CN1157568A - 硬组织刺激剂 - Google Patents
硬组织刺激剂 Download PDFInfo
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Abstract
壳聚糖和固定于其上并选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖的多糖在生产可刺激硬组织再生药剂中的用途；刺激硬组织再生即所谓骨整合的方法；整合到硬组织特别是骨组织中的移植物。
Description
技术领域
本发明涉及刺激或加速硬组织再生(即所谓的骨整(osseointegration))的新技术，例如在硬组织特别是骨组织中寻求移植外来移植物的效果。本发明也涉及实施这种骨整合同时施用本发明新技术的方法。另外，本发明涉及在骨组织缺损或者需要骨组织时新骨的生成。
发明背景
将移植物固定在硬组织特别是骨组织中已越来越多地用于牙科学、矫形外科学、神经外科学、手外科以及整形和再造外科学。用钛可将移植物长期固定在骨中，可以设想以钛为基础的材料将来也可更广泛地选用作移植和修复材料。
处理所谓骨整合时的临床问题是移植物在骨充分固定前不能负载，这种固定需要6至9个月。因此在临床上最重要的是通过提供有关移植物的刺激骨生成来加速愈合过程。也需要使骨再生而连接缺损处或已发生骨吸收的部位，例如颌骨的无齿部分或者是由于诸如创伤、肿瘤或手术等已丢失骨组织的部位。
发明概述
本发明的主要目的是刺激硬组织细胞如骨细胞的生长，从而增加硬组织体积。
本发明的另一目的是提供一种可形成主要是层状致密型再生骨组织的方法，同时使疤痕组织形成的程度最小化。
本发明的另一目的是提供一种可使硬组织中移植物刺激硬组织例如骨组织再生的新药剂。
本发明的另一目的是提供一种使外来移植物移植在骨组织中同时刺激组织再生的改进骨整合方法。
本发明的另一目的是提供用刺激硬组织再生的药剂处理的移植物。
这些以及其它目的将随下文的公开而明朗，为此通过本发明提供一种壳聚糖以及固定于其的多糖的新用途，所述多糖选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖。这种新用途涉及使硬组织再生的药剂的生产方法。这种刺激再生可以提供给例如硬组织如骨组织中的移植物。
多糖可以以多种方式固定到壳聚糖基质上，例如通过离子键、通过多点或端点共价结合或者通过在壳聚糖基质中使壳聚糖从溶液中沉淀的机械固定方法。离子键和共价键是优选的固定方式。
本发明的硬组织刺激剂可以不同物理形式存在，例如膜、粉末、凝胶、小珠或溶液。在移植物的情况下，整合到硬组织中的那部分移植物可以浸湿以使药物涂覆于其上。当然，药物也可直接用于硬组织，例如骨组织中的腔洞。
移植优选的材料是钛，但也可使用其它移植材料。
壳聚糖是线性1，4-结合的多糖，连接单位是β-D-葡糖胺。通过将壳多糖(特别是从昆虫和贝类壳中形成的一种聚合物)N-脱乙酰化而生产壳聚糖。商业上，壳多糖是从渔业废弃物中的蟹和虾壳中回收而得。通过控制壳多糖的碱处理，可以生产出不同N-乙酰化程度的壳聚糖。当用强碱(通常是氢氧化钠)处理壳多糖时，可发生N-脱乙酰化，即乙酰氨基转化为氨基而形成壳聚糖。
影响壳聚糖用途的物理性质取决于N-乙酰化程度、分子量和均匀性。壳多糖可以通过消化系统中的壳质酶以及体内的溶菌酶和其它酶而被生物降解。
用于本发明时，优选壳聚糖的N-乙酰化程度最多约为90％，更优选最多约为50％。特别优选N-乙酰化程度少于约25％。
固定到壳聚糖基质上的多糖优选肝素或硫酸肝素。将肝素共价结合到含有氨基的基质上的特定技术描述在美国专利4,613,665中。
本发明还提供了在例如所谓的骨整合中刺激和/或加速硬组织再生的方法。该方法的特征是，在移植前，将适用于刺激量的所定义药剂施用于移植物和/或硬组织，该药剂是从壳聚糖和固定于其的多糖制备而得，所述多糖选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖。骨整合是将非自身移植物以及各种外来材料长期固定到硬组织特别是骨组织中的最佳形式。
实施该方法时，药剂的形式可以是粉末、溶液、凝胶、小珠、薄膜或膜状。另外，可以通过将欲整合到硬组织中的那部分移植物浸入到适当组成的壳聚糖和固定于其的多糖溶液中而使用该药剂。
本发明还包括整合到硬组织特别是骨组织中的移植物。其中，将整合的那部分移植物用刺激硬组织再生的药剂包衣，该药剂含有壳聚糖和固定到壳聚糖上的多糖，所述多糖选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖。特别优选移植物包括钛。
优选的实施方案
通过以下非限定性实施例阐明本发明。除非另外说明，百分比意指重量百分比。
实施例1
用壳聚糖包衣钛螺钉
将钛螺钉浸入壳聚糖2％的乙酸溶液(1％w/v)中并保持在所述溶液中15分钟。壳聚糖是Sea Cure 313(Pronova Biopolymer，15％N-乙酰化)。然后将处理后的钛螺钉在烘箱中于70℃干燥16小时，然后在1MNaOH中中和，用蒸馏水反复漂洗，再于烘箱中干燥。将螺钉包装在“peelopen”型的包装袋中并用环氧乙烷灭菌。
实施例2
带有离子结合肝素的钛螺钉
将如实施例1用壳聚糖包衣的螺钉转入含有125毫克肝素(PigMucosa，Kabivitrum)的500毫升蒸馏水溶液中并保持约16小时，然后在蒸馏水中漂洗，于室温干燥。将螺钉包装在“peel open”型的包装袋中并用环氧乙烷灭菌。所固定的肝素量是约20μg/cm2。
实施例3
带有共价结合肝素的钛螺钉(端点接合)
将肝素溶于水(300毫升)。将该溶液于冰水中冷却至0℃并保持冷却状态。搅拌下先向溶液加入亚硝酸钠(NaNO3 10毫克)，然后加入乙酸(2毫升)。将反应混合物于0℃保持2小时，透析并冻干。产率为0.7克。
将如实施例1用壳聚糖包衣的螺钉转入含有125毫克上述亚硝酸盐降解的肝素、15毫克NaCNBH3的500毫升蒸馏水溶液中，用0.1M的盐酸调节pH值至3.9。将反应混合物于室温保持16小时。然后将螺钉在蒸馏水中漂洗，于室温干燥。将螺钉包装在“peel open”型的包装袋中并用环氧乙烷灭菌。所固定的肝素量是约1.5μg/cm2。
实施例4
带有共价结合肝素的钛螺钉(多点接合)
如下制备过碘酸钠氧化的肝素钠溶液：将1克过碘酸钠NaIO4溶于200毫升蒸馏水中。在该溶液中加入10克肝素钠并在暗处将溶液搅拌过夜。在所得溶液中加入10毫升甘油并搅拌2小时后于水中透析。每1小时交换一次水。由此而得含有过碘酸盐氧化的肝素溶液，浓度约为19mg/ml。
将如实施例用壳聚糖包衣的螺钉转入含有125毫克上述过碘酸盐氧化的肝素、15毫克NaCNBH3的500毫升蒸馏水溶液中。然后完全按照实施例3进行反应。
实施例5
壳聚糖膜的生产
将5克壳聚糖盐酸盐(50％乙酰化，Pronova)溶于蒸馏水(0.5L，1％v/w)。将所得的10毫升溶液转入培替氏培养皿中，在烘箱中于70℃蒸发干燥24小时而形成壳聚糖膜。通过加入磷酸钠缓冲液(0.2M，pH9.0)中和所得薄膜。室温下将薄膜放置在含有该缓冲液的培替氏培养皿中2-4小时，然后用水洗涤3-4次并干燥。
实施例6
带有共价结合肝素的薄膜(端点接合)
在如实施例1制备的中和壳聚糖薄膜中加入20毫升含有125毫克亚硝酸盐降解的肝素溶液(如实施例3所制备，溶于0.5L水并含有4.4克氯化钠)。在此溶液中加入15毫克氰基硼氢化钠。用0.5M盐酸或其它酸将该溶液的pH值调节至3.9。将含有壳聚糖膜的溶液于室温放置14小时，然后用水洗涤所得薄膜3-4次并干燥。
实施例7
带有离子接合肝素的薄膜
在如实施例1制备的中和壳聚糖薄膜中加入20毫升含有125毫克溶于0.5升水并含有4.4克氯化钠的肝素溶液中。将含有壳聚糖膜的溶液于室温放置14小时，然后用水洗涤3-4次并干燥。可以将所得薄膜磨成粉以用于本发明的骨整合。
实施例8
生物试验
试验动物为成年兔，麻醉后在无菌条件下手术，除去兔膝部毛发。
在膝关节距骺软骨区胫骨近端35-40mm处切开远侧皮肤。横切骨膜，通过持续供给无菌缓冲盐水溶液而冷却下，用3.5mm的钻以低旋转速在腿至骨髓钻孔。然后，穿入一个4mm长的六角形头钛螺钉和6mm钛螺钉，两个螺钉的直径为3.5mm。用单线缝合面和皮肤伤口。在该实验中，除了使用如实施例1-3处理的钛螺钉外，还使用未处理的钛螺钉。
4和12周后，分别将兔麻醉。剪去膝部毛发，在膝关节至胫骨远侧切开皮肤。剖割并鉴定螺钉，确定邻近螺钉的拆线时间。将远侧螺钉用于光学显微术，移植物仍保留在所在骨中。
实施例9
带有或不带有肝素包衣的钛粉
基本上按照实施例1用壳聚糖包衣钛粉，按照实施例3进行固定。
暴露两侧后腿的腓骨，沿中轴分离约10mm长的肌肉组织。除去暴露腓骨(连同骨和骨膜)的6mm长片断，骨末端间的缺损处用钛粉填充。用PTFE制的膜滤器缠绕而连接缺损处并且防止肉芽组织侵入该区域。一端放置肝素包衣的钛粉，另一端放置未包衣的钛粉。封闭伤口。在第二次检测和处死前3周使大鼠自由活动。对两侧腓骨缺损处的检测表明，骨、网状骨质及层状骨质连接了缺损处。但是，骨形成最多的地方是肝素化钛粉处及其周边。此外，在肝素化钛粉中检测到了更多的层状即组织化骨。
因此，如上用肝素包衣的钛粉甚至在没有骨膜存在下也可刺激骨的重新生成。
实施例10
通过腓骨裂孔连接技术评价离子肝素化壳聚糖膜的成骨活性
暴露麻醉大鼠的一侧后腿腓骨，沿中轴分离约10mm长的肌肉组织。除去暴露腓骨(连同骨和骨膜)的6mm长片断，用壳聚糖膜缠绕骨端间的缺损处。
在左侧放置如实施例5制备的壳聚糖膜(15％乙酰化的壳聚糖)，右侧腓骨缺损处放置如实施例7制备的肝素化壳聚糖膜(15％乙酰化的壳聚糖)。
为了避免连接骨端间6mm裂孔的薄膜形成的管塌陷，沿裂孔放置小骨碎片。
三周后检测表明，在两只动物右侧(即有肝素化壳聚糖膜的一侧)骨基质和骨有显著形成。
实施例11
通过颅骨裂孔中骨的形成评价肝素化壳聚糖膜的成骨活性
已确知，如果骨中的缺损超过一定尺度，则通过形成连接骨中缺损的纤维性疤痕组织膜而使这些缺损愈合。成年大鼠颅骨中裂孔的临界尺度是8mm，即8mm或者更大直径的裂孔不会通过骨组织闭合。
在大鼠鼻额骨区至外枕骨隆凸切开旁侧皮肤。分离皮肤及下属组织，包括两侧的大部分颞肌。用特制的环钻在颅骨两侧钻出8mm的孔。特别注意不要损伤脑脊膜和大脑。
在右侧将如实施例9制备的离子结合肝素的壳聚糖膜放置在硬脑脊膜上，将多个骨碎片放置在该膜上，另外将相同的膜放置在颅骨上。然后，于左侧将如实施例5制备的非肝素化壳聚糖膜与空隙骨碎片按照相同方式放置。然后闭合帽状腱膜和皮肤。
3周后将大鼠麻醉，检测头颅。与左侧相比，有更多的类骨质和新骨组织覆盖在右侧缺损处。此外，在肝素化壳聚糖膜上少有明显炎症反应。
实施例12
制备用硫酸葡聚糖或肝素或者软骨素-4-硫酸盐包覆的壳聚糖小珠
用注射器将壳聚糖水溶液(2％W/v，18％乙酰化)滴加到硫酸葡聚糖或肝素或者软骨素-4-硫酸盐(0.1％w/v)的三聚磷酸盐(tripolyphosfate)缓冲液中。在玻璃滤器上回收所得小珠并用水(1升)漂洗，于30℃干燥过夜。
实施例13
通过在颅骨骨膜下沉积后的骨形成来评价壳聚糖小珠的成骨活性
将待测成骨活性的化合物放置在颅骨骨膜下是一种确知的方法。
将用壳聚糖和肝素制备的小珠、以硫酸葡聚糖包衣的壳聚糖小珠以及以软骨素-4-硫酸盐包衣的壳聚糖小珠(如实施例12制备)放置在成年大鼠额骨骨膜下。每侧放置一个小珠。3周后评价骨的形成。
壳聚糖-肝素小珠是成骨性的，其在额骨形成类骨质和骨组织。硫酸软骨素包衣的壳聚糖小珠和硫酸葡聚糖包衣的小珠同样也表现出成骨活性。辨认出的炎性细胞不定，通常是低范围的。
这些实验表明，壳聚糖和某些多糖结合可表现出成骨活性。
将本发明和生长因子结合可以获得更好的愈合刺激性。用碘125标记的aFGF(酸性成纤维细胞生长因子，Bachem California)进行的体外实验表明，在肝素化螺钉上特异性结合的生长因子显著比非肝素化螺钉上结合的高。即使本发明并不局限于任何特殊理论，但是看来当螺钉包衣有壳聚糖-肝素时(其导致刺激骨再生)，在移植物和周围骨的界面之间富含内源性生长因子。
本发明并不局限于所描述的实施方案，其可用于所有整合到硬组织特别是骨组织中的移植物。因此，本发明可用于各种领域，例如牙科学、矫形外科学、神经外科学、手外科以及整形和再造外科学。对于牙科应用来说，本发明特别有用。
Claims (20)
1.壳聚糖和固定于其上的选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖的多糖在生产可刺激硬组织再生药剂中的用途。
2.权利要求1的用途，其特征在于硬组织的刺激性再生是提供给在硬组织如骨组织中的移植物的。
3.权利要求1或2的用途，其特征在于多糖通过离子键固定到壳聚糖上。
4.权利要求1或2的用途，其特征在于多糖通过共价键固定到壳聚糖上。
5.前述权利要求中的任一权利要求的用途，其特征在于多糖是肝素或硫酸肝素。
6.前述权利要求中的任一权利要求的用途，其特征在于药剂是粉末或溶液的形式。
7.权利要求1至5任一权利要求的用途，其特征在于药剂是凝胶形式。
8.权利要求1至5任一权利要求的用途，其特征在于药剂是小珠形式。
9.前述权利要求中的任一权利要求的用途，其特征在于壳聚糖的N-乙酰化程度最多约90％，优选最多约50％。
10.权利要求9的用途，其特征在于壳聚糖的N-乙酰化程度少于约25％。
11.权利要求2至10任一权利要求的用途，其特征在于移植物包含钛。
12.一种刺激和/或加速硬组织再生的方法，其特征是将刺激活性量的药剂施用于适当位置，所述药剂包括壳聚糖和固定于其并选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖的多糖。
13.权利要求12的方法，其中的再生是骨整合(osseointegration)。
14.权利要求13的方法，其特征在于骨整合是在硬组织如骨组织中的移植物的整合。
15.权利要求12至14的方法，其特征在于所述药剂以粉末方式施用。
16.权利要求12至14的方法，其特征在于所述药剂是以凝胶方式施用。
17.权利要求12至16任一权利要求的方法，其特征在于多糖由肝素或硫酸肝素组成。
18.权利要求13、14或17的方法，其特征在于通过将整合到硬组织中的那部分移植物浸入到壳聚糖和多糖溶液中而施用药剂。
19.整合到硬组织中的移植物，其特征在于至少是将欲整合的那部分移植物用刺激硬组织再生的药剂包衣，所述药剂包括壳聚糖和固定于其上并选自肝素、硫酸肝素、硫酸软骨素和硫酸葡聚糖的多糖。
20.权利要求19的移植物，其特征在于其含有钛。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101432310B (zh) * | 2006-04-26 | 2012-09-05 | B·布朗·梅尔松根有限公司 | 经修饰的多糖-脱乙酰壳多糖化合物的制备和用途以及hes-药物化合物的改进生产方法 |
| CN105142399A (zh) * | 2013-03-14 | 2015-12-09 | 赫姆孔医疗技术公司 | 生物相容的和生物可吸收的衍生的壳聚糖组合物 |
Families Citing this family (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9402528D0 (sv) * | 1994-07-19 | 1994-07-19 | Astra Ab | Hårdvävnadsstimulerande med el |
| KR100237738B1 (ko) * | 1997-04-26 | 2000-01-15 | 이용찬 | 생채 매식용 의료기구 임플란트의 기능 향상방법 |
| DE19724869C2 (de) * | 1997-06-12 | 1999-05-12 | Henkel Kgaa | Verwendung von Citosanderivaten zur Oberflächenbeschichtung |
| EP0899247B1 (en) * | 1997-08-28 | 2002-11-06 | Ngk Spark Plug Co., Ltd | Calcium phosphate cement and calcium phosphate cement composition |
| JP4215884B2 (ja) * | 1998-03-23 | 2009-01-28 | 日本特殊陶業株式会社 | リン酸カルシウムセメント及びリン酸カルシウムセメント組成物 |
| US20030147860A1 (en) * | 2002-02-07 | 2003-08-07 | Marchosky J. Alexander | Compositions and methods for forming and strengthening bone |
| US6306125B1 (en) | 1998-06-22 | 2001-10-23 | Neovasys, Inc. | Angiogenic implant delivery system and method |
| US6806260B1 (en) * | 1998-11-10 | 2004-10-19 | Netech, Inc. | Functional chitosan derivative |
| FR2791262B1 (fr) * | 1999-03-22 | 2001-09-28 | Virbac Sa | Compositions a base de chondroitine et de chitosan pour la protection, le traitement ou le remplacement des tissus conjonctifs |
| AU782394B2 (en) | 1999-06-29 | 2005-07-21 | J. Alexander Marchosky | Compositions and methods for forming and strengthening bone |
| GB9920393D0 (en) * | 1999-08-27 | 1999-11-03 | Medix Scient Uk Limited | Plant extract mixtures and their uses |
| FI19991852A (fi) | 1999-09-01 | 2001-03-01 | Yli Urpo Antti | Uusi monikerroksinen materiaali, joka käsittää vaikuttavan ainesosan, ja sen valmistus |
| AU1375301A (en) * | 1999-11-15 | 2001-05-30 | Bio Syntech Canada Inc | Temperature-controlled and ph-dependant self-gelling biopolymeric aqueous solution |
| EP1255576B1 (en) * | 1999-12-09 | 2003-08-20 | Biosyntech Canada Inc. | Mineral-polymer hybrid composition |
| US20030158302A1 (en) * | 1999-12-09 | 2003-08-21 | Cyric Chaput | Mineral-polymer hybrid composition |
| DK1294414T3 (da) * | 2000-06-29 | 2006-07-24 | Biosyntech Canada Inc | Præparat og fremgangsmåde til heling og regenerering af brusk og andre væv |
| ES2169681B1 (es) * | 2000-08-10 | 2003-10-01 | Osfarma S L | Metodo de produccion de filmes de quitosan con una alta capacidad de adherencia celular, producto obrenido y aplicaciones. |
| DE60125973D1 (de) * | 2000-11-15 | 2007-02-22 | Biosyntech Canada Inc | Verfahren zur wiederherstellung einer geschädigten bandscheibe |
| ES2353116T3 (es) * | 2002-07-16 | 2011-02-25 | Bio Syntech Canada Inc. | Composiciones para disoluciones de quitosano citocompatibles, inyectables, autogelificantes para encapsular y administrar células vivas o factores biológicamente activos. |
| US20040054414A1 (en) | 2002-09-18 | 2004-03-18 | Trieu Hai H. | Collagen-based materials and methods for augmenting intervertebral discs |
| FR2844717B1 (fr) * | 2002-09-23 | 2006-07-07 | Richard Cancel | Plaque de renfort comprenant notamment du chitosane |
| JP2006515765A (ja) * | 2002-11-15 | 2006-06-08 | エスディージーアイ・ホールディングス・インコーポレーテッド | 滑膜性関節を治療するためのコラーゲンベース材料および方法 |
| US20040186471A1 (en) * | 2002-12-07 | 2004-09-23 | Sdgi Holdings, Inc. | Method and apparatus for intervertebral disc expansion |
| DE10338110A1 (de) * | 2003-08-15 | 2005-03-10 | Biomet Deutschland Gmbh | Mit Chitosan beschichteter metallischer Gegenstand sowie Verfahren zu dessen Herstellung |
| WO2005065396A2 (en) * | 2003-12-31 | 2005-07-21 | Osteotech, Inc. | Improved bone matrix compositions and methods |
| US20070231788A1 (en) * | 2003-12-31 | 2007-10-04 | Keyvan Behnam | Method for In Vitro Assay of Demineralized Bone Matrix |
| FR2866571B1 (fr) * | 2004-02-20 | 2007-09-21 | Philippe Zanchetta | Utilisation d'un melange de polysaccharides specifiques denomme par l'inventeur ezbone, comprenant de l'acide hyaluronique, de la chondroitine 6 sulfate, du dermatane sulfate et de l'heparine en cicatrisation osseuse. |
| AU2005239977B2 (en) * | 2004-05-07 | 2010-11-11 | The University Of Queensland | Composition for stimulating bone growth and differentiation and method for isolating same |
| WO2005107772A1 (en) * | 2004-05-07 | 2005-11-17 | The University Of Queensland | Composition for stimulating bone growth and differentiation and method for isolating same |
| CA2577447C (en) | 2004-08-16 | 2017-08-01 | Cellresearch Corporation Pte Ltd | Isolation of stem/progenitor cells from amniotic membrane of umbilical cord |
| US20080118542A1 (en) * | 2005-01-19 | 2008-05-22 | Bonoss Medical Ab | Growth Factor Composition |
| EP1937326B1 (en) | 2005-10-21 | 2018-09-12 | CellResearch Corporation Pte Ltd | Isolation and cultivation of stem/progenitor cells from the amniotic membrane of umbilical cord and uses of cells differentiated therefrom |
| AU2006308534B2 (en) | 2005-11-01 | 2013-02-07 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
| CA2628244A1 (en) * | 2005-11-04 | 2007-05-10 | Bio Syntech Canada Inc. | Gel formation of polyelectrolyte aqueous solutions by thermally induced changes in ionization state |
| US8399619B2 (en) * | 2006-06-30 | 2013-03-19 | Warsaw Orthopedic, Inc. | Injectable collagen material |
| US8118779B2 (en) * | 2006-06-30 | 2012-02-21 | Warsaw Orthopedic, Inc. | Collagen delivery device |
| EP1977739A1 (en) * | 2007-04-03 | 2008-10-08 | Bioiberica, S.A. | Nanoparticulate composition of chitosan and chondroitin sulfate |
| US9554920B2 (en) * | 2007-06-15 | 2017-01-31 | Warsaw Orthopedic, Inc. | Bone matrix compositions having nanoscale textured surfaces |
| EP3207948B1 (en) * | 2007-06-15 | 2020-02-26 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
| AU2008265852B2 (en) * | 2007-06-15 | 2014-04-17 | Warsaw Orthopedic, Inc. | Method of treating tissue |
| WO2008157492A2 (en) * | 2007-06-15 | 2008-12-24 | Osteotech, Inc. | Osteoinductive demineralized cancellous bone |
| WO2009009684A1 (en) * | 2007-07-10 | 2009-01-15 | Osteotech, Inc. | Delivery system |
| US20110054408A1 (en) * | 2007-07-10 | 2011-03-03 | Guobao Wei | Delivery systems, devices, tools, and methods of use |
| ES2446544T3 (es) | 2007-10-19 | 2014-03-10 | Warsaw Orthopedic, Inc. | Composiciones de matrices óseas desmineralizadas y métodos |
| GB2463474B (en) * | 2008-09-11 | 2012-05-02 | Agency Science Tech & Res | Therapeutic bone growth and regeneration |
| US9101475B2 (en) * | 2009-02-12 | 2015-08-11 | Warsaw Orthopedic, Inc. | Segmented delivery system |
| MX2014008404A (es) | 2012-01-27 | 2014-08-22 | Hoffmann La Roche | Quitosan enlazado covalentamente con antagonista de la integrina de molecula pequeña para suministro dirigido. |
| CN105126165B (zh) * | 2015-01-21 | 2017-12-08 | 中国人民解放军第三〇七医院 | 一种钛牙种植体材料及其制备方法与应用 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL163522B (nl) * | 1970-07-20 | 1980-04-15 | Montedison Spa | Werkwijze om een katalysator te bereiden voor de polymerisatie van alkenen-1. |
| US5510418A (en) * | 1988-11-21 | 1996-04-23 | Collagen Corporation | Glycosaminoglycan-synthetic polymer conjugates |
| US5256447A (en) * | 1991-12-31 | 1993-10-26 | Minnesota Mining And Manufacturing Company | Adhesive composition and method |
| BR9207010A (pt) * | 1991-12-31 | 1995-12-05 | Minnesota Mining & Mfg | Composição adesiva e processo de aderência de um material restaurador a um substrato |
| SE9402528D0 (sv) * | 1994-07-19 | 1994-07-19 | Astra Ab | Hårdvävnadsstimulerande med el |
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1994
- 1994-07-19 SE SE9402528A patent/SE9402528D0/xx unknown
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- 1995-07-13 ES ES95926565T patent/ES2178675T3/es not_active Expired - Lifetime
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- 1995-07-13 NZ NZ290219A patent/NZ290219A/en unknown
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-
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| CN101432310B (zh) * | 2006-04-26 | 2012-09-05 | B·布朗·梅尔松根有限公司 | 经修饰的多糖-脱乙酰壳多糖化合物的制备和用途以及hes-药物化合物的改进生产方法 |
| CN105142399A (zh) * | 2013-03-14 | 2015-12-09 | 赫姆孔医疗技术公司 | 生物相容的和生物可吸收的衍生的壳聚糖组合物 |
| US9846163B2 (en) | 2013-03-14 | 2017-12-19 | Tricol Biomedical, Inc. | Biocompatible and bioabsorbable derivatized chitosan compositions |
| US9925310B2 (en) | 2013-03-14 | 2018-03-27 | Tricol Biomedical, Inc. | Biocompatible and bioabsorbable derivatized chitosan compositions |
| CN105142399B (zh) * | 2013-03-14 | 2018-06-12 | 金珂生物医疗公司 | 生物相容的和生物可吸收的衍生的壳聚糖组合物 |
| CN108610437A (zh) * | 2013-03-14 | 2018-10-02 | 金珂生物医疗公司 | 生物相容的和生物可吸收的衍生的壳聚糖组合物 |
| US10709817B2 (en) | 2013-03-14 | 2020-07-14 | Tricol Biomedical, Inc. | Biocompatible and bioabsorbable derivatized chitosan compositions |
| US11229724B2 (en) | 2013-03-14 | 2022-01-25 | Tricol Biomedical, Inc. | Biocompatible and bioabsorbable derivatized chitosan compositions |
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