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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671351/
• 关键词: Bone morphogenetic protein; Carrier; Drug delivery system; Biodegradable polymer; Poly-D,L-lactic acid-polyethylene glycol block copolymer; Bone; ポリ乳酸-ポリエチレングリコールブロック共重

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

人骨的再生潜力似乎受到限制，因为在这些情况下通常观察不到大骨缺损的修复，而大骨缺损通常与粉碎性开放性骨折或骨肿瘤切除相关。在这些严重的病例中，通常需要进行自体或同种异体骨移植，但这些方法需要外科手术。人们正在寻求侵入性较小的替代疗法，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）。 BMP 是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远离注射部位。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。我们研究的目标是开发可注射的 BMP 递送系统，用于微创治疗骨缺损或骨折。我们测试了合成可生物降解聚合物（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)）对 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。它们是 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 PLA 与 PEG 的比例几乎保持相同（大约 60 比 40）。当温度低于80℃时，P9500很难注射。另一方面，P2100 由于其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 形成的骨中的钙含量明显较低，这可能是由于这种聚合物快速扩散远离注射部位。 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得坚硬，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，不需要手术来去除它们。因此得出的结论是，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，其可用于例如大骨缺损的治疗。较少的

项目成果

Itoh H, Ebara S, Kamimura M, Tateiwa Y, Kinoshita T, Yuzawa Y, Takaoka K: "Experimental spinal fusion with use of recombinant human bone morphogenetic protein 2"Spine. 24. 1402-1405 (1999)

Itoh H、Ebara S、Kamimura M、Tateiwa Y、Kinoshita T、Yuzawa Y、Takaoka K：“使用重组人骨形态发生蛋白 2 进行实验性脊柱融合”脊柱。

Shimizu T, Mehdi R, Yoshimira Y, Nomura S, Miyazono K, Takaoka K.: "Sequential expression of bone morphogenetic protein, tumor necrosis factor, and their receptors in bone-forming reaction after mouse femoral marrow ablation."Bone. 23. 127-133 (1998)

Shimizu T、Mehdi R、Yoshimira Y、Nomura S、Miyazono K、Takaoka K.：“小鼠股骨骨髓消融后骨形成反应中骨形态发生蛋白、肿瘤坏死因子及其受体的顺序表达。”骨。

Takaoka K, Saito N, Miyamoto S, Okada T: "New synthetic degradable polymers as carrier materials for BMP. In Wise DL(ed), Biomaterials engineering and devices: human applications, vol 1"The Humana Press, New Jersey, (in press).

Takaoka K、Saito N、Miyamoto S、Okada T：“作为 BMP 载体材料的新型合成可降解聚合物。在 Wise DL（编）中，生物材料工程和设备：人类应用，第 1 卷”The Humana Press，新泽西州，（在

斎藤直人: "骨形成因子(BMP)と人工担体による骨組織の再生"信州医誌. 47. 189-190 (1999)

Naoto Saito：“使用骨形态发生蛋白（BMP）和人工载体再生骨组织”信州医学杂志 47. 189-190（1999）。

Shimizu T, Mehdi R, Yoshimura Y, Nomura S, Miyazono K, Takaoka K: "Sequential expression of bone morphogenetic protein, tumor necrosis factor, and their receptors in bone-forming reaction after mouse femoral marrow ablation"Bone. 23. 127-133 (1998)

Shimizu T、Mehdi R、Yoshimura Y、Nomura S、Miyazono K、Takaoka K：“小鼠股骨骨髓消融后骨形成反应中骨形态发生蛋白、肿瘤坏死因子及其受体的顺序表达”Bone。