Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia-Mimetic Hydrogel
Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia-Mimetic Hydrogel
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DOI：
10.1002/adfm.202008515
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发表时间：
2020-10-25
影响因子：
19
通讯作者：
Liu, Changsheng
中科院分区：
文献类型：
--
作者：
Sun, Lili;Ma, Yifan;Liu, Changsheng
由于灌注能力有限，传统的膜内成骨（IMO）往往无法重现大多数长骨和颅面骨的自然再生过程。另外，软骨内骨化（ECO）策略已经出现，并已被证明可以规避IMO常规应用中的缺点。在这里，一种可注射的，聚（甘油癸二酸酯）-共-聚（乙二醇）/聚丙烯酸（PEGS/PAA）水凝胶成功地开发，以诱导缺氧模拟环境，随后重演ECO通过原位铁螯合。由于PAA的掺入，这些水凝胶在注射后呈现出显著的粘弹性和高的铁离子螯合效力，从而引起HIF-1 α信号通路的激活和炎症反应的抑制，从而在早期阶段改善软骨形成分化，并在后期阶段促进血管化，从而触发典型的ECO。更重要的是，通过在整个再生过程中由PEGS/PAA水凝胶调节的HIF-1 α的持续和稳定表达，可以达到和谐的成软骨/成骨平衡，从而与PEGS相比加速ECO的进展。这些发现提供了一种有效的策略，通过基于生物材料的铁离子螯合和随后的低氧模拟来实现原位ECO，代表了未来在骨再生中应用的新的和有前途的概念。
Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)-co-poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia-mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion-chelating after injection, giving rise to the activation of HIF-1 alpha signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF-1 alpha regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial-based iron ion-chelating and ensuing hypoxia-mimicking, representing a novel and promising concept for future application in bone regeneration.