Louis-Ugbo John, Kim Hak-Sun, Boden Scott D, Mayr Matthew T, Li Ronald C, Seeherman Howard, D'Augusta Darren, Blake Cara, Jiao Aiping, Peckham Steve
Department of Orthopaedic Surgery, School of Medicine, Emory University, Altanta, GA 30322, USA.
J Orthop Res. 2002 Sep;20(5):1050-9. doi: 10.1016/S0736-0266(02)00011-6.
The purpose of this study was to characterize the retention kinetics of recombinant human bone morphogenetic protein-2 (rhBMP-2) applied to two calcium-based delivery matrices. Biphasic calcium phosphate (BCP) and a composite containing BCP in an absorbable collagen sponge (BCP/ACS) were evaluated using a spinal fusion model in rabbits. rhBMP-2 labeled with radioactive iodine (125I) was used as a tracer to assess in vivo retention of rhBMP-2 in the presence of these materials (nine animals per material studied). Over a 36 day study period, animals were assessed for the following: percent administered dose retained at the implant site as measured by scintigraphic imaging (counting) with a gamma camera (all animals), radiography of the implant site (all animals), radioactivity in blood and plasma (all animals), and radioactivity in the urine and feces (three animals for each material). Radioactivity data were corrected for the decay of 125I and the attenuation between the implant in vivo and the gamma camera. Differences observed between the two materials for the area under the retention vs. time profile (AUC; 988%*day for BCP vs. 1070%*day for BCP/ACS, p = 0.57) and the mean residence time (MRT; 10.2 days for BCP vs. 7.6 days for BCP/ACS, p = 0.06) were not statistically significant. Initial retention/incorporation of rhBMP-2 was slightly higher for rhBMP-2/BCP/ACS than for rhBMP-2/BCP (96.8% vs. 86.0%, p < 0.05). Animals receiving rhBMP-2/BCP showed a longer terminal retention half-life (t1/2) than did those receiving rhBMP-2/BCP/ACS (7.5 vs. 4.5 days, p < 0.05). The urinary radioactivity recovery data supported the data obtained by scintigraphy. Over the 36 day collection period, essentially complete recovery of radioactivity (dose) in urine was observed for rhBMP-2/BCP and rhBMP-2/BCP/ACS and the majority of the radioactivity (approximately 95%) was soluble in trichloroacetic acid, suggesting extensive catabolism of rhBMP-2 before renal excretion. Fecal recovery of radioactivity was low, approximately 2-3%. In conclusion, rhBMP-2 was retained at the implant site when delivered with either BCP or BCP/ACS based on mean residence time and area under the retention curve vs. time profile. Use of these matrices resulted in detectable rhBMP-2 levels at the surgical site for over a week in contrast to data reported with several other matrices that lasted less time. Systemic catabolism and elimination of the rhBMP-2 was extensive and systemic presence of the protein was negligible.
本研究的目的是表征应用于两种钙基递送基质的重组人骨形态发生蛋白-2（rhBMP-2）的保留动力学。使用兔脊柱融合模型评估了双相磷酸钙（BCP）和一种在可吸收胶原海绵中含有BCP的复合材料（BCP/ACS）。用放射性碘（125I）标记的rhBMP-2用作示踪剂，以评估在这些材料存在下rhBMP-2在体内的保留情况（每种材料研究9只动物）。在为期36天的研究期间，对动物进行了以下评估：通过γ相机进行闪烁成像（计数）测量植入部位保留的给药剂量百分比（所有动物）、植入部位的X线摄影（所有动物）、血液和血浆中的放射性（所有动物）以及尿液和粪便中的放射性（每种材料3只动物）。放射性数据针对125I的衰变以及体内植入物与γ相机之间的衰减进行了校正。观察到两种材料在保留量与时间曲线下的面积（AUC；BCP为988%*天，BCP/ACS为1070%*天，p = 0.57）和平均驻留时间（MRT；BCP为10.2天，BCP/ACS为7.6天，p = 0.06）方面的差异无统计学意义。rhBMP-2/BCP/ACS中rhBMP-2的初始保留/掺入略高于rhBMP-2/BCP（96.8%对86.0%，p < 0.05）。接受rhBMP-2/BCP的动物的终末保留半衰期（t1/2）比接受rhBMP-2/BCP/ACS的动物长（7.5天对4.5天，p < 0.05）。尿放射性回收数据支持了闪烁显像获得的数据。在36天的收集期内，观察到rhBMP-2/BCP和rhBMP-2/BCP/ACS的尿液中放射性（剂量）基本完全回收，并且大部分放射性（约95%）可溶于三氯乙酸，这表明rhBMP-2在经肾排泄之前发生了广泛的分解代谢。粪便中放射性回收较低，约为2 - 3%。总之，基于平均驻留时间和保留曲线下面积与时间曲线，当rhBMP-2与BCP或BCP/ACS一起递送时，它会保留在植入部位。与其他几种持续时间较短的基质所报道的数据相比，使用这些基质在手术部位可检测到rhBMP-2水平超过一周。rhBMP-2的全身分解代谢和消除广泛，该蛋白在全身的存在可忽略不计。
