This application is a divisional application filed on application No. 201580066936.7, having a filing date of 2015, 12/10, and entitled "collagen construct and method for producing the same".
Disclosure of Invention
According to one aspect, the present application provides a collagen construct comprising:
a plurality of elongate strips that have been segmented by a collagen membrane comprising a plurality of collagen fibers wherein a majority of the fibers are aligned substantially parallel to each other in a common direction, each strip having a length;
each strip comprising a plurality of collagen fibres aligned substantially along the length of the respective strip;
wherein the strips are brought together to produce the collagen construct.
At least one collagen fibre in each strip may extend continuously along the entire length of its respective strip.
At least 50% or at least 80% of the collagen fibrils in each strip may extend continuously along the entire length of each respective strip.
In one embodiment, each strip may have a thickness of 50 μm to 400 μm. In another embodiment, each strip may have a thickness of 100 μm to 200 μm.
In one embodiment, each strip may have a width of 50 μm to 5mm. In another embodiment, each strip has a width of 1mm to 3mm.
A plurality of the strips may be interwoven, braided, woven or braided together to form one or more collagen strands.
A plurality of the collagen strands may be interwoven, braided or knotted together to form one or more collagen cables.
The collagen construct may have a length of 0.5cm to 50cm. In one embodiment, the collagen construct may have a length of from 2cm to 20cm.
The collagen construct may have a cross-sectional area of 0.002mm2 To 18mm2 . In one embodiment, the collagen construct may have a cross-sectional area of 0.6mm2 To 2mm2 。
The collagen construct is capable of withstanding a tensile load of 650N without breaking or undergoing any permanent deformation or damage.
The collagen construct may comprise a tendon or ligament prosthesis. In one embodiment, the prosthesis may be an anterior cruciate ligament prosthesis.
According to another aspect, the present application provides a method for producing a collagen construct comprising the steps of:
a) Forming a collagen membrane comprising a plurality of collagen fibers, wherein a majority of the fibers are aligned substantially parallel to each other in a common direction;
b) Dividing the film along a dividing line oriented substantially parallel to the common direction, thereby separating the elongated strips from the film; and
c) Gathering the elongated strips together to form the collagen construct.
The method may comprise the steps of: the membrane is treated with acetone and then dried, thereby fixing the collagen fibers in their aligned orientation.
The method may include dividing the membrane as follows: such that each strip has a width sufficient to allow at least one of said collagen fibres to extend continuously along the entire length of its respective strip.
The step of gathering the strips may comprise interweaving, braiding, weaving, interweaving or intertwining a plurality of the collagen strips together to produce a collagen rope.
The method may compriseSufficient ribbon is gathered so that the collagen rope has a cross-sectional area of 0.002mm2 To 18mm2 。
The method may include gathering together sufficient strips to produce a collagen rope of sufficient size to be used as an anterior cruciate ligament prosthesis.
The present invention extends to provide a medical kit for anterior cruciate ligament replacement comprising a collagen construct as described herein, packaged in a sterile package.
The invention further extends to collagen constructs as described herein and collagen constructs produced by the methods described herein for use in the replacement of tendons or ligaments, such as the anterior cruciate ligament.
According to another aspect, the present application provides a method of repairing a partial or complete tear of an anterior cruciate ligament comprising:
providing a collagen construct as described herein;
implanting the collagen construct to augment, repair or replace the anterior cruciate ligament; and
fixing the collagen construct in situ.
Other embodiments of the invention relate to implantable collagen constructs in the form of a rope that provides a new and alternative replacement for a ligament or tendon that has been broken, such as an Anterior Cruciate Ligament (ACL).
In some embodiments, the implantable collagen construct is constructed from a plurality of collagen fibers interwoven and/or woven together such that it can withstand a maximum tensile load of 650N without breaking or undergoing any permanent deformation or damage. In one embodiment, the collagen construct has a diameter of 10mm or less and a cross-sectional area of about 75 to 80mm2 。
Other features, advantages and details of the present invention will be appreciated by those skilled in the art from a reading of the following drawings and detailed description of the embodiments, which merely exemplify the invention.
Detailed Description
The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.
Like numbers refer to like elements throughout. In the drawings, the thickness of some lines, layers, components, elements or features may be exaggerated for clarity. The broken lines illustrate optional features or operations unless otherwise noted.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. Phrases such as "between X and Y" and "between about X and Y" as used herein should be construed to include X and Y. As used herein, phrases such as "between about X and Y" mean "between about X and about Y". Phrases such as "about X to Y" as used herein refer to "about X to about Y".
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of this specification and the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.
It will be understood that when an element is referred to as being "on," attached to, "connected to," coupled to, "in contact with," etc. another element, it can be directly on, attached to, connected to, coupled to or in contact with the other element or intervening elements may also be present. In contrast, when an element is referred to as being "directly on," "directly attached" to, "directly connected" to, "directly coupled" with, or "directly in contact with" another element, there are no intervening elements present. Those skilled in the art will also recognize that references to a structure or feature that is arranged "adjacent" another feature may have portions that overlap or underlie the adjacent feature.
It will be understood that, although the terms "first", "second", etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the present invention. The sequence of operations (or steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise.
The terms "implant", "prosthesis" and "construct" are used interchangeably in this application to refer to an implantable collagen construct in the form of a collagen rope or wire that is configured to replace a (at least part of) native tendon or ligament of a mammalian subject (veterinary or medical (human)). The ligament may be an anterior cruciate ligament. The term "implantable" means that the collagen construct can be inserted, embedded, implanted, or otherwise chronically attached to or placed on or in a patient.
The term "collagen construct" as used herein refers to a material comprising collagen. The collagen construct may be in a finished or final form for use or in an unfinished or pre-finished form. The collagen construct may comprise native collagen, native collagen tissue, synthetic collagen, and/or any combination thereof. The term "synthetic collagen" as used herein refers to a collagen material that has been formed and chemically and/or physically altered from its naturally occurring state into elongated fibers or bundles of collagen fibers. In one embodiment, the collagen material may be obtained from a collagen film produced according to the method described in WO 2013/185173. In other embodiments, the collagen may be non-denatured collagen, such as intact or fragmented native collagen fibers from tendons or skin.
Exemplary collagen constructs include, but are not limited to, collagen fibers and bundles of collagen fibers arranged as a rope, a braided rope, a strip, a braid, a cable, a ligament or tendon prosthesis, or the like. The collagen fibers or bundles may be rotated, intertwined, woven, braided or interwoven so as to define a correspondingly rotated, intertwined, woven, braided or interwoven collagen construct.
Collagen fibers are composed of three polypeptide chains, which intertwine to form a right-handed triple helix. Each collagen polypeptide chain is called an alpha chain and is rich in glycine, proline and hydroxyproline. There are numerous different alpha chains and different combinations of these alpha chains correspond to different types of collagen. In some embodiments, the collagen membrane of the present invention comprises type I collagen. Type I collagen consists of two α 1 chains and one α 2 chain.
In some embodiments, the collagen fibers or bundles are provided by dense connective tissue isolated from a source. The term "dense connective tissue" as used herein refers to a matrix comprising mainly type I collagen fibers or bundles, which is present in the tendons, ligaments and dermis of all mammals. Dense connective tissue is distinct from "loose connective tissue". Loose connective tissue is characterized by loosely arranged fibers and a large number of cells and is present, for example, under the upper skin covering the body surface and supporting internal organs.
In some embodiments, the present invention provides collagen membranes comprising greater than 80% type I collagen. In other embodiments, the collagen membrane comprises at least 85% type I collagen. In other embodiments, the collagen membrane comprises greater than 90% type I collagen.
Collagen "microfibrils", "fibrils", "fibers" and "natural fibers" refer to naturally occurring structures present in ligaments. The diameter of the microfibrils is about 3.5 to 50nm. The fibrils have a diameter of about 50nm to 50 μm. The diameter of the natural fibres is higher than 50 μm. In some embodiments, the fibers and/or collagen constructs may contain cells, engineered cells, stem cells, and the like, and combinations thereof.
The term "suture" refers to a flexible, elongated material used to attach the collagen construct to the target anatomy, thereby helping to hold the collagen construct in place on the body. The sutures may be absorbable or non-absorbable, synthetic or natural. The suture may be configured to hold the implant in place for at least the initial post-implantation stage, i.e., at least about 1 week, but may be permanently located within the body or may be substantially resorbed over time as described above. The suture may be a monofilament or multifilament (interwoven) suture, a floss, a gut or a metal wire or combination thereof, which may be used to hold a portion of the implant against or attached to a target structure, typically bone and/or tissue. The suture may comprise absorbable or non-absorbable biocompatible materials. Examples of suture materials include elastic materials such as polymers, copolymers and/or derivatives thereof including VicrylTM And other materials include NITINOL and combinations thereof. Sutures may be used with suture anchors (bone or tissue anchors).
The term "flexible" means that the elements involved may be flexed or bent.
The terms "interweave" and "weave" and derivatives thereof refer to interweaving and/or weaving, interlacing, and/or interlocking a plurality (typically three or more) of fibers or fiber bundles together and/or with one another in any manner, including manually or automatically weaving, interlacing, knitting, and/or knotting, as well as combinations of these or other interlocking or interlacing configurations.
Figure 1 shows a collagen scaffold 10 comprising a collagen membrane 12. The membrane 12 is in the form of a substantially flat web or sheet from which individual elongate strips 14 can be repeatedly divided until the entire membrane 12 is divided into such strips 14 or until sufficient strips 14 are obtained. The singulation is typically done using a laser singulation machine, but may also be done using a conventional mechanical singulation machine or scissors.
Although the membrane 12 is shown as being rectangular when viewed in plan, it will be appreciated that the membrane 12 may be provided in any other geometric shape, such as circular, oval or trapezoidal. The specific shape of the membrane 12 may depend on the source from which the membrane 12 is obtained. The term "source" as used herein refers to any collagenous tissue containing dense connective tissue in any mammal. In some embodiments, the tissue containing dense connective tissue is a tendon. Tendons are tissues that connect muscles and bones in mammals. In some embodiments, the collagen-containing tissue may be isolated from any mammal, including but not limited to sheep, cattle, pigs, or humans. In other embodiments, the collagen-containing tissue is isolated from a human.
In an exemplary embodiment, the film 12 is produced according to a method as described in WO 2013/185173.
The membrane 12 comprises collagen containing tissue fragments obtained from lining internal organs of pigs, which are treated to remove all non-collagenous tissue from the fragments. In the initial treatment, all adipose tissue is physically removed from the tissue segment, which is then chemically treated to denature non-collagen. The tissue fragments are then centrifuged and washed to remove residual solution and nucleic acids from the tissue fragments. The tissue segments are stretched over the frame to reduce their cross-sectional thickness to obtain a membrane 12 having a desired thickness. The thickness of the membrane 12 is selected depending on the intended use of the collagen construct, such as the desired diameter of the collagen construct to be formed from the membrane 12, and thus may be used to replace an Anterior Cruciate Ligament (ACL) that has been fractured. In one embodiment, the membrane 12 has a thickness of 50 μm to 400 μm. In another embodiment, the membrane 12 has a thickness of 100 μm to 200 μm. In another embodiment, the membrane 12 has a thickness of about 100 μm.
The membrane 12 may be treated with acetone and air dried while still stretched over a frame to fix the collagen fibers and fiber bundles therein in their natural alignment. However, it should be appreciated that other methods for immobilizing the collagen fibers in their native alignment are possible, such as treating the membrane 12 with an alkali-acid. The membrane 12 may then be pressed and/or rolled to create a smooth surface on the opposite side of the membrane 12.
Fig. 2 shows a Scanning Electron Microscopy (SEM) image (× 100) of membrane 12. It is observed that the membrane 12 comprises a plurality of fibers 16, a majority of which are substantially aligned with one another in a common direction. The plurality of fibers 16 may be substantially parallel to one another. It was observed that the alignment of the fibers 16 gave a clear micro-texture to the film 12, similar to that found in paper. The fibers 16 may be branched into smaller fibers or filaments that may be recombined with each other or with other fibers 16. Thus, the fibers 16 form an interconnected web in the membrane 12. A plurality of microfibrils and/or filaments 20 extend laterally from the fibers 16, which help to interconnect the network of membranes 12.
When the strips 14 are divided by the film 12, the direction or orientation of the dividing line 18 along which the film 12 is divided is aligned with the microtexture, i.e. with the direction in which the fibres 16 are elongated. The dividing line 18 is represented in fig. 2 by a dashed line. Although the parting lines 18 are shown in fig. 2 as being positioned relatively close to each other and spaced apart by only about 250 μm, it should be appreciated that adjacent parting lines 18 may be spaced apart to varying degrees to produce a strip 14 having a desired width. In one embodiment, the strips 14 have a width of 50 μm to 5mm. In another embodiment, the strips 14 have a width of 1mm to 3mm. In another embodiment, the strips 14 have a width of about 2mm. Each strip 14 in this manner will contain at least some fibers 16 that extend continuously along the entire length of the strip 14. In some embodiments, the width of the strip 14 and the alignment of the dividing lines 18 are selected such that at least 50% of the fibers 16 in the strip 14 will run continuously along the entire length of the strip 14. In another embodiment, at least 80% of the fibers 16 in the ribbon 14 will extend continuously along its entire length. In another embodiment, at least 90% of the fibers 16 in the strip 14 will extend continuously along its entire length.
It should be appreciated that in some embodiments, the strips 14 may be segmented to contain individual fibers 16.
One or more of the strips 14 are then aggregated in the manner in which the collagen construct is formed. Prior to such gathering, the strips 14 may optionally be rolled along their length, i.e., in a direction parallel to the aligned fibers 16, to form a cylindrical or tubular shape. Alternatively, the strips 14 may be knotted or rotated to form an elongated line. In one embodiment shown in fig. 3, the strips 14 are interwoven together to form a collagen construct in the form of a collagen rope 22. The interwoven fabric may be a relatively tight interwoven fabric to form the collagen rope 22 having a relatively rigid cylindrical structure. Alternatively, the interwoven fabric may be a relatively loose interwoven fabric having less structural rigidity and thereby providing greater flexibility. The choice of tightly or loosely intertwined fabrics will depend on the target location in the patient's body where tendon or ligament replacement is desired and the desired mechanical properties that need to be exhibited. In some embodiments, a loosely interwoven fabric or braided structure is preferred because it reduces shear forces in the strips 14 that are created by abutting pressure from adjacent strips 14 during buckling or tensioning of the collagen rope 22.
In some embodiments, the collagen rope 22 may comprise three or more strips 14 interwoven together. In other embodiments, the collagen rope 22 may comprise three or more strips 14 braided together. If it is desired to make the resulting collagen construct thicker than the collagen strands 22, a plurality of collagen strands 22 may be interwoven or braided together to form a collagen cable.
In some embodiments, the collagen rope 22 has a length of 0.5-50cm, typically about 1-25cm and in some embodiments about 2-20cm. In some embodiments, the collagen rope 22 may have a cross-sectional area of about 0.002-6mm2 And is usually about 0.6 to 2mm2 . In some embodiments, the collagen cables can have a cross-sectional area of about 1-18mm2 . In one embodiment, the collagen construct has a diameter of 10mm or less and a cross-sectional area of about 75 to 80mm2 . In some embodiments, the collagen rope 22 or cable can withstand a maximum tensile load of 650N without breaking or undergoing any permanent deformation or damage. The term "maximum tensile load" as used herein refers to the maximum tensile load that the collagen rope can withstand. Which is represented on the load versus extension curve by the peak load on the curve.
The collagen rope 22 may optionally include coating, impregnating, and/or mixing with, for example, a gel or other material. The coating may be arranged to promote fibroblast and/or comprise one or more anti-inflammatory, antibiotic or other therapeutic agents.
The collagen strands 22 are biocompatible and may be absorbed, resorbed, and/or biodegraded over time.
The collagen rope 22 may be configured to have similar or greater tensile strength, stiffness, and dynamic flexibility as compared to a natural tendon or ligament, such as a natural Anterior Cruciate Ligament (ACL). Embodiments of the invention are particularly suitable for strengthening, repairing or replacing tendons and ligaments that may have broken, in particular ACL. In such cases, the collagen rope 22 is constructed, sized and shaped to constrain the ACL. Optionally, the collagen rope 22 may be implanted into the patient using one or more of sutures, suture anchors, bone channels, and the like. Typically, the collagen rope 22 will be implanted at the repair site and secured in place by any conventional means known to those skilled in the art, such as sutures, suture anchors, bone fixation devices, and bone or biodegradable polymer screws.
The collagen rope 22 may be provided in a medical kit for ACL replacement. A medical kit comprises an implantable collagen construct as described above and a sterile package in which the collagen construct is hermetically encapsulated.
The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
The present invention relates to the following embodiments:
1. a collagen construct, comprising:
a plurality of elongate strips that have been segmented by a collagen membrane comprising a plurality of collagen fibers wherein a majority of the fibers are aligned substantially parallel to each other in a common direction, each strip having a length;
each strip comprising a plurality of collagen fibres aligned substantially along the length of the respective strip;
wherein the strips are brought together to produce the collagen construct.
2. The collagen construct of embodiment 1, wherein the at least one collagen fiber in each strip extends continuously along the entire length of its respective strip.
3. The collagen construct of embodiment 1 or 2, wherein at least 50% of the collagen fibers in each band extend continuously along the entire length of each respective band.
4. The collagen construct of embodiment 3, wherein at least 80% of the collagen fibers in each band extend continuously along the entire length of each respective band.
5. The collagen construct of any one of the preceding embodiments, wherein each band has a thickness of 50 μm to 400 μm.
6. The collagen construct of embodiment 5, wherein each band has a thickness of 100 μm to 200 μm.
7. The collagen construct of any one of the preceding embodiments, wherein each band has a width of 50 μm to 5mm.
8. The collagen construct of embodiment 7, wherein each strip has a width of 1mm to 3mm.
9. A collagen construct according to any one of the preceding embodiments, wherein a plurality of the strips are interwoven, braided, woven or knotted together to form one or more collagen strands.
10. The collagen construct of embodiment 9, wherein a plurality of the collagen strands are interwoven, braided, woven or braided together to form one or more collagen cables.
11. A collagen construct according to any one of the preceding embodiments, having a length of from 0.5cm to 50cm.
12. The collagen construct of embodiment 11, having a length of 2cm to 20cm.
13. A collagen construct as claimed in any one of the preceding embodiments, having a cross-sectional area of 0.002mm2 To 18mm2 。
14. A collagen construct as claimed in any one of the preceding embodiments, having a cross-sectional area of 0.6mm2 To 2mm2 。
15. The collagen construct of any one of embodiments 11 to 15, which is capable of withstanding a tensile load of 650N without breaking or undergoing any permanent deformation or damage.
16. A collagen construct according to any one of the preceding embodiments, comprising a tendon or ligament prosthesis.
17. The collagen construct of embodiment 16, wherein the prosthesis is an anterior cruciate ligament prosthesis.
18. A method for producing a collagen construct, comprising the steps of:
a) Forming a collagen membrane comprising a plurality of collagen fibers, wherein a majority of the fibers are aligned substantially parallel to each other in a common direction;
b) Dividing the film along a dividing line oriented substantially parallel to the common direction, thereby separating the elongated strips from the film; and
c) Gathering the elongated strips together to form the collagen construct.
19. The method of embodiment 18, comprising the steps of: the membrane is treated with acetone and then dried, thereby fixing the collagen fibers in their aligned orientation.
20. The method of embodiment 18 or 19, comprising dividing the membrane in the following manner: such that each strip has a width sufficient to allow at least one of said collagen fibres to extend continuously along the entire length of its respective strip.
21. The method of any of embodiments 18 to 20, wherein the step of gathering the strips comprises interweaving, braiding, weaving, interweaving or intertwining a plurality of the collagen strips together to produce a collagen rope.
22. The method of embodiment 21, comprising gathering sufficient ribbons such that the collagen rope has a cross-sectional area of 0.002mm2 To 18mm2 。
23. The method of any of embodiments 18 through 22, wherein the step of gathering the strips comprises gathering sufficient strips together to produce a collagen rope of sufficient size to be used as an anterior cruciate ligament prosthesis.
24. A medical kit for anterior cruciate ligament replacement comprising: (ii) (a) a collagen construct according to any one of embodiments 1 to 17; and (b) a sterile package enclosing said collagen construct.
25. A collagen construct according to any one of embodiments 1 to 17 for use in repairing a tendon or ligament.
26. A collagen construct produced by the method of any one of embodiments 18 to 23 for use in repairing a tendon or a ligament.
27. A method of repairing a partial or complete tear of an anterior cruciate ligament comprising:
providing a collagen construct according to any one of embodiments 1 to 17;
implanting the collagen construct to augment, repair or replace the anterior cruciate ligament; and
fixing said collagen construct in situ.