Connect public, paid and private patent data with Google Patents Public Datasets

一种修复关节软骨缺陷的软骨修复构造物

Info

Publication number
CN1200656C
CN1200656C CN 97199207 CN97199207A CN1200656C CN 1200656 C CN1200656 C CN 1200656C CN 97199207 CN97199207 CN 97199207 CN 97199207 A CN97199207 A CN 97199207A CN 1200656 C CN1200656 C CN 1200656C
Authority
CN
Grant status
Grant
Patent type
Prior art keywords
structure
repairing
chondral
defect
joint
Prior art date
Application number
CN 97199207
Other languages
English (en)
Other versions
CN1241918A (zh )
Inventor
亨里克·维伯-汉森
夏洛特·伦斯戈德
阿曼德·伊道雷恩
库尔特·B·奥瑟尔
Original Assignee
维里根国际移植服务股份公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date
Family has litigation

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/28Bones
    • A61F2/2846Support means for bone substitute or for bone graft implants, e.g. membranes or plates for covering bone defects
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30756Cartilage endoprostheses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491Surgical glue applicators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/38Joints for elbows or knees
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/28Bones
    • A61F2002/2835Bone graft implants for filling a bony defect or an endoprosthesis cavity
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/30004The prosthesis made from materials having different values of a given property at different locations within the same prosthesis
    • A61F2002/30016The prosthesis made from materials having different values of a given property at different locations within the same prosthesis differing in hardness, e.g. Vickers, Shore, Brinell
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30062(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30316The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
    • A61F2002/30535Special structural features of bone or joint prostheses not otherwise provided for
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30756Cartilage endoprostheses
    • A61F2002/30761Support means for artificial cartilage, e.g. cartilage defect covering membranes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30756Cartilage endoprostheses
    • A61F2002/30762Means for culturing cartilage
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A61F2250/0019Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in hardness, e.g. Vickers, Shore, Brinell
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/06Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Abstract

本发明公开了向关节连接面缺损部分进行有效的软骨细胞/软骨移植的方法以及实施本发明所用的特定工具和用具盒。

Description

一种修复关节软骨缺陷的软骨修复构造物

本发明涉及的领域为软骨细胞的移植术、骨和软骨的移植及愈合、关节修复和关节炎疾病的预防,具体地说为移植位点的准备方法、该准备工作所用的工具以及向已准备好的移植位点进行自体移植所用的工具。

在美国,每年要作超过50万例关节成形手术和整个关节的替换。在欧洲,类似手术的数量与此相近。这个数目中包括欧洲每年约有9万例整个膝部替换和5万例左右的膝部缺损修复手术。在美国,各种手术数量亦基本相同(载于:Praemer A.,Furner S.,Rice D.P.,美国肌骨胳动态Musculoskeletal Conditions in the United States),美国整形外科研究院,Park Ridge III,1992,125)。一种软骨再生疗法可能是非常有用的,这种方法可以在关节损伤的早期实施,从而减少必须作人造关节替换外科手术患者的数目。这种预防性疗法也会减少发展成为骨关节炎的患者数目。

关节内软骨构造的表面修整技术曾经主要是试图采用软骨下钻、磨和其它方法来作软骨修复,结果是切除了病变软骨和软骨下的骨质,使血管已经形成的网状骨质裸露(Insall,临床整形杂志(J.,Clin.Orthop.)1974,101,61;Ficat R.P.等,临床整形杂志(Clin.Orthop.)1979,144,74;Johnson L.L.,手术整形(Operative Arthroscopy),McGinty J.B.编,Raven Press,New York,1991,341)。

Coon和Cahn在科学(Science)1966,153,1116上描述了一种由小鸡胚胎体节合成的软骨细胞的培养技术。Later Cahn和Lasher(PNAS USA 1967,58,1131)利用此系统来分析作为软骨分化的前提的DNA合成所涉及到的事物。软骨细胞通过生长来应答EFG和FGF二者(Gospldarowicz和Mescher细胞生理杂志(J.,CellPhysiology)1977,93,117),但最终失去其分化功能(Benya等,细胞(Cell)1978,15,1313)。种植软骨细胞的方法是由Brittberg,M.等人描述并经较小修正后主要由他们进行应用的(新英格兰医学杂志(NewEngl.J.Med.)1994,331,889)。这种方法种植的细胞被用于患者膝关节中的自体移植。另外,Kolettas等人借助于延长细胞培养研究了诸如胶原和含蛋白多糖等软骨特性分子的表达(细胞科学杂志(J.Cell Science)1995,108,1991)。他们发现,尽管在单层培养物中进行培养时存在形态学变化(Aulthouse,A.等,体内细胞发育生物学(In vitro Cell Dev.Biol.)1989,25,659;Archer,C.等,细胞科学杂志(J.Cell Sci.)1990,97,361;Hanselmann,H.等,细胞科学杂志(J.Cell Sci.)1994,107,17;Bonaventure,J.等,实验细胞研究(Exp.Cell Res,)1994,212,97),但当与琼脂糖凝胶、海藻胶质珠粒上生长的悬浮体培养物或与由不同的科学家所试验过的旋转培养物(保持圆的细胞形态)相比,诸如II型和IX型胶原的软骨细胞表达标记没有变化,大的聚集态含蛋白多糖、aggrecan、versican以及键合蛋白质没有变化(Kolettas,E.等,细胞科学杂志(J.Cell Science)1995,108,1991)。

关节软骨细胞是只存在于软骨中的特殊的间质衍生细胞。软骨是一种无血管供应的组织,它的物理性质取决于软骨细胞产生的胞外间质。软骨内的骨化软骨细胞的老化导致细胞肥大,其特征为X型胶原表达的出现(Upholt,W.B和Olsen,R.R.,载于Cartilage Molecular Aspects(hall,B&Newman,S.编),CRC Boca Raton 1993,43;Reichenberger,E.等,Dev.Biol.1991,148,562;Kirsch,T.等,Differentiation,1992,52,89;Stephens,M.等,J.Cell Sci.1993,103,1111)。

关节软骨的表面或外层中的II型胶原亦可由于骨关节炎而使其过度退化。胶原网状组织因而削弱并随之发生原纤维化,这样含蛋白多糖一类的基质材类丢失并最终完全被排出。被骨关节炎削弱的软骨的纤维化可以发展到软骨钙化并扩展到软骨下骨质内(Kempsos,G.E.等,Biochim.Biophys,Acta 1976,428,741;Roth,V.和Mow,V.C,,J.Bone Joint Surgery,1980,62A,1102;Woo,S.L.-Y.等,Handbook of Bioengineering(R.Skalak和S.Chien编),McGraw-Hill,New York,1987,P.4.1~4.44)。

有关基础研究、骨的组织解剖学和微观解剖学、软骨和其它类似的结缔组织的描述可从例如Wheater,Burkitt和Daniels的Functional Histology第二版(Churchill Livingston,London,1987,chp.4)中找到。有关骨、软骨和其它类似的结缔组织中的缺损的组织解剖学基础的论述可从例如Wheater,Burkitt,Stevens和Lowe的Basic Histipathology(ChurchillLivingston,London,1985,Chp.21)中找到。

尽管在软骨细胞培育、骨和软骨的处理方面取得进展,用于修理受损的铰接表面的软骨或软骨细胞移植工作却并末取得很大的成功。本发明所具有的技术提供了实在而有效的手段,有助于在关节的接缝和其它为软骨所覆盖的骨表面损伤处进行软骨和/或软骨移植,从而使软骨再生以修整缺损。本发明还提供了用于移植位点准备工作的外科手术工具,从而更容易使移植材料与移植位点有效地成为一体。

本发明提供一种通过一个止血屏障和无细胞的覆盖补片将适宜基质中的软骨移植到待治疗表面上来有效地治疗关节连接表面软骨的方法,该方法包括:首先在紧贴待治疗表面的位置上放置一止血屏障,再在该待治疗表面上方止血屏障的顶部上置放处于适宜基质中的软骨细胞,然后在该待治疗表面上覆盖一无细胞的覆盖补片。止血屏障如同后面将进一步说明那样是一道抑制或阻止正形成血管的细胞和组织渗透到移植材料内的屏障。具体地说,本方法所提供的止血屏障是一种可吸收的半渗透材料,该材料抑制或阻止血管渗过屏障。在一个实施方案中,该止血屏障包含了胶原。这里所用的无细胞一词与本领域中的一样,是指一种材料基本上没有完整的,具有进一步细胞分裂、传播能力或具有生物活性的细胞。在一个优选实施方案中,无细胞材料中是没有任何完整的有核细胞的。在一个实施方案中,本方法使用了一种包含半渗透胶原基质的无细胞覆盖补片。在本方法的一个优选实施方案中,无细胞覆盖补片的多孔的一面朝向移植材料。

本发明还提供了将胶原或软骨细胞移植到移植位点的自体移植术,其中首先是用外科操作进行移植位点的准备工作,以使其更好地接受移植材料。在一个实施方案中,移植位点经过雕刻,因而移植位点的壁面整修成波纹状,因此当置放在移植位点内的移植材料膨胀而与移植位点壁面相接触时,该壁面将阻挡整个移植物相对于移植位点迁移或被挤出。本发明还提供设计成可按照本发明的方法所教导对移植位点进行雕刻的外科工具。

本发明还提供一种用来在关节的连接表面上作软骨和/或软骨细胞移植的用具盒,其中所述用具盒内装有止血屏障、无细胞半渗透覆盖补片以及有机胶。在另一实施方案中,该用具盒带可任选地装有一种或多种能按照本发明所提供的方法对移植位点进行雕刻的外科工具。

下面诸图说明了本发明的某些性质,通过这些图可对本发明有更好的理解,这些图为:图1A所示为一典型的关节骨端。典型地,在骨质的铰接表面上覆盖了一层软骨质。

图1B所示为一软骨质帽出现缺损或受伤(软骨裂)的例子,这种缺损可以直接治疗、稍予扩大或在治疗以前先用外科方法加以雕刻以接受移植物。

图1C表示止血屏障(1)如何置放在软骨质帽的缺损内以抑制或阻止血管化从原来的骨中进入再生软骨中。然后,将要植入缺损穴内的软骨细胞放置在该止血屏障的顶部上。

图2所示为软骨质帽内经过治疗的缺损(软骨裂)被一层无细胞半渗透材料(2)所覆盖,该材料(2)是用来在缺损位点上面形成一个盖子/补片或绷带的。此盖子被安放在适当的位置上,或是与穴边缘的健康软骨相缝接或是贴附在上面。此盖子遮盖住关节的缺损部位,培养好的软骨细胞/软骨或是预先放置在缺损部位内,或是事后放到部分贴附在穴上的盖子下面。

图3A所示为分界区两侧的较硬软骨和较软软骨对压缩力和剪切力的不同响应。

图3B所示为缺损处经过雕刻以后移植位点具有的波纹状壁。

图3C所示为处于关节表面软骨(4)内,带有止血屏障(1),移植物质(3)和无细胞覆盖补片(2)的经过雕刻的移植位点。

图4A所示为本发明外科器械的一个实施方案,图中可见到切削牙(5)和凸出的定位销(6)。右边的截面图所示为切削刀片的两个可能的构形。

图4B所示为本发明外科器械的第二个实施方案。

图5所示为移植位点经过雕刻以后较硬软骨和较软软骨对压缩力和剪切力的不同响应得到改良的情况。

图6A为一头猪膝部的磁共振图象,显示出在左(中)髁处的软骨缺损。

图6B为同一头猪膝部治疗后三个月时的磁共振图象。

本发明涉及到某些产品的使用,这些产品在向软骨的缺损处进行自体软骨细胞移植过程中能防止血管组织的形成,如能防止诸如毛细血管绊伸到正在建立的软骨中去。来自原来的骨质的血管组织的形成将倾向于伸到将要形成的新软骨中去,这导致除了所要求的间质的特殊软骨细胞以外的其它细胞的出现。

由血管形成所导致的污染细胞可能侵蚀并过度发育而进入通过软骨细胞的植入而将要形成的软骨中。商品中有一种叫做Surigcel(Ethicon有限公司,英国)的可以用在本发明中,它可以在7至14天后被吸收。这种材料在本发明的方法中的使用与诸如Surigcel包装插页中Ethicon有限公司所登载的止血器材的正常使用是相反的。

我们意外地发现,在希望防止软骨内血管形成的情况下,一种止血材料会起凝胶状人造凝结物的作用。本应当出现在关节软骨缺损处整个厚度内的血红细胞被这样的止血屏障遮盖住时,该血细胞会化学变化成高铁血红素,从而不能诱发血管发育。于是一种例如Surigcel这样的止血产品用作血管再形成的抑制屏障(无论有没有血纤蛋白粘结剂),对于本发明所设想的方法都是有效的。本发明的另一部分内容是使用一个无细胞元件作为补片来遮盖住关节的受损部位,该受损部位中使用自体软骨细胞培养出来的软骨细胞/软骨正在进行移植。本发明的方法也考虑使用同种异体的软骨细胞或异种的软骨细胞来修理软骨缺损。

因此,本发明教导了对关节的连接骨质表面上的软骨缺损进行有效地修理或治疗的方法,该方法包括提供一种药剂或器件来阻断血管向软骨等修理位点的侵入;还包括提供一种无细胞的屏障来隔离修理位点并保持被移植细胞的应有位置。因此本发明还提供一个用具盒,该工具盒中装有用来放入待修理位点的止血屏障元件,这对血管形成的侵入待修理位点具有有效的抑制作用。一旦待移植的软骨细胞放入待修理位点,一种无细胞半通透屏障便覆盖在修理位点上,这使得软骨细胞保持在正确的位置,而且仍能获得通向营养素的通道。

一种采用体外实验系统进行的关于软骨细胞在其与某种阻止血管组织形成的产品或几种产品的复合物接触时的行为的研究结果已经给本发明的某些方面作了例证。该体外试验结果预示了某些试验物质所具有的对血管形成的抑制能力,这种血管形成将发生在体内对软骨的缺损部位进行软骨细胞自体移植过程中,在该过程中毛细血管绊会伸入正在建立的软骨中。

适用的止血产品将具有能抑制血管组织、骨细胞、成纤维细胞等发育或侵入正生长中的软骨的特征。一种适用的止血材料必将实现本发明的方法的目标,因为为了使软骨的形成最佳,以及使关节软骨中的任何缺损在整个厚度上都得到修复,应当防止血管以及细胞向正在发育的软骨入侵。理想的情况是在整个软骨得到修复的期间内止血屏障都是稳定的,而过了这段时间后是能被吸收的,否则便被分解掉。有一种鉴定为适用的材料叫做SurigcelW1912(一种可吸收止血剂,含有氧化再生的无菌纤维素;LotGG3DH,Ethicon有限公司,英国)。另一例适用材料为BioBide(一种商业供应的I型胶原基质衬垫;Geistlich Sohne瑞士)。

可以从商品中找到的适用的有机胶液材料例如为TisseelTissucol(血纤蛋白基粘结剂;ImmunoAG,奥地利),粘性蛋白(Cat.#A-2707,SigmaChemical,美国)以及Dow Corning医用粘结剂B(Cat.#895-3,Chemical,美国)。

本发明所考虑的外科工具可用适宜于制作一次性使用或多次重复使用外科工具的金属和/或塑料制造。切削工具上的切削齿可以是整圆周的或平板的,或两者之间的任何装置。因为软骨是一种相对较软的物质,用硬塑料切削刀刃来加工比较好,这样就能在雕刻软骨的时候不致损坏骨层。这种切削工具可以制成带有通路的,以便用来引入液体、吸去切屑和液体以及插入用来对缺损位点进行照明和观察的光学纤维索。

通过下面几个实例的说明可以对本发明的某些方面有更好的了解,这些实例的含意是对发明的说明,而不是对发明的限制。

实施例1为了使Surgice得以按照本发明用来阻止血管发育进入自体移植的软骨或软骨细胞,首先要用戊二醛那样的固定剂对Surgicel进行处理。简单地说,Surgicel要在0.6%戊二醛中处理1分钟,然后多次清洗以去除残留的戊二醛,否则可能会使组织中毒。也可以在进行戊二醛处理之前,先将Surgicel用叫做Tisseel的血纤蛋白粘结剂如例2所述进行处理。这里发现,Surgicel用戊二醛这样的固定剂固定,并用无菌生理盐水(0.9%)洗涤后在冰箱里保存1至2月不会分解。一般地说,外科用料在7至14天期间会被吸收。这个时间可能是太短了,因为在植入的软骨细胞发育成为固态的软骨层,从而得以从周圈的软骨中获取营养之前要阻止血管或血管化由骨结构进入所植入的软骨需要一个更长的时间。换句话说,必须在更长的时间,例如1个月之内能够有效地防止血管形成。在这个时间之前,产品不应显著地被吸收;另一方面,产品最终必须被吸收。因此,用作抑制屏障的有机物质都应具有这些能力。已经发现,经上述方法处理过的Surgicel具有这个功能。

实施例2在Surgicel上还包覆上一种有机胶液。在本例中,该胶液用的是Tisseel。但也可以采用其它胶液。该产品与Surgicel一起产生了一个对本发明的特殊目的适用的屏障。任何其它止血剂或血管抑制屏障均可以使用。Tisseel按后面所述的方法配制。Surgicel上包覆Tisseel的方法为:先在Surgicel材料的两面喷洒Tisseel直至湿透,然后让Tisseel(血纤蛋白胶液)在室温下固化。在完全固化之前要及时地将包覆好的Surgicel放入0.6%的戊二醛中1分钟,然后用0.9%的无菌生理盐水洗涤。然后用磷酸盐缓冲盐水(PBS)和/或NaOH调整PH值,直至PH值稳定在7.2至7.4之间。在这之后,经如此处理的Surgice要在诸如最低必需培养基/F12加15毫摩尔的Hepes缓冲剂组成的组织培养剂中洗涤。

如本例所述,我们使用了Tisseel作为血纤蛋白粘结剂来包覆Surgicel。除此之外,血纤蛋白粘结剂或胶液亦可直接加到损伤的底层,面向骨层,在这上面再粘上Surgicel。用来替代体内试验的体外试验系统包括一个用作细胞研究的NUNCLONTMDelta 6穴无菌一次性使用培养皿。每个穴的直径约为4厘米。

任何一种粘结剂,只要它与血纤蛋白组分一起制得的胶液可为人体所容许,便可用作本发明血纤蛋白粘结剂中的粘结剂(Ihara,N等,Burus Incl.Therm.Inj.,1984,10,396)。本发明亦考虑可用任何其它胶液成分来替代血纤蛋白粘接剂。在本发明中,我们用了Tisseel或Tissucol(ImmunoAG,Vienna,奥地利)。Tisseel用具盒装有下列组分:Tisseel,冻干,病毒灭活封闭剂,包括可凝蛋白质、它的血纤蛋白血浆纤连蛋白(CIG)和第十三因子以及纤溶酶原。

抑肽酶溶液(牛的)凝血酶4(牛的)凝血酶500(牛的)氯化钙溶液Tisseel用具盒中还装有一套DUPLOJECT涂敷系统。血纤蛋白粘结剂或使用Tisseel用具盒的双成分封密剂用下文根据Immuno AG的产品盒插页中的方法混合。

实施例3软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5%的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S,Symbion Science Park的100级实验室内进行操作。软骨细胞还可能用别的成分的培养基进行培养。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化,并在Burker-Turk箱中用台盼兰(TrypanBule)生存力染色进行计数。细胞计数调整到每毫升7.5×105个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。

将Surgicel止血屏障切割成合适的尺寸,置放在NUNCLONTM组织培养皿的井穴的底部。本例的具体情况为,尺寸约为4厘米的圆片(亦可为任何可能的尺寸)在无菌条件下放到6穴NUNCLONTMDelta细胞研究工作用无菌一次性使用培养皿(NUNC,IterMed,Roskilde,丹麦)的穴底上。放到穴底上的止血屏障按照例1中所述进行过预处理。该处理明显地延缓了Surgicel的吸收。该止血屏障然后在蒸馏水中洗几次,接着又是几次,直到未反应的戊二醛被洗掉。再加上少量的含血清细胞培养基,它们将被吸收进入止血屏障内,同时会保持穴底的止血屏障潮湿。

每毫升约106个细胞的培养基直接放到止血屏障的顶上,分散在如上面所说用0.4%戊二醛预处理过的止血屏障的表面上。接下来将培养皿在CO2培养箱内在37℃下培养60分钟。然后小心地向装有细胞的穴内倒入2至5毫升含5至7.5%血清的组织培养基。为了避免溅到细胞上,在倒入培养基时,滴管口要与穴的侧壁相切。可以看到,培养基的PH值是太低了(约6.8)。将PH值调到7.4至7.5。第二天,有些软骨细胞已开始在止血屏障上生长并排列成簇,有一些细胞由于调整PH值之前暴露在低PH下而已经死亡。培养皿要培养3至7天,第3天时要更换培养基。

培养期终了时,轻轻地倒出培养基,并倒入冷藏的作为细胞标本和以后电子显微镜标本的载体(止血屏障)的固定剂的、含0.1摩尔二甲次胂酸钠盐(亦称作卡可酸钠,用HCL将PH值调到7.4)的2.5%戊二醛。

实施例4软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5%的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S,Symbion Science Park的100级实验室内进行操作。软骨细胞还可能用别的成分的培养基进行培养。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化,并在Burker-Turk箱中用台盼兰(TrypanBule)生存力染色进行计数。细胞计数调整到每毫升7.5×105个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。

用作止血屏障的Surgicel如例1所述那样以0.6%的戊二醛处理1分钟,并以0.9%无菌氯化钠溶液或最好以PBS那样的缓冲剂或MEM/F12那样的培养剂清洗,因为在戊二醛处理以后,PH为6.8,而最好的应当为7.0至7.5。用DUPLOJECT系统将Tisseel喷洒在Surgicel的两面,从而对Surgicel的两面进行了包覆,即为带有血纤蛋白粘结剂的待用的补片。胶液在无菌条件下干燥至少3至5分钟。“包覆”好的止血屏障被放到NUNCLONTMDelta细胞研究工作用的6穴无菌一次性使用培养皿的穴底,加上少量的血清的组织培养基,它们将被吸收进入止血屏障。每毫升约106个细胞的含血清的组织培养基直接放到止血剂的顶上,分散在止血屏障的表面上。然后将培养皿在CO2培养箱内在37℃下培养10分钟。接下来小心地向装有细胞的穴内倒入2至5毫升含5至7.5%血清的组织培养基。为了避免溅到细胞上,在倒入培养剂时,滴管口要与穴的侧壁相切。3到6天后,显微镜检测表明,细胞正附着在Surgicel上并正在向里面生长。这很好地说明了Surgicel对软骨细胞不显现毒性。骨细胞在Surgicel中以良好的方式生长。

培养皿培养3到7天,第3天时要更换培养基。培养期终了时,轻轻地倒出培养基,并倒入冷藏的作为细胞标本和以后电子显微镜标本的载体(止血屏障)的固定剂的、含0.1摩尔二甲次胂酸钠盐(亦称作卡可酸钠,用HCL将PH值调到7.4)的2.5%戊二醛。

实施例5软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5%的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S,Symbion Science Park的100级实验室内进行操作。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化,并在Burker-Turk箱中用台盼兰(Trypan Bule)生存力染色进行计数。细胞计数调整到每毫升7.5×105至2×106个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。

已经发现,Bio-Gide可以作为一种可吸收的双层薄膜来用作覆盖在关节缺损部位上的补片或绷带,该缺损内放置有止血屏障和正在移植的培育软骨细胞。Bio-Gide是由标准的受控加工工艺过程生产出来的一种纯胶原薄膜(由E.D.Geistlish Sohne AG,CH-6110 Wolhusen生产)。该胶原是从兽医认证的猪身上萃取,经小心地精制以避免抗原反应,并在双重泡形罩内以伽玛射线消过毒的。该薄膜是用I型和III型胶原制成的,没有经过进一步的交联或化学反应。胶原可在24周以内被吸收。薄膜甚至在湿的时候也能保持其结构完整性。并且可以用缝合线或钉子来固定。也可用Tisseel那样的血纤蛋白粘结剂来替代缝合线或是与缝合线一起将薄膜“胶合”在周围的软骨或组织上。

在100级实验室中将Bio-Gide启封,并且在无菌的条件下将其放入到细胞研究工作用NUNCLONTMDelta 6穴无菌一次性使用培养皿的穴底部,双层薄膜或是疏松面朝上或是致密面朝上。每毫升约106个细胞的含血清的组织培养基直接放到Bio-Gide顶上,分散在Bio-Gide的疏松表面或致密表面上。将培养皿在CO2培养箱内在37℃下培养60分钟,然后小心地向装有细胞的穴内倒入2至5毫升含5至7.5%血清的组织培养基。为了避免溅到细胞上,在倒入培养基时,滴管口要与穴的侧壁相切。

在软骨细胞放入带有Bio-Gide的穴内二天之后,用一台Nikon倒装显微镜来对细胞进行检测。我们注意到,有些软骨细胞附着在Bio-Gide的边缘上。当然用显微镜是不可能透过Bio-Gide看它自己的。

培养皿培养3至7天,第3天时要更换培养基。培养期终了时,轻轻地倒出培养基,将冷藏的、作为细胞标本和Bio-Gide载体标本的固定剂的含0.1M二甲次胂酸钠盐(也称为卡可酸钠,用HCL将PH值调到7.4)的2.5%戊二醛。该载体的疏松面或致密面上繁殖有细胞。然后将Bio-Gide补片送到丹麦Herlev医院病理部作电子显微镜检测。

电子显微镜检测表明,繁殖在Bio-Gide致密面上的软骨细胞没有生长进入Bio-Gide的胶原结构中,而繁殖在疏松表面上的确实生长进入了胶原结构,而且还显示有蛋白聚糖的存在,而没有成纤维细胞构造的征兆。此结果表明,当胶原补片,例如Bio-Gide补片在缝合到软骨缺损处时,补片的疏松面应该朝下,面向将要注入培育好的软骨细胞的缺损位点。这样,软骨细胞便能透入胶原而形成一个平滑的,与未受损表面齐平的软骨表面,而且在此区域内将建立起平滑的蛋白聚糖层。反之,若胶原的致密表面朝向缺损里面,则植入的软骨细胞便不与胶原合成一体,而细胞将不会形成如上所述的平滑表面。

实施例6软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5%的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S,Symbion Science Park的100级实验室内进行操作。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化,并在Burker-Turk箱中用台盼兰(Trypan Bule)耐久性染色进行计数。细胞计数调整到每毫升7.5×105至2×106个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。

Bio-Gide用作可吸收的双层薄膜也可以与Tisseel这样的有机胶一起使用,但附加的抑肽酶含量要比Tisseel产品使用说明所说的正常值明显地高。将抑肽酶增加到约25000KIU/ml,材料的吸收期将从正常范围的几天延长到几个星期。

为了在体外检验该项性能,将Tisseel加到NUNCLONTM培养皿的穴底上,并且允许不完全凝固。然后将Bio-Gide那样的胶原补片加到Tisseel上面并粘在穴底上。这样的Bio-Gide和Tisseel组合是设计用作止血屏障的,它将抑制或阻止血管的发展或渗透进入软骨细胞移植区。这种复合胶原现在可用来既作为伤口底部紧贴待修理表面的止血屏障,同时又是软骨形成的支撑物,因为胶原补片朝上的一面可以是疏松面,从而促进软骨细胞和软骨基质的渗透。这种复合胶原也可用来盖在植入物顶上,胶原的疏松面朝下,面向植入的软骨细胞和形成顶部的屏障。抑肽酶含量增高了的复合胶原又可以直接放入缺损处,靠本身的固有粘力粘附,而不需用Tisseel那样的有机胶液,因而这种胶原补片既可用作止血屏障,又可将其疏松面朝向植入物的软骨细胞/软骨而用作修理位点/移植位点的无细胞盖罩。另一个变型是由II型胶原组成的胶原补片(即使用Geistlich Sohne AG,CH-6110 Wolhusen)。

这样,本发明提供了一种复合胶原补片,所述补片具胶原基材料其抑肽酶组分增高,最好约为25000KIU/ml,与一种有机材料胶液配套使用。这里胶原组分为类似于Bio-Gide的可吸收双层材料或II型胶原,而有机胶液为类似于Tisseel的材料。另一个实施方案为复合胶原补片不使用任何有机胶液来贴到修理位点上。

实施例7由于骨关节炎软骨构造已被削弱,植到受损软骨移植位点中去的培育好的自体软骨细胞的附着力会受到抑制,因此在新植入的软骨/软骨细胞和周围的已有软骨之间形成了一个边缘区(分界线区)。如果移植位点在作移植准备时将壁面制备成为直的平滑的直线方式,则该边缘区将是非常明显的。在移植位点被切割成直线形时,跨越这种边缘区两边的剪切力和压缩力将对移植物作用以很大的力来将其排出。这个边缘区以及材料沿着这个边缘区的不同的运动将抑制移植材料与周边材料之间的愈合。当邻接材料的硬度不相同时,这种边缘区剪切会更恶化。在很多情况下,移植材料较周边材料更软,然而在某些骨关节炎病例中,周边软骨可能事实上较植入的软骨细胞/软骨还要硬。

所以,为了解决这个问题,本发明的方法教导了使用外科工具来雕刻移植位点的壁面,使壁面是非直线型的,因而提供了波纹状表面,这将减轻边缘区剪切力,并使移植材料得以锚固。也可以对移植位点整形,使其接近骨表面处的直径大于远离骨表面并位于待修理软骨表面处的直径,因而存在一个“倒漏斗”效应。表面上的狭窄开口将有助于减小边缘区的剪切力,减轻移植物从移植位点的挤出。在一个优选实施方案中,移植位点雕刻成类似一个可以拧入螺栓或螺钉的螺孔(图3B),这可称作“阴”和“阳”螺纹,因而提供了抵御移植位点对移植物的压缩和排斥的机械阻力。

本发明所考虑的外科工具可用适宜于制作一次性使用或多次重复使用外科工具的金属和/或塑料制造。因为软骨是一种相对较软的物质,用硬塑料切削刀刃来加工较好,这样就能在雕刻软骨的时候不致损坏骨层。这种切削工具可以制成带有通路的,以便用来引入液体、吸去切屑和液体以及插入用来对缺损位点避行照明和观察的光学纤维索。在工具的某些实施方案中,工具的基面可以具有凸出点或销形构造,这将有助于将工具导引并定位在移植位点内。当然,这样的销必定设计成对底下的骨层破坏最小。

尽管工具的切削表面可以是单齿的、多齿的,或象在金属零件上加工螺孔的丝锥那样成为螺旋形状的,切削工具必须具有的性能为移植位点最后雕成的侧面为波纹形的和非直线的。例如,在某些实施方案中,工具的切削刃可整修成类似于图4A或图4B所示的形状。在绕着切削工具直径的方向上,切削刃可以是平直的或是圆形的。可以设计出很多其它形状来达到本发明的方法的目的,产生一个界面来对作用在移植材料和周边材料上的压缩和剪切力所引起的各种反作用力提供机械阻抗。

实施例8一头出生四个月的约克郡混种猪在受到一般的麻醉后腹部朝上地平躺着。猪在经过清洗后送进亚利桑那州费尼克斯Harrington炎研究中心的外科手术室。整个外科程序是在无菌状态下实施的。猪的左后腿和邻近的腿关节部以及腹股沟区域用碘酒清洗。膝关节作了定位并固定髌骨。从髌骨后部起做个约3厘米的正中切口,并基本上割去皮下组织、肌肉层和韧带,形成通向中股髁的通道。用一圆形切割器在覆盖在中髁后中部上的白软骨内制造一个伤口,伤口与该软骨的外缘间的边缘宽度为0.5至1厘米。该0.5至1厘米大的缺损的位置是在中髁(左髁,见图6A)承受尾部重量的部位内。整个外科进程中,左股骨上没有用止血带。皮肤和各层进行了适当的缝合。

第3天时,又将动物带进外科手术室,与上面一样地放在手术台上并施以一般的麻醉。左后腿、腹部和腹股沟区域如上面所述用碘酒离子化(ionized)。割掉缝合线,打开手术区。注意到膝关节内存在中度的血肿。除去血液凝块并检查缺损处。缺损中存在血液凝块。将该血液凝块除去。将一个具有阳螺纹形切削刃、尺寸相当于伤痕的周边或稍大的无菌外科工具小心地拧入缺损处。将一块Bio-Gide补片剪裁成与缺损的底部尺寸相同。将一种粘性蛋白(A-2707,Sigma Chemical,美国)首次用胶涂覆在经过整修的止血屏障补片的致密面上,并将该补片致密面朝下放入伤痕的底部,形成上面所说的屏障。我们发现,该胶液似乎干得不是非常快,此时伤痕底面轻微的出血立刻停止了。第二块Bio-Gide的周边剪裁得比伤痕要大一些,并且如前面所说致密面朝上(所以其疏松面朝向移植物)地放在伤痕上。

然后将该无细胞覆盖补片缝合在空穴上,留下一个边缘敞着口,将要取出的软骨细胞可从这个开口处注入移植位点。补片的四周边缘涂盖上第二次用胶,即Dow Coming医用粘结剂B(Cat.#895-3,Dow Corning,美国)。这种第二次用胶干得非常快,而且较首次用胶更有效。我们发现,在上述这一特定的操作过程中,在着手进行盖罩的缝合时,首次胶尚末充分干燥到可使止血屏障就位。紧贴移植位点表面上的主要屏障是由该胶液本身形成的。

用一个1毫升的注射管和一个16号针头将约0.6毫升的软骨细胞的细胞悬浮体吸入注射管的圆筒内。再将16号针头换成23号短针头,并将细胞悬浮体(约10×106个细胞)注入所缝合的覆盖补片下面的移植位点内。接下来在撤出针头之前粘合盖罩的敞口边缘,然后再小心地撤去针头。没有看到细胞的漏出。然后如前面那样将伤口缝合,并且没有使用止血带,也没有看到出血。最后将皮肤层缝合。缝合后没有发生皮肤隆起,这表明不存在血肿。术后恢复是没有事故的。

正如希望的那样,植入的软骨细胞所生成的软骨基质充分地修复了试验猪膝关节软骨表面内所制造的缺损。图6A为猪膝部的磁共振图象,表示在膝内(左髁,中髁)处造成的软骨损伤;图6B为同一头猪膝部治疗后三个月时的磁共振图象,表示该缺损的修复。

实施例9

一个由实施本发明的方法有用的元件组成的用具盒可使本发明的方法在外科移植中得以方便地实施。在一个优选实施方案中,本发明的用具盒将提供适于在外科条件下容易地使用的无菌元件,并将提供适用的止血屏障、适用的覆盖补片,如果需要还将提供有机胶液。一个本发明的用具盒还可提供无菌的,适于用来承载自体软骨细胞的无细胞基质材料,该自体软骨细胞是将植入关节铰接表面缺损内的。在一个实施方案中,一个本发明的用具盒内装有Surgicel止血屏障和带有适宜的涂覆层Tisseel有机胶的Bio-Gide覆盖补片。这里的Surgicel和Tisseel是已经按照本发明的教导作了延长吸收时间处理的。在Tisseel预先涂覆好的情况下,在一个实施方案中,Tisseel增补了额外的抑肽酶来增长吸收时间。

在另一个优选实施方案中,止血屏障和覆盖补片二者都是一种半渗透胶原基质,它们都是经过处理来延长吸收时间的。也还可能以增强型的形式将Tisseel胶液作为独立的组分来提供,在需要的时候再涂覆。这是因为每个修复/移植程序会遇到的固有可变性以及各种独特的情况。

本发明用具盒的又一个实施方案内装有如例7中所说的那种外科工具或它的适用的改进型。

本专业人员都了解,由具体的实施方案所表示的本发明可以进行许多变更和/或修改,这些变更和/或修改没有脱离本发明的所述精神和范围。

Claims (11)

1.一种修复关节软骨缺陷的软骨修复构造物,包括一种无细胞的膜,所述膜具有一多孔表面与一致密表面;和与所述膜的多孔表面相邻的软骨细胞。
2.权利要求1的软骨修复构造物,其中所述软骨细胞粘附于所述多孔表面。
3.权利要求1的软骨修复构造物,其中所述膜为胶原。
4.权利要求1的软骨修复构造物,其中所述膜为I型和III型胶原。
5.权利要求1的软骨修复构造物,其中所述膜是可再吸收的。
6.权利要求1的软骨修复构造物,其中所述软骨细胞是自源的。
7.权利要求1的软骨修复构造物,其中所述软骨细胞是外源的。
8.权利要求1的软骨修复构造物,其中所述软骨细胞是异体的。
9.权利要求1的软骨修复构造物,其中进一步包括生物兼容的粘合剂,该粘合剂邻近于所述膜。
10.权利要求1的软骨修复构造物,其中使所述膜适于覆盖关节软骨缺陷。
11.权利要求1的软骨修复构造物,其中使所述膜适于放置在软骨缺陷之中。
CN 97199207 1996-08-30 1997-08-29 一种修复关节软骨缺陷的软骨修复构造物 CN1200656C (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08704891 US5759190A (en) 1996-08-30 1996-08-30 Method and kit for autologous transplantation
US08857090 US5989269A (en) 1996-08-30 1997-05-15 Method, instruments and kit for autologous transplantation

Publications (2)

Publication Number Publication Date
CN1241918A true CN1241918A (zh) 2000-01-19
CN1200656C true CN1200656C (zh) 2005-05-11

Family

ID=27107401

Family Applications (2)

Application Number Title Priority Date Filing Date
CN 03155328 CN1500447A (zh) 1996-08-30 1997-08-29 自体移植术的方法、工具和用具盒
CN 97199207 CN1200656C (zh) 1996-08-30 1997-08-29 一种修复关节软骨缺陷的软骨修复构造物

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN 03155328 CN1500447A (zh) 1996-08-30 1997-08-29 自体移植术的方法、工具和用具盒

Country Status (11)

Country Link
US (9) US5989269A (zh)
JP (2) JP2002502272A (zh)
KR (2) KR20030097603A (zh)
CN (2) CN1500447A (zh)
CA (2) CA2264138C (zh)
DE (6) DE69728569D1 (zh)
DK (5) DK1384452T3 (zh)
EP (4) EP1459709A1 (zh)
ES (3) ES2211722T3 (zh)
RU (2) RU2214197C2 (zh)
WO (1) WO1998008469A3 (zh)

Families Citing this family (175)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050186673A1 (en) * 1995-02-22 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US5940807A (en) * 1996-05-24 1999-08-17 Purcell; Daniel S. Automated and independently accessible inventory information exchange system
US6569172B2 (en) * 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US5989269A (en) 1996-08-30 1999-11-23 Vts Holdings L.L.C. Method, instruments and kit for autologous transplantation
US20020173806A1 (en) * 1996-08-30 2002-11-21 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US20060025786A1 (en) * 1996-08-30 2006-02-02 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US8858981B2 (en) * 1997-10-10 2014-10-14 Ed. Geistlich Soehne Fuer Chemistrie Industrie Bone healing material comprising matrix carrying bone-forming cells
US9034315B2 (en) * 1997-10-10 2015-05-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Cell-charged multi-layer collagen membrane
US20050186283A1 (en) * 1997-10-10 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US20100030340A1 (en) * 1998-06-30 2010-02-04 Wolfinbarger Jr Lloyd Plasticized Grafts and Methods of Making and Using Same
US6293970B1 (en) 1998-06-30 2001-09-25 Lifenet Plasticized bone and soft tissue grafts and methods of making and using same
WO2000009179A3 (en) * 1998-08-14 2000-06-02 Verigen Transplantation Serv Methods, instruments and materials for chondrocyte cell transplantation
US20020116063A1 (en) * 1999-08-02 2002-08-22 Bruno Giannetti Kit for chondrocyte cell transplantation
EP1656960A1 (en) * 1998-08-14 2006-05-17 Verigen AG Methods, instruments and materials for chondrocyte cell transplantation
WO2002022014A1 (en) 2000-09-14 2002-03-21 The Board Of Trustees Of The Leland Stanford Junior University Assessing the condition of a joint and devising treatment
DE69941304D1 (de) 1998-09-14 2009-10-01 Univ R Zustandsbestimmung eines gelenks und schadenvorsorge
US7239908B1 (en) 1998-09-14 2007-07-03 The Board Of Trustees Of The Leland Stanford Junior University Assessing the condition of a joint and devising treatment
US7615373B2 (en) 1999-02-25 2009-11-10 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed collagen and tissue engineering
US7476250B1 (en) * 1999-04-06 2009-01-13 Mansmann Kevin A Semi-permeable membranes to assist in cartilage repair
US20080077251A1 (en) * 1999-06-07 2008-03-27 Chen Silvia S Cleaning and devitalization of cartilage
US6179840B1 (en) 1999-07-23 2001-01-30 Ethicon, Inc. Graft fixation device and method
US20020095157A1 (en) 1999-07-23 2002-07-18 Bowman Steven M. Graft fixation device combination
ES2239608T3 (es) * 1999-07-28 2005-10-01 Interface Biotech A/S Reparacion in vitro de defectos de hueso y/o cartilago.
CA2391819A1 (en) 1999-08-02 2001-02-08 Verigen Transplantation Service International Ag Kit for chondrocyte cell transplantation
CA2638625C (en) * 1999-12-03 2012-07-24 University Of Leeds Fixation technology for bone repair
US6626945B2 (en) * 2000-03-14 2003-09-30 Chondrosite, Llc Cartilage repair plug
US8388624B2 (en) 2003-02-24 2013-03-05 Arthrosurface Incorporated Trochlear resurfacing system and method
ES2324282T3 (es) * 2000-05-01 2009-08-04 Arthro Surface, Inc. Sistema de reparacion de la superficie de una articulacion.
US7678151B2 (en) 2000-05-01 2010-03-16 Ek Steven W System and method for joint resurface repair
US7713305B2 (en) * 2000-05-01 2010-05-11 Arthrosurface, Inc. Articular surface implant
US6520964B2 (en) 2000-05-01 2003-02-18 Std Manufacturing, Inc. System and method for joint resurface repair
US8177841B2 (en) 2000-05-01 2012-05-15 Arthrosurface Inc. System and method for joint resurface repair
US6610067B2 (en) 2000-05-01 2003-08-26 Arthrosurface, Incorporated System and method for joint resurface repair
US8366787B2 (en) 2000-08-04 2013-02-05 Depuy Products, Inc. Hybrid biologic-synthetic bioabsorbable scaffolds
US6638312B2 (en) 2000-08-04 2003-10-28 Depuy Orthopaedics, Inc. Reinforced small intestinal submucosa (SIS)
US20020081732A1 (en) 2000-10-18 2002-06-27 Bowlin Gary L. Electroprocessing in drug delivery and cell encapsulation
EP1315756A2 (en) 2000-09-01 2003-06-04 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed fibrin-based matrices and tissues
WO2002022013A1 (en) 2000-09-14 2002-03-21 The Board Of Trustees Of The Leland Stanford Junior University Assessing condition of a joint and cartilage loss
US20020127265A1 (en) * 2000-12-21 2002-09-12 Bowman Steven M. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US6852330B2 (en) * 2000-12-21 2005-02-08 Depuy Mitek, Inc. Reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
CA2365376C (en) * 2000-12-21 2006-03-28 Ethicon, Inc. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US6599323B2 (en) * 2000-12-21 2003-07-29 Ethicon, Inc. Reinforced tissue implants and methods of manufacture and use
US7537780B2 (en) * 2002-03-22 2009-05-26 Histogenics Corporation Method for preparing and implanting a cartilage construct to treat cartilage lesions
US20040151705A1 (en) 2002-03-22 2004-08-05 Shuichi Mizuno Neo-cartilage constructs and a method for preparation thereof
US6713085B2 (en) 2001-04-27 2004-03-30 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method and membrane for mucosa regeneration
US8439926B2 (en) 2001-05-25 2013-05-14 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools
US7534263B2 (en) 2001-05-25 2009-05-19 Conformis, Inc. Surgical tools facilitating increased accuracy, speed and simplicity in performing joint arthroplasty
US8623026B2 (en) 2006-02-06 2014-01-07 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools incorporating anatomical relief
US8083745B2 (en) 2001-05-25 2011-12-27 Conformis, Inc. Surgical tools for arthroplasty
CA2447694A1 (en) 2001-05-25 2002-12-05 Imaging Therapeutics, Inc. Methods and compositions for articular resurfacing
US8882847B2 (en) 2001-05-25 2014-11-11 Conformis, Inc. Patient selectable knee joint arthroplasty devices
US8556983B2 (en) 2001-05-25 2013-10-15 Conformis, Inc. Patient-adapted and improved orthopedic implants, designs and related tools
US8545569B2 (en) 2001-05-25 2013-10-01 Conformis, Inc. Patient selectable knee arthroplasty devices
US8735773B2 (en) 2007-02-14 2014-05-27 Conformis, Inc. Implant device and method for manufacture
US8771365B2 (en) 2009-02-25 2014-07-08 Conformis, Inc. Patient-adapted and improved orthopedic implants, designs, and related tools
US8500740B2 (en) 2006-02-06 2013-08-06 Conformis, Inc. Patient-specific joint arthroplasty devices for ligament repair
US8234097B2 (en) 2001-05-25 2012-07-31 Conformis, Inc. Automated systems for manufacturing patient-specific orthopedic implants and instrumentation
US7618451B2 (en) 2001-05-25 2009-11-17 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools facilitating increased accuracy, speed and simplicity in performing total and partial joint arthroplasty
US7468075B2 (en) 2001-05-25 2008-12-23 Conformis, Inc. Methods and compositions for articular repair
US9603711B2 (en) 2001-05-25 2017-03-28 Conformis, Inc. Patient-adapted and improved articular implants, designs and related guide tools
US8480754B2 (en) 2001-05-25 2013-07-09 Conformis, Inc. Patient-adapted and improved articular implants, designs and related guide tools
US6723102B2 (en) 2001-06-14 2004-04-20 Alexandria Research Technologies, Llc Apparatus and method for minimally invasive total joint replacement
US6482209B1 (en) * 2001-06-14 2002-11-19 Gerard A. Engh Apparatus and method for sculpting the surface of a joint
EP1416886A4 (en) 2001-07-16 2007-04-18 Depuy Products Inc Cartilage repair and regeneration scaffold and method
WO2003007805A3 (en) * 2001-07-16 2004-02-12 Depuy Products Inc Cartilage repair apparatus and method
JP2005515802A (ja) 2001-07-16 2005-06-02 デピュイ・プロダクツ・インコーポレイテッド 混成生物/合成品型多孔質細胞外基質支持骨格
US7201917B2 (en) 2001-07-16 2007-04-10 Depuy Products, Inc. Porous delivery scaffold and method
US8337537B2 (en) 2001-07-16 2012-12-25 Depuy Products, Inc. Device from naturally occurring biologically derived materials
US20040166169A1 (en) * 2002-07-15 2004-08-26 Prasanna Malaviya Porous extracellular matrix scaffold and method
US8025896B2 (en) 2001-07-16 2011-09-27 Depuy Products, Inc. Porous extracellular matrix scaffold and method
JP4294474B2 (ja) 2001-07-16 2009-07-15 デピュイ・プロダクツ・インコーポレイテッド 半月板再生装置
US7819918B2 (en) 2001-07-16 2010-10-26 Depuy Products, Inc. Implantable tissue repair device
US7163563B2 (en) * 2001-07-16 2007-01-16 Depuy Products, Inc. Unitary surgical device and method
EP1438067A4 (en) * 2001-09-24 2006-06-14 Verigen Ag Autologous growth factor cocktail composition, method of production and use
JP4330991B2 (ja) * 2001-10-01 2009-09-16 スキャンディウス・バイオメディカル・インコーポレーテッド 関節軟骨の欠陥を修復するための装置及び方法
CA2412012C (en) * 2001-11-20 2011-08-02 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage
WO2003061653A9 (en) * 2002-01-22 2003-12-24 Charlotte Moira Norfo Allerton 3-(imidazolyl)-2-aminopropanoic acids for use as tafi-a inhibitors for the treatment of thrombotic diseases
US20030180263A1 (en) * 2002-02-21 2003-09-25 Peter Geistlich Resorbable extracellular matrix for reconstruction of bone
EP1501452A4 (en) * 2002-05-01 2008-02-27 Verigen Ag Injectable chondrocyte implant
US7811267B2 (en) * 2002-05-16 2010-10-12 Amo Groningen B.V. Kit and method in eye surgery
US20040136968A1 (en) 2002-09-27 2004-07-15 Verigen Ag Autologous cells on a support matrix for tissue repair
JP2006501977A (ja) 2002-10-07 2006-01-19 コンフォーミス・インコーポレイテッドConforMIS, Inc. 関節表面に適合する3次元外形を伴う最小限侵襲性関節インプラント
US7824701B2 (en) 2002-10-18 2010-11-02 Ethicon, Inc. Biocompatible scaffold for ligament or tendon repair
US20040078090A1 (en) 2002-10-18 2004-04-22 Francois Binette Biocompatible scaffolds with tissue fragments
EP1555963A4 (en) 2002-10-23 2008-12-31 Mako Surgical Corp Modular femoral component for a total knee joint replacement for minimally invasive implantation
JP2006505366A (ja) 2002-11-07 2006-02-16 コンフォーミス・インコーポレイテッドConforMIS, Inc. 半月板サイズおよび形状の決定および工夫した処置の方法
US7537664B2 (en) 2002-11-08 2009-05-26 Howmedica Osteonics Corp. Laser-produced porous surface
US7951163B2 (en) 2003-11-20 2011-05-31 Arthrosurface, Inc. Retrograde excision system and apparatus
US7163541B2 (en) 2002-12-03 2007-01-16 Arthrosurface Incorporated Tibial resurfacing system
EP1765201A4 (en) 2004-06-28 2013-01-23 Arthrosurface Inc System for articular surface replacement
US7901408B2 (en) 2002-12-03 2011-03-08 Arthrosurface, Inc. System and method for retrograde procedure
EP1845890A4 (en) 2003-11-20 2010-06-09 Arthrosurface Inc System and method for retrograde procedure
US7828853B2 (en) 2004-11-22 2010-11-09 Arthrosurface, Inc. Articular surface implant and delivery system
WO2004071354A1 (en) * 2003-02-12 2004-08-26 Australian Surgical Design And Manufacture Pty Limited Arthroscopic chondrocyte implantation method and device
US8197837B2 (en) 2003-03-07 2012-06-12 Depuy Mitek, Inc. Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof
US7067123B2 (en) 2003-04-29 2006-06-27 Musculoskeletal Transplant Foundation Glue for cartilage repair
USRE43258E1 (en) 2003-04-29 2012-03-20 Musculoskeletal Transplant Foundation Glue for cartilage repair
US20050064042A1 (en) * 2003-04-29 2005-03-24 Musculoskeletal Transplant Foundation Cartilage implant plug with fibrin glue and method for implantation
US7488348B2 (en) 2003-05-16 2009-02-10 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
WO2004110512A3 (en) * 2003-06-12 2005-05-06 Interface Biotech As A method for cell implantation
US8226715B2 (en) 2003-06-30 2012-07-24 Depuy Mitek, Inc. Scaffold for connective tissue repair
US20050046915A1 (en) * 2003-08-22 2005-03-03 Fuji Photo Film Co., Ltd. Hologram recording material composition, hologram recording material and hologram recording method
DE10349722A1 (de) 2003-10-23 2005-06-16 Beschorner, Katharina, Dr. Zusammensetzung zur Arthrose-/Arthritisbehandlung, insbesondere von Gelenken
GB0325141D0 (en) * 2003-10-28 2003-12-03 Xiros Plc Repair of damaged tissue on a bone site
JP2007512108A (ja) 2003-11-20 2007-05-17 アースロサーフィス・インコーポレーテッド 表面再形成デバイスの退歩的配送
US7316822B2 (en) 2003-11-26 2008-01-08 Ethicon, Inc. Conformable tissue repair implant capable of injection delivery
US7901461B2 (en) 2003-12-05 2011-03-08 Ethicon, Inc. Viable tissue repair implants and methods of use
EP2338442B1 (en) 2003-12-11 2013-01-30 Isto Technologies Inc. Particulate cartilage system
US20050177249A1 (en) * 2004-02-09 2005-08-11 Kladakis Stephanie M. Scaffolds with viable tissue
EP1576957A1 (en) * 2004-03-18 2005-09-21 Universiteit Twente Tissue repair using pluripotent cells
US8137686B2 (en) 2004-04-20 2012-03-20 Depuy Mitek, Inc. Nonwoven tissue scaffold
US8221780B2 (en) 2004-04-20 2012-07-17 Depuy Mitek, Inc. Nonwoven tissue scaffold
US8657881B2 (en) 2004-04-20 2014-02-25 Depuy Mitek, Llc Meniscal repair scaffold
US7569233B2 (en) * 2004-05-04 2009-08-04 Depuy Products, Inc. Hybrid biologic-synthetic bioabsorbable scaffolds
CA2470463C (en) * 2004-06-09 2012-09-18 Lornamead Brands, Inc. Tooth whitening products and methods of making the same
CA2541827C (en) * 2004-07-30 2013-05-14 Histogenics Corporation Method for in situ repair of injured, damaged, diseased or aged articular cartilage using neo-cartilage constructs and a method for preparation thereof
US8697139B2 (en) 2004-09-21 2014-04-15 Frank M. Phillips Method of intervertebral disc treatment using articular chondrocyte cells
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
US7513866B2 (en) 2004-10-29 2009-04-07 Depuy Products, Inc. Intestine processing device and associated method
WO2006050213A3 (en) * 2004-10-29 2006-08-24 Alexander E Michalow Methods of promoting healing of cartilage defects and method of causing stem cells to differentiate by the articular chondrocyte pathway
US7354627B2 (en) * 2004-12-22 2008-04-08 Depuy Products, Inc. Method for organizing the assembly of collagen fibers and compositions formed therefrom
US20060147332A1 (en) * 2004-12-30 2006-07-06 Howmedica Osteonics Corp. Laser-produced porous structure
CN100384390C (zh) 2005-01-13 2008-04-30 中国人民解放军第三军医大学第一附属医院 组织工程骨与软骨复合组织及其体外构建方法
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
WO2007025290A3 (en) 2005-08-26 2007-10-18 H Davis Adkisson Iv Implants and methods for repair, replacement and treatment of joint disease
KR20080065606A (ko) * 2005-09-02 2008-07-14 인터페이스 바이오텍 에이/에스 세포 이식 방법
CA2623106C (en) 2005-09-19 2013-12-24 Histogenics Corp. Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
CA2623834A1 (en) 2005-09-30 2007-04-12 Conformis, Inc. Joint arthroplasty devices
CN101384230A (zh) 2005-11-21 2009-03-11 福特真公司 治疗小面关节、钩椎关节、肋椎关节和其他关节的装置和方法
US8728387B2 (en) 2005-12-06 2014-05-20 Howmedica Osteonics Corp. Laser-produced porous surface
EP1803513B1 (en) * 2005-12-30 2017-03-29 Howmedica Osteonics Corp. Method of manufacturing implants using laser
EP2649951A3 (en) 2006-02-06 2013-12-25 ConforMIS, Inc. Patient selectable joint arthroplasty devices and surgical tools
US20090117087A1 (en) * 2007-04-13 2009-05-07 Wake Forest University Methods and compositions for printing biologically compatible nanotube composites of autologous tissue
US20070288021A1 (en) * 2006-06-07 2007-12-13 Howmedica Osteonics Corp. Flexible joint implant
US8147861B2 (en) * 2006-08-15 2012-04-03 Howmedica Osteonics Corp. Antimicrobial implant
US20100040667A1 (en) * 2006-09-07 2010-02-18 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method of treating bone cancer
KR20080037883A (ko) * 2006-10-27 2008-05-02 세원셀론텍(주) 메디컬 키트 및 이의 사용방법
WO2008073404A3 (en) 2006-12-11 2008-08-21 Arthrosurface Inc Retrograde resection apparatus and method
US7871440B2 (en) 2006-12-11 2011-01-18 Depuy Products, Inc. Unitary surgical device and method
US8163549B2 (en) 2006-12-20 2012-04-24 Zimmer Orthobiologics, Inc. Method of obtaining viable small tissue particles and use for tissue repair
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
WO2008101090A3 (en) 2007-02-14 2008-11-27 Conformis Inc Implant device and method for manufacture
US7758643B2 (en) * 2007-02-26 2010-07-20 Biomet Sports Medicine, Llc Stable cartilage defect repair plug
WO2009111069A1 (en) 2008-03-05 2009-09-11 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
CA2684040C (en) 2007-04-12 2016-12-06 Isto Technologies, Inc. Method of forming an implant using a mold that mimics the shape of the tissue defect site and implant formed therefrom
WO2008157412A3 (en) 2007-06-13 2009-04-09 Raymond A Bojarski Surgical cutting guide
EP2182887B1 (en) 2007-08-20 2016-12-14 Histogenics Corporation A method for improvement of differentiation of mesenchymal stem cells using a double-structured tissue implant
US8685107B2 (en) 2007-07-03 2014-04-01 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US9125743B2 (en) * 2007-07-16 2015-09-08 Lifenet Health Devitalization and recellularization of cartilage
US9744043B2 (en) * 2007-07-16 2017-08-29 Lifenet Health Crafting of cartilage
WO2009014718A1 (en) 2007-07-24 2009-01-29 Porex Corporation Porous laser sintered articles
US20110014267A1 (en) * 2008-02-29 2011-01-20 Hanne Everland Biosynthetic cartilaginous matrix and methods for their production
EP2698173A1 (en) 2008-02-29 2014-02-19 Coloplast A/S Compositions and methods for augmentation and regeneration of living tissue in a subject
EP2262448A4 (en) 2008-03-03 2014-03-26 Arthrosurface Inc Bone resurfacing system and method
WO2009111626A3 (en) 2008-03-05 2010-01-14 Conformis, Inc. Implants for altering wear patterns of articular surfaces
EP2303193A4 (en) 2008-05-12 2012-03-21 Conformis Inc Devices and methods for treatment of facet and other joints
GB0812631D0 (en) * 2008-07-10 2008-08-20 Imp Innovations Ltd Modular knee implants
US8808297B2 (en) 2009-02-24 2014-08-19 Microport Orthopedics Holdings Inc. Orthopedic surgical guide
US9017334B2 (en) 2009-02-24 2015-04-28 Microport Orthopedics Holdings Inc. Patient specific surgical guide locator and mount
US8808303B2 (en) 2009-02-24 2014-08-19 Microport Orthopedics Holdings Inc. Orthopedic surgical guide
US9662126B2 (en) 2009-04-17 2017-05-30 Arthrosurface Incorporated Glenoid resurfacing system and method
WO2010121246A1 (en) 2009-04-17 2010-10-21 Arthrosurface Incorporated Glenoid resurfacing system and method
EP2754419A3 (en) 2011-02-15 2014-10-08 Conformis, Inc. Patient-adapted and improved orthopedic implants, designs and related tools
US9066716B2 (en) 2011-03-30 2015-06-30 Arthrosurface Incorporated Suture coil and suture sheath for tissue repair
US9364896B2 (en) 2012-02-07 2016-06-14 Medical Modeling Inc. Fabrication of hybrid solid-porous medical implantable devices with electron beam melting technology
US9180010B2 (en) 2012-04-06 2015-11-10 Howmedica Osteonics Corp. Surface modified unit cell lattice structures for optimized secure freeform fabrication
US9135374B2 (en) 2012-04-06 2015-09-15 Howmedica Osteonics Corp. Surface modified unit cell lattice structures for optimized secure freeform fabrication
US9486226B2 (en) 2012-04-18 2016-11-08 Conformis, Inc. Tibial guides, tools, and techniques for resecting the tibial plateau
US9186053B2 (en) * 2012-05-03 2015-11-17 Covidien Lp Methods of using light to repair hernia defects
US9675471B2 (en) 2012-06-11 2017-06-13 Conformis, Inc. Devices, techniques and methods for assessing joint spacing, balancing soft tissues and obtaining desired kinematics for joint implant components
US9468448B2 (en) 2012-07-03 2016-10-18 Arthrosurface Incorporated System and method for joint resurfacing and repair
US9492200B2 (en) 2013-04-16 2016-11-15 Arthrosurface Incorporated Suture system and method
US20150250602A1 (en) 2014-03-07 2015-09-10 Arthrosurface Incorporated Implant and anchor assembly
US20160331539A1 (en) * 2015-05-12 2016-11-17 Elwha Llc Modifiable implants

Family Cites Families (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2933174A1 (de) 1978-10-06 1980-04-10 Sulzer Ag Implantat fuer einen teilweisen ersatz einer gleitflaeche eines menschlichen gelenkes
DE3160759D1 (de) 1980-02-21 1983-09-22 Coats Ltd J & P Device for use in the treatment of damaged articular surfaces of human joints
US4649918A (en) * 1980-09-03 1987-03-17 Custom Medical Devices, Inc. Bone core removing tool
US4553272A (en) 1981-02-26 1985-11-19 University Of Pittsburgh Regeneration of living tissues by growth of isolated cells in porous implant and product thereof
US4393874A (en) 1982-04-26 1983-07-19 Telectronics Pty. Ltd. Bradycardia event counting and reporting pacer
GB2137209B (en) * 1983-03-23 1986-10-15 Univ Ramot Repair of cartilage and of bones
US4559936A (en) * 1983-09-29 1985-12-24 Hill Edward B Bone plugging apparatus
JPS61500302A (zh) * 1983-10-20 1986-02-27
US4620327A (en) 1984-07-05 1986-11-04 Caplan Arnold I Process of adapting soluble bone protein for use in stimulating osteoinduction
US4789663A (en) * 1984-07-06 1988-12-06 Collagen Corporation Methods of bone repair using collagen
US4877020A (en) * 1984-11-30 1989-10-31 Vich Jose M O Apparatus for bone graft
US4642117A (en) 1985-03-22 1987-02-10 Collagen Corporation Mechanically sheared collagen implant material and method
US5902741A (en) 1986-04-18 1999-05-11 Advanced Tissue Sciences, Inc. Three-dimensional cartilage cultures
US5736372A (en) 1986-11-20 1998-04-07 Massachusetts Institute Of Technology Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure
US5041138A (en) * 1986-11-20 1991-08-20 Massachusetts Institute Of Technology Neomorphogenesis of cartilage in vivo from cell culture
NL8700113A (nl) * 1987-01-19 1988-08-16 Groningen Science Park Entstuk, geschikt voor behandeling door reconstructieve chirurgie, met weefsel specifieke porositeit, alsmede werkwijze ter vervaardiging van het entstuk.
GB8705985D0 (en) 1987-03-13 1987-04-15 Geistlich Soehne Ag Dressings
US4846835A (en) * 1987-06-15 1989-07-11 Grande Daniel A Technique for healing lesions in cartilage
US5158574A (en) 1987-07-20 1992-10-27 Regen Corporation Prosthetic meniscus
US5258043A (en) 1987-07-20 1993-11-02 Regen Corporation Method for making a prosthetic intervertebral disc
US5306311A (en) 1987-07-20 1994-04-26 Regen Corporation Prosthetic articular cartilage
US5116374A (en) 1989-03-02 1992-05-26 Regen Corporation Prosthetic meniscus
CA1329089C (en) 1987-09-02 1994-05-03 Russell Warren Surgical fastener
JPH01121223A (en) 1987-09-18 1989-05-12 Ethicon Inc Stable freeze-dried composition containing growth factor
CA1339083C (en) 1987-11-13 1997-07-29 Steven R. Jefferies Bone repair material and delayed drug delivery system
JP2820415B2 (ja) * 1988-03-14 1998-11-05 ティーエイチエム・バイオメディカル・インコーポレイテッド 生分解性および骨形成性を有する移植骨片代用組成体
US5201745A (en) * 1988-03-15 1993-04-13 Imedex Visceral surgery patch
US4904259A (en) * 1988-04-29 1990-02-27 Samuel Itay Compositions and methods for repair of cartilage and bone
US4975526A (en) 1989-02-23 1990-12-04 Creative Biomolecules, Inc. Bone collagen matrix for zenogenic implants
US5108436A (en) 1988-09-29 1992-04-28 Collagen Corporation Implant fixation
WO1990004974A1 (en) 1988-11-02 1990-05-17 Genentech, Inc. Method for the treatment of periodontal disease
US5162430A (en) 1988-11-21 1992-11-10 Collagen Corporation Collagen-polymer conjugates
US5510418A (en) 1988-11-21 1996-04-23 Collagen Corporation Glycosaminoglycan-synthetic polymer conjugates
US5092883A (en) * 1988-12-28 1992-03-03 Eppley Barry L Method for promoting soft connective tissue growth and repair in mammals
WO1990009783A1 (en) 1989-02-22 1990-09-07 Massachusetts Institute Of Technology Delivery system for controlled release of bioactive factors
WO1990013302A1 (en) 1989-04-28 1990-11-15 Brigham And Women's Hospital Novel materials and methods for guided tissue regeneration
US5062845A (en) * 1989-05-10 1991-11-05 Spine-Tech, Inc. Method of making an intervertebral reamer
US5129906A (en) 1989-09-08 1992-07-14 Linvatec Corporation Bioabsorbable tack for joining bodily tissue and in vivo method and apparatus for deploying same
US5067964A (en) * 1989-12-13 1991-11-26 Stryker Corporation Articular surface repair
US5019108A (en) * 1990-02-02 1991-05-28 Bertin Kim C Modular implant
US6413511B1 (en) * 1990-12-20 2002-07-02 University Of Pittsburgh Of The Commonwealth System Of Higher Education Cartilage alterations by administering to joints chondrocytes comprising a heterologous polynucleotide
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
US5853746A (en) * 1991-01-31 1998-12-29 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier
US5206028A (en) 1991-02-11 1993-04-27 Li Shu Tung Dense collagen membrane matrices for medical uses
DK0590015T3 (da) * 1991-06-17 2000-11-06 Pharmacia & Upjohn Ab Sammensætning til vævsbehandling omfattende fibrin eller fibrinogen og bionedbrydelig og bioforligelig polymer
FR2679778B1 (fr) 1991-08-02 1995-07-07 Coletica Utilisation de collagene reticule par un agent de reticulation pour la fabrication d'une membrane suturable, biocompatible, a resorption lente, ainsi qu'une telle membrane.
US5259835A (en) * 1991-08-29 1993-11-09 Tri-Point Medical L.P. Wound closure means and method using flowable adhesive
US5270300A (en) * 1991-09-06 1993-12-14 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone
GB2263407B (en) * 1992-01-21 1996-08-07 Simcha Milo A punch or device for opening passages between two compartments
DE69307299T2 (de) * 1992-02-14 1997-04-30 Univ Texas Mehrphasiges, biologisch abbaubares implantat/träger und verfahren zu seiner herstellung
US5326357A (en) 1992-03-18 1994-07-05 Mount Sinai Hospital Corporation Reconstituted cartridge tissue
WO1994000484A1 (en) * 1992-06-22 1994-01-06 Young Henry E Scar inhibitory factor and use thereof
WO1994009118A1 (en) 1992-10-13 1994-04-28 The General Hospital Corporation Immortalized human chondrocytes
US5455597A (en) * 1992-12-29 1995-10-03 Canon Kabushiki Kaisha Image-forming apparatus, and designation of electron beam diameter at image-forming member in image-forming apparatus
DE4300039C1 (de) 1993-01-04 1994-06-09 Imz Fertigung Vertrieb Befestigungsnagel und Setzwerkzeug hierfür
DE4306661C2 (de) 1993-03-03 1995-04-20 Michael Dipl Biol Sittinger Verfahren zum Herstellen eines Implantates aus Zellkulturen
DE4431598C2 (de) 1993-03-03 1997-03-20 Michael Sittinger Verfahren zum Herstellen eines Implantates aus Zellkulturen
DE4317448A1 (de) * 1993-05-19 1994-11-24 Gross Ulrich Gelenkflächenersatz
CA2130295A1 (en) 1993-08-26 1995-02-27 Richard A. Berg Ionically crosslinked glycosaminoglycan gels for soft tissue augmentation and drug delivery
US5423858A (en) 1993-09-30 1995-06-13 United States Surgical Corporation Septoplasty fasteners and device for applying same
GB9400163D0 (en) 1994-01-06 1994-03-02 Geistlich Soehne Ag Membrane
US5354283A (en) 1994-01-07 1994-10-11 Little Rapids Corporation Trocar retention apparatus
CA2142209A1 (en) 1994-03-29 1995-09-30 George H. Chu Collagen implants having improved tensile properties
WO1995030742A1 (en) * 1994-05-05 1995-11-16 Genzyme Corporation Methods and compositions for the repair of articular cartilage defects in mammals
EP0692227A1 (de) 1994-07-11 1996-01-17 SULZER Medizinaltechnik AG Flächiges Implantat
EP0804127A1 (en) 1994-07-28 1997-11-05 Ronald Noseworthy Bioprosthetic implants and method of making and using same
US5769899A (en) 1994-08-12 1998-06-23 Matrix Biotechnologies, Inc. Cartilage repair unit
DE4425456A1 (de) * 1994-09-07 1996-03-21 Matthias Dr Med Honl Radialparalleles Knochensägeblatt
US5569252A (en) 1994-09-27 1996-10-29 Justin; Daniel F. Device for repairing a meniscal tear in a knee and method
US5713374A (en) 1995-02-10 1998-02-03 The Hospital For Joint Diseases Orthopaedic Institute Fixation method for the attachment of wound repair materials to cartilage defects
US6080194A (en) 1995-02-10 2000-06-27 The Hospital For Joint Disease Orthopaedic Institute Multi-stage collagen-based template or implant for use in the repair of cartilage lesions
GB9503492D0 (en) 1995-02-22 1995-04-12 Ed Geistlich S Hne A G F R Che Chemical product
US6132463A (en) * 1995-05-19 2000-10-17 Etex Corporation Cell seeding of ceramic compositions
WO1997004665A1 (en) 1995-07-31 1997-02-13 Alta Spinner Australia Pty. Limited Surface moisture removal from food products
US5659252A (en) * 1995-08-25 1997-08-19 Sony Corporation Apparatus and method for detecting arcing in a CRT
EP0801676A2 (de) 1995-10-20 1997-10-22 Gerd R. Burmester Neue künstliche gewebe, verfahren zu ihrer herstellung und ihre verwendung
DE19540487A1 (de) 1995-10-20 1997-04-24 Olaf Schultz Zellinteraktionssystem zur Induktion künstlicher Gewebe
DE19601477C2 (de) 1996-01-17 1999-12-16 Axel Kirsch Befestigungsnagel
US5842477A (en) 1996-02-21 1998-12-01 Advanced Tissue Sciences, Inc. Method for repairing cartilage
DE19654884C2 (de) 1996-03-04 1999-07-29 Kirsch Axel Formkörper
WO1997046665A1 (de) 1996-06-04 1997-12-11 Sulzer Orthopedics Ltd. Verfahren zur herstellung von knorpelgewebe und von implantaten
US5989269A (en) * 1996-08-30 1999-11-23 Vts Holdings L.L.C. Method, instruments and kit for autologous transplantation
EP0842670A1 (en) 1996-11-13 1998-05-20 ISE International Co., Ltd. Biomedical materials
US6187053B1 (en) 1996-11-16 2001-02-13 Will Minuth Process for producing a natural implant
DE19648876C2 (de) 1996-11-16 1999-10-07 Will Minuth Verfahren zum Herstellen eines natürlichen Implantats
WO1998035653A1 (en) 1997-02-13 1998-08-20 Benedict, James, A. Implantable collagen-containing putty material
GB9721585D0 (en) 1997-10-10 1997-12-10 Geistlich Soehne Ag Chemical product
DE19957388A1 (de) 1999-11-24 2001-06-13 Michael Sittinger Chondroinduktive und implantierbare Substrate zur Knorpelheilung und -protektion
DE10006822A1 (de) 2000-02-08 2001-08-23 Michael Sittinger Künstliche Knochenchips, Verfahren zu ihrer Herstellung und ihre Verwendung

Also Published As

Publication number Publication date Type
US6283980B1 (en) 2001-09-04 grant
US7048750B2 (en) 2006-05-23 grant
EP1006950B1 (en) 2004-04-07 grant
DE69726896T2 (de) 2004-10-28 grant
US5989269A (en) 1999-11-23 grant
US20020116014A1 (en) 2002-08-22 application
US20060195122A1 (en) 2006-08-31 application
KR20030097603A (ko) 2003-12-31 application
CN1241918A (zh) 2000-01-19 application
CA2264138A1 (en) 1998-03-05 application
US20020091396A1 (en) 2002-07-11 application
EP1006950A2 (en) 2000-06-14 application
US6379367B1 (en) 2002-04-30 grant
US20020151912A1 (en) 2002-10-17 application
US6592598B2 (en) 2003-07-15 grant
CA2419644A1 (en) 1998-03-05 application
US20030195532A1 (en) 2003-10-16 application
US6599301B2 (en) 2003-07-29 grant
DE69728569D1 (de) 2004-05-13 grant
RU2002103570A (ru) 2003-10-10 application
RU2214197C2 (ru) 2003-10-20 grant
WO1998008469A3 (en) 1998-04-23 application
EP1384452B1 (en) 2009-04-15 grant
DE29724585U1 (de) 2002-05-16 grant
DE69726896D1 (de) 2004-01-29 grant
DK1384452T3 (da) 2009-07-27 grant
JP2007296371A (ja) 2007-11-15 application
EP1181908B1 (en) 2003-12-17 grant
JP2003159266A (ja) 2003-06-03 application
US6599300B2 (en) 2003-07-29 grant
ES2211722T3 (es) 2004-07-16 grant
ES2218697T3 (es) 2004-11-16 grant
US20020116015A1 (en) 2002-08-22 application
JP2002502272A (ja) 2002-01-22 application
ES2325206T3 (es) 2009-08-28 grant
CA2264138C (en) 2003-05-27 grant
KR100686412B1 (ko) 2007-02-23 grant
KR20000035886A (ko) 2000-06-26 application
DK200200177U1 (da) 2002-06-04 application
DE69739363D1 (de) 2009-05-28 grant
DK1006950T3 (da) 2004-07-19 grant
DK1181908T3 (da) 2004-04-13 grant
US6592599B2 (en) 2003-07-15 grant
EP1181908A1 (en) 2002-02-27 application
DE69728569T2 (de) 2005-04-07 grant
EP1459709A1 (en) 2004-09-22 application
CN1500447A (zh) 2004-06-02 application
EP1384452A1 (en) 2004-01-28 application
CA2419644C (en) 2009-10-13 grant
DK200200178U1 (da) 2002-06-04 application
WO1998008469A2 (en) 1998-03-05 application

Similar Documents

Publication Publication Date Title
Marlovits et al. Cartilage repair: generations of autologous chondrocyte transplantation
Glowacki et al. Collagen scaffolds for tissue engineering
Buckwalter et al. Articular cartilage repair and transplantation
US7901461B2 (en) Viable tissue repair implants and methods of use
US7156880B2 (en) Devices and methods for treating defects in the tissue of a living being
US5713374A (en) Fixation method for the attachment of wound repair materials to cartilage defects
US7476250B1 (en) Semi-permeable membranes to assist in cartilage repair
Robinson et al. Regenerating hyaline cartilage in articular defects of old chickens using implants of embryonal chick chondrocytes embedded in a new natural delivery substance
Iwasa et al. Clinical application of scaffolds for cartilage tissue engineering
US8834568B2 (en) Surgical technique using a contoured allograft cartilage as a spacer of the carpo-metacarpal joint of the thumb or tarso-metatarsal joint of the toe
US6623963B1 (en) Cellular matrix
US6419702B1 (en) Treating degenerative disc disease through transplantation of the nucleus pulposis
US20050222687A1 (en) Cartilage implant assembly and method for implantation
US5855608A (en) Device and methods for in vivo culturing of diverse tissue cells
US20050064042A1 (en) Cartilage implant plug with fibrin glue and method for implantation
Driesang et al. Delamination rates of tissue flaps used in articular cartilage repair
US20070275032A1 (en) Use Of A Mixture For The Production Of An Agent For Treating Defective Or Degenerated Cartilage In The Production Of Natural Cartilage Replacement In Vitro
US20040006393A1 (en) Implantable prosthetic knee for lateral compartment
US6964685B2 (en) Biologic replacement for fibrin clot
US6884621B2 (en) Method and carrier for culturing multi-layer tissue in vitro
US20070128155A1 (en) Cartilage repair methods
US7468192B2 (en) Method for repair of cartilage lesions
US20090112315A1 (en) Medical implants and methods for delivering biologically active agents
US20050177118A1 (en) Resorbable polymeric device for localized drug delivery
US20040197311A1 (en) Device for regeneration of articular cartilage and other tissue

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C10 Entry into substantive examination
C41 Transfer of patent application or patent right or utility model
ASS Succession or assignment of patent right

Owner name: VICTORIA REAGAN INTERNATIONAL TRANSPLANTATION SER

Free format text: FORMER OWNER: VTS HOLDINGS, LTD.

Effective date: 20010725

C14 Grant of patent or utility model
CF01