Hu Tao, Abbah Sunny Akogwu, Wang Ming, Toh Soo Yein, Lam Raymond Wing Moon, Naidu Mathanapriya, Bhakta Gajadhar, Cool Simon M, Bhakoo Kishore, Li Jun, Goh James Cho-Hong, Wong Hee-Kit
*Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore †Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore ‡Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore; and §Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore.
Spine (Phila Pa 1976). 2015 May 1;40(9):613-21. doi: 10.1097/BRS.0000000000000841.
A rodent posterolateral spinal fusion model.
This study evaluated a protamine-based polyelectrolyte complex (PEC) developed to use heparin in enhancing the biological activity of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion.
rhBMP-2 is commonly regarded as the most potent bone-inducing molecule. However, poor pharmacokinetics and short in vivo half-life means that large amounts of the bioactive growth factor are required for consistent clinical outcomes. This has been associated with a number of adverse tissue reactions including seroma and heterotopic ossification. Glycosaminoglycans including heparin are known to stabilize rhBMP-2 bioactivity. Previous studies with poly-L-lysine (PLL) and heparin-based PEC carriers amplified the therapeutic efficacy of low-dose BMP-2. However, questions remained on the eventual clinical applicability of relatively cytotoxic PLL. In the present study, a protamine-based PEC carrier was designed to further enhance the safety and efficacy of BMP-2 by delivering lower dose within the therapeutic window.
A polyelectrolyte shell was deposited on the surface of alginate microbead templates using the polycation (protamine)/polyanion (heparin) layer-by-layer polyelectrolyte self-assembly protocol. rhBMP-2 was loaded onto the outermost layer via heparin affinity binding. Loading and release of rhBMP-2 were evaluated in vitro. The bone-inductive ability of 20-fold reduction of rhBMP-2 with the different carrier vehicle was evaluated using a posterolateral spinal fusion model in rats.
In vitro uptake and release analysis, protamine-based PEC showed higher uptake and significantly enhanced control release than PLL-based PEC (P < 0.05). In vivo implantation with protamine-based and PLL-based PEC showed better fusion performances than absorbable collagen sponge-delivered same dose of rhBMP-2, and negative control group through manual palpation, micro-computed tomography, and histological analyses.
Solid posterolateral spinal fusion was achieved with 20-fold reduction of rhBMP-2 when delivered using protamine-based PEC carrier in the rat posterolateral spinal fusion model.
N/A.
一种啮齿动物后外侧脊柱融合模型。
本研究评估了一种基于鱼精蛋白的聚电解质复合物（PEC），该复合物旨在利用肝素增强低剂量重组人骨形态发生蛋白-2（rhBMP-2）在脊柱融合中的生物活性。
rhBMP-2通常被认为是最有效的骨诱导分子。然而，其药代动力学不佳且体内半衰期短，这意味着为了获得一致的临床效果需要大量的生物活性生长因子。这与包括血清肿和异位骨化在内的多种不良组织反应有关。已知包括肝素在内的糖胺聚糖可稳定rhBMP-2的生物活性。先前关于聚-L-赖氨酸（PLL）和基于肝素的PEC载体的研究放大了低剂量BMP-2的治疗效果。然而，相对具有细胞毒性的PLL的最终临床适用性仍存在疑问。在本研究中，设计了一种基于鱼精蛋白的PEC载体，通过在治疗窗口内递送较低剂量来进一步提高BMP-2的安全性和有效性。
使用聚阳离子（鱼精蛋白）/聚阴离子（肝素）逐层聚电解质自组装方案在藻酸盐微珠模板表面沉积聚电解质壳。通过肝素亲和结合将rhBMP-2加载到最外层。在体外评估rhBMP-2的加载和释放。使用大鼠后外侧脊柱融合模型评估不同载体对rhBMP-2剂量降低20倍后的骨诱导能力。
体外摄取和释放分析表明，基于鱼精蛋白的PEC比基于PLL的PEC表现出更高的摄取率和显著增强的控释效果（P < 0.05）。通过手动触诊、微型计算机断层扫描和组织学分析，基于鱼精蛋白和基于PLL的PEC的体内植入显示出比可吸收胶原海绵递送相同剂量的rhBMP-2更好的融合性能，以及比阴性对照组更好的融合性能。
在大鼠后外侧脊柱融合模型中，使用基于鱼精蛋白的PEC载体递送时，rhBMP-2剂量降低20倍仍可实现坚实的后外侧脊柱融合。
无。
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