Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 320003, Israel.
ACS Biomater Sci Eng. 2020 Jan 13;6(1):100-111. doi: 10.1021/acsbiomaterials.9b00672. Epub 2019 Nov 5.
Growth factor delivery using acellular matrices presents a promising alternative to current treatment options for bone repair in critical-size injuries. However, supra-physiological doses of the factors can introduce safety concerns that must be alleviated, mainly by sustaining delivery of smaller doses using the matrix as a depot. We developed an acellular, biodegradable hydrogel implant composed of poly(ethylene glycol) (PEG) and denatured albumin to be used for sustained delivery of bone morphogenic protein-2 (BMP2). In this study, poly(ethylene glycol)-albumin (PEG-Alb) hydrogels were produced and loaded with 7.7 μg/mL of recombinant human BMP2 (rhBMP2) to be tested for safety and performance in a critical-size long-bone defect, using a rodent model. The hydrogels were formed ex situ in a 5 mm long cylindrical mold of 3 mm diameter, implanted into defects made in the tibia of Sprague-Dawley rats and compared to non-rhBMP2 control hydrogels at 13 weeks following surgery. The hydrogels were also compared to the more established PEG-fibrinogen (PEG-Fib) hydrogels we have tested previously. Comprehensive in vitro characterization as well as in vivo assessments that include: histological analyses, including safety parameters (i.e., local tolerance and toxicity), assessment of implant degradation, bone formation, as well as repair tissue density using quantitative microCT analysis were performed. The in vitro assessments demonstrated similarities between the mechanical and release properties of the PEG-Alb hydrogels to those of the PEG-Fib hydrogels. Safety analysis presented good local tolerance in the bone defects and no signs of toxicity. A significantly larger amount of bone was detected at 13 weeks in the rhBMP2-treated defects as compared to non-rhBMP2 defects. However, no significant differences were noted in bone formation at 13 weeks when comparing the PEG-Alb-treated defects to PEG-Fib-treated defects (with or without BMP2). The study concludes that hydrogel scaffolds made from PEG-Alb containing 7.7 μg/mL of rhBMP2 are effective in accelerating the bridging of boney defects in the tibia.
使用去细胞基质传递生长因子为临界尺寸损伤的骨修复提供了一种有前途的替代当前治疗选择。然而，超生理剂量的因子会带来安全问题，必须通过基质作为储存库来持续输送较小剂量来缓解。我们开发了一种由聚乙二醇（PEG）和变性白蛋白组成的无细胞、可生物降解的水凝胶植入物，用于持续输送骨形态发生蛋白-2（BMP2）。在这项研究中，制备了聚乙二醇-白蛋白（PEG-Alb）水凝胶，并负载 7.7 μg/mL 的重组人骨形态发生蛋白-2（rhBMP2），以在使用啮齿动物模型的临界尺寸长骨缺损中测试其安全性和性能。水凝胶在 3 毫米直径的 5 毫米长圆柱形模具中体外形成，植入到 Sprague-Dawley 大鼠胫骨中的缺损中，并在手术后 13 周与非 rhBMP2 对照水凝胶进行比较。还将水凝胶与我们之前测试过的更成熟的 PEG-纤维蛋白原（PEG-Fib）水凝胶进行了比较。进行了全面的体外表征以及体内评估，包括：组织学分析，包括安全性参数（即局部耐受性和毒性）、植入物降解、骨形成以及使用定量 microCT 分析修复组织密度的评估。体外评估表明，PEG-Alb 水凝胶的机械和释放特性与 PEG-Fib 水凝胶相似。安全性分析显示在骨缺损中具有良好的局部耐受性，没有毒性迹象。与非 rhBMP2 缺陷相比，在 rhBMP2 治疗的缺陷中，在 13 周时检测到明显更多的骨。然而，当将 PEG-Alb 治疗的缺陷与 PEG-Fib 治疗的缺陷（有或没有 BMP2）进行比较时，在 13 周时，在骨形成方面没有观察到显著差异。该研究得出结论，含有 7.7 μg/mL rhBMP2 的 PEG-Alb 水凝胶支架可有效加速胫骨骨缺损的桥接。
