Biodegradable Poly-d,l-Lactic Acid-Polyethylene Glycol Block Copolymers as a BMP Delivery System for Inducing Bone
Biodegradable Poly-d,l-Lactic Acid-Polyethylene Glycol Block Copolymers as a BMP Delivery System for Inducing Bone
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可生物降解的聚-d,l-乳酸-聚乙二醇嵌段共聚物作为诱导骨的 BMP 输送系统
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发表时间：
2001
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通讯作者：
K. Takaoka
中科院分区：
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作者：
N. Saito;T. Okada;H. Horiuchi;Narumichi Murakami;Jun Takahashi;M. Nawata;H. Ota;S. Miyamoto;K. Nozaki;K. Takaoka
背景：骨形态发生蛋白（BMPs）是具有生物活性的分子，能够诱导新骨形成。与生物材料结合，这些蛋白质可在临床环境中用作骨移植替代品，以促进骨修复。动物来源的胶原蛋白此前一直是动物实验中的首选载体材料。最近，合成的生物可降解聚合物已被测试作为骨诱导剂的递送载体。在我们实验室进行的早期研究中，发现聚乳酸均聚物（PLA 650）和聚-d，l-乳酸-聚乙二醇嵌段共聚物（PLA 650-PEG 200）是可用作BMP递送系统的粘性液体。研究方法：为了获得表现出更大塑性的新PLA-PEG聚合物，增加共聚物链中PLA和PEG链段的分子尺寸。合成具有各种分子大小和PLA/PEG比率的塑料PLA-PEG聚合物，与重组人（rh）BMP-2混合，并植入小鼠背部肌肉3周以评估其引起新骨形成的能力。为了比较塑料PLA-PEG聚合物与液体PLA 650-PEG 200聚合物，将这两种聚合物与rhBMP-2组合，植入并在3周后收获。采用单能X线骨密度仪（SXA）测量异位新骨的骨矿含量（BMC）、骨面积和骨密度（BMD）。结果：所有含10或20 g rhBMP-2的PLA 6，500-PEG 3，000种植体均显示新骨形成。相比之下，在含有rhBMP-2的其他塑料PLA-PEG植入物中观察到很少或没有骨形成。缺乏rhBMP-2的对照植入物没有显示新骨形成。X线片和组织学检查显示，植入3周后收获的含rhBMP-2的PLA 6，500-PEG 3，000植入物具有正常的骨特性，具有造血骨髓和骨小梁。SXA分析显示，使用塑料PLA 6，500-PEG 3，000聚合物和rhBMP-2得到的新骨的骨矿物质含量（BMC）、骨面积和骨矿物质密度（BMD）值显著高于使用液体PLA 650-PEG 200聚合物得到的值（三个值中的每一个p < 0.001）。结论：这些结果表明，PLA 6，500-PEG 3000嵌段共聚物具有可塑性，可有效用作BMP递送系统。这些数据表明，总分子大小和PLA大小与PEG大小的比率是确定BMP递送系统功效的重要因素。在植入后，PLA 6，500-PEG 3，000颗粒可能吸收了组织液并肿胀，导致骨形成超过原始植入物的尺寸。这种膨胀特性是一种潜在的有益特性，考虑到该聚合物在骨缺损修复中的预期实际应用，临床相关性：新的合成生物可降解递送系统将在rhBMPs的临床应用中发挥重要作用，其中需要通过骨诱导移植材料局部形成骨。在这些植入物被广泛应用于临床之前，需要进一步的临床前和临床工作来确定其安全性。
Background: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-d,l-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems. Methods: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA). Results: All of the PLA6,500-PEG3,000 implants with 10 or 20 g of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values). Conclusions: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects.Clinical Relevance:New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.