Synthetic biodegradable polymers as injectable delivery systems for BMPs

人类骨骼的再生潜力似乎是有限的，因为在这些情况下，通常没有观察到与粉碎性开放性骨折或骨肿瘤切除相关的大骨缺损的修复。在这些严重的病例中，自体或异体骨移植是常规的，但这些方法需要外科手术。人们一直在寻找侵入性较小的替代治疗方法，其中一种可能的方法是注射具有骨诱导能力的细胞因子，如骨形态发生蛋白（BMPs）。bmp是一种生物活性分子，能够在体内诱导新骨形成。然而，先前的研究表明，单独注射少量的纯BMP并不足以在原位诱导新骨形成，这可能是由于蛋白质从注射部位迅速扩散。因此，一个有效的递送系统必须能够平衡BMP在植入部位的保留和释放，使其在足够长的时间内发挥其固有的生物活性。我们研究的目的是开发可注射的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（聚d， l -乳酸-聚乙二醇嵌段共聚物（PLA-PEG））的组织相容性和可降解性对bmp递送系统的适用性。合成了四种不同分子量（< 10000）的聚乳酸和聚乙二醇聚合物。这些是PLA1500-PEG600 (P2100), PLA2200-PEG1000 (P3200),PLA4400-PEG2000 （P6400）和PLA6500-PEG3000 （P9500）。对这四种聚合物的比较表明，尽管总分子量发生了很大的变化，但PLA与PEG的比例几乎保持不变（约60比40）。P9500在温度低于80℃时难以注射。另一方面，由于P2100在低温下的高流动性，它具有最适合用于注射给药系统的性能。但P2100形成的骨中的Ca含量明显较低，可能是由于这种聚合物从注射部位迅速扩散。P3200和P6400被认为更适合于bmp的注射给药系统。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，它们变得坚固，从而在体内形成固体聚合物植入物。此外，由于它们的生物降解性，不需要手术切除。因此，这两种类型的PLA-PEG/BMP复合材料适合用于可注射的骨诱导材料，例如用于治疗大型骨缺损。少

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