CN1027346C - 制备用于治疗伤口的组合物的方法 - Google Patents
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- CN1027346C CN1027346C CN87101250A CN87101250A CN1027346C CN 1027346 C CN1027346 C CN 1027346C CN 87101250 A CN87101250 A CN 87101250A CN 87101250 A CN87101250 A CN 87101250A CN 1027346 C CN1027346 C CN 1027346C
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Abstract
通过用一种组合物给哺乳动物治疗来愈合其外部伤口或使其骨头再生，该组合物包含提纯的血小板衍生的生长因子和提纯的类胰岛素生长因子。
Description
本申请是Antoniades等人于1986年11月14日在美国提交的序号为930，762、题目为“治疗外部伤口”申请案的部分后继申请，该申请案通过引用被结合到本申请中。
本发明涉及伤口治疗
生长因子是刺激一种确定的靶细胞群体的多肽激素。生长因子的例子有血小板衍生的生长因子（PDCF），类胰岛素生长因子（ICF-I），转化生长因子培带（TGF-β），表皮生长因子（EGF）和成纤维细胞生长因子（FGF）。PDGF是一种在循环血小板颗粒中发现的阳离子的、热稳定蛋白质，已知它有刺激体外蛋白质合成和通过成纤维细胞刺激胶原蛋白生成的作用。它还对成纤维细胞，平滑肌细胞和神经胶质细胞起体外促细胞***剂和趋化性剂的作用。
已有人提出过利用PDGF来促进活体伤口愈合，例如，Grotendorst 1984年在“Trauma”杂志24期549-552页描述了把PDGF加在一种用胶原蛋白的凝胶浸渍过、并植入鼠背的亨特-希林（Hunt-Schilling）金属丝筛盒中，发现PDGF提高了新胶原蛋白的合成量。然而，Leitzel等人1985年在Dermatol.Surg.Oncol.杂志11期617-622页上认为单独使用PDGF或与FGF和EGF结合使用都不能加速仓鼠正常伤口的愈合。
Michaeli等人1984年在纽约Praeger出版社出版的“Soft and Hard Tissue Repair”（软组织和硬组织的修复）一书（Hunt，T.K.等人编辑）的380-394页中报导了应用一种从富血小板血浆中提取的PDGF的部分提纯制品，植入家兔角膜时，刺激血管的生成。因为PDGF不是一种生成血管的生长因子，所以研究者认为在他们的部分提纯的PDGF制品中，有一种未知的因子导致了生成血管的效果。
一般来说，本发明的特点一个方面是，通过将有效量的包括有提纯PDGF和提纯IGF-I的一种组合物施加于伤口上，治愈哺乳动物，例如一个病人的外部伤口。该组合物通过促进上皮和***的生长及促进全部蛋白质和胶原的合成，帮助愈合或者至少部分愈合伤口。采用本发明的组合物治疗伤口比未经处理（即没有施加外源剂）或只是提纯的PDGF，或只用提纯的IGF-I处理能达到更好的效果。
本发明的特点另一方面是，通过对病人施加药物，最好向受伤的区域或缺失骨头的区域施加有效量的包括了提纯PDGF和提纯IGF-I的一种组合物，使哺乳动物、例如一个病人的骨头再生。组合物通过促进***、骨头和牙骨质的生长及刺激蛋白质和胶原的合成，帮助骨头再生或至少部分再生。采用本发明的组合物促进再生要比未经处理（即不用外源剂）或仅是提纯的PDGF或仅用提纯的IGF-I处理达到更好的效果。
在发明这两方面的优选的实施方案中，组合物是通过在一种药物学上可接受的载体物质，例如商业上可买到的惰性凝胶或液体中（例如，加有清蛋白或甲基纤维素的盐水）将提纯的PDGF和IGF-I（两者都是商业上可买到的）相结合来制取的。提纯的PDGF和IGF-I的组合，最好按重量比在1∶4到25∶1之间。优选的范围为1∶2到10∶1，更好的范围是1∶1或2∶1。提纯的PDGF和IGF-I可从人的血小板中获得。或借助重组体DNA技术获得。这样，对于术语“PDGF”和“IGF-I”，我们指的是哺乳类的、特别是灵长类的血小板得到的和重组体材料两者;灵长类中，人是最好的，但也可以是黑猩猩和其它灵长类。重组体PDGF可以是异种二聚体重组体，其形成可以是通过将编码了原核生物或真核生物细胞两者亚基的DNA序列***到原核生物细胞或真核生物细胞中，然后让该转译的亚基被细胞加工形成异种二聚体，或也可仅将编码了一个亚基（最好是培带
（beta）或“2”链）的DNA***细胞，然后将其培养产生同种二聚体的PDGF（PDGF-1或PDGF-2同种二聚体）。
此处所用的术语“提纯的”指PDGF或IGF-I在彼此混合前，其重量占95%或更多，即大体是没有其它蛋白质、脂类和碳氢化合物的，而这些物质是天然与其相结合的。
一种提纯的蛋白质制品对PDGF或IGF-I的每种亚基一般在聚丙烯酰胺凝胶上产生一个单一的主带。本发明的组合物中采用的提纯的PDGF和IGF-I最好用氨基末端的氨基酸序列分析判断是纯的。
本发明的组合物为治愈哺乳类动物的外部伤口，例如褥疮、裂伤、烧伤提供了一个快速有效的方法。本组合物同自然治疗（即不加外源剂）或仅用纯的PDGF或IGF-I相比增强了***的形成。与仅用纯的PDGF不同，本组合物促进新的***增长大约250%，促进上皮组织生长增大95%，得到的上皮组织层比自然治疗产生的要厚，并且还包含更多的将其同新的***相连接的上皮突起，因此，它结合得更坚牢，更有保护性。此外，疤痕形成被减至最小。
本发明组合物还为有牙周疾病史的哺乳类动物，例如人的***和骨头的再生提供了一种快速有效的方法，同自然治疗（即不用外源剂）或仅采用纯的PDGF或IGF-I相比，组合物增强了***和骨头的形成。
本发明的其它特点和优点从下面优选实施方案的说明和权利要求中将明显看到。
现在，我们对本发明的优选实施方案进行说明。
按照本发明，用纯的PDGF和IGF-I结合制备的PDGF/IGF-I混合物来处理外部伤口，例如褥疮和烧伤，使骨头和***再生。IGF-I是可以通过商业渠道从Amgen公司（Thousand Oaks，CA）和Kabi公司（瑞典）买到的。提纯的重组体PDGF和从人的血小板中得到的提纯的PDGF可以通过商业渠道从PDGF公司（马萨诸塞州，波士顿），合作研究所（Waltham，MA），和Amgen公司（Thousand Oaks，CA）买到的。提纯的PDGF也可以按以下方法制备：
将500到1000单位洗净的人血小板小丸悬浮在1M氯化钠中，（每个血小板单位2毫升）在100℃的温度下加热15分钟，然后借助离心方法将上清液分离，沉淀物用1M氯化钠提取两次。
将提取物合并，用0.08M氯化钠-0.01M磷酸钠缓冲液（pH7.4）进行透析，在4℃温度下同用所述缓冲液平衡的CM-Sephadex C-50（一类交联葡萄糖）混合过夜。然后将混合物例入一个柱内（5×100cm），用0.08M氯化钠-0.01M磷酸钠缓冲液（pH7.4）彻底清洗，并用1M氯化钠洗脱，同时收集到10毫升馏分。
将活性馏分汇集起来，对0.3M氯化钠-0.01磷酸钠缓冲液（pH7.4）进行透析，离心分离，并在4℃下通过一个2.5×25厘米的用0.3M氯化钠-0.01M磷酸钠的缓冲液（pH7.4）平衡过的蓝Sepharose（一种琼脂糖）层析柱。然后用该缓冲液清洗该柱，并用一种由1M氯化钠和1，2-亚乙基二醇以1∶1组成的溶液洗脱部分提纯的PDGF。
将部分提纯的PDGF馏分用1M氯化钠稀释，对1M醋酸进行透析，并冷冻干燥。将冷冻干燥的样品溶解在0.8M氯化钠-0.01M磷酸钠缓冲液（pH7.4）中，并通过一个用该缓冲液平衡的CM-Sephadex C-50的1.2×40厘米的层析柱，然后用氯化钠梯度（0.08到1M）洗脱PDGF。
合并活性馏分，对1M醋酸进行透析，冷冻干燥并溶解在少量的1M醋酸中，将0.5毫升的蛋白质加到1.2×100厘米的一个用1M醋酸平衡过的Biogel P-150（一种生物凝胶）（100到200目）层析柱中，然后用1M醋酸洗脱PDGF，同时收集2毫升馏分。
将每一种包含100～200毫克蛋白质的活性馏分冷冻干燥，溶解在100毫升0.4%的三氟醋酸中，并在一个苯基键合层析柱（Phenyl Bondapak Column）上进行逆相高效液相层析。用线性的乙腈梯度（0到60%）洗脱，产生纯的PDGF。
可按下述步骤制备用重组体DNA技术制造的PDGF：
从人血小板得到的血小板衍生的生长因子（PDGF）包括了两个多肽序列（PDGF-1和PDGF-2多肽;Antoniades，H.N.和Hunkapiller，M在1983年“Science”杂志220期963-965页）。PDGF-1由位于第7条染色体的基
因编码（Betscholtz，C等人在“Nature”杂志320期695-699页），而PDGF-2由位于第22条染色体（Dalla-Favera，R1982年在“Science”218期686-688页）的Sis癌基因（Doolittle，R等人1983年“Science”211期275-277页）编码。该SiS基因编码了同PDGF-2多肽密切相关的猿猴肉瘤病毒（SSV）的转化蛋白，人类细胞的C-Sis也编码了PDGF-2链（Rao，C，D，等人1986年Proc.Natl.Acad.Sci.USA.83期2392-2396页）。因为PDGF的两条多肽链是由位于分开的染色体上的两个不同的基因编码的，所以存在这样的可能性，人的PDGF是由PDGF-1和PDGF-2的一个二硫化物连接的异种二聚体组成、或由两个同种二聚体（PDGF-1同种二聚体和PDGF-2同种二聚体）的混合物组成、或由异种二聚体和两个同种二聚体的混合物组成。
在培养中感染了包含编码了PDGF-2链的基因的猿猴肉瘤病毒的哺乳动物细胞已被证明能合成PDGF-2多肽并能将它加工成二硫化物连接的同种二聚体（Robbins，K.等人1983年“Nature”305期605-608页）。此外，PDGF-2同种二聚体对反抗人类PDGF而产生的抗血清起反应。而且，分泌的PDGF-2同种二聚体的功能特性与由血小板衍生的PDGF相似，因为它在培养的成纤维细胞内刺激DNA的合成，它在一个185Kd细胞膜蛋白质的铬氨酸残基上诱发磷化作用，并且它在接合到特殊的细胞表面PDGF受体方面同人类（125I）-PDGF具有可比拟的能力（Owen，A等人1984年“Science”225期54-56页），由培养的通常的人细胞（例如人的动脉内皮细胞）或者表达SiS/PDGF-2基因的人类恶性细胞中得到的SiS/PDGF-2基因产物也表现出类似的性质（Antoniades，H等人1985年“Cancer Cells”3期145-151页）。
重组体PDGF-2同种二聚体是通过利用一个表达载体将C-SiS/PDGF-2基因的cDNA克隆引入小鼠细胞而得到的。用于表达的C-SiS/PDGF-2克隆是由通常的人的培养的内皮细胞获得的（Collins，T等人1985年“Nature”216期748-750页）。
为了确定PDGF/IGF-I混合物在促进伤口愈合方面的有效性，进行了以下实验。
将10-15公斤的约克夏小白猪（Parson农场·Hadley，MA）在外科手术前至少禁食6小时，然后麻醉。在无菌条件下将其胸及背部的毛剃去，用和缓的肥皂及水洗涤干净。然后用70%的酒精，将要进行创伤的区域消毒。
采用一种改进的Castroviejo电角膜刀开出一些1厘米×2厘米、深为0.5毫米的伤口（Storz，St.Louis，MO，由Brownells公司改进的电角膜刀）。这些伤口使上皮及埋在下面的真皮蛋白质被完全除去（可与二度烧伤相比）。各个伤口至少有15毫米未损伤的皮肤隔开。接受同样处理的伤口被划为一组，并同其它组至少相隔3厘米，不接受生长因子处理的伤口同接受这种处理的伤口至少相隔10厘米。
在伤口上直接用单独一种悬浮于生物相容凝胶中的生长因子处理，1）500毫微克纯的人类PDGF（用高效液相层析法提纯了的）或单独使用重组体PDGF;2）将500毫微克纯的PDGF与下述每一种的组合：a）500毫微克EGF;b）500毫微克EGF加500毫微克IGF-I;c）500毫微克IGF-I。
在切出伤口后，从第3天到第10天采集活检样品。供组织结构评价的活检样品呈楔形，约3毫米深，并被放置在10%的***溶液中。用于生化分析和自动射线照相法的样品是用电角膜刀切取的。样品的最终尺寸是1.5毫米×10毫米×1.5毫米。每个伤口采集3个样品用于生化分析，而每个伤口采集2个样品用于自动射线照相法。样品采集后，将其贮藏于冷的加有10%的牛胎血清的EMEM（Eagie′s Modified Essential Medium）介质中。活检样品按下述方法分析。
自动射线照相法
将活检样品放在0.3毫升的加入了10%的每毫升含15微居里3H-胸甙的牛胎血清的EMEM介质中，培养1小时，然后用10%的***溶液将样品洗涤两次。采用标准的石蜡浸渍和埋置技术将样品制成4微米的切片。然后，脱去石蜡，浸入核示踪感光乳胶NTB-2（柯达牌）中，并曝光两星期。接着用苏木精和四溴萤光素将其显影和染色。
通过计算示踪细胞总数对该区域内细胞总数的关系，将染色样品的自动射线照片记录在相等分布
的一些点上（每个细胞5个点或更多）。
组织结构分析
采用标准石蜡浸渍和埋置技术制备组织结构分析样品。将其制成4微米的切片并用过泸的Harris苏木精和酒精曙红染色;然后在显微镜下观察。由两个试验者对所有样品在遍布该切片的等分布点上盲目地进行记录。上皮和***层的宽度用放在显微镜目镜内的网格进行计算;然后在相同观察条件下，用测微器将测量值转换成毫米数。
体外新陈代谢示踪
活检样品被移放到各个试管中，试管内有0.3毫升加了10%牛胎血清、15微居里3H-胸甙和5微居里14C-亮氨酸的EMEM，在37℃温度下培养1小时。在1小时末了时，去掉介质，并加入0.5毫升冷的5%的高氯酸使组织的新陈代谢停止。然后将样品细细切碎并洗涤三遍;将产生的沉淀物重新悬浮在0.5毫升14.8M氢氧化胺中并用超声处理，超声处理后，样品在密封试管中在45℃温度下培养16-24小时，两次超声处理，并用带有交叉通道计数的标准液体闪烁法测定其放射性。
DNA和蛋白质的测定
确定DNA是采用Labara等人1980年在“Anal.Biochem.”120期344-352提出的方法的改进方案进行的。将50微升在浓氢氧化胺中的组织提取物的等分试样加入到400微升含1M磷酸钠和2M氯化钠的缓冲液（pH7.0）中;用盐酸将得到的溶液的pH值调节到7.4。之后，使最后溶液的体积达到500微升，同时使pH值保持在7.4。然后将该溶液加入到被缓冲过的Hoesht染料溶液（染料1.14毫克/毫升，缓冲液为0.05M磷酸钠和2M氯化钠，pH＝7.4）中，在352毫微米波长的激励下诱发荧光并在454毫微米处测量辐射，通过相同处理制备的小牛胸腺DNA被用来形成标准曲线。
在浓氢氧化胺中的组织提取物的蛋白质含量是以牛的血清清蛋白为标准用Bradford方法（Bradford 1976年“Anal.Biochem.”72期248-254页）测定的。
结果
组织结构分析结果表明：用提纯的人类PDGF或重组体PDGF和IGF-I结合处理伤口与对伤口不作处理、或仅用纯的IGF-I、纯的PDGF、或PDGF与其它生长因子结合相比，具有较厚的***和上皮层，并有更广泛的上皮突起同上皮层相连，直至处理后的6个星期都没有出现形成疤痕的迹象。自动射线照相术揭示，用PDGF/IGF-I处理伤口比对伤口不作处理或仅用PDGF，IGF-I处理的伤口，3H-胸甙-示踪细胞的百分比有提高。新陈代谢示踪的结果表明，用提纯的PDGF/IGF-I制品处理的伤口，3H-胸甙和14C-亮氨酸的吸收比不作处理的伤口要大;类似地，PDGF/IGF-I处理的伤口具有更高的DNA和蛋白质含量。
对用前面所述方法制备的重组体提纯的PDGF-2同种二聚体，也在部分粗皮肤伤口上单独地或与IGF-I结合地做过试验。对六天时间的伤口进行的组织结构分析指出单独应用PDGF-2或IGF-I在控制***或表皮形态结构方面不产生实质性区别。然而，当PDGF-2和IGF-I结合时，在手术后第六天就使新的***层的宽度增加2倍，表皮的厚度增加20%，手术后第九天，单独使用PDGF-2使新的***和表皮厚度都只增加22%，而PDGF-2与IGF-I的结合使新的***和表皮层均增加75%。用PDGF-2/IGF-I处理过的伤口的***具有明显的光极化区域，表示这些伤口比只接受PDGF-2单独处理或未作处理的伤口包含更多成熟的***。
利用上面描述的动物模型将重组体PDGF-2应用于伤口愈合上，产生的效果与提纯的人类PDGF同重组体IGF-I结合时的情况是类似的。重组体PDGF-2和IGF-I的结合在新的成纤维细胞数量、胶原合成速率和相伴随的真皮和表皮增生方面，同没有处理或仅用重组体PDGF-2或IGF-I单独处理的对照实验动物相比都有引人注目的增长（有2.5倍的总增长）。
这些结果表明，重组体PDGF-2同种二聚体和天然的提纯的人类PDGF在局部施加到伤口上时，都能同IGF-I协同地相互作用。
剂量
为了确定提纯的PDGF的合适剂量，除了用相当于每平方毫米伤口2.5毫微克、5毫微克和10毫微克分散在30微升生物相容的凝胶中的PDGF
对伤口进行处理外，重复前述的实验。结果表明最佳的效果在PDGF含量为每平方毫米5毫微克或更高时产生。
为了确定纯的PDGF加IGF-I的合适剂量，如上所述对PDGF与IGF-I的重量比在1∶10到25∶1范围的组合进行了评价。最佳结果是在两者之比为1∶1与2∶1之间达到。
骨头再生
为了确定PDGF/IGF-I制品在促进牙周组织和/或骨头生长方面的效果，进行了下述实验。
在最初的射线照相检查基础上，选择若干有自然发生牙周病的小猎兔犬。用超声波仪器先估定出呈现30%到80%骨缺失的牙齿，然后进行外科瓣和根整平术，用在药物学上可接受的载体物质中含有提纯的PDGF和IGF-I的组合物处理实验的牙齿，这种载体例如商业上可买到的惰性凝胶，如甲基纤维素，其余的在四分之一圆弧内的牙齿只单独接受对照凝胶或纯的PDGF或IGF-I的处理。手术后两星期，采集骨头和牙齿活检块，并用标准的去无机盐和处理技术准备进行组织学分析。
结果
对牙周组织和骨头的组织学分析结果表明，邻接实验试样（即用PDGF/IGF-I组合物处理的那些牙）的齿根表面存在着新骨形成的明显区域，并在与新骨邻接的齿根表面有一层类似牙骨质的沉积物。新骨也存在于试样的骨膜表面，在韧带尖端的区域范围内存在关节强硬的区域。一层类成骨细胞的稠密层和***把新形成的骨头和新形成的***新形成的牙骨质中的胶原纤维连系起来。
在对照试样中没有新骨形成的迹象，也没有新的类牙骨质沉积物，并且***与骨头表面垂直取向，形成盖在原有骨头上的一个“帽子”。这样的结果表明了本发明的PDGF/IGF-I组合物增强了成骨和***的应答。
其它实施方案包含在以下的权利要求中。
Claims (3)
1、制备治疗伤口的组合物的方法，包括将纯化的血小板衍生的生长因子和纯化的类胰岛素生长因子相混合，并将该生长因子混合物与药物载体相混合，其中纯化的血小板衍生的生长因子和纯化的类胰岛素生长因子的重量比为1∶4-25∶1。
2、根据权利要求1的方法，其中纯化的血小板衍生的生长因子和纯化的类胰岛素生长因子的重量比为1∶2-10∶1。
3、根据权利要求1的方法，其中纯化的血小板衍生的生长因子和纯化的类胰岛素生长因子的重量比为1∶1或2∶1。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93076286A | 1986-11-14 | 1986-11-14 | |
| US930,762 | 1986-11-14 | ||
| US930762 | 1986-11-14 |
Publications (2)
| Publication Number | Publication Date |
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| CN87101250A CN87101250A (zh) | 1988-06-08 |
| CN1027346C true CN1027346C (zh) | 1995-01-11 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CN87101250A Expired - Lifetime CN1027346C (zh) | 1986-11-14 | 1987-11-14 | 制备用于治疗伤口的组合物的方法 |
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| EP (1) | EP0289584B1 (zh) |
| JP (1) | JPH01500199A (zh) |
| KR (1) | KR960005708B1 (zh) |
| CN (1) | CN1027346C (zh) |
| AT (1) | ATE88899T1 (zh) |
| AU (1) | AU600069B2 (zh) |
| DE (1) | DE3785758T2 (zh) |
| DK (1) | DK175889B1 (zh) |
| IE (1) | IE60517B1 (zh) |
| MX (1) | MX170454B (zh) |
| NO (1) | NO883127L (zh) |
| NZ (1) | NZ222551A (zh) |
| OA (1) | OA09159A (zh) |
| WO (1) | WO1988003409A1 (zh) |
| ZA (1) | ZA878566B (zh) |
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| US4889919A (en) * | 1986-08-13 | 1989-12-26 | Zymogenetics, Inc. | Biologically active PDGF derived A-chain homodimers |
| US5474982A (en) * | 1986-08-13 | 1995-12-12 | Zymogenetics, Inc. | PDGF analogs and methods of use |
| US4885163A (en) * | 1987-02-24 | 1989-12-05 | Eli Lilly And Company | Topical use of IGF-II for wound healing |
| IL95641A0 (en) * | 1989-09-15 | 1991-06-30 | Curative Tech Inc | Preparation of a platelet releasate product |
| ZA9010332B (en) * | 1989-12-22 | 1991-08-28 | Ciba Geigy | Method of reducing or preventing adverse effect of steroid therapy and compositions therefor |
| WO1991015231A1 (en) * | 1990-04-10 | 1991-10-17 | Institute Of Molecular Biology, Inc. | Wound healing |
| ATE222117T1 (de) * | 1990-05-30 | 2002-08-15 | Harvard College | Kombination aus igf-i und tgf-beta zur knochenregenerierung |
| US6197325B1 (en) | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7189410B1 (en) | 1990-11-27 | 2007-03-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US6117425A (en) | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
| US6054122A (en) | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| WO1993008825A1 (en) * | 1991-11-04 | 1993-05-13 | Zymogenetics, Inc. | Pdgf gel formulation |
| FR2691911B1 (fr) * | 1992-06-05 | 1994-11-25 | Delmas Olivier | Dispositif permettant l'obtention d'un surnageant de thrombocytes activés, procédé mettant en Óoeuvre le dispositif et surnageant obtenu. |
| JPH06510065A (ja) * | 1992-06-08 | 1994-11-10 | カイロン コーポレーション | 成長因子ｉｇｆ−ｉおよび／またはｉｇｆ−ｉｉの用法 |
| FR2696095B1 (fr) * | 1992-09-30 | 1994-11-25 | Inoteb | Colle biologique à base de protéines coagulables par la thrombine, enrichie en facteurs plaquettaires, sa préparation et son application. |
| CN1055023C (zh) * | 1993-01-03 | 2000-08-02 | 周至譓 | 伤口护理剂 |
| US7026299B2 (en) | 1994-07-12 | 2006-04-11 | Human Genome Sciences, Inc. | Connective tissue growth factor-2 |
| JPH10502534A (ja) | 1994-07-12 | 1998-03-10 | ヒューマン・ジェノム・サイエンシズ・インコーポレイテッド | 結合組織増殖因子−２ |
| US5712249A (en) * | 1994-09-08 | 1998-01-27 | Ciba-Geigy Corporation | Use of insulin-like growth factors I and II for inhibition of inflammatory response |
| ES2293137T3 (es) * | 1995-10-11 | 2008-03-16 | Novartis Vaccines And Diagnostics, Inc. | Combinacion de pdgf, kgf,igf e igfbp para curacion de heridas. |
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| US6663870B2 (en) | 1998-12-07 | 2003-12-16 | Zymogenetics, Inc. | Methods for promoting growth of bone using zvegf3 |
| US6468543B1 (en) | 1999-05-03 | 2002-10-22 | Zymogenetics, Inc. | Methods for promoting growth of bone using ZVEGF4 |
| GB2369572A (en) | 2000-11-29 | 2002-06-05 | Raft Trustees Ltd | Wound treatment composition comprising insulin |
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| US7622562B2 (en) | 2002-06-26 | 2009-11-24 | Zimmer Orthobiologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
| US7473678B2 (en) | 2004-10-14 | 2009-01-06 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods of use thereof |
| BRPI0618794A2 (pt) | 2005-11-17 | 2011-09-13 | Biomimetic Therapeutics Inc | uso de uma matriz biocompatìvel, kit e composição para aumento ósseo, especialmente para aumento do osso maxilofacial |
| ES2427993T3 (es) | 2006-02-09 | 2013-11-05 | Biomimetic Therapeutics, Llc | Composiciones y métodos para el tratamiento de hueso |
| US9161967B2 (en) | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
| WO2008005427A2 (en) | 2006-06-30 | 2008-01-10 | Biomimetic Therapeutics, Inc. | Pdgf-biomatrix compositions and methods for treating rotator cuff injuries |
| AU2007333425B2 (en) | 2006-11-03 | 2014-03-27 | Biomimetic Therapeutics, Llc | Compositions and methods for arthrodetic procedures |
| RU2010137106A (ru) | 2008-02-07 | 2012-03-20 | Байомайметик Терапьютикс, Инк. (Us) | Композиции и способы для дистракциионного остеогенеза |
| CA2735885C (en) | 2008-09-09 | 2018-08-28 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries |
| BR112012020566B1 (pt) | 2010-02-22 | 2021-09-21 | Biomimetic Therapeutics, Llc | Composição de fator de crescimento derivado de plaqueta |
| CN102397534B (zh) * | 2010-09-07 | 2013-10-23 | 中国人民解放军总医院 | 胰岛素在制备促进颌骨组织愈合的药物中的用途 |
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| US4479896A (en) * | 1981-12-11 | 1984-10-30 | Antoniades Harry N | Method for extraction localization and direct recovery of platelet derived growth factor |
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1987
- 1987-11-13 AT AT87907900T patent/ATE88899T1/de not_active IP Right Cessation
- 1987-11-13 KR KR1019880700829A patent/KR960005708B1/ko not_active IP Right Cessation
- 1987-11-13 JP JP63500179A patent/JPH01500199A/ja active Granted
- 1987-11-13 AU AU83289/87A patent/AU600069B2/en not_active Expired
- 1987-11-13 DE DE8787907900T patent/DE3785758T2/de not_active Expired - Lifetime
- 1987-11-13 IE IE307587A patent/IE60517B1/en not_active IP Right Cessation
- 1987-11-13 WO PCT/US1987/002975 patent/WO1988003409A1/en active IP Right Grant
- 1987-11-13 EP EP87907900A patent/EP0289584B1/en not_active Expired - Lifetime
- 1987-11-14 CN CN87101250A patent/CN1027346C/zh not_active Expired - Lifetime
- 1987-11-16 ZA ZA878566A patent/ZA878566B/xx unknown
- 1987-11-16 MX MX009367A patent/MX170454B/es unknown
- 1987-11-16 NZ NZ222551A patent/NZ222551A/xx unknown
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1988
- 1988-07-13 NO NO883127A patent/NO883127L/no unknown
- 1988-07-14 OA OA59385A patent/OA09159A/xx unknown
- 1988-07-14 DK DK198803932A patent/DK175889B1/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA878566B (en) | 1989-07-26 |
| ATE88899T1 (de) | 1993-05-15 |
| MX170454B (es) | 1993-08-24 |
| AU8328987A (en) | 1988-06-01 |
| KR960005708B1 (ko) | 1996-05-01 |
| JPH0581569B2 (zh) | 1993-11-15 |
| OA09159A (en) | 1992-03-31 |
| CN87101250A (zh) | 1988-06-08 |
| IE873075L (en) | 1988-05-14 |
| DK393288A (da) | 1988-09-13 |
| NZ222551A (en) | 1989-11-28 |
| KR890700033A (ko) | 1989-03-02 |
| EP0289584B1 (en) | 1993-05-05 |
| NO883127D0 (no) | 1988-07-13 |
| AU600069B2 (en) | 1990-08-02 |
| WO1988003409A1 (en) | 1988-05-19 |
| EP0289584A4 (en) | 1990-01-08 |
| DE3785758T2 (de) | 1993-08-05 |
| JPH01500199A (ja) | 1989-01-26 |
| NO883127L (no) | 1988-09-12 |
| DK175889B1 (da) | 2005-05-30 |
| EP0289584A1 (en) | 1988-11-09 |
| DK393288D0 (da) | 1988-07-14 |
| DE3785758D1 (de) | 1993-06-09 |
| IE60517B1 (en) | 1994-07-27 |
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