用于快速和自我维持软骨内骨化的双相骨血管仿生支架,Advanced Healthcare Materials

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用于快速和自我维持软骨内骨化的双相骨血管仿生支架
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2021-04-21 , DOI: 10.1002/adhm.202100070
Hwan D Kim _{1,

2,

3} , Xuechong Hong _{1,

2} , Young-Hyeon An ₄ , Mihn Jeong Park ₄ , Do-Gyoon Kim ₅ , Arin K Greene ₆ , Bonnie L Padwa ₆ , Nathaniel S Hwang ₄ , Ruei-Zeng Lin _{1,

2} , Juan M Melero-Martin _{1,

2,

7}

Affiliation

大骨的再生仍然是手术中的一个挑战。最近的发育工程工作旨在重现软骨内骨化（EO），这是骨形成的关键步骤。然而，这个过程需要将间充质干细胞（MSC）浓缩成软骨模板，这需要长期培养，并且规模化具有挑战性。在这里，开发了一种仿生支架，可以快速且自我维持 EO，而无需最初的肥大软骨形成。该设计包括装饰有白磷矿磷酸钙纳米粒子的多孔硫酸软骨素冷冻凝胶和占据多孔空间的软水凝胶。这种复合支架使人内皮集落形成细胞 (ECFC) 和 MSC 能够快速组装成免疫缺陷小鼠的骨血管微环境。这些生态位包含 ECFC 衬里的血管和血管周围 MSC，在体内一周后分化为 RUNX2 ⁺ OSX ^{+前成骨细胞。}随后，形成多个骨化中心，导致八周时从头形成骨组织，包括成熟的人 OCN ⁺ OPN ⁺成骨细胞、富含胶原蛋白的矿化细胞外基质、羟基磷灰石、破骨细胞活性和逐渐的机械能力。血管的早期建立至关重要，不含 ECFC 的移植物无法产生骨血管生态位和骨化中心。研究结果提出了一种新的生物工程方法，可以在人类骨再生的背景下重现 EO。

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A Biphasic Osteovascular Biomimetic Scaffold for Rapid and Self-Sustained Endochondral Ossification

Regeneration of large bones remains a challenge in surgery. Recent developmental engineering efforts aim to recapitulate endochondral ossification (EO), a critical step in bone formation. However, this process entails the condensation of mesenchymal stem cells (MSCs) into cartilaginous templates, which requires long-term cultures and is challenging to scale up. Here, a biomimetic scaffold is developed that allows rapid and self-sustained EO without initial hypertrophic chondrogenesis. The design comprises a porous chondroitin sulfate cryogel decorated with whitlockite calcium phosphate nanoparticles, and a soft hydrogel occupying the porous space. This composite scaffold enables human endothelial colony-forming cells (ECFCs) and MSCs to rapidly assemble into osteovascular niches in immunodeficient mice. These niches contain ECFC-lined blood vessels and perivascular MSCs that differentiate into RUNX2⁺OSX⁺ pre-osteoblasts after one week in vivo. Subsequently, multiple ossification centers are formed, leading to de novo bone tissue formation by eight weeks, including mature human OCN⁺OPN⁺ osteoblasts, collagen-rich mineralized extracellular matrix, hydroxyapatite, osteoclast activity, and gradual mechanical competence. The early establishment of blood vessels is essential, and grafts that do not contain ECFCs fail to produce osteovascular niches and ossification centers. The findings suggest a novel bioengineering approach to recapitulate EO in the context of human bone regeneration.

更新日期：2021-04-21

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