only could act as a mechanically and biologically compatible framework, but also act as an osteoinductive graft by sustained delivering of rhBMP2 in a therapeutic window for differentiation of hBFPSCs towards the osteoblast lineage. The proposed scaffold model can be suggested for delivering of cells and other growth factors such as vascular endothelial growth factor (VEGF), alone or in combination, for future investigations.

Growth factors (GFs) are very critical in stem cell differentiation and tissue regeneration. Therefore GF delivery carriers have been a major subject in tissue engineering research. In this study, we prepare and optimize core-shell microcapsules (C-S MCs) for dual GF delivery. The C-S MCs, composed of an alginate shell and poly(lactic-co-glycolic) acid (PLGA) core, are fabricated using an electrodropping method via custom-made coaxial needles. They are 198±38 µm in diameter with an average core size of 90±13 µm, and they are fabricated using an alginate concentration of 1% (w/v), an electrical voltage of 11 kV, and an inner syringe flow rate of 50 µL/min. Using this platform, dual GFs, bone morphogenetic protein (BMP-2) and vascular endothelial growth factor (VEGF) are encapsulated in the alginate shell and PLGA core, respectively. In vitro release tests of dual GF-loaded C-S MCs reveal early release of BMP-2, followed by VEGF on a temporal release profile of 28 days. In vitro study of the dual GF-loaded MCs demonstrates their osteogenic activity with preosteoblasts; osteogenic markers (osteocalcin and type I collagen) are upregulated and both calcium content and alkaline phosphatase (ALP) activity also increased. In addition, C-S MCs combined with collagen and preosteoblasts were subcutaneously transplanted to the dorsal region of nude mice for 3 weeks. Analysis of the retrieved constructs exhibits that both osteogenesis and angiogenesis were more active in the group containing dual GF-loaded MCs, along with deep penetration of blood vessels inside the construct, compared to blank MCs or single GF (BMP-2)-loaded MCs. This study proposes a dual GF delivery carrier using C-S MCs and demonstrates the feasibility of C-S MCs in the induction of osteogenesis and angiogenesis.

C oronary heart disease resulting in myocardial infarction (MI) is the major cause of death in men and women. 1 Each year about 735 000 people in the United States have an MI and most suffer irreversible tissue damage, leading to ventricular remodeling, hypertrophy, dilatation, and eventually heart failure. 2 After MI, the adult heart undergoes a sequence of molecular and cellular events that delineate the different stages of tissue repair. Initially, cardiomyocytes within infarcted myocardium begin to die within minutes after coronary artery occlusion. 3 Toxic products and signals released from dying cells induce endothelial cell adhesion proteins, as well as cytokines and chemokines, to recruit inflammatory cells that remove tissue debris, and activate proteases to degrade extra-cellular matrix. 4 After debris is cleared, usually within 2 to 3 days after MI, the gap is filled with granulation tissue that is composed of proliferating cells, mainly endothelial cells that form new capillaries, and myofibroblasts that secrete collagen and other matrix proteins. 5 Two to 3 weeks after the original Rationale: We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown. Objective: To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury. Methods and Results: Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss-(Grem2 −/−) and gain-(TG Grem2) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2 −/− mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect. Conclusions: Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI. (Circ Res. 2016;119:434-449.