EP2515797A1 - Construction de fibres de collagène pour le remplacement de ligaments croisés - Google Patents

Construction de fibres de collagène pour le remplacement de ligaments croisés

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Publication number
EP2515797A1
EP2515797A1 EP10795706A EP10795706A EP2515797A1 EP 2515797 A1 EP2515797 A1 EP 2515797A1 EP 10795706 A EP10795706 A EP 10795706A EP 10795706 A EP10795706 A EP 10795706A EP 2515797 A1 EP2515797 A1 EP 2515797A1
Authority
EP
European Patent Office
Prior art keywords
collagen
construct
cruciate ligament
fiber construct
fibers
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10795706A
Other languages
German (de)
English (en)
Inventor
Daniel Roland Haddad
Meike Haddad-Weber
Ulrich NÖTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CoBaLT Implantate GmbH
Original Assignee
CoBaLT Implantate GmbH
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
Application filed by CoBaLT Implantate GmbH filed Critical CoBaLT Implantate GmbH
Publication of EP2515797A1 publication Critical patent/EP2515797A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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 or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F2/00—Filters 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/08—Muscles; Tendons; Ligaments
    • 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
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/081—Gamma radiation
    • 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
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61L27/3604—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 human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2220/0025—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
    • A61F2220/0075—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements sutured, ligatured or stitched, retained or tied with a rope, string, thread, wire or cable
    • 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
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20—Targets to be treated
    • A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
    • 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
    • A61L2430/10—Materials or treatment for tissue regeneration for reconstruction of tendons or ligaments
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2913—Rod, strand, filament or fiber
    • Y10T428/2915—Rod, strand, filament or fiber including textile, cloth or fabric
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T442/00—Fabric [woven, knitted, or nonwoven textile or cloth, etc.]
    • Y10T442/40—Knit fabric [i.e., knit strand or strip material]

Definitions

  • the present invention relates to a collagen fiber construct of collagen single fibers which is sterilized with alcohol and radiation and not occupied by cells, the collagen single fibers being isolated from mammalian collagen-containing tissue. Furthermore, the present invention relates to a collagen fiber construct wherein the collagen single fibers are isolated from rat tails. In addition, collagen fiber constructs are included, wherein several collagen single fibers are knotted into a collagen thread. In addition, the present invention includes a collagen fiber construct wherein one or more collagen threads are entangled into a collagen cord which, in turn, may be twisted into a collagen cord.
  • the present invention also relates to a method for producing a collagen fiber construct from collagen single fibers which is sterilized with alcohol and radiation and which is not occupied by cells, whereby the collagen single fibers are isolated from collagen-containing tissue from rat tails.
  • the use of the collagen fiber constructs as a xenoimplant is described.
  • the present invention relates to collagen fiber constructs, which are preferably cruciate ligament constructs.
  • the anterior cruciate ligament is one of the main stabilizing structures of the knee joint.
  • VKB injury therefore leads to instability of the joint, leading to damage of the secondary stabilizers (especially the inner meniscus) and eventually to gonarthrosis (Woo, et al, Clin Orthop Relat Res, S312-323 (1999)).
  • the possibilities for spontaneous healing of the band after a rupture are limited. Therefore, various approaches have been followed to replace the damaged cruciate ligament with other structures. From the mid-eighties, allogeneic tendon implants (often implants derived from corpses) were performed.
  • allogeneic implantation the implanted tissue is not from the recipient, but a donor of the same kind.
  • WO 2010/009511 A1 describes a woven collagen construct which is extensively interwoven, sterilized with alcohol and which withstands a maximum tensile load (tensile load strength) of 140 N.
  • the construct described therein has a "planar" character and serves to cover larger areas (e.g., in wound healing).
  • the specified maximum tensile load is far from sufficient. Its in vivo application has not been tested.
  • the technical problem is solved by providing a collagen fiber construct of collagen single fibers which is sterilized with alcohol and / or radiation sterilized and unoccupied with the collagen single fibers isolated from mammalian collagenous tissue.
  • the present invention thus relates to a collagen fiber construct of collagen single fibers, which is sterilized with alcohol and irradiation and is not occupied by cells, wherein the collagen single fibers are isolated from collagen-containing tissue from rat tails.
  • the gist of the invention is the preparation of a collagen fiber construct, preferably a cruciate ligament construct, and in another preferred embodiment, an anterior cruciate ligament construct of mammalian collagen fibers.
  • these cell-free constructs are pathogen-free and immunogen-free. Therefore, the advantage of such constructs over previous autologous therapies is mainly the lack of "donor site morbidity.”
  • an advantage of the construct over allogeneic implants is the lack of risk of rejection and transmission of infectious diseases.
  • a collagen fiber construct shows these advantages. This is, as described in more detail below, made of collagen fibers that have been knotted into a collagen thread (hereinafter referred to as "cruciate ligament type 1") and subsequently knitted into a collagen cord, the cords then being wound several times and finally twisted (US Pat. hereinafter referred to as "cruciate ligament type 2"). It is surprisingly shown that all animals with in particular the collagen fiber construct described above have an intact "cruciate replacement" and that ignore inflammatory reactions.
  • the tear strength of the collagen constructs surprisingly was in the range of the initial tear strength of the constructs prior to implantation or could even be increased.
  • the constructs described herein in contrast to those described in the prior art, are characterized by a consistent tear strength and a very good potential for emolliation.
  • the constructs used are well-accepted by the body of the experimental animals and ligamentization can be observed.
  • collagenous tissue includes not only mammalian tissue and, in a preferred embodiment, rat tails, but also tissue from other organisms and body parts, such as kangaroo, bovine, and tuber In a preferred embodiment, the collagenous tissue is isolated from rat tails.
  • unoccupied does not only include collagen fibers that are completely cell-free or do not carry any cells at all.
  • the term also includes collagen fibers that carry smaller, minimum amounts of cells, whereby this minimum amount is preferably up to a maximum of 1 In a highly preferred embodiment, the minimum amount is up to a maximum of 0.3% of the total collagen mass.
  • the isolation and sterilization of the collagen single fibers and the preparation of the collagen fiber constructs optionally include the following steps: (a) isolating collagenous tissue; (b) withdrawing individual and / or multiple collagen single fibers from the collagenous tissue; (c) incubation of the collagen single fibers in an isotonic or iso-osmolar solution, wherein in a further special embodiment the incubation of the collagen fibers takes place in a 0.9% NaCl solution or phosphate buffered saline (PBS) isotonic or iso-osmolar solution is preferably sterilized; (d) sterilizing the collagen single fibers in alcohol; (e) optionally Repeating the washing and sterilization steps according to items (c) and (d); (f) preparing the collagen fiber constructs described in detail below, or the cruciate ligament types "0", "1", "2", “3” and / or "4"; (g) then sterilizing the collagen fiber construct in alcohol; and (
  • the isolation of collagenous tissue may according to the invention comprise single and / or several of the following steps: (a) washing the rat tails with an isotonic / isoosmolar solution, wherein in a further particular embodiment the washing is carried out in a 0.9% NaCl solution or (B) sterilizing the rat tails with alcohol, wherein the sterilization is preferably carried out with at least 60% alcohol (EtOH) Sterilization is carried out with 60%, 65%, 70%, 75%, 80%, 85% or 90% EtOH
  • EtOH alcohol
  • the rat tails are sterilized with 70% EtOH, but sterilization can also be performed at lower EtOH concentrations such as 45%, 50% or 55%
  • the invention includes a collagen fiber construct wherein the collagen fiber construct in a preferred embodiment is a ligament and / or tendon construct. More preferably, the collagen fiber construct is a cruciate ligament construct.
  • the above-described comprises a collagen fiber construct wherein the collagen single fibers are preferably sterilized with at least 60% EtOH. Sterilization is preferably carried out with 60%, 65%, 70%, 75%, 80%, 85% or 90% EtOH. In a highly preferred embodiment, the collagen single fibers are sterilized with 70% EtOH. Sterilization can also be carried out at lower EtOH concentrations such as 45%, 50% or 55%. In highly preferred embodiments, the present invention encompasses several collagen fiber constructs, which will be referred to and described below as "cruciate ligament type 0", “cruciate ligament type 1", cruciate ligament type 2 ",” cruciate ligament type 3 "and” cruciate ligament type 4 ".
  • the present invention includes a collagen fiber construct ("cruciate support") in which a plurality of single collagen fibers are fixed to a bundle at the ends as described above.
  • the bundle is preferably from 20 to
  • a plurality of bundles are sewn together at the ends
  • the bundles are sewn together at the ends via a so-called "baseball seam”.
  • baseball suture as described herein, is to be understood as follows: The baseball suture is a medical suture technique used, inter alia, in the fixation of cruciate ligament grafts, where the ends are joined together with a continuous suture ( Figure 12).
  • Non-absorbable suture material is used to make the baseball suture, and a baseball stitch is applied at both ends to reinforce the implant by up to 3 cm at both ends
  • the thread with needle comes from underneath the implant, runs over the implant and is inserted again at the outer edge, the thread always comes out at the same angle diagonally downwards again At the end of the implant, it goes back, so that an opposite Mus ter arises.
  • preferably 2 to 30 bundles, more preferably 6 bundles are sewn together.
  • the collagen fiber construct consists of two bundles of preferably 20 to 300 collagen single fibers, more preferably each of 150 collagen single fibers, which are sewn together at a certain angle. In a particular embodiment, the angle is preferably 20 to 45 °.
  • the present invention does not only include the above-described sewing together of the above-described linear bundle constructs, but also applies to all collagen fiber constructs shown below in accordance with the invention, and preferably also the entangled collagen fiber construct described in more detail below. The described embodiments thus apply not only to the collagen fiber constructs specifically described above, but, mutatis mutandis, to all constructs described.
  • the length of the collagen fiber constructs is. preferably the cruciate ligament constructs, preferably 2.5 to 9.0 cm and the diameter 0.6 to 1, 0 cm.
  • the diameter is in the range of 0.6 to 1.2 cm.
  • the diameter is 0.8 cm.
  • the Kollagenmaschinekonstrukt or cruciate ligament construct in the patient or in the joint should preferably be 2.0 to 7.0 cm long, the length may optionally contain parts for anchoring and / or also optionally can be increased by further shares for anchoring.
  • one skilled in the art may work in any of the following described areas to tailor the length of the collagen fiber construct in the patient or joint, with the present invention not being limited to the ranges indicated, and those skilled in the art may choose other areas accordingly work in these.
  • a depth gauge the depth of the femoral (usually 1.0 to 3.5 cm, more preferably 2.0 cm) and tibial borehole (usually 1.5 to 4.0 cm, preferably 2.6 cm ) certainly.
  • the mtraarticular length is determined individually by the surgeon, as a rule this is between 2.2 and 2.4 cm, more preferably between 2.0 and 3.0 cm.
  • the depth gauge can be the drill or a dipstick. The depth gauge is inserted into the wellbore at one end and advanced to the end.
  • the depth gauge either has a length scale that can be used to directly determine the depth of the borehole, or the corresponding length of the depth gauge corresponding to the depth of the borehole is then measured.
  • the determination of the depth of the patient's drill holes is preferably performed during cruciate ligament surgery.
  • the present invention includes another collagen fiber construct ("cruciate ligament construct 1"), wherein preferably a plurality of single collagen fibers are knotted into a collagen thread
  • cruciate ligament construct 1 another collagen fiber construct
  • the named nodes are described as catchy in the literature (Clifford W. Ashley: The Ashley Book of Knots Over 3800 knots, what they look like, what they are used for, how they are made, Edition Maritim, Hamburg, 2005. ISBN 3-89225-527-X).
  • the individual collagen fibers can be knotted together with a sack stitch, a cross hit or an overhand knot (Figure 11).
  • a loop is laid in a first step with the parallel ends of the collagen fibers, so that the two ends of the collagen fibers are at the top.
  • a second step the ends of the collagen fibers are pulled from the bottom through the middle, so that the ends are up again.
  • step 3 and 4 the beginning and end of the two collagen fibers are carefully pulled, respectively, so that the loops contract more and more, thus forming a knot.
  • Steps 1-4 can be repeated again, creating a 3-way node.
  • a loop is placed in a first step with the end of the collagen fiber so that this piece of collagen fiber is at the top (arrows 1-6).
  • the end of the collagen fibers is pulled from the bottom through the middle, so that the end is up again.
  • the beginning and the end of the collagen fiber become Carefully pulled each so that the loops contract more and more and make a knot. Steps 1-4 are repeated twice more, so that at the end 3 knots are on top of each other.
  • a first step 1 2 collagen fibers are superimposed to give an X.
  • the collagen fiber (a) below is placed over the upper collagen fiber (b) and collagen fiber (a) pulled under collagen fiber (b) again.
  • the beginning of collagen fiber (b) is laid over the end of collagen fiber (a) and in step 4, the end of collagen fiber (b) is laid under first and then over collagen fiber (b).
  • the collagen fibers (a) and (b) are gently pulled in the opposite direction. Steps 3-5 can be repeated again, creating a double overhand node.
  • the present invention comprises a collagen fiber construct in which the collagen thread described above or several collagen threads are entangled to form a collagen cord.
  • Knitting is preferably done with a knitted fabric (see figures 8 to 10).
  • a knitting nappy preferably consists of a cylinder with a central bore (tube) having at one end preferably 4 to 8 pins, hooks or the like (see Figure 8) to hold the collagen thread during knitting.
  • a simple Strickliesel from a 1 ml syringe (as a tube) and 4 pins (as pins) produce.
  • a semi-automatic variant is called "Strickmühle”.
  • the collagen thread when the collagen thread is knitted into a collagen cord, the collagen thread is first clamped in the knitted fabric. In this case, one end of the collagen thread is threaded through the central bore of the cylinder and held below the cylinder. The top of the cylinder protruding part of the collagen thread is wound around the first pin / hook counterclockwise, then led to the second pin hook to the left and wrapped again counterclockwise. These steps are repeated until all the pins are wrapped, leaving a stitch on each pin / hook (see Figure 9). All information regarding the thread guide can also be reversed in a further embodiment, ie the pins are each wound in a clockwise direction. After the first pin, the one next to the right follows, and so on.
  • the actual knitting of the collagen thread is preferably carried out by projecting the free end of the collagen thread outside the next left (reverse order on the right) is stretched by the last (newest) stitch lying pin / hook (# 1).
  • the collagen thread is stretched above the loop around this pin hook (see Figure 10 a and b).
  • this mesh is thrown inward over the new collagen thread and the pin / hook ( Figure 10c) so that a new stitch is placed around said pin / hook and the "old" stitch can slip into the central bore of the cylinder ( see Figure 10 d).
  • stretch the free end of the collagen thread from the outside of pin / hook # 2 see Figure 10 e) to create a new loop by running the above steps and slide the old loop into the central hole.
  • Performing the specified steps repeatedly on all pins / hooks creates a collagen cord, which runs down from the Strickliesel.
  • the length of the cord can be chosen freely.
  • the knitting or guiding of the stitches by means of a needle, bent tweezers or the like can be carried out. be relieved and, for finishing, you can drive the collagen thread through one or more of the last stitches and knot it and optionally secured by additional knots. It is important that, in addition to the collagen threads or sections of collagen threads extending in the longitudinal direction of the collagen fiber construct, collagen threads or sections of collagen threads run perpendicular to the longitudinal direction of the collagen fiber construct and / or at an angle to the longitudinal direction.
  • the present invention comprises a co-fiber construct in which one or, optionally, several of the collagen cords described above (the collagen thread entangled into a collagen cord) are twisted.
  • the term "twisting”, as described herein, describes the mutual twisting and helical winding of fibers or wires. Twisting of wires and fenimelding technique is also referred to as stranding, and in connection with the present invention, the term “ Twisting "especially and preferably the mutual twisting and helical wrapping of collagen cords circumscribes.
  • the collagen cord described above is additionally "folded over.”
  • individual and / or several twisted collagen cords are preferably folded in the middle. This shortens the Length, for example, to half and the then juxtaposed Kollagenkordelanmaschine can twist together (due to the previous twisting).
  • the collagen cords can be twisted and / or folded several times.
  • the present invention comprises a collagen fiber construct in which the collagen thread described above or several collagen threads are wound up so that several portions of the thread come to lie parallel to one another.
  • the collagen thread so wound can be used as a collagen fiber construct, in a highly preferred embodiment as a cruciate ligament construct.
  • the collagen fiber construct may have any adjustable length.
  • the length of the collagen fiber construct is in the range of preferably 2.5 to 9.0 cm and the diameter is in the range of preferably 0.6 to 1.0 cm.
  • the diameter is in the range of 0.6 to 1.2 cm.
  • the diameter of the collagen fiber constructs prepared as described above is 0.8 cm.
  • the Kollagenfaserkonstrukt or cruciate ligament construct in the patient or in the joint should preferably be 2.5 to 7.0 cm long, which may optionally contain parts for anchoring in this length and / or may also optionally be added to the length of further shares to the Anchor collagen fiber construct or cruciate ligament construct.
  • the collagen fiber construct produced as described above can be reinforced at the ends by additional collagen thread and / or collagen fibers.
  • the collagen fiber construct produced as described above can be reinforced at the ends by additional collagen fibers or collagen fibers.
  • the present invention includes another collagen fiber construct ("cruciate ligament construct 2"), preferably one or more of the collagen filaments described above are twisted, and as previously described, the present invention includes the term “twisting” in one more Embodiment with the mutual twisting and the helical wrapping of collagen threads circumscribes.
  • the previously described twisted and / or wound collagen threads can be "folded over.”
  • individual and / or several twisted collagen threads are preferably folded together in the middle, thereby shortening the length, for example, to half and then shortening adjacent collagen thread portions may twist together (due to the previous twisting).
  • the collagen threads can be twisted and / or folded several times.
  • the above-described cruciate construct ie, one made of collagen fibers knotted to a collagen thread ("cruciate ligament type 1") and then knitted into a collagen cord, the cords are then wound several times and finally twisted (“cruciate ligament type 2 ”) surprisingly has a number of advantages over the constructs described in the prior art, as illustrated in the in vivo transplantation assays of the examples below.
  • these constructs made of pure collagen fibers are characterized by a constant tensile strength and a very good Einheilungspotential, i. Ignore inflammatory reactions and the tear strength of the KoUagenkonstrukte was in the range of the initial tensile strength of the constructs before implantation or could even be increased.
  • the constructs used are well accepted by the body of the experimental animals, because it was possible to observe a ligamentization.
  • the present invention encompasses another collagen fiber construct (“cruciate ligament construct 3"), where preferably one or more of the collagen threads and / or collagen cords described above are intertwined , preferably comprises the regular interlacing of several strands (collagen threads and / or collagen cords), which are thereby guided over and under each other, so that they run in the braided state in and / or counterclockwise around each other.
  • 3 strands can be interwoven, in particular in the following manner (see FIG.
  • the braiding scheme can be applied to a larger number of strands.
  • the procedure is analogous to steps 2 to 5.
  • the braiding is preferably carried out with 3 to 6 collagen thread and / or collagen cords, which are alternately guided over each other.
  • the collagen fiber construct can consist of a combination of the previously described embodiments.
  • the present invention includes another collagen fiber construct ("cruciate ligament construct 4").
  • the collagen fiber construct thereby forms with 2 fiber bundles (consisting preferably of 20 to 300 collagen single fibers, respectively , more preferably each of 150 collagen single fibers), the geometry of a natural tendon or a natural ligament, said collagen fiber construct in a highly preferred embodiment being a cruciate ligament consisting of two fiber bundles "Double bundle”.
  • the present invention comprises a collagen fiber construct, more preferably a cruciate ligament construct, wherein the collagen fiber construct is sterilized with gamma radiation.
  • the radiation intensity and dose during sterilization with gamma radiation can be varied as required.
  • the irradiance and dose in a particular embodiment are governed by the Medical Devices Act.
  • sterilization for medical devices is based on the sterilization standards DIN EN 550, 552, 556 and DIN EN ISO 17664 valid at the time of registration
  • Embodiment is irradiated depending on the classification with an energy dose of at least 15 kGy, in another embodiment, with energy doses of at least 15 to 35kGy, in a highly preferred embodiment with energy doses of more than 25 kGy to eliminate germs (bacteria, fungi, viruses).
  • an irradiance and dose (energy dose) of at least 28.3 kGy are chosen.
  • the gamma irradiation is preferably carried out with cobalt 60.
  • the cruciate ligament construct stored in a container filled with buffer solution (eg a 50 ml reaction vessel), is stored in a cardboard box or a styrofoam box (referred to below as a transport box) and analogously to the gamma-ray tube. Irradiation of medical devices irradiated.
  • the container is then first loaded into an aluminum container before it is pushed through the irradiation cell with a compressed air cylinder.
  • gamma-irradiation takes place with an energy dose of at least 25 kGy, in a further preferred embodiment an irradiance and dose (absorbed dose) of at least 28 kGy are selected.
  • the transport box did not have to be opened during the gamma irradiation. More precise process data for the process of irradiation can be found in the IAEA guidelines (see also "Trends in radiation of health care products" IAEA (International Atomic Energy Agency) 2008).
  • the present invention includes a collagen fiber construct wherein the collagen fiber construct in a highly preferred embodiment is an anterior cruciate ligament and / or a posterior cruciate ligament.
  • the present invention also includes collagen fiber constructs in accordance with the above, wherein the collagen fiber constructs are modified by the binding of biomolecules.
  • the biomolecules promote ligamentization.
  • Ligamentization is a remodeling process in which the implant biochemically adapts. This means that cells (especially fibroblasts) attach to the implant, proliferate, migrate and form a ligamentous (band-specific) matrix.
  • the present invention also encompasses the modification of collagen fiber constructs modified by the binding of biomolecules, wherein the biomolecules preferably induce chemotaxis, cell proliferation, cell migration and / or matrix production.
  • the biomolecules are selected from the group consisting of chemokines, growth factors, cytokines and active peptides.
  • the biomolecules are selected from the group consisting of platelet derived growth factor (PDGF), growth promoting growth factor (TGF), fibroblast growth factor (FGF), bone morphogenic growth factor, bone morphogenic protein (BMP), epidermal growth factor (EGF), insulin growth factor (IGF) and fibronectin; for the biomolecules, see in particular also Table 1.
  • the collagen fiber construct is to be colonized by the body after transplantation alone with fibroblasts and / or epithelial cells, wherein the colonization can be promoted by the biomolecules described above.
  • the modification of the collagen fiber construct described herein by binding biomolecules is further described below:
  • the cruciate ligament construct After implantation ( Figure 3) in a rupture of the anterior cruciate ligament, the cruciate ligament construct is to be colonized by fibroblasts and epithelial cells.
  • the collagen fiber constructs should be colonized by cells as quickly as possible, which then produce a ligament- or tendon-specific extracellular matrix ("ligamentization").
  • Biomolecules such as chemokines, growth factors, cytokines and active peptides can thus promote "ligamentization”.
  • biomolecules include (see also Table 1):
  • Platelet derived growth factor (PDGF-AA, PDGF-AB, PDGF-BB)
  • TGF-ß1 and -ß2 Transforming growth factor
  • FGF-1 fibroblast growth factor-1, FGF-2 and bFGF
  • Bone morphogenetic protein (BMP-12 and 13)
  • EGF Epidermal growth factor
  • IGF insulin growth factor
  • PDGF increases proliferation and stimulates u.a. the production of collagen III and V, components of tendons and ligaments (Table 1).
  • the combination of different biomolecules e.g. PDGF-BB with TGF-ß1 may exacerbate the effects.
  • the present invention encompasses a method for producing a collagen fiber construct from collagen single fibers which is sterilized with alcohol and / or irradiation and unoccupied, isolating the collagen single fibers from coagenoid tissue from mammals.
  • the present invention encompasses a method of making a collagen fiber construct from collagen single-cell, sterilized with alcohol and radiation, and unoccupied with cells, isolating the collagen single fibers from coagenoid tissue from mammals.
  • collagenous tissue includes not only mammalian tissue and, in a preferred embodiment, rat tails, but also tissue from other organisms and body parts, such as kangaroo, bovine and the like People come in. In a strong In a preferred embodiment, the collagenous tissue is isolated from rat tails.
  • the invention includes a method of making a collagen fiber construct wherein the collagen fiber construct in a preferred embodiment is a ligament and / or tendon construct. More preferably, it is a method of making a collagen fiber construct wherein the collagen fiber construct is a cruciate ligament construct.
  • the present invention includes a method of making any of the collagen fiber constructs described above, wherein the isolation and sterilization of the collagen single fibers and the preparation of the collagen fiber constructs optionally comprises the steps of: (a) isolating collagenous tissue; (b) withdrawing individual and / or multiple collagen single fibers from the collagenous tissue; (c) Incubation of the collagen single fibers in an isotonic or isoosmolar solution, wherein in a further particular embodiment the incubation of the collagen fibers takes place in a 0.9% NaCl solution or phosphate buffered saline (PBS) (i) optionally repeating the washing and sterilizing steps of (c) and (d); (f) optionally, fixing a plurality of isolated and sterilized single collagen fibers to one another Bundle, whereby preferably the above-described collagen fiber construct or the cruciate ligament type "0" results; (g) optionally at the ends, sewing together several bundles into a collagen fiber construct; (h
  • the present invention comprises a method wherein the described collagenous tissue isolation comprises single and / or more of the following steps: (a) washing the rat tails with an isotonic / isoosmolar solution, in another particular embodiment washing while in a 0.9% NaCl solution or phosphate buffered saline (PBS), this isotonic or iso-osmolar solution is preferably sterilized; (b) sterilizing the rat tails with alcohol, at least 60% EtOH, in preferred embodiments be sterilized with 60%, 65%, 70%, 75%, 80%, 85% or 90% EtOH. In a highly preferred embodiment, the rat tails are sterilized with 70% EtOH.
  • PBS phosphate buffered saline
  • the sterilization can also be carried out at lower EtOH concentrations such as 45%, 50% or 55%; (c) skinning the tails; and (d) washing the skinned tails with a sterile isotonic / iso-osmolar solution, wherein in a further particular embodiment the washing is carried out in a 0.9% NaCl solution or phosphate buffered saline (PBS) isotonic or isoosmolar solution is preferably sterilized.
  • PBS phosphate buffered saline
  • the present invention is a method wherein the collagen fibers, after withdrawal from the isolated collagen-containing tissue, are placed in a sterile NaCl solution and sterilized in alcohol.
  • the incubation and sterilization steps of the collagen single fibers are repeated several times, in a preferred embodiment repeated three times.
  • the bundles in the above-described method are sewn together at the ends via a so-called "baseball seam.”
  • baseball seam as described herein is to be understood as follows:
  • the baseball seam is a continuous seam Production of the baseball suture is used non-resorbable surgical thread material.
  • a baseball stitch (“baseball stitch”) is provided at both ends of up to 3 cm. The continuous suture is started with a puncture from outside at a certain angle.
  • the thread end is prevented with a knot or a sling from slipping.
  • the thread with needle comes from below from the implant, runs over the implant and is inserted again at the outer edge.
  • the thread comes out at the same angle obliquely down again out of the implant. Once at the end of the implant, it goes back, creating an opposite pattern.
  • preferably 2 to 30 bundles, more preferably 6 bundles are sewn together.
  • the present invention includes a method of making a cruciate ligament construct (cruciate ligament type "1") wherein single or multiple collagen single fibers are knotted into a collagen thread.
  • the method for producing a cruciate ligament construct may comprise a method in which, as described above, individual and / or multiple collagen threads are entangled to form a collagen cord.
  • individual and / or multiple collagen cords can be twisted in the method and, optionally, in a further preferred embodiment, as described above, transferred. In particular, these steps can be carried out several times in succession if necessary.
  • the present invention encompasses a method of making a cruciate ligament construct (cruciate ligament type "2"), which method comprises twisting single or multiple collagen threads as described above.
  • cruciate ligament type "2” cruciate ligament type "2”
  • the twisted collagen threads are folded.
  • the present invention comprises a method for producing a cruciate ligament construct, wherein in this method single or multiple collagen threads are wound up so that several portions of thread come to lie parallel to one another.
  • the wound up collagen thread can be used as a collagen fiber construct, in a highly preferred embodiment as a cruciate ligament construct.
  • the Kollagenmaschinekonstrukt can have any adjustable length.
  • the length of the collagen fiber construct is in the range of preferably 2.5 to 9.0 cm and the diameter is in the range of preferably 0.6 to 1.0 cm.
  • the diameter is in the range of 0.6 to 1.2 cm.
  • the diameter of the collagen fiber constructs produced according to the method is 0.8 cm.
  • the Kollagenmaschinekonstrukt or Cruciate ligament construct in the patient or in the joint preferably be 2.5 to 7.0 cm in length, which may optionally contain parts for anchoring in this length and or may optionally also be added to the length of further proportions to anchor the collagen fiber construct or cruciate ligament construct.
  • the collagen fiber construct produced according to the method can be reinforced at the ends by additional collagen threads and / or collagen fibers.
  • the collagen fiber construct produced according to the method can be reinforced at the ends by additional collagen fibers or collagen fibers.
  • the present invention also encompasses a method of making a cruciate ligament construct (cruciate ligament type "3"), which method intertwines one or more of the above-described cruciate ligaments and / or collagen cords as set forth above 3 to 6 collagen threads and / or collagen cords, which are alternately superimposed as described above
  • the interlacing takes place as described above and as illustrated in FIG.
  • the methods described above can be carried out several times in succession and / or combined with one another.
  • the present invention further comprises a method for producing a cruciate ligament construct (cruciate ligament type "4") in which the collagen fiber construct is branched,
  • the collagen fiber construct is constructed in this method so that the collagen fiber construct is composed of 2 fiber bundles (consisting of preferably from 20 to 300 collagen single fibers each, more preferably from each individual collagen fiber of the individual fibers) imitates the geometry of a natural tendon or a natural ligament, this collagen fiber construct in a highly preferred embodiment being a cruciate ligament consisting of two fiber bundles fiction, according to this method is, as described herein, also referred to by the term "double bundle".
  • the present invention encompasses a method of making a collagen fiber construct, more preferably a cruciate ligament construct, wherein the collagen fiber construct is gamma-irradiated as described above in this method.
  • the irradiance and dose (absorbed dose) in the gamma radiation sterilization may be varied as required, as described above.
  • the irradiation is carried out in this method with an energy dose of at least 28.3 kGy.
  • energy doses of more than 25 kGy are irradiated.
  • an irradiance and dose (absorbed dose) of at least 28.3 kGy are chosen.
  • gamma irradiation may be with an energy dose of at least 25 kGy, in a highly preferred embodiment with an irradiance and dose (energy dose) of at least 28.3 kGy.
  • the present invention is preferably a process for producing a collagen fiber construct, more preferably a cruciate ligament construct, wherein the incubation and washing steps described above, preferably in an isotonic or isoosmolar solution, wherein the incubation and washing steps in a courtn special embodiment in a 0.9% NaCl solution or phosphate buffered saline (PBS)
  • PBS phosphate buffered saline
  • the sterilization steps described above are preferably carried out with them at least 60% EtOH, preferably with 60%, 65%, 70%, 75%, 80%, 85% or 90% EtOH
  • the sterilization steps are carried out with 70% EtOH EtOH concentrations such as 45%, 50% or 55% take place.
  • the length of the collagen fiber constructs is selected to be preferably 2.5 to 9.0 cm and the diameter preferably 0.6 to 1.0 cm.
  • the diameter is in the range of 0.6 to 1.2 cm.
  • the diameter of the collagen fiber constructs produced according to the method is 0.8 cm.
  • the Kollagenmaschinekpnstrukt or Wienbandkons trukt in the patient or in the joint preferably be 2.5 to 7.0 cm long
  • the Kollagenfaserkonstrukt or cruciate ligament construct may optionally contain parts for anchoring and / or also optionally added to the anchorage further shares to the length can.
  • those skilled in the art may work in any of the following described areas to tailor the length of the collagen fiber construct in the patient or joint, but the present invention is not limited to the ranges indicated and one skilled in the art may choose other areas accordingly and work in these.
  • a depth gauge the depth of the femoral (usually 1.0 to 3.5 cm, more preferably 2.0 cm) and tibial borehole (usually 1.5 to 4.0 cm, preferably 2.6 cm ) certainly.
  • the mtraarticular length is determined individually by the surgeon, as a rule this is between 2.2 and 2.4 cm, more preferably between 2.0 and 3.0 cm.
  • the depth gauge can be the drill or a dipstick. The depth gauge is fed into the wellbore at one end and advanced to the end.
  • the depth gauge either has a length scale that can be used to directly determine the depth of the borehole, or the corresponding length of the depth gauge corresponding to the depth of the borehole is then measured.
  • the determination of the depth of the patient's drill holes is preferably performed during cruciate ligament surgery.
  • the present invention also includes, in accordance with the above, a method of making collagen fiber constructs wherein the collagen fiber constructs are modified by the binding of biomolecules.
  • the biomolecules promote ligamentization.
  • Ligamentization is a remodeling process in which the implant biochemically adapts. This means that cells (especially fibroblasts) attach to the implant, proliferate, migrate and form a ligamentous matrix.
  • the method of the present invention also includes the modification of the collagen fiber constructs modified by the binding of biomolecules, wherein the biomolecules preferably induce chemotaxis, cell proliferation, cell migration and / or matrix production.
  • the biomolecules of the method described above are selected from the group consisting of chemokines, growth factors, cytokines and active peptides.
  • the biomolecules are selected from the group consisting of platelet derived growth factor, transforming growth factor, fibroblast growth factor, bone morphogenic growth factor, epidermal growth factor, insulin growth factor and fibronectin (Table 1).
  • the method comprises the production of a collagen fiber construct which, after implantation in the body, is colonized on its own with fibroblasts and / or epithelial cells, the colonization of which may be required by the biomolecules described above.
  • the present invention comprises a collagen fiber construct producible or manufactured according to one of the methods described above.
  • the forms of ammunition disclosed in connection with the method of the present invention also apply, mutatis mutandis, to the collagen fiber construct, preparable or manufactured according to one of the methods described above.
  • the collagen fiber construct preparable or made by any of the methods described above is preferably a tendon and / or ligament construct, in a highly preferred embodiment a cruciate ligament construct.
  • the present invention encompasses the collagen fiber construct described above for use in the treatment of orthopedic disorders and / or as a xeno-implant.
  • the embodiments described and disclosed above in connection with the method of the present invention and the collagen fiber construct of the present invention apply mutatis mutandis, also for use in the treatment of orthopedic diseases and / or as a xeno-implant.
  • the present invention comprises the collagen fiber construct described above, wherein the orthopedic disorder is a cruciate ligament rupture.
  • the present invention comprises the collagen fiber construct described above, wherein the orthopedic disorder is an Achilles tendon rupture.
  • the orthopedic disorder may be an injury and / or degeneration of the tendons of the rotator cuff (shoulder).
  • the orthopedic disorder may be an injury rupture of the outer ligaments at the knee or ankle (ankle).
  • the orthopedic disorder may also be an injury rupture or degeneration of the medial patellofemoral ligament (MPFL).
  • the collagen fiber construct is a cruciate ligament construct for use in the treatment of orthopedic disorders and / or as a xeno-implant.
  • the collagen fiber construct for use in the treatment of orthopedic disorders and / or as a xeno-implant may be an Achilles tendon construct, a rotator cuff visual construct, a knee or ankle outer construct, or a construct of the MPFL.
  • the present invention comprises the use of the above-described collagen fiber construct as a xeno-implant.
  • the collagen fiber construct described above can be used as a xenograft and / or graft of human collagen.
  • the embodiments described and disclosed above in connection with the method of the present invention and the collagen fiber construct of the present invention mutans mutandis also apply to the use as xeno-implant, xenograft, human collagen graft or graft.
  • the use of the present invention is the use of a tendon and / or ligament construct, which in another highly preferred embodiment is a cruciate ligament construct.
  • the present invention comprises a container containing the above-described Kollagenmaschinekonstrukte, preferably funnelbandkons trukte, contained in a suitable solution.
  • the solution is an isotonic iso-osmolar solution, wherein in a further particular embodiment, the storage and / or transport of the constructs in this container in a 0.9% NaCl solution or phosphate buffered saline PBS), wherein this isotonic or iso-osmolar solution is preferably sterilized stored solution and / or transported to avoid dehydration of the constructs.
  • the tear strength may be below the theoretical tear strength of the cruciate ligament construct. This is due to the different length and bias of the single fibers used, i. after a certain tension, the shortest fibers always tear off in order, as they have to carry the total force alone.
  • the tear strength per area (unit N / mm 2 ) describes the quotient of the tensile strength of a collagen fiber construct and the cross-sectional area of this co-fiber structure in order to be able to compare different collagen fiber constructs.
  • a modified construct of the present invention in a preferred embodiment, is constructed so that the applied force is automatically distributed across all the fibers, i. a length and / or force compensation between the individual fibers or substructures of the constructs can take place.
  • the distribution of force can be uniform or uneven.
  • the (re-) distribution of the force applied to a fiber on the adjacent fibers or the construct as a whole can be done differently.
  • a flexible integration of the individual fibers into the construct, so that the individual fibers still have a certain mobility in the construct (for example shifting to balance forces) can be advantageous.
  • the following possibilities are used, which have been tested in simple experiments and have led to a significant improvement in tear strength:
  • the indicated possibilities can be applied in accordance with the above to fibers with the same cross-section and / or to fibers with different cross-section, eg for joining a fiber having a cross-section greater than 0.25 mm 2 with a fiber having a cross-section smaller than 0.25 mm 2 .
  • a single step may well reduce tear strength (e.g., due to a higher proportion of shear forces).
  • the present invention relates to collagen fiber constructs, and in a preferred embodiment, cruciate ligament constructs defined by various tear strengths per area.
  • Tear strength can be determined by stressing the co-fiber structure.
  • the KoUagenmaschinekonstrukt is clamped at both ends. While one end is held, the other end is pulled continuously.
  • the tensile force increases continuously.
  • the tensile force is measured continuously.
  • the tensile force at which the co-fiber structure or a part of the collagen fiber construct breaks off is equal to the tensile strength of the collagen fiber construct.
  • the tensile strength of a natural cruciate ligament lies in the range of 800 to 1800 N, depending on such. on the age, sex and weight of the person.
  • the maximum tear strength is in men around the age of 22 years (Woo, et al., Am J. Sports Med. 27, 533-543 (1999)).
  • an arbitrary length construct of the invention is described herein to allow the use of the engineered constructs for other applications.
  • These include, but are not limited to, e.g. use as Achilles tendon replacement, ligament / tendon replacement in the elbow joint or in the shoulder (including rotator cuff) and use in domestic and farm animals, e.g. (Race) horses.
  • a construct of any desired adjustable length can also be produced. This is individually tunable for different applications and is no longer limited to the pure cruciate ligament construct for use in humans. Further potential applications are as described above e.g. use as Achilles tendon replacement, ligament / tendon replacement in the elbow joint or in the shoulder (including rotator cuff) and use in domestic and farm animals, e.g. (Racing) horses, dogs.
  • an endobutton is understood to mean a titanium button / plate with 4 holes through which the tendon grafts or implants can be pulled and then fixed.
  • the tibial and femoral drill canal Prior to installation of the construct, the tibial and femoral drill canal is placed at the insertion points of the original cruciate ligament. Then the graft is sutured with special thread material and a small plate (endobutton) and pulled into the joint via 2 drill channels. The titanium endobutton is tipped over at the upper end and thus holds the construct on the thighbone. The fixation of the construct on the lower leg takes place either via a small titanium disc (Suture Disk) or with a screw / dowel.
  • a small titanium disc Suture Disk
  • constructs according to the invention can be realized in various forms, which can also be attached to more than two anchoring points.
  • shape of a natural cruciate ligament is divided into different bundles (see Figure 5).
  • An additional possibility for producing a stable tendon or ligament construct of the embodiments described above is the combination of the collagen fibers and / or collagen constructs with other materials.
  • the basic stability can be increased.
  • the additional materials can be connected to each other and / or the collagen fibers and / or the collagen constructs by means of the possibilities described above (see connecting several individual fibers).
  • a material may encapsulate the other material (s), e.g.
  • the connected collagen fibers may be enclosed by a sheath of silk tissue, or a silk strand may be enclosed by a tubular construct of collagen fibers.
  • the composite construct produced in this way can in turn be further processed by the possibilities described for connecting the individual fibers and / or anchored as described above.
  • the above-described collagen fiber constructs of the present invention are not limited to cruciate ligaments (anterior and posterior cruciate ligaments) but can be used for all tendons and ligaments (eg, Achilles tendon, in the shoulder, inter alia, rotator cuff, medial and lateral collateral ligament, medial patellofemoral ligament, patellar tendon, etc.) Replacement can be used.
  • cruciate ligaments anterior and posterior cruciate ligaments
  • tendons and ligaments eg, Achilles tendon, in the shoulder, inter alia, rotator cuff, medial and lateral collateral ligament, medial patellofemoral ligament, patellar tendon, etc.
  • the collagen fiber constructs of the present invention described above are not limited to human use but may also be used for tendon and ligament replacement in small and large animals (e.g., dog, horse, camel, bovine, etc.).
  • the collagen fibers of the invention described above can be used not only from rat tails but also from other animals e.g. from kangaroo tails, cattle tails, dog tails, squirrel tails, pig tendons, beef tendons.
  • the collagen fibers can also be obtained from human tissue.
  • cruciate ligament constructs for human use, generally all different types can be made and used. In principle, therefore, all the different described Kreuzbandkonstrukt types can be used.
  • a cruciate ligament construct can be made in which collagen fibers are connected by a knot to make a collagen thread. Single or more collagen threads can then be wound up, so that several thread portions come to lie parallel to each other.
  • the Kollagenmaschinekonstrukt can have any adjustable length.
  • the length is in the range of preferably 2.5 to 9.0 cm and the diameter is in the range of preferably 0.6 to 1.0 cm.
  • the diameter is in the range of 0.6 to 1.2 cm.
  • the cruciate ligament should be in the patient or in the joint preferably 2.5 to 7.0 cm long (depending on age, gender and physique). Possibly. This means that they already contain or need to be anchored enough, depending on the method with which the collagen fiber construct is anchored. Corresponding methods are generally known to the person skilled in the art and described in the prior art.
  • the collagen fiber construct can be reinforced at the ends by additional collagen thread and / or collagen fibers. It is for example possible to protect the construct by simply wrapping the ends with collagen threads against abrasion. Suturing the ends of the construct with a collagen thread (eg, cross stitch or baseball stitch) allows mechanical stabilization of the construct ends.
  • the person skilled in the art is generally aware that the surgical technique used can be transmitted minimally invasively to humans.
  • the cruciate ligaments are guided through holes in the femur and tibia, e.g. attached with an endobutton suture button or steel pin (cruciate ligament anchor).
  • endobutton suture button or steel pin cruciate ligament anchor
  • all known and clinically used variants of cruciate ligament anchor can be used.
  • Surgical loops were used to connect the collagen fiber constructs with the suture buttons (suture buttons from Arthrex were used in implantation of the cruciate ligament constructs in the minipig) on both sides.
  • Figure 1 Isolation of the collagen fibers from the rat's tail.
  • A rat tail
  • B skinned rat tail
  • C isolated collagen fiber
  • D Comparison of collagen fiber - skinned rat tail.
  • Figure 2 Collagen fiber-based cruciate construct.
  • the construct consists of 6 collagen fiber bundles of 50 individual fibers, which are sewn together at the ends with a so-called baseball seam.
  • the length is about 7 cm, the diameter is 8 mm.
  • Figure 3 Anterior (VKB) and posterior cruciate ligament (HKB) in the knee.
  • Cruciate ligament construct is e.g. used in a cracked VKB.
  • Collagen Cord a collagen fiber construct made with a “knitted nappy", showing a collagen cord made with a 4-ply knit nib
  • the production process is described in detail in Figures 8 - 10.
  • the V-shaped is clearly shown Structure of the individual meshes of the collagen cord, using a simple collagen thread and making a cord of about 14 cm in length, which can be used directly or further processed (eg, by intertwining with other collagen cords, see Figure 7).
  • Figure 5 Schematic representation of a construct with a dividing structure. This anchorage of the construct at several attachment points is possible (here 2 or 3).
  • Figure 6 Modification of collagen fiber constructs with biomolecules.
  • Biomolecules help cells to migrate and grow faster, resulting in faster ligamentization of the construct.
  • Figure 7 Intertwined collagen thread and / or collagen cords. When interlacing preferably several strands (collagen threads and / or collagen cords) are regularly interlocked, which are doing over and under each other, so that they in the braided state in the and or counterclockwise running around each other.
  • collagen threads and / or collagen cords are regularly interlocked, which are doing over and under each other, so that they in the braided state in the and or counterclockwise running around each other.
  • several collagen thread and / or collagen cords can be combined into one strand.
  • the braiding scheme can be applied to a larger number of strands. The procedure is analogous to steps 2 to 5.
  • FIG. 8 Constriction of collagen thread into a collagen cord with the "Strickliesel” - structure of a "Strickliesel”.
  • a Strickliesel preferably consists of a cylinder with a central bore (tube), preferably at one end 4 to 8 pins, hooks o. owns to hold the collagen thread during knitting.
  • Figure 9 Constricting collagen thread into a collagen cord with the "knitting nappy" - tensioning the collagen thread Thread one end of the collagen through the central bore of the cylinder and hold it below the cylinder, reversing the top of the cylinder protruding counterclockwise wrap the first pin / hook, then go to the second pin hook to the left and wrap it again counterclockwise. These steps repeat until all the pins are wrapped and thus there is a stitch on each pin hook.
  • Figure 10 Constricting collagen sutures into a collagen cord with the "knitting nappy" knitting of the collagen thread
  • the actual knitting of the collagen thread takes place by moving the free end of the collagen thread out to the left (reverse arrangement to the right) of the last (newest) stitch
  • the collagen thread is stretched above the loop around this pin hook ((a) and (b)), then this stitch is thrown inward over the new collagen thread and the pin hook (Fig. c), so that a new stitch comes to rest around said pin hook and the "old” stitch in the central Bore of the cylinder can slip (d).
  • the free end of the collagen thread is tensioned from the outside in front of pin / hook no.
  • Figure 11 Illustration of a blindfold, a cross-stroke and an overhand knot.
  • the individual collagen fibers can be knotted together with a sack stitch, a cross hit or an overhand knot (Figure 11).
  • FIG 12 Illustration of a baseball seam.
  • the baseball seam is a continuous seam.
  • Non-absorbable surgical thread material is used to make the baseball suture.
  • a baseball stitch (“baseball stitch") is provided at both ends up to 3 cm.
  • the continuous suture is started with a puncture from outside at a certain angle.
  • the thread end is prevented with a knot or a sling from slipping.
  • the thread with needle comes from below from the implant, runs over the implant and is re-inserted at the outer edge. The thread comes out at the same angle obliquely down again out of the implant.
  • Arrived at the end of the implant it goes back, creating a counter-pattern.
  • the cruciate ligament constructs according to the invention are composed of collagen single fibers.
  • the collagen single fibers are obtained from the tails of rats ( Figure 1).
  • the rat tails are washed with a sterile 0.9% saline solution (0.9% NaCl, pH 7.4, 290 mOsm), sterilized with 70% EtOH for 10 min and gently skinned.
  • the skinned tails are washed again with 0.9% NaCl solution (pH 7.4, 290 mOsm).
  • the individual collagen fibers are carefully withdrawn, placed in 0.9% NaCl solution (pH 7.4, 290 mOsm) and again sterilized with 70% EtOH for 10 min.
  • the washing and sterilization steps are thoroughly performed a total of three times. Thereafter, the collagen fibers are stored in 0.9% NaCl solution (pH 7.4, 290 mOsm).
  • Another possibility is to sew together 2 bundles of 150 collagen single fibers at a certain angle (about 20 to 45 °).
  • the length and diameter of the cruciate ligament constructs are based on the previously used cruciate ligament grafts and is 7 x 0.8 cm. Of these, 2 cm are required at the ends for the baseball seam or for anchoring in the bone, so that in the middle of the cruciate ligament has an effective length of 3 cm.
  • the final sterilization procedure is gamma-irradiation to ensure sterility (see example 3).
  • the Gariima irradiation is preferably carried out with Cobalt 60.
  • Das Kreuzbandkonstrukt stored in a container filled with buffer solution (eg a SO ml reaction vessel) is stored in a cardboard box or a Styrofoam box (hereinafter referred to as transport box) and irradiated analogously to the gamma irradiation of medical devices.
  • the container is then first loaded into an aluminum container before it is pushed through the irradiation cell with a compressed air cylinder.
  • gamma-irradiation takes place with a dose (energy dose) of at least 25 kGy.
  • the transport box did not have to be opened during the gamma irradiation. More detailed process data after the irradiation process can be found in the IAEA guidelines (see also "Trends in radiation of health care products" IAEA (International Atomic Energy Agency) 2008).
  • Tear strength can be determined by stressing the collagen fiber construct.
  • the collagen fiber construct is clamped at both ends in a material data engine. While one end is held, the other end is pulled continuously.
  • the tensile force increases continuously.
  • the tensile force is measured continuously.
  • the tensile force at which the collagen fiber construct or a part of the collagen fiber construct breaks off is equal to the tensile strength of the collagen fiber construct.
  • cruciate ligament type 1 As an alternative to the method described in Example 3, the cruciate ligament constructs are produced in two further different ways, which are referred to below as “cruciate ligament type 1" and “type 2 rejuvenation belt”:
  • the tear strength of parallel collagen single fibers lies below that, based on the number of collagen single fibers used, theoretically calculated tear strength. This is due to the different length and bias of the single fibers used, i. after a certain tension, the shortest fibers always tear off in order, as they have to carry the total force alone.
  • a modified construct is therefore constructed so that the applied force is automatically distributed across all the fibers, i. a length and / or force compensation between the individual fibers or substructures of the constructs can take place.
  • the distribution of force can be uniform or uneven.
  • the (re-) distribution of the force applied to a fiber on the adjacent fibers or the construct as a whole can be done differently.
  • a flexible integration of the individual fibers into the construct, so that the individual fibers still have a certain mobility in the construct (for example displacement to balance forces) can be advantageous, but need not necessarily be realized.
  • the following options are used, some of which have already been tested in experiments and have led to a significant improvement in tear strength (see below):
  • Bonding the individual fibers by biological reaction e.g., coalescence of individual fibers / strands
  • the options given can be applied in each case to individual individual fibers and / or a bundle of individual fibers. They can also be used to connect single fibers with a bundle of single fibers.
  • a single step may well reduce tear strength (e.g., due to a higher proportion of shear forces).
  • Cross-band type 1 Knots of the individual collagen fibers are used to create “threads” which are subsequently knitted with a knitted nappy into a “collagen cord” (see Figure 4).
  • a first step 1 2 collagen fibers are superimposed to give an X.
  • the collagen fiber (a) below is placed over the upper collagen fiber (b) and collagen fiber (a) pulled under collagen fiber (b) again.
  • the beginning of collagen fiber (b) is laid over the end of collagen fiber (a) and in step 4, the end of collagen fiber (b) is laid under first and then over collagen fiber (b).
  • step 5 gently pull the collagen fibers (a) and (b) in the opposite direction. Steps 3-5 can be repeated again, resulting in duplicate overhand nodes.
  • the collagen cords can be produced from a single "collagen thread” or from several parallel collagen threads.
  • the collagen threads can also be wound up to increase the tear strength and then used directly as a collagen construct.
  • the collagen cords can also be wound up to increase tear strength and be used directly as a collagen construct.
  • the collagen cords can be twisted twisted, the twisted / twisted cords are partially additionally "folded” or "folded” to further increase the tensile strength.
  • twisting / twisting individual and / or several parallel collagen cords are used.
  • the tensile strength of the construct thus produced can be further increased by several consecutive twisting / twisting steps.
  • “Cruciate ligament type 2” The collagen threads produced by knotting are directly connected by twisting / twisting. In part, the twisted / twisted collagen thread are then folded folded additionally. It can be used again single or parallel collagen threads. The tensile strength of the construct thus produced can be further increased by several successive twisting / chirping steps. When twisting the collagen thread, one end of the collagen thread is turned to the right and the other end is turned to the left until resistance is created. The twisted collagen threads can then be folded over / folded / halved. Here, the two folded Kollagenfadenstrnature twist together.
  • cruciate ligament constructs with different tear strength can therefore be produced, e.g. Tear strength greater than 500 N, 500 to 1000 N, 1000 to 2000 N, 2000 to 3000 N, greater than 3000 N.
  • the cruciate ligament construct After implantation (Figure 3) in a rupture of the anterior cruciate ligament, the cruciate ligament construct is to be colonized by fibroblasts and epithelial cells. Different cells (mainly fibroblasts) attach themselves to the implant, proliferate, migrate and form a ligamentous matrix. Furthermore, endothelial cells migrate, leading to vascularization.
  • collagen fiber collagen fiber constructs were first prepared as previously described, which were knotted into a collagen thread and then knitted into a collagen cord (cruciate ligament type 1, which was entangled in addition to a collagen cord).
  • the cords were then wound several times and finally twisted (cruciate ligament type 2).
  • the number of turns varies with the thickness of the collagen fibers used and is chosen to approximate the desired diameter of the collagen fiber construct. The exact diameter is achieved by the final twisting. In this case, 2 to 20 revolutions are used, depending on requirements and fibers used, since during twisting care must be taken not to compress the collagen fibers too much, otherwise the water contained is forced out and the fibers then become brittle. Accordingly, the bias in twisting and the number of revolutions are manually selected so that no or little liquid escapes from the fibers.
  • the cruciate ligament implants were prepared for use in a mini-pig animal study and have the following dimensions: length 3.9 - 4.1 cm, diameter 3.0 - 3.2 mm in the not fully loaded condition.
  • the number of turns in manufacture depends on the thickness of the individual fibers, which in turn varies from rat tail to rat tail. Usually 13 ⁇ 17 windings were used for the desired diameter.
  • the tear strength of these cruciate ligament implants before implantation varies depending on the starting material used and is in the range of 200 to 400 N. This results in a tear strength per surface of 25 to 57 N / mm 2 . For a cruciate ligament implant with 8 mm diameter, as it is to be produced preferably for use in humans, this results in a tensile strength of 1250 to 2844 N.
  • the cruciate ligament constructs are guided through holes in the femur and tibia, eg with an endobutton / suture button or steel pin (cruciate ligament anchor).
  • Surgical loops were used to connect the collagen fiber constructs to the suture buttons on both sides (implantation of cruciate ligament constructs in the inipig, Arthrex suture buttons). It is possible to fine tune the overall length anchor / button - Surgical Loop - Construct - Surgical Loop - Anchor / Button by selecting the appropriate length of the Surgical Loops.
  • a sufficiently long piece of Koulagen construct in the bone canals femur and tibia
  • Suitable here are, for example, 1.5 to 4 cm on each side in humans and 1.0 to 2.5 cm in minipig.
  • the animals were either biomechanically examined as described below (see 7.3.3), or the implants were histologically processed and evaluated (see 7.3.2).
  • the tensile strength of the collagen constructs was in the range of the initial tensile strength of the constructs (prior to implantation).
  • the measured tear strength was in the range of 222 to 385 N 6 months after implantation.
  • the tear strength could thus be almost completely maintained (> 96%) or even increased (+ 11%).
  • a cruciate ligament implant with 8 mm diameter as it is preferred for use in humans to be produced, this results in a tensile strength of 1388 to 2738 N.
  • the tear strength of the collagen constructs was in the range of the initial tear strength of the constructs before implantation or could even be increased.
  • the constructs described herein are characterized by a consistent tear resistance and a very good healing potential.
  • the additional use of synthetic fibers to the collagen fibers for mechanical stability is considered necessary. This is not necessary with the constructs described herein.
  • the collagen construct alone is sufficient.

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Abstract

La présente invention concerne une construction de fibres de collagène à partir de fibres individuelles de collagène, qui est stérilisée avec de l'alcool et par irradiation et n'est pas occupée par des cellules, les fibres individuelles de collagène étant isolées de tissus contenant du collagène à partir de mammifères. La présente invention concerne un procédé de fabrication d'une construction de fibres de collagène à partir de fibres individuelles de collagène, qui est stérilisée avec de l'alcool et par irradiation et n'est pas occupée par des cellules, les fibres individuelles de collagène étant isolées de tissus contenant du collagène à partir de queues de rats. L'invention décrit enfin l'utilisation de constructions de fibres de collagène comme xéno-implant.
EP10795706A 2009-12-21 2010-12-20 Construction de fibres de collagène pour le remplacement de ligaments croisés Withdrawn EP2515797A1 (fr)

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DE102009059901A DE102009059901A1 (de) 2009-12-21 2009-12-21 Kollagenfaserkonstrukte für den Kreuzbandersatz
PCT/EP2010/070312 WO2011085920A1 (fr) 2009-12-21 2010-12-20 Construction de fibres de collagène pour le remplacement de ligaments croisés

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EP3185918B1 (fr) * 2014-08-28 2021-08-18 MiMedx Group, Inc. Greffe de tissu renforcée par collagène
CN109475403B (zh) * 2016-03-02 2022-02-22 密歇根大学董事会 用于旋转袖修复的工程化肌腱移植物
CN105671723A (zh) * 2016-04-07 2016-06-15 张立文 一种以胶原纤维为主作为皮层的包芯纱及其加工方法
US20200205963A1 (en) * 2018-10-08 2020-07-02 Kambiz Behzadi Connective tissue grafting
AU2021246472B2 (en) * 2020-03-31 2023-10-26 3-D Matrix, Ltd. Sterilization of self-assembling peptides by irradiation

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US5171273A (en) * 1989-01-13 1992-12-15 University Of Medicine And Dentistry Of New Jersey Synthetic collagen orthopaedic structures such as grafts, tendons and other structures
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WO2008085493A2 (fr) * 2006-12-27 2008-07-17 Shriners Hospitals For Children Bioprothèse tendineuse ou ligamentaire et procédés pour la produire
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CA2785136A1 (fr) 2011-07-21

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