Synthetic biodegradable polymers as injectable delivery systems for BMPs

合成生物可降解聚合物作为 BMP 的注射输送系统

基本信息

批准号：
10671351
负责人：
SAITO Naoto
金额：
$ 2.18万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

The regenerating potential of human bone appears to be limited since the repair of large bone defects, which are often associated with comminuted open fractures or bone tumor resections, is typically not observed in these situations. In these severe cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require surgical procedures. Less-invasive alternative treatments have been sought and one possible approach involves the injection of cytokines with bone inducing capacity, such as bone morphogenetic proteins (BMPs). BMPs are biologically active molecules capable of eliciting new bone formation in vivo. However, previous studies have indicated that injection of a small amount of pure BMP alone is not sufficient to induce new bone formation in situ, probably due to the rapid diffusion of the protein away from the site of injection. Therefore, an effective delivery system must be able to balance the retention and release of the BMP at the implant … More ed site for a period long enough for the protein to exercise its inherent biological activity. The goal of our study was to develop injectable BMP-delivery systems for a minimally invasive treatment of bone defects or fractures.We tested the suitability for BMP-delivery systems of synthetic biodegradable polymer, a poly-D,L-lactic acid-polyethylene glycol block copolymer (PLA-PEG) with tissue-compatiblity and degradablity. Four types of polymers with various molecular weights (<10,000) of PLA and PEG were synthesized. These were PLA1500-PEG600 (P2100), PLA2200-PEG1000 (P3200),PLA4400-PEG2000 (P6400), and PLA6500-PEG3000 (P9500). A comparison of these four polymers indicated that, even though the total molecular weight was altered substantially, almost the same ratio of PLA to PEG (approximately 60 to 40) was maintained. P9500 was difficult to inject when the temperature is lower than 80℃. On the other hand, P2100 had the most suitable properties for an injectable drug delivery system because of its high fluidity at low temperature. But the Ca content of the bone formed by P2100 was significantly low, probably due to the rapid diffusion of this polymer away from the site of injection. P3200 and P6400 were considered to be more suitable for injectable delivery systems for BMPs. When heated, they can be injected percutaneously with a syringe, thus avoiding the need for surgical implantation. Subsequently, they become firm when they cool down to body temperature, resulting in solid polymeric implants in the body. Moreover, surgery is not required for their removal because of their biodegradability. It is therefore concluded that these two types of PLA-PEG/BMP composite are suitable for injectable osteoinductive material which can be used, for example, in the treatment of large osseous defects. Less

人类骨骼的再生潜力似乎受到限制，因为在这些情况下通常无法观察到大骨缺损的修复，而大骨缺损通常与粉碎性开放性骨折或骨肿瘤切除有关，在这些情况下，通常无法观察到自体或同种异体骨移植。已被常规指出，但这些方法需要外科手术，人们正在寻找侵入性较小的替代治疗方法，一种可能的方法是注射具有骨诱导能力的细胞因子，例如骨形态发生蛋白（BMP）。能够在体内引发新骨形成的生物活性分子然而，先前的研究表明，单独注射少量纯 BMP 不足以诱导原位新骨形成，可能是由于蛋白质快速扩散。因此，有效的递送系统必须能够在足够长的时间内平衡 BMP 在植入部位的保留和释放，以便蛋白质发挥其固有的生物活性。是开发可注射的 BMP 递送系统用于骨缺损或骨折的微创治疗。我们测试了合成生物可降解聚合物（一种具有组织相容性和可降解性的聚-D,L-乳酸-聚乙二醇嵌段共聚物 (PLA-PEG)）的 BMP 递送系统的适用性合成了四种不同分子量（<10,000）的PLA和PEG聚合物，即PLA1500-PEG600。 (P2100)、PLA2200-PEG1000 (P3200)、PLA4400-PEG2000 (P6400) 和 PLA6500-PEG3000 (P9500) 这四种聚合物的比较表明，尽管总分子量发生了很大变化，但其比例几乎相同。 PLA 与 PEG（大约 60 比 40）保持不变。 P9500在温度低于80℃时难以注射，而P2100由于其在低温下的高流动性而具有最适合注射给药系统的特性，但P2100形成的骨中的Ca含量较低。显着低，可能是由于这种聚合物从注射部位快速扩散，因此 P3200 和 P6400 被认为更适合 BMP 的注射递送系统。加热后，可以用注射器经皮注射，从而避免了手术植入的需要。随后，当它们冷却到体温时就会变硬，从而在体内形成固体聚合物植入物，而且不需要手术将其取出。由于它们的生物降解性，因此得出结论，这两种类型的 PLA-PEG/BMP 复合材料适用于可注射的骨诱导材料，例如可用于治疗大骨缺损。