Madani S Zahra M, Reisch Anne, Roxbury Daniel, Kennedy Stephen M
Department of Chemical Engineering, University of Rhode Island, 2 East Alumni Avenue, Kingston, Rhode Island 02881, United States.
Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, 2 East Alumni Avenue, Kingston, Rhode Island 02881, United States.
ACS Biomater Sci Eng. 2020 Mar 9;6(3):1522-1534. doi: 10.1021/acsbiomaterials.9b01746. Epub 2020 Feb 12.
The sequence and timing of growth factor delivery plays a crucial role in bone regeneration. While a variety of biomaterial scaffolds have been developed to provide multiple growth factor deliveries, there still exists a strong need for on-demand control over sequential delivery profiles to optimize regenerative outcomes. One particular growth factor, bone morphogenetic protein-2 (BMP-2), has established effects in the osteodifferentiation process; however, the optimal timing of its delivery is not yet known. Here, we investigate the effect of the timing of BMP-2 delivery on osteodifferentiation on both 2D and 3D cell cultures in vitro. It was shown that immediate BMP-2 delivery inhibited mouse mesenchymal stem cell (mMSC) proliferation and therefore resulted in suboptimal levels of mMSC osteodifferentiation (as measured by alkaline phosphatase activity) compared to mMSC cultures exposed to delayed BMP-2 delivery (4 day delay). Because of this, we aimed to develop a biomaterial system capable of rapidly recruiting mMSCs and exposing them to BMP-2 in a delayed manner (i.e., after a strong mMSC population has been established). This biomaterial system consisted of (i) an outer porous gelatin compartment that could be loaded with an mMSC recruitment factor (stromal cell-derived factor 1-α (SDF-1α)) for rapid establishment of a 3D mMSC culture and (ii) an inner ferrogel compartment that could deliver BMP-2 in an immediate or delayed manner, depending on when magnetic stimulation was applied. It was shown that the outer compartment was able to recruit and harbor mMSCs and that the rapidity of this recruitment could be enhanced by loading the compartment with SDF-1α. The inner ferrogel compartment enabled magnetically triggered release of BMP-2 where the timing of release could be remotely controlled from immediate to a delay of up to 11 days. This hydrogel system provides controllability over the timing between bone progenitor recruitment and osteodifferentiation factor release and can thus potentially enhance therapies that require new bone growth by optimizing the timing of these deliveries.
生长因子递送的顺序和时机在骨再生中起着至关重要的作用。虽然已经开发出多种生物材料支架来实现多种生长因子的递送，但仍然迫切需要对顺序递送模式进行按需控制，以优化再生效果。一种特定的生长因子，骨形态发生蛋白-2（BMP-2），在骨分化过程中具有既定的作用；然而，其递送的最佳时机尚不清楚。在此，我们在体外二维和三维细胞培养中研究了BMP-2递送时机对骨分化的影响。结果表明，与延迟BMP-2递送（延迟4天）的间充质干细胞（mMSC）培养相比，立即递送BMP-2会抑制小鼠间充质干细胞（mMSC）的增殖，因此导致mMSC骨分化水平次优（通过碱性磷酸酶活性测量）。因此，我们旨在开发一种生物材料系统，该系统能够快速招募mMSC，并以延迟的方式使其暴露于BMP-2（即，在建立强大的mMSC群体之后）。这种生物材料系统由（i）一个外部多孔明胶隔室组成，该隔室可以装载mMSC招募因子（基质细胞衍生因子1-α（SDF-1α））以快速建立三维mMSC培养，以及（ii）一个内部铁凝胶隔室组成，该隔室可以根据施加磁刺激的时间以立即或延迟的方式递送BMP-2。结果表明，外部隔室能够招募并容纳mMSC，并且通过在隔室中装载SDF-1α可以提高这种招募的速度。内部铁凝胶隔室能够实现磁触发的BMP-2释放，其中释放时间可以从立即到延迟长达11天进行远程控制。这种水凝胶系统提供了对骨祖细胞招募和骨分化因子释放之间时间的可控性，因此通过优化这些递送的时间，有可能增强需要新骨生长的治疗方法。
