DK154892B - BONE COMPOSITION MATERIAL WITH IMPROVED BIOLOGICAL STABILITY BASED ON MODIFIED COLLAGEN - Google Patents
BONE COMPOSITION MATERIAL WITH IMPROVED BIOLOGICAL STABILITY BASED ON MODIFIED COLLAGEN Download PDFInfo
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- DK154892B DK154892B DK530279AA DK530279A DK154892B DK 154892 B DK154892 B DK 154892B DK 530279A A DK530279A A DK 530279AA DK 530279 A DK530279 A DK 530279A DK 154892 B DK154892 B DK 154892B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/365—Bones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
Abstract
Description
iin
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Opfindelsen angår et knogleerstatningsmateriale med forbedret biologisk stabilitet på basis af modificeret collagen.The invention relates to a bone substitute material with improved biological stability based on modified collagen.
I kirurgien er det gang på gang nødvendigt at forsyne knogledefekter med et fyldmateriale. Dette er frem for alt nødven-5 digt efter ulykker med kvæstelser, som har ført til knoglebrud med knoglematerialetab eller knogledeformation. Der findes dog talrige yderligere anvendelser som f.eks. defektfyldning efter fjernelse af knogletumorer eller tømning af knoglecyster. Yderligere bliver et knoglefyldmateriale nødvendigt i de til-10 fælde, hvor kirurgen i forbindelse med korrekturforanstaltninger på knogler må udfylde et allerede tilstedeværende eller af kirurgen selv tilvejebragt hulrum.In surgery, it is necessary time and again to provide bone defects with a filling material. This is especially necessary after accidents involving injuries that have resulted in bone fractures with bone loss or bone deformation. However, there are numerous additional uses such as e.g. defective filling after removal of bone tumors or emptying of bone cysts. In addition, a bone filling material becomes necessary in cases where the surgeon, in connection with bone correction measures, must fill a cavity already present or by the surgeon himself.
Ifølge det nuværende stade af den kirurgiske teknik er det bedst egnede materiale autologe spongiosa eller en autolog 15 kortiko spongiøs spån (Litteratur: Unfallheilkunge, 81, 565 -567 (1978)). I dette tilfælde er modtageren tillige knogledonoren.According to the present state of the surgical technique, the most suitable material is autologous spongiosa or an autologous corticoid spongiose chip (Literature: Unfallheilkunge, 81, 565-567 (1978)). In this case, the recipient is also the bone donor.
Overføringen af humane knogler fra en person til en anden, den homologe transplantation, er ligeledes almindelig. Her-20 til er der enkelte steder oprettet knoglebanker, som holder egnet materiale parat. Desuden er overføringen af dyreknog-ler, som blev underkastet en egnet tilberedningsbehandling som f.eks. indlejring i cialitopløsning eller ifølge den i DE-PS 961.654 angivne fremgangsmåde, kendt og almin-25 delig.The transfer of human bones from one person to another, the homologous transplant, is also common. Here-and-there are some places where bone banks have been set up that keep suitable material ready. In addition, the transfer of animal bones that were subjected to a suitable preparation treatment, e.g. embedding in cialite solution or according to the method disclosed in DE-PS 961.654, known and common.
De bedste kirurgiske egenskaber på implantationsområdet er hidtil uden tvivl blevet opnået, når man også har udtaget knoglerne fra den samme patient , som skal have dette materiale (autolog transplantation).The best surgical properties in the field of implantation have so far been achieved, when the bones have also been taken from the same patient who will have this material (autologous transplant).
30 Herved findes to forskellige ulemper: 230 Here are two distinct disadvantages: 2
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1. Knogleerstatningsmaterialet skal her udvindes ved en yderligere operation. Det yderligere operative indgreb fører til en forlængelse af den samlede opera tionstid, hvilket for patienten kan være meget uheldigt^ i nogle tilfælde endog livs- 5 truende. Dette rammer specielt hårdt kvæstede gamle mennesker eller af andre almene sygdomme, der er uafhængige af det nødvendige kirurgiske indgreb, forbelastede mennesker. Den yderligere operation fører desuden til større blodtab og er ubehagelig for de ramte mennesker på grund af smerterne, som op-10 står. Desuden giver hvert operative indgreb en risiko for komplikationer, som yderligere i enkelte tilfælde ikke altid forudseeligt kan bevirke yderligere skader.1. The bone replacement material must be extracted here by a further operation. The further operative intervention leads to an extension of the total operation time, which for the patient can be very unfortunate ^ in some cases even life threatening. This affects especially severely injured old people or other people who are independent of the necessary surgical procedure, pre-stressed people. The additional surgery also leads to greater blood loss and is uncomfortable for the affected people due to the pain that ups 10. In addition, every surgical procedure presents a risk of complications which, in some cases, may not always foresee further damage.
2. Den til rådighed værende mængde autologe knogler er begrænset. Den eksisterende reserve udgøres af bækkenkammene i 15 begge sider, ribbenene, skinnebenshovedet og de til legemet ikke fæstnede dele af spolebenet. Selv den fuldstændige udnyttelse af disse kilder, som så nødvendiggør flere operative indgreb, giver ikke i alle tilfælde en tilstrækkelig mængde knogleerstatningsmateriale. Såfremt behovet er større, er lægen, som foretager 20 det operative indgreb, tvunget til enten ikke.‘at· .anvende tilstrækkelige mængder knogleerstatningsmateriale eller at gribe til anvendelsen af mindre velegnede knogler fra andre mennesker eller fra dyr.2. The amount of autologous bone available is limited. The existing reserve is made up of the pelvic ridges on both sides, the ribs, the tibia head and the parts of the coil bone not attached to the body. Even the full utilization of these sources, which then necessitates multiple surgical interventions, does not in all cases provide a sufficient amount of bone replacement material. If the need is greater, the physician performing the surgical procedure is either forced not to use sufficient amounts of bone replacement material or to resort to the use of less suitable bones by other people or animals.
Ved den homologe knogletransplantation fra et menneske til et 25 andet bliver transplantatet ofte ikke optaget acceptabelt af modtageren. Ansvarlig herfor er frem for alt dannelsen af modstoffer mod fremmedæggehvide. Egnet materiale kan desuden kun vanskeligt tilvejebringes. I reglen må man gribe til anvendelsen af fra lig udtagne knogler, som allerede har kraftigt re-30 duceret værdi. Overføringen af infektioner til modtageren er ikke udelukket.In the homologous bone graft from one human to another, the graft is often not accepted acceptably by the recipient. Responsible for this is, above all, the formation of antidotes against foreign egg whites. In addition, suitable material can only be difficult to provide. As a rule, one must resort to the use of equally removed bones, which have already greatly reduced value. The transmission of infections to the recipient is not excluded.
Mangeårig anvendelse heterologt transplantationsmateriale, f.eks. det fra DE-patentskrift 96 .654 kendte Kieler Knochen-span har vist, at dette materiale af nogle patienter ikke 3Many years of use heterologous transplant material, e.g. the Kieler Knochen-span known from DE patent 96,665 has shown that this material by some patients does not 3
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blev optaget tilfredsstillende. De af kirurgen indførte knoglestykker blev hyppigt ikke omdannet til levende knoglevæv, men blev liggende i vævet som dødt materiale.was admitted satisfactorily. Frequently, the pieces of bone inserted by the surgeon were not transformed into living bone tissue, but remained in the tissue as dead material.
5 Formålet med opfindelsen er derfor at tilvejebringe et hidtil ukendt knogleerstatningsmateriale, som står til rådighed i ønsket mængde, ikke danner antistoffer ved implantation i et menneskes eller dyrs legeme, har god vævsforligelighed og efter implantering i legemet bliver ombygget til knoglevæv.The object of the invention is therefore to provide a novel bone replacement material which is available in the desired amount, does not form antibodies by implantation in a human or animal body, has good tissue compatibility, and after implantation in the body is converted to bone tissue.
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Dette opnås med de i kravene definerede materialer.This is achieved with the materials defined in the claims.
Som udgangsmateriale for knogleerstatningsmaterialet ifølge opfindelsen tjener knogler og specielt bovint knoglemateriale, 15 f.eks. fra kalv. Der kan dog også anvendes andre udgangsmaterialer, såsom humane knogler eller lignende collagenholdigt materiale fra andre dyr. Nedenfor belyses fremgangsmåden til fremstillingen af knogleerstatningsmaterialet ifølge opfindelsen ved hjælp af kalveknogler som udgangsmateriale.As the starting material for the bone substitute material according to the invention, bones and especially bovine bone material, e.g. from calf. However, other starting materials such as human bones or similar collagen-containing material from other animals may also be used. Below, the process for preparing the bone substitute material of the invention is illustrated by using calf bones as the starting material.
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Fremgangsmåden udgør en kombination af forskellige trin, som skal gennemføres i den anførte rækkefølge for at opnå knogleerstatningsmaterialet ifølge opfindelsen med forbedret biologisk stabilitet.The process constitutes a combination of different steps to be performed in the order listed to obtain the bone substitute material of the invention with improved biological stability.
25 I et første trin udvandes knoglerne i et vist tidsrum til fjernelse af blodfarvestoffet og andre vandopløselige proteiner. Dette tidsrum udgør fortrinsvis 2-3 dage. Ved denne udvanding bliver vaskevæsken hyppigt fornyet. Udvandingen kan også gen-30 nemføres som udvanding med strømmende vand. En særlig temperatur er ikke nødvendig, dog udvandes der hensigtsmæssigt ved omgivelsernes temperatur.In a first step, the bones are diluted for a certain period of time to remove the blood dye and other water-soluble proteins. This period is preferably 2-3 days. During this dilution, the washing liquid is frequently renewed. The dilution can also be carried out as dilution with flowing water. A special temperature is not necessary, however, it is conveniently diluted at ambient temperature.
Et andet trin tjener til fjernelse af yderligere ikke vandop-35 løselige proteinmængder. Det er vigtigt, at fremmede proteiner uden for collagenet som f.eks. knogleceller bliver fjernet for at undgå modreaktioner på grund af antistofdannelse også af enzymatisk art. Fjernelsen af proteinandele i dette trinAnother step serves to remove additional non-water-soluble protein amounts. It is important that foreign proteins outside the collagen such as Bone cells are removed to avoid back reactions due to antibody formation also of enzymatic nature. The removal of protein shares in this step
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4 - . - sker ved indlejring af knoglematerialet i en ^(^-opløsning. Denne E^C^-opløsning skal udvise en koncentration på over 10%. Behandlingens varighed udgør normalt 2-3 dage.4 -. - occurs by embedding the bone material in a ^ (^ solution. This E ^ C ^ solution must exhibit a concentration above 10%. The duration of treatment usually lasts 2-3 days.
Også her må opløsningen fornyes flere gange for at sikre en 5 fuldstændig fjernelse af æggehvideandelene.Here, too, the solution must be renewed several times to ensure a complete removal of the egg white proportions.
Det tredje fremstillingstrin består igen i et skylningstrin, i hvilket det i andet trin opnåede materiale bliver udvandet med koldt vand til udvaskning og bortførelse af de opløste bløddele. Det er her af fordel at anvende strømmende vand.The third manufacturing step again consists of a rinsing step in which the material obtained in the second step is diluted with cold water to leach and remove the dissolved soft parts. It is advantageous here to use running water.
10 I det fjerde fremstillingstrin affedtes det således opnåede materiale. Affedtningen sker ved hjælp af organiske opløsningsmidler. Egnede opløsningsmidler er f.eks. acetone eller ether eller specielt en kombination af disse opløsningsmidler. Affedtningen kan gennemføres· i et vilkårligt dertil egnet appa-15 ratur. Et Soxhlet-apparatur er særligt egnet til denne affedtning.In the fourth preparation step, the material thus obtained is degreased. Degreasing is done using organic solvents. Suitable solvents are e.g. acetone or ether or especially a combination of these solvents. The degreasing can be carried out in any suitable apparatus. A Soxhlet apparatus is particularly suitable for this degreasing.
I fremgangsmådens femte trin behandles det i fjerde trin opnåede materiale ved hjælp af kompleksdannere eller ionbyttere. Dette trin tjener det formål at eliminere knoglens mineralandel ved kompleksdannelse. Saltene af ethylendiamintetraeddikesyre 20 er egnede kompleksdannere.In the fifth step of the process, the material obtained in the fourth step is processed by complexing agents or ion exchangers. This step serves the purpose of eliminating bone mineral content by complexing. The salts of ethylenediaminetetraacetic acid 20 are suitable complexing agents.
Et til afkalkning egnet opløsningsmiddel kan fremstilles ifølge en i Remeis "Lehrbuch der mikroskopischen Technik" angivet fremgangsmåde. Derved behandles 250 g dinatriumethylendiamintetraeddikesyre med 200 ml destilleret vand, og der opvarmes. Under vedvarende 25 omrøring tilsættes 50 ml af en 40%ig natriumhydroxid, og det hele suppleres med destilleret vand til 800 ml. Ved tildryp-ning af 40%ig natriumhydroxid indstilles pH-værdien på 7,4, og det samlede volumen indstilles på 1000 ml med destilleret vand.A solvent suitable for decalcification can be prepared according to a method specified in Remeis "Lehrbuch der microscopischen Technik". Thereby, 250 g of disodium ethylenediaminetetraacetic acid is treated with 200 ml of distilled water and heated. With continuous stirring, 50 ml of a 40% sodium hydroxide is added and the whole is supplemented with distilled water to 800 ml. By adding 40% sodium hydroxide, the pH is adjusted to 7.4 and the total volume is adjusted to 1000 ml with distilled water.
30 Knoglematerialet anbringes i en sådan, opløsning og forbliver d&ri et lamgere tidsrum, f.eks. i flere uger, indtil der er dannet et kautsjukagtigt elastisk produkt.The bone material is placed in such a solution and remains for a longer period of time, e.g. for several weeks until a rubbery elastic product is formed.
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Det således opnåede kautsjukagtige elastiske produkt vaskes i et sjette fremstillingstrin på ny for at fjerne de tilstedeværende saltrester. Vaskningen sker i strømmende vand i et tilstrækkeligt tidsrum som f.eks. 2-3 dage.The rubbery elastic product thus obtained is washed again in a sixth manufacturing step to remove the salt residues present. The washing takes place in flowing water for a sufficient period of time, e.g. 2-3 days.
5 Det derved opnåede materiale underkastes så i et syvende fremstillingstrin eventuelt en frysetørring på sædvanlig måde.The material thus obtained is then subjected, in a seventh manufacturing step, to a freeze drying in the usual manner.
Det opnåede materiale underkastes så i et ottende fremstillingstrin den sædvanlige sterilisation, specielt strålesterilisa-10 tionen. Strålesterilisationen kan ske med sædvanlige doser, f. eks. med en dosis på 2,5 megarad.The material obtained is then subjected to the usual sterilization, especially the radiation sterilization, in an eighth manufacturing step. The radiation sterilization can be done at usual doses, eg with a dose of 2.5 megarad.
Ved den ovenfor beskrevne kombinationsmetode er trinene 1-4 og trin 5 i og for sig kendte. Ganske vist bliver der ifølge DE-patentskrift 961.654 efter arbejdstrin 3 indskudt et tørringstrin, som gen-15 nemføres ved højst 40°C i løbet af et tidsrum på 12-24 timer.By the combination method described above, steps 1-4 and step 5 are known per se. Of course, according to DE patent 961.654, after working step 3, a drying step is carried out which is carried out at a maximum of 40 ° C over a period of 12-24 hours.
Ved den foreliggende fremgangsmåde skal dette tørringstrin ikke anvendes, da man ellers ikke kommer til det opfinderiske resultat. Det er altså væsentligt, at efter fremstillingstrin 3, d.v.s. udvandingen, gennemføres det i og for sig kendte 20 arbejdstrin 4 uden et tørringstrin, d.v.s. affedtningen med organiske opløsningsmidler.In the present process, this drying step is not to be used, otherwise the inventive result will not be reached. Thus, it is essential that after preparation step 3, i.e. the dilution, the 20 known working steps 4 are carried out without a drying step, i.e. degreasing with organic solvents.
Fremgangsmådetrinet 5 kendes som sådant, f.eks. fra den nævnte Lehrbuch der mikroskopischen Technik” af Romeis. Derimod kendes kombinationen af fremgangsmådetrinene 1-4 ifølge 25 den foreliggende ansøgning med fremgangsmådetrin 5 ifølge ansøgningen ikke.The process step 5 is known as such, e.g. from the said Lehrbuch der microscopische Technik ”by Romeis. In contrast, the combination of process steps 1-4 of the present application with method steps 5 of the application is not known.
Ved fremgangsmådetrinene 6-8 drejer det sig om sædvanlige i og for sig kendte fremgangsmådetrin. Dog kendes heller ikke disse trin i kombination med fremgangsmådetrinene 1-5 ifølge 30 den foreliggende ansøgning.The process steps 6-8 are the usual process steps known per se. However, these steps are also not known in combination with the process steps 1-5 of the present application.
Ved den opfinderiske kombination af de hver for sig i og for sig kendte enkelt-fremgangsmådetrin er det blevet muligt atIn the inventive combination of the individually known single process steps, it has become possible to
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opnå et knogleerstatningsmateriale af renset collagen og specielt kalvecollagen, som ved omhyggelig undgåelse af alle skadelige faktorer, son f.eks. syre ved afkalkningsprocessen, i vid udstrækning fås i dets molekylstruktur, idet der ikke sker nogen nedbrydning af collagen på grund af hydrolyse.obtain a bone replacement material of purified collagen and especially calf collagen, which by careful avoidance of all harmful factors, e.g. acid in the descaling process, is largely obtained in its molecular structure, with no collagen degradation due to hydrolysis.
5 Det således opnåede grundmateriale viser ved implantationen i legemet som knogleerstatningsmateriale forbavsende gode egenskaber. F.eks. er resorptionstiden væsentligt højere end ved andre kendte materialer. Desuden har finvævsundersøgelser, som blev udtaget efter implantation i forsøgsdyr på forskellige 10 tidspunkter, vist en fremragende forligelighed uden udstødningsreaktioner af legemet. Allerede efter 14 dages forløb kunne der påvises en begyndende omdannelse i knoglevævet. Finvævsundersøgelser viste indlejringer af mineralstof, bindevævceller, indribbede blodkar og knogledannende celler.5 The base material thus obtained shows by the implantation in the body as bone replacement material astonishingly good properties. Eg. the resorption time is substantially higher than that of other known materials. In addition, fine tissue examinations taken after implantation in test animals at various times have shown excellent compatibility without ejection reactions of the body. Already after 14 days, a beginning transformation in the bone tissue could be detected. Fine tissue studies showed deposits of mineral substance, connective tissue cells, embedded blood vessels, and bone-forming cells.
15 Det på ovennævnte måde opnåede grundmateriale kan med hensyn til dets fremragende egenskaber som knogleerstatningsmateriale endnu forbedres væsentligt, når man blander dette materiale med en ringe mængde af hormonet calcitonin, også benævnt thyreo-calcitonin. Hertil egner sig f.eks. i handelen værende calci-20 toninopløsninger. Det væsentligt forbedrede resultat tillader den slutning, at det her drejer sig om en synergistisk virkning mellem knogleerstatningsgrundmaterialet og hormonet calcitonin. Knoglenydannelsestiden kan med et sådant med calcitonin behandlet knogleerstatningsmateriale forkortes væsentligt 25 mere..The basic material obtained in the above-mentioned manner, with respect to its excellent properties as a bone substitute material, can still be substantially improved by mixing this material with a small amount of the hormone calcitonin, also known as thyroid calcitonin. For example, suitable for this purpose. commercially available calcium-20 tonin solutions. The significantly improved result allows the conclusion that this is a synergistic effect between the bone substitute and the hormone calcitonin. The bone formation time with a bone substitute treated with calcitonin can be significantly shortened 25 more.
Opfindelsen belyses nærmere ved hjælp af det efterfølgende udførelseseksempel .The invention is further elucidated by means of the following exemplary embodiment.
Eksempel 1 kg kalveknogler (spongiosastykke) vaskes omhyggeligt og be-30 fries så for grove blodrester. Denne knoglemængde anbringes så i et egnet kar med til- og fraløbsmuligheder og gennemskylles . så i 72 timer ved hjælp af s tremmende ledningsvand (trin 1). Knogle- 7Example 1 kg calf bone (spongiosis piece) is washed thoroughly and then frozen for coarse blood residue. This bone quantity is then placed in a suitable vessel with inlet and outlet options and flushed. then for 72 hours using s teasing tap water (step 1). Bone 7
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mængden anbringes så i en H202~opløsning (15%) i 72 timer. Opløsningen udskiftes 3-4 gange (trin 2). Behandlingen med flydende ledningsvand gentages så i 24 timer (trin 3). Derpå foretages affedtningen i et Soxhlet-apparat med 60% acetone og 5 40% diethylether i løbet af ca. 12 timer (trin 4).the amount is then placed in a H 2 O 2 solution (15%) for 72 hours. The solution is replaced 3-4 times (step 2). The liquid tap water treatment is then repeated for 24 hours (step 3). The degreasing is then carried out in a Soxhlet apparatus with 60% acetone and 40% diethyl ether over approx. 12 hours (step 4).
1250 g dinatriumethylendiamintetraeddikesyre behandles med 1000 ml destilleret H2O og opvarmes. Under vedvarende omrøring tilsættes 200 ml NaOH (40%) og derpå suppleres med destilleret 10 vand til 4000 ml. Ved dråbevis tilsætning af 40%ig NaOH indstilles pH-værdien på 7,4, og der suppleres til 5000 ml med destilleret vand.1250 g of disodium ethylenediaminetetraacetic acid are treated with 1000 ml of distilled H 2 O and heated. With continued stirring, 200 ml of NaOH (40%) is added and then supplemented with distilled water to 4000 ml. By the dropwise addition of 40% in NaOH, the pH is adjusted to 7.4 and supplemented with 5000 ml with distilled water.
I den således opnåede opløsning anbringes de som ovenfor be-15 skrevet behandlede knogler, indtil flere udtagne prøver viser sig at være mineralfri. Ved stuetemperatur kræves hertil alt efter enkeltstykkernes størrelser ca. 3-4 uger (trin 5).In the solution thus obtained, place the treated bones as described above until several samples taken are found to be mineral-free. At room temperature, depending on the sizes of the individual pieces, approx. 3-4 weeks (step 5).
Dernæst vaskes ved hjælp af strømmende vand for at fjerne 20 restsalte (trin 6). Derpå frysetørres (trin 7). Efter egnet folieemballering steriliseres derpå ved bestråling med 2,5 me-garad (trin 8).Next, wash with running water to remove 20 residual salts (step 6). Then freeze-dry (step 7). After suitable foil packaging is then sterilized by irradiation with 2.5 meGarad (step 8).
I det følgende beskrives forsøg og resultaterne heraf, i hvil-25 ke forsøg der er blevet implanteret knogleerstatningsmateriale ifølge opfindelsen.In the following, experiments and the results thereof are described in which experiments have been implanted bone replacement material according to the invention.
Knogleerstatningsmaterialet ifølge eksemplet blevfpå rotter og kaniner afprøvet med hensyn til dets egenskaber.The bone substitute material of the example was then rats and rabbits tested for its properties.
3030
Collagenmatrixen blev implanteret under huden xrg i dyrenes rygmuskulatur. Ved forskellige grupper blev implamtaterne udtaget og undersøgt histologisk efter 1,2,4,8 og '1*2 ugers foi— løb.The collagen matrix was implanted under the skin xrg in the animals' back muscles. In various groups, the implants were sampled and histologically examined after 1,2,4,8 and 1 * 2 weeks.
3535
Efter 1 uges forløb kunne der allerede konstateres indvoksning af de fineste blodkar og celler.After 1 week, the finest blood vessels and cells could already be detected.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2854490A DE2854490C2 (en) | 1978-12-16 | 1978-12-16 | Bone substitute material with improved biological stability based on collagen |
| DE2854490 | 1978-12-16 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK530279A DK530279A (en) | 1980-06-17 |
| DK154892B true DK154892B (en) | 1989-01-02 |
| DK154892C DK154892C (en) | 1989-06-05 |
Family
ID=6057451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK530279A DK154892C (en) | 1978-12-16 | 1979-12-13 | BONE COMPOSITION MATERIAL WITH IMPROVED BIOLOGICAL STABILITY BASED ON MODIFIED COLLAGEN |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0012959B1 (en) |
| JP (1) | JPS5584161A (en) |
| AT (1) | ATE944T1 (en) |
| CA (1) | CA1142430A (en) |
| DE (2) | DE2854490C2 (en) |
| DK (1) | DK154892C (en) |
| ES (1) | ES486893A1 (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4430760A (en) * | 1981-12-18 | 1984-02-14 | Collagen Corporation | Nonstress-bearing implantable bone prosthesis |
| DE3124981A1 (en) * | 1981-06-25 | 1983-01-13 | Dr. Ruhland Nachfolger GmbH, 8425 Neustadt | ACTIVE INGREDIENT COLLAGEN INSERT FOR INSERTION INTO BONES OR SOFT PARTS AND METHOD FOR THEIR PRODUCTION |
| ATE31616T1 (en) * | 1983-10-20 | 1988-01-15 | Oscobal Ag | BONE REPLACEMENT MATERIAL BASED ON NATURAL BONES. |
| US4789663A (en) * | 1984-07-06 | 1988-12-06 | Collagen Corporation | Methods of bone repair using collagen |
| JPS6162459A (en) * | 1984-07-06 | 1986-03-31 | コラ−ゲン コ−ポレイシヨン | Repairing of bone using collagen |
| US5522894A (en) * | 1984-12-14 | 1996-06-04 | Draenert; Klaus | Bone replacement material made of absorbable beads |
| US4627853A (en) * | 1985-05-29 | 1986-12-09 | American Hospital Supply Corporation | Method of producing prostheses for replacement of articular cartilage and prostheses so produced |
| US4678470A (en) * | 1985-05-29 | 1987-07-07 | American Hospital Supply Corporation | Bone-grafting material |
| US5053049A (en) * | 1985-05-29 | 1991-10-01 | Baxter International | Flexible prostheses of predetermined shapes and process for making same |
| AT398373B (en) * | 1987-12-17 | 1994-11-25 | Immuno Ag | BIOLOGICAL RESORBABLE IMPLANTATION MATERIAL AND METHOD FOR PRODUCING THE SAME |
| US4975526A (en) * | 1989-02-23 | 1990-12-04 | Creative Biomolecules, Inc. | Bone collagen matrix for zenogenic implants |
| DE3835237C1 (en) * | 1988-10-15 | 1989-12-28 | B. Braun Melsungen Ag, 3508 Melsungen, De | |
| EP0424159A3 (en) * | 1989-10-19 | 1991-11-06 | Osteotech, Inc., | Aseptic processing of allograft bone and tissue |
| US5531791A (en) * | 1993-07-23 | 1996-07-02 | Bioscience Consultants | Composition for repair of defects in osseous tissues, method of making, and prosthesis |
| DE4425776C2 (en) * | 1994-07-13 | 2002-08-29 | Britta Hofmann | Process for the preparation of an improved collagen graft with a loosened structure |
| IT1268641B1 (en) * | 1994-10-24 | 1997-03-06 | Giuseppe Oliva | INACTIVATION AND ELIMINATION OF ORGANIC MATRIX FROM ANIMAL BONE FOR HETEROTOPICAL XENOTOPLANTS. |
| FR2752382B1 (en) * | 1996-08-16 | 1998-10-09 | Assist Publ Hopitaux De Paris | PROCESS FOR THE TREATMENT OF HUMAN OR ANIMAL PRODUCTS FOR THERAPEUTIC USE |
| US5972368A (en) * | 1997-06-11 | 1999-10-26 | Sdgi Holdings, Inc. | Bone graft composites and spacers |
| DE10157182A1 (en) * | 2001-11-22 | 2003-06-05 | Matricel Gmbh | Process for the treatment of materials of biological origin and elastin product |
| AT413075B (en) * | 2003-02-25 | 2005-11-15 | Austria Wirtschaftsserv Gmbh | METHOD FOR PRODUCING A BONE IMPLANT MATERIAL AND DEVICE FOR CARRYING OUT THIS METHOD |
| GB2431408A (en) * | 2005-10-19 | 2007-04-25 | Osta Technologies Cc | Bone material and a process for the preparation of bone material |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE961654C (en) * | 1954-06-16 | 1957-04-11 | Armin Bauermeister | Process for the preparation of bones suitable for transplantation |
| GB1068587A (en) * | 1963-12-06 | 1967-05-10 | Biorex Laboratories Ltd | Dental fillers and bone cements comprising collagen |
| SU498005A1 (en) * | 1971-08-13 | 1976-01-05 | Центральный научно-исследовательский институт стоматологии | Stimulating anti-inflammatory agent for treatment in dentistry |
-
1978
- 1978-12-16 DE DE2854490A patent/DE2854490C2/en not_active Expired
-
1979
- 1979-12-13 CA CA000341820A patent/CA1142430A/en not_active Expired
- 1979-12-13 DK DK530279A patent/DK154892C/en active
- 1979-12-14 DE DE7979105190T patent/DE2962750D1/en not_active Expired
- 1979-12-14 EP EP79105190A patent/EP0012959B1/en not_active Expired
- 1979-12-14 AT AT79105190T patent/ATE944T1/en not_active IP Right Cessation
- 1979-12-14 ES ES486893A patent/ES486893A1/en not_active Expired
- 1979-12-15 JP JP16344279A patent/JPS5584161A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES486893A1 (en) | 1980-07-01 |
| DK530279A (en) | 1980-06-17 |
| DE2854490B1 (en) | 1980-06-12 |
| JPS5584161A (en) | 1980-06-25 |
| DE2962750D1 (en) | 1982-06-24 |
| JPS619857B2 (en) | 1986-03-26 |
| DK154892C (en) | 1989-06-05 |
| EP0012959B1 (en) | 1982-05-05 |
| DE2854490C2 (en) | 1981-04-09 |
| EP0012959A1 (en) | 1980-07-09 |
| ATE944T1 (en) | 1982-05-15 |
| CA1142430A (en) | 1983-03-08 |
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