Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charitéplatz 1, 10117 Berlin, Germany.
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies, Department of Rheumatology and Clinical Immunology, Charitéplatz 1, 10117 Berlin, Germany.
Acta Biomater. 2018 Mar 15;69:290-300. doi: 10.1016/j.actbio.2018.01.036. Epub 2018 Feb 2.
Chemokines are guiding cues for directional trafficking of mesenchymal stem cells (MSC) upon injury and local chemokine delivery at injury sites is an up-to-date strategy to potentiate and prolong recruitment of MSC. In this study we present the chemokine CCL25, also referred to as thymus-expressed chemokine, to mobilize human MSC along positive but not along negative gradients. We hence proceeded to design a biodegradable and injectable release device for CCL25 on the basis of poly(lactic-co-glycolic acid) (PLGA). The conducted studies had the objective to optimize PLGA microparticle fabrication by varying selected formulation parameters, such as polymer type, microparticle size and interior phase composition. We found that microparticles of D∼75 µm and fabricated using end-capped polymers, BSA as carrier protein and vortex mixing to produce the primary emulsion yielded high chemokine loading and delayed CCL25 release. To determine bioactivity, we investigated CCL25 released during the microparticle erosion phase and showed that deacidification of the release medium was required to induce significant MSC mobilization. The designed PLGA microparticles represent an effective and convenient off-the-shelf delivery tool for the delayed release of CCL25. However, continuative in vivo proof-of-concept studies are required to demonstrate enhanced recruitment of MSC and/or therapeutical effects in response to CCL25 release microparticles.
With the discovery of chemokines, particularly CXCL12, as stimulators of stem cell migration, the development of devices that release CXCL12 has proceeded quickly in the last few years. In this manuscript we introduce CCL25 as chemokine to induce mobilization of human MSC. This study proceeds to demonstrate how selection of key formulation parameters of CCL25 loading into PLGA microparticles exerts considerable influence on CCL25 release. This is important for a broad range of efforts in in situ tissue engineering where the candidate chemokine and the delivery device need to be selected carefully. The use of such a cell-free CCL25 release device may provide a new therapeutic option in regenerative medicine.
趋化因子是间充质干细胞（MSC）在损伤时定向迁移的导向线索，在损伤部位局部递呈趋化因子是增强和延长 MSC 募集的最新策略。在这项研究中，我们提出趋化因子 CCL25，也称为胸腺表达趋化因子，以沿正梯度而非负梯度动员人 MSC。因此，我们着手设计基于聚（乳酸-共-乙醇酸）（PLGA）的 CCL25 可生物降解和可注射释放装置。进行的研究旨在通过改变选定的配方参数（如聚合物类型、微粒大小和内部相组成）来优化 PLGA 微粒的制备。我们发现，D∼75 µm 的微粒和使用端封聚合物、BSA 作为载体蛋白和涡旋混合来制备初级乳液制成的微粒具有较高的趋化因子载量和延迟的 CCL25 释放。为了确定生物活性，我们研究了在微粒侵蚀阶段释放的 CCL25，并表明需要释放介质的去酸化来诱导显著的 MSC 动员。设计的 PLGA 微粒代表了一种有效且方便的即用型递送工具，用于延迟释放 CCL25。然而，需要进行连续的体内概念验证研究，以证明 CCL25 释放微粒对 MSC 募集的增强和/或治疗效果。
随着趋化因子（特别是 CXCL12）作为干细胞迁移刺激物的发现，在过去几年中，释放 CXCL12 的装置的开发进展迅速。在本文中，我们介绍 CCL25 作为趋化因子来诱导人 MSC 的动员。本研究继续证明了如何选择 CCL25 加载到 PLGA 微粒中的关键配方参数对 CCL25 释放有很大影响。这对于原位组织工程的广泛努力非常重要，在这些努力中需要仔细选择候选趋化因子和递送装置。使用这种无细胞的 CCL25 释放装置可能为再生医学提供新的治疗选择。
