Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair.
Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair.
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DOI：
10.3389/fbioe.2023.1190371
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发表时间：
2023
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
目前，还没有fda批准的非手术生物方法来加速骨折的修复。设计用于刺激骨愈合的注射疗法是外科植入生物制剂的一个令人兴奋的替代方案，然而，由于需要安全有效的药物输送，有效的骨诱导疗法的转化仍然具有挑战性。基于水凝胶的微颗粒平台可能是一种临床相关的解决方案，可以创建可控和局部的药物输送来治疗骨折。在这里，我们描述了以聚乙二醇二甲基丙烯酸酯（PEGDMA）为基础的微颗粒，其形状为微棒，装载了β神经生长因子（β-NGF），以促进骨折修复。方法：采用光刻法制备聚乙二醇二甲基丙烯酸酯微棒。用β-NGF负载PEGDMA微棒，观察其体外释放。随后，使用表达TF-1酪氨酸受体激酶A （Trk-A）的细胞系进行体外生物活性测定。最后，使用我们建立的小鼠胫骨骨折模型进行体内研究，并使用微计算机断层扫描（µCT）和组织形态学测量技术，单次注射加载β-NGF的PEGDMA微棒、未加载PEGDMA微棒或可溶性β-NGF来评估骨折愈合程度。结果：体外释放研究表明，通过物理化学相互作用，蛋白质在聚合物基质中保留超过168小时。用TF-1细胞系证实了蛋白的生物活性。使用我们的小鼠胫骨骨折模型进行的体内研究表明，在骨折部位注射PEGDMA微棒可以在骨痂附近保持7天以上。重要的是，单次注射含有β-NGF的PEGDMA微棒可以改善骨折愈合，与可溶性β-NGF对照相比，骨折痂骨百分比、骨小梁结缔组织密度和骨矿物质密度显著增加，表明组织内药物潴留改善。伴随的软骨部分减少支持了我们之前的工作，表明β-NGF促进软骨向骨的软骨内转化，以加速愈合。讨论：我们展示了一种新颖的转化方法，其中β-NGF可以被封装在PEGDMA微棒中进行局部递送，并保持β-NGF的生物活性，从而改善骨折修复。
Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (β-NGF) for the purpose of promoting fracture repair. Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with β-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the β-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble β-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry. Results: In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of β-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble β-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that β-NGF promotes endochondral conversion of cartilage to bone to accelerate healing. Discussion: We demonstrate a novel and translational method wherein β-NGF can be encapsulated within PEGDMA microrods for local delivery and that β-NGF bioactivity is maintained resulting in improved bone fracture repair.
DOI：
10.4161/biom.17849
发表时间：
2011-10
期刊：
Biomatter
影响因子：
--
作者：
Conovaloff AW;Beier BL;Irazoqui PP;Panitch A
通讯作者：
Panitch A
影响因子：
2.8
作者：
Doroudian, Golnar;Pinney, James;Ayala, Perla;Los, Tamara;Desai, Tejal A.;Russell, Brenda
通讯作者：
Russell, Brenda