Synthesis and Characterization of a Biocomposite Bone Bandage for Controlled Delivery of Bone-Active Drugs in Fracture Nonunions,ACS Biomaterials Science & Engineering

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Synthesis and Characterization of a Biocomposite Bone Bandage for Controlled Delivery of Bone-Active Drugs in Fracture Nonunions
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-03-30 , DOI: 10.1021/acsbiomaterials.9b01574
Deepak Bushan Raina ₁ , Alexandra Glencross _{1,

2} , Nadia Chaher _{1,

2} , Yang Liu ₁ , Lars Lidgren ₁ , Hanna Isaksson _{1,

3} , Magnus Tägil ₁

Affiliation

Fracture nonunions are common in orthopedics and their treatment often involves multiple surgical interventions. The aim of this study was to fabricate and characterize a gelatin–nano-hydroxyapatite membrane (GM)-based bone bandage for controlled delivery of bio-active molecules; recombinant human bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) to promote osteoinduction and prevent callus resorption, respectively. In vitro cell–material interaction experiments using MC3T3 cells seeded on the GM indicated good biocompatibility. rhBMP-2-functionalized GM promoted osteogenic differentiation of MC3T3 cells and the rhBMP-2 bio-activity thus remained, as indicated by increased levels of alkaline phosphatase compared to only GM. The GM released a small amount (1.1%) of rhBMP-2 in vitro over a period of 5 weeks, demonstrating a strong interaction of rhBMP-2 with the GM. In the first animal study, the GM specimens loaded with rhBMP-2 or with the combination of rhBMP-2 + ZA were placed in the abdominal muscle pouch of rats. In the GM + rhBMP-2 + ZA group, significantly higher bone volume (21.5 ± 5.9 vs 2.7 ± 1.0 mm³) and area (3.3 ± 2.3 vs 1.0 ± 0.4 mm²) of bone were observed compared to GM + rhBMP-2 after 4 weeks, as indicated by micro-computed tomography and histomorphometry, respectively. Finally, a nonunion model in rats was used to evaluate the efficacy of the GM bandage and bio-active molecules in healing of fracture nonunions. The GM functionalized with rhBMP-2 + ZA led to higher bone formation around the fracture (63.9 ± 19.0 vs 31.8 ± 3.7 mm³) and stronger fracture callus (110.8 ± 46.8 vs 45.6 ± 17.8 N) compared to the empty controls. However, the overall union rate was only marginally improved. The GM alone or combined with ZA did not aid in bone healing in this model. Thus, this study shows that controlled delivery of rhBMP-2 + ZA via the developed GM is a promising approach that could aid in earlier full load bearing in patients with nonunion.

中文翻译：

生物复合骨绷带的合成和表征，用于控制骨折不愈合中骨活性药物的递送

骨折不愈合在骨科中很常见，其治疗通常涉及多种外科手术干预。这项研究的目的是制造和表征基于明胶-纳米羟基磷灰石膜（GM）的骨绷带，以控制生物活性分子的递送。重组人骨形态发生蛋白2（rhBMP-2）和唑来膦酸（ZA）分别促进骨诱导和防止愈伤组织吸收。使用接种在GM上的MC3T3细胞进行的体外细胞-材料相互作用实验显示出良好的生物相容性。rhBMP-2功能化的GM促进了MC3T3细胞的成骨分化，因此rhBMP-2的生物活性得以保留，这与碱性磷酸酶相比仅GM的水平有所提高。GM在5周内体外释放了少量（1.1％）rhBMP-2，证明了rhBMP-2与GM有很强的相互作用。在第一个动物研究中，将装有rhBMP-2或rhBMP-2 + ZA组合的GM标本放在大鼠的腹肌袋中。在GM + rhBMP-2 + ZA组中，骨体积显着增加（21.5±5.9 vs 2.7±1.0 mm与GM + rhBMP-2相比，在4周后观察到³）和³的骨面积（3.3±2.3 vs 1.0±0.4 mm ²），分别由微计算机断层扫描和组织形态学测定表明。最后，在大鼠中使用骨不愈合模型来评估GM绷带和生物活性分子在骨折骨不愈合中的疗效。用rhBMP-2 + ZA功能化的GM导致骨折周围更高的骨形成（63.9±19.0 vs 31.8±3.7 mm ³）和比空对照组更强的骨折call（110.8±46.8 vs 45.6±17.8 N）。但是，总工会率仅略有提高。在该模型中，单独使用GM或与ZA联合使用均无助于骨愈合。因此，这项研究表明，通过发达的GM控制rhBMP-2 + ZA的递送是一种有前途的方法，可以帮助骨不连的患者更早地承受满负荷。

更新日期：2020-03-30

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