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首页> 外文期刊>Stem cells translational medicine. >Controlled Dual Growth Factor Delivery From Microparticles Incorporated Within Human Bone Marrow-Derived Mesenchymal Stem Cell Aggregates for Enhanced Bone Tissue Engineering via Endochondral Ossification
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Controlled Dual Growth Factor Delivery From Microparticles Incorporated Within Human Bone Marrow-Derived Mesenchymal Stem Cell Aggregates for Enhanced Bone Tissue Engineering via Endochondral Ossification

机译：从纳入人骨髓源间充质干细胞聚集体中的微粒中控制的双重生长因子传递，用于通过软骨内骨化增强骨骼组织工程

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Bone tissue engineering via endochondral ossification has been explored by chondrogenically priming cells using soluble mediators for at least 3 weeks to produce a hypertrophic cartilage template. Although recapitulation of endochondral ossification has been achieved, long-term in vitro culture is required for priming cells through repeated supplementation of inductive factors in the media. To address this challenge, a microparticle-based growth factor delivery system was engineered to drive endochondral ossification within human bone marrow-derived mesenchymal stem cell (hMSC) aggregates. Sequential exogenous presentation of soluble transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) at various defined time courses resulted in varying degrees of chondrogenesis and osteogenesis as demonstrated by glycosaminoglycan and calcium content. The time course that best induced endochondral ossification was used to guide the development of the microparticle-based controlled delivery system for TGF-β1 and BMP-2. Gelatin microparticles capable of relatively rapid release of TGF-β1 and mineral-coated hydroxyapatite microparticles permitting more sustained release of BMP-2 were then incorporated within hMSC aggregates and cultured for 5 weeks following the predetermined time course for sequential presentation of bioactive signals. Compared with cell-only aggregates treated with exogenous growth factors, aggregates with incorporated TGF-β1- and BMP-2-loaded microparticles exhibited enhanced chondrogenesis and alkaline phosphatase activity at week 2 and a greater degree of mineralization by week 5. Staining for types I and II collagen, osteopontin, and osteocalcin revealed the presence of cartilage and bone. This microparticle-incorporated system has potential as a readily implantable therapy for healing bone defects without the need for long-term in vitro chondrogenic priming.This study demonstrates the regulation of chondrogenesis and osteogenesis with regard to endochondral bone formation in high-density stem cell systems through the controlled presentation of inductive factors from incorporated microparticles. This work lays the foundation for a rapidly implantable tissue engineering system that promotes bone repair via endochondral ossification, a pathway that can delay the need for a functional vascular network and has an intrinsic ability to promote angiogenesis. The modular nature of this system lends well to using different cell types and/or growth factors to induce endochondral bone formation, as well as the production of other tissue types.
机译：已经通过使用可溶性介体对软骨进行软骨致敏至少3周以产生增生性软骨模板来探索通过软骨内骨化的骨组织工程。尽管已经实现了软骨内骨化的概述，但是通过在培养基中反复补充诱导因子来引发细胞，需要长期的体外培养。为了解决这一挑战，设计了一种基于微粒的生长因子递送系统，以驱动人骨髓源间充质干细胞（hMSC）聚集体内的软骨内骨化。可溶性转化生长因子-β1（TGF-β1）和骨形态发生蛋白-2（BMP-2）在各种规定的时间过程中的顺序外源性表达导致软骨形成和成骨的程度不同，如糖胺聚糖和钙含量所示。使用最佳诱导软骨内骨化的时间过程来指导TGF-β1和BMP-2的基于微粒的受控递送系统的开发。然后将能够相对快速释放TGF-β1的明胶微粒和允许BMP-2持续释放的矿物涂层羟基磷灰石微粒掺入hMSC聚集体中，并在预定的时间范围内培养5周以依次呈现生物活性信号。与用外源生长因子处理的仅细胞聚集体相比，掺入了TGF-β1-和BMP-2的微粒的聚集体在第2周的软骨形成和碱性磷酸酶活性增强，到第5周的矿化程度更高。 II型胶原蛋白，骨桥蛋白和骨钙素揭示了软骨和骨骼的存在。这种结合了微粒的系统具有潜在的易于植入的疗法，可以治愈骨缺损，而无需长期进行体外成软骨作用。这项研究证明了高密度干细胞系统中软骨形成和成骨对软骨内骨形成的调节作用。通过控制引入的微粒诱导因子的表达。这项工作为快速植入的组织工程系统奠定了基础，该系统可通过软骨内骨化促进骨修复，该途径可延迟对功能性血管网络的需求，并具有促进血管生成的内在能力。该系统的模块化性质非常适合使用不同的细胞类型和/或生长因子来诱导软骨内骨形成以及其他组织类型的产生。

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