CA2119750A1 - Graft for promoting autogenous tissue growth - Google Patents
Graft for promoting autogenous tissue growthInfo
- Publication number
- CA2119750A1 CA2119750A1 CA002119750A CA2119750A CA2119750A1 CA 2119750 A1 CA2119750 A1 CA 2119750A1 CA 002119750 A CA002119750 A CA 002119750A CA 2119750 A CA2119750 A CA 2119750A CA 2119750 A1 CA2119750 A1 CA 2119750A1
- Authority
- CA
- Canada
- Prior art keywords
- graft
- segment
- tissue
- tunica
- ligament
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
- A61B17/1146—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of tendons
-
- 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
-
- 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
- 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
- A61L27/3629—Intestinal tissue, e.g. small intestinal submucosa
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/365—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/3662—Ligaments, tendons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3695—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this
-
- 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
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/915—Method or apparatus for preparing biological material
Abstract
Surgical repair of diseased or damaged endogenous connective tissue can be accomplished using a tissue graft formed from a delaminated segment of intestinal tissue. The tissue graft comprises the intestinal tunica submucosa, muscularis mucosa and stratum compactum delaminated from the tunica muscularis and the luminal portion of the tunica mucosa. The graft can be conditioned by stretching and formed as a multilayer composition for high tensile strength and resistance to tearing at its points of attachment to existing physiological structures.
Description
WO 93/05798 ~ 7 ~ O Pcr/US92~08~47 GRAFT FOR PRO~qOTING ~UTOGE~0~3 TI8~UE: GRow~r~
Field of the Inverltion This invention relates to novel tissue graft constructs and their use to promote regrowth and healing of damaged or diseased tissue structures. More particularly this invention is directed to use o~ intestinal tissue grafts as connective tissue substitutes, and most particularly to their use in surgical repair of ligamentæ
and tendons and for their use as a surgically applied bone wrap to promote healing of bone fra~ture-c.
Backaround and Summarv of the Invention Researchers in the surgical arts have been working for many years to develop new techniques and materials for use as grafts to replace or repair damaged or ~-~
diseased tissue structures, particularly bones and -connective tissues, such as ligaments and tendons, and to -~
hasten fracture healing. It is very common today, for instance, for an orthopaedic surgeon to harvest a patellar tendon of autogenous or allogenous origin for use as a replacement for a torn ~ruciate ligament. The surgical methods for such techniques are well known. Further it has become common for surgeons to use implantable prostheses formed from plastîc, metal and/or ceramic material for reconstruction or replacement of physiological structures.
Yet despite their wide use, surgically implanted prostheses present many attendant risks to the patient. It will suffice to say that surgeons are in need of a non-immunogenic, high tensile strength graft material which canbe used for surgical repair of bones, tendons, ligaments and othe~ ~un~tional tissue structures.
Researchers have been attempting to develop satis~actory polymer or plastic materials to serve as ligament, or tendon replacements or as replacements for -WO93/057g8 PCT/US92/~7 ~
.
7 ~ O ~ `
Field of the Inverltion This invention relates to novel tissue graft constructs and their use to promote regrowth and healing of damaged or diseased tissue structures. More particularly this invention is directed to use o~ intestinal tissue grafts as connective tissue substitutes, and most particularly to their use in surgical repair of ligamentæ
and tendons and for their use as a surgically applied bone wrap to promote healing of bone fra~ture-c.
Backaround and Summarv of the Invention Researchers in the surgical arts have been working for many years to develop new techniques and materials for use as grafts to replace or repair damaged or ~-~
diseased tissue structures, particularly bones and -connective tissues, such as ligaments and tendons, and to -~
hasten fracture healing. It is very common today, for instance, for an orthopaedic surgeon to harvest a patellar tendon of autogenous or allogenous origin for use as a replacement for a torn ~ruciate ligament. The surgical methods for such techniques are well known. Further it has become common for surgeons to use implantable prostheses formed from plastîc, metal and/or ceramic material for reconstruction or replacement of physiological structures.
Yet despite their wide use, surgically implanted prostheses present many attendant risks to the patient. It will suffice to say that surgeons are in need of a non-immunogenic, high tensile strength graft material which canbe used for surgical repair of bones, tendons, ligaments and othe~ ~un~tional tissue structures.
Researchers have been attempting to develop satis~actory polymer or plastic materials to serve as ligament, or tendon replacements or as replacements for -WO93/057g8 PCT/US92/~7 ~
.
7 ~ O ~ `
-2- ~
other connective tissues, such as those involved in hernias `
and joint-dislocation injuries. It has been found that it is difficult to provide a tough, durable plastic material ~-;
which is suitable for long term connective tissue replacement. Plastic material~ can become infected and difficulties in treating such infections often lead to graft failure.
In accordance with the present invention ther~ is provided tissue graft constructs for orthopaedic and other surgical applications which in experiments to date have been shown to exhibit many of the desirable characteristics ~-~ important for optimal graft function.
The graft construct in accordance with this invention is prepared from a delaminated segment of intestinal tissue of a warm-blooded vertebrate, the segment comprising the tunica submucosa, the musculari~ mucosa and the stratum compactum of the tunica mucosa. The tunica submucosa, muscularis mucosa and stratum compactum are delaminated from the tunica muscularis and the lumina~
portion of the tunica mucosa of the segment of intestinal tis$ue. The resulting segment is a tubular, very tough, -;
fibrous, collagenous material which is fully described in U.S. Patents 4,902,508 issued February 20, 1990 and 4,956,178 issued September 11, l99o, which patents are expressly incorporated herein by reference-. In those patents, the tissue graft material is primarily described ~-in connection with vascular graft applications.
Intestinal submucosa graft material may be harvested from a biological source such as animals raised for meat production, including, for example, pigs, cattle and æheep or other warm-blooded vertebrates. Older sows having a weight between 400 and 600 lbs. have been found to be par~icularly good sources of graft material for use for this invention. A graft gegment removed ~rom ~uch an older 35 sow can have a tensile strength of up to 1700 psi in the ~;-W093/057~8 PCT/US92/~7 longitudinal direction of the intestine. Thus, ther~ i5 a ready source of intestinal submuc~sa ~raft material in slaughter houses around the country, ready to be harvested and utilized in accordance with the present invention.
The tri-layer întestinal segments used to form the graft constructs in accordance with this invention can be used in their delaminate tubular form or they can be cut longitudinally or laterally to form elongated tissue segments. In either form, such segments have an intermediate portion and opposite ~nd portions and opposite lateral portions which can be formed or surgical . attachment to existing physiological structures, us~ng :;~
surgically acceptable techniques.
An advantage of the intestinal submudosa graft formed ~or surgical repair in accordance with the present invention i~ its resistance to infection. ~he intestinal:~
~ubmucosa graft material, fully described in the aforesaid -~
patents, have high infection resistance, long shelf life and st~rage characteristics. It has been found that xenogeneic intestinal submucosa is compatible with hosts following implantation as vascular grafts, ligaments and tendons because of its basic composition. The intestinal submucosa connective tissue is apparently very similar among species. It is not recognized by the host's immune system as "foreign" and therefore is not reje~ted. Further the intestinal submucosa grafts appear to be extre~ely resistant to infection because of their trophic properties toward vascularization and toward endogenous tissues surgi~cally affixed or otherwise associated with the implant .
graft. In fact, most of the studies made with intestinal submueosa grafts to date have i~volved non-sterile grafts, and no infection problems have been encountered. Of :~
cour~e, appropriate sterilization technique~ acceptable to th~ Federal Drug Administration (FDA) may well be used to treat grafts in accoxdance with the present invention.
. .
W093/OS798 PCT/US92/08~7 ~
7~D :~`
It has been found tha unsterilized clean intestinal submucosa graft material can be kept at 4OC
(refrigerated) for at least one month without loss of gra~t performance. When the intestinal submucosa graft material is sterilized by known m thods, it will stay in good condition for at least two months at room temperature without any resultant loss in graft perfor2ance.
It has also been found that the grafts formed and used in accordance with this invention upon implantation undergo biological remodelling. They serve as a rapidly vascuIarized matrix for support and growth of new endogenous connective tissue. The graft material used in ~~ accordance with this invention has been found to be trophic for host tissues with which it is attached or otherwise a~sociated in its implanted environment. In multiple experiments the graft material has been found to be remodelled (resorbed and replaced with autogenous differentiated tissue) to assume the characterizing features of the tissue(s) with which it is associated at the site of implantation. In tendon and ligament replacement studies the graft appears to develop a surface ;
that is synovialized. Additionally, the boundaries between the graft and endogenous tissue are no longer discernible.
Indeed, where a single graft "sees" multiple i;~
25 microenvironments as implanted, it is differentially `~
remodeled along its length. Thus when used in cruciate ligament rep}acement experiments not only does the portion of th~ graft traversing the joint become vascularized and actually grow to look and function like the original ligament, but the portion of the graft in the femoral and tibial bone tunnels rapidly incorporates into and promotes development of the cortical and cancellous bone in those ~-`
tunnels. In fact, it has been found that after six months, it is not possible to identify the tunnels radiographically. It appears that intestinal submucosa , .
W093/05798 PCT/US92/~7 serves as a matrix for and stimulates bone regrowth (remodeling) within the tunnels~ The bone tunnels with the encompassed intestinal submucosa graft have never been shown to be a weak point in the tensile-strength evaluations after sacrifice of test dogs accomplished to date.
It is one object of the present invention, therefore, to provide graft constructs f oF use as connective tissue substitute, particularly as a substitute for ligaments and tendons. The graft is formed from a segment of intestinal tissue of a warm-blooded vertebrate.
The graft construct comprises the tunica submucosa, the muscularis mucosa and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portions of the tunica mucosa of the segment of intestinal tissue. The graft construct has a longitudinal dimension corresponding to the length of the segment of intestinal tissue and a ~ateral d.~mension proportioned to the diameter of the segment of intestinal tissue. For tendon and ligament replacement applications, the resulting segment is typically preconditioned by stretching longitudinally to a length longer than the length of the intestinal tissue segment from which it was 2S formed. For example, the segment is conditioned by suspending a weight from said segment, for a period of time sufficient to allow about ten to about twenty percent elongation of the tissue segment. Optionally, the graft I mat OE ial can be preconditioned by stretching in the lateral ~'!
dimension. (The graft material exhibits similar viscoelastic properties in the longitudinal and lateral di~ensions). The graft segment is then formed in a variety of shapes and configurations, for example, to serve as a liga-ent or tendon replacement or substitute or a p~tch for 35 a broken or severed tendon or ligament. Preferably, the 093/05798 PCT/US92/0~7 r~ ~3 segment is shaped and formed to have a layered or even a multilayered configuration with at least the opposite end portions and/or opposite lateral portions being formed to;~;
have multiple layers of the graft material to provide s reinforcement for attachment to physiological structures, including bone, tendon, ligament, cartilage and muscle. In a ligament replacement application, opposite ends are attached to first and second bones, respectively, the bones typically being articulated as in the case of a knee joint.
10 It is understood that ligaments serve as connective tis~ue~`
for bones, i.e., between articulated bones, while tendon~
~- serve as connective tissue to attach muscle to a bon~
When a segment of intestine is first harvested and delaminated as described above, it will be a tubular segment having an intermediate portion and opposite end portions. The end portions are then formed, ~anipulated or shaped to be attached, for example, to a bone structure in ~;~
a manner that will reduce the possibility o~ graft tearing at the point of attachment. Preferably it can be folded or .
partially everted to provide multiple layers for gripping, for example, with spiked washers or staples.
Alternatively, the segment may be folded back on itself to join the end portions to provide a first connective portion ~:
to be attached, for example, to a first bone and a bend in 25 the intermediate portion to provlde a second connective ~:
portion to be attache to a second bone articulated with respect to the first bone.
For example, one of the end portio~s may be adapted to be pulled through a tunnel in, for example, the ~
30 femur and attached thereto, while the other of the end :-portions may be adapted to be pulled through a tunnel in the tibia and attached thereto to pro~ide ~ substitute for the natural cruciate ligament, the segment~eing adapted to :
~e placed under tenslon between the tunnels to provide a WOg3/05798 PCT/US~2/~8~7 ~ :
ligament function, i.e., a tensioning and positioning function provided by a normal ligament.
The intestinal submucosa segment, which in its preferred embodiment consists essentially of the tunica submucosa, muscularis mucosa and stratum compactu~, has been found to have good mechanical strength characteristics in the same delaminated tubular form in which it is produced following the described delamination procedure.
It has been found that having the stratum compactum layer inside the tubular form in a tendon or ligament graft provides good trophic properties for va~cularization. It ~- is believed that grafts u~ed in accordance with the present invention with the intestinal segment inverted, i.e., with the stratum compactum on the outside will exhibit like functionality, but further testing is required to determine ~:
the vascularization characteristics with that structure ~:
utilized, for example, as a tendon or ligament graft~
Another object of the present invention is to provide a method for surgical repair of diseased or damaged 20 tissues connecting first and second tissue structures ~:
selected from the group consisting of bone, ligament, tendon, cartilage and muscle. The method comprises the step of attaching the first and second structures to .
opposite end portions or opposite lateral portions of a tissue graft construct ormed in accordance with the above described embodiments. The graft comprises the tunica sub~ucosa, the muscularis mucosa and t:e stratum compactum of a segment of intestinal tissue of a warm-blooded ;
vertebrate, said tunica submucosa, muscularis mucosa and ~tratum compactum being delaminated from the tunîca muscularis:and the luminal portion of the tunica mucosa of said intestina} tissue.
Because grafts used in orthopaedic applications :~
are typically pl~ced under tension in their ~urgical :`
installation, it may be preferable to combine two or even ~`
W093/05798 PCT/USg2/~N~7 ~
h~
-8- :
more tissue segments to provide a multi-ply (multi-layered) graft ~onstruct. It i5 another object of the present invention, therefore, to provide such grafts in which two or more intestinal segments are arranged ts have their end poxtions joined together with the joined end portions and/or lateral portions adapted to be attached to a bone, tendon, ligament or other physiological structure. One ;~
methcd for providing a double intestinal segment may be to pull one tubular segment internally within another segment to provide a double-walled tube, the joined ends of which can be attached, for example, to a bone, tendon or ~::
ligament. These doubled seg~ents will provide enhanced -~
tensile strength and resistance to stretching under tension.
- A further object of the present invention is tc ~:
provide such a graft in which one of said end portions is ~:
adapted to be pulled through a tunnel in, for example, the femur and attached thereto and the other of said end portion is adapted to be pulled throu~h a tunnel in the tibia and attached thereto to provide a substitute for the natural cruciate ligament, the segment being adapted to be placed under tension between the tunnels to provide a :~
ligament function. Similar procedures aan be employed to provide ligament function to other articulating bones.
Still a further object of the present invention is to provide an orthopaedic graft for use as connective tissue to hold f~actured bone pieces together and in proper~:
orientation in the body, the segment being formed to serve :~
I as a fracture wrap about segments of fractured bone and to be attached to the bone.
One other object of this invention is to provide a method for promoting the healin~ and/or regrowth of ~:`
diseased or da~aged tiæsue structures by surgically repairing such structures with a tissue graft construct prepared from a segment o~ intestinal submucosal tissue as ~093/0S798 PCT/US92/~N~7 ~
described above. The implanted graft construct is trophic toward vascularization and differentiated tissue growth and is essentially remodelled to assume the structural and functional characteristics of the repaired s~ructure.::.
Other objects and features of bhe present invention will become apparent as this descriptio~
pro~resses.
~, ~
Brief Description of the Drawinas Fig. 1 shows a lateral view of a knee With a graft in accordance with the present invention extending ~-~ through a tunnel through the tibia and wrapped over the top of a femur. . .
Fig. 2 shows an anterior view of the lèft 15 stifle showing the graft arrangement of Fig. 1. I
Fig. 3 shows an anterior view of the left stifle ~ `
with a graft in accordance with the present invention extending through tunnels in both the tibia and the femur with the end portions of the graft attached by screws and spiked washers in accordance with standard orthopaedic surgery practices.
Fig. 4 shows a medial view of the left stifle showing a graft in accordance with the present invention used as a medial collateral ligament replacement with opposite end portions of the graft attached-~y sutures to existing connective tissues.
Fig. 5 is a fragmentary view showing an achilles tendon with a graft placement in accordance with the ' present invention adapted to join a break in the tendon.
Fig. 6 is a frag~entary perspective view showing the graft of Fig. 5 being attached.
Fig. 7 is a sectional view showing how the graft is wrapped twice about the tendon in Figs. S and 6.
: ~ .
, w093/0~798 PCI/US92/08W?
~ L ;i 75 O
--10-- ,~
Fig. 8 shows a tubular section of the graft folded back on itsel~ to provide a double thickness of -~
intestinal sub~ucosa segment.
Fig. 9 is a fragmentary perspective view showin~
a graft segment pulled within another graft segment to provide a double-walled or tube-within-a-tube arrangement.
D~tailed Descri~tion of the In~en~iQa The intestinal submucosa graft of the prasent invention is harvested and delaminated in accorddnce with the description in the prior U.S. Patents 4,956,178 and 4,902,508. An intestinal submucosa segment is there~y obtained.
To date, of course, such grafts have been used only on test animals. The following description is based upon the experimental uses made or contemplated to date.
In Figs. 1 and 2, a femur is shown above the tibia with a lateral view in Pig. 1 and an anterior view of the left stifle in Fig. 2. As best seen in Fig. 2, a graft 10 is installed through a bone tunnel 12 in the tibia in a fashion well-known in orthopaedic surgery. The end portion `
of the graft 10 is attached as indicated at 14 by a spiked washer and screw arrangement to provide the connection to the tibia. The other end portion of the graft 10 is pulled up through the space between the condylar portions and wrapped over the lateral femoral condyle to be att~ched as indicated at 16 by another æpiked washer and screw arrangement. It will be appreciated that surgeonæ will I generally place such grafts under tension between connections 14, 16.
The arrangement shown in Figs. 1 and 2 may well be more adaptable for testing in dogs than it is for repair of human knees. Thus, Fig. 3 shows a likely human application of the graft 10 extending through aligned-tunnels 20, 22 in the femur and tibia with the opposite WOs3Jo5798 PCT/US92/~7 ~ i ~J~
ends of the graft lo being connected by teflon spiked washers and screws as indicated at 14 and 16. Such screws ;
and spiked washers may be replaced with spiked bone staples or any other type of soft-tissue-to-bone fixation devices commonly used in orthopaedic surgery. When the graft is pulled through the tunnels 20, 22 and placed under tension by the attachments indicated at 14, 16, the graft ~erves a ligament function between the femur and tibia. The graft ~
also apparently stimulates bone growth in the tunnels such ~-that the tunnels close in on the grafts to make connections which, after a period of time, do not have to be supplemented by the screw and washer arrangements. ~;~
Fig. 4 illustrates an intestinal submucosa gra~t `
10 used as a medial collateral ligament replacement attached by sutures to existing adjacent tissues. Thus lateral edg~s 23, 25 of the tubular gra~t 10 are sutured to the posterior oblique ligament 24 and the patellar tendon 26 while opposite ends 27, 29 of graft 10 are sutured to ligament/tendon tissues associated with the femur and `~
tibia, respective~y. The graft 10 is preferably placed under moderate tension~ As discussed above, the graft may -~
comprise one or more intestinal segments layered together to provide additional strength.
Figs. 5, 6 and 7 show how a segment of intestinal submucosa 30 may be shaped and formed to connect a broken or severed achilles tendon. The seqment 30 is shown as an elongated sheet, its longest dimension corresponding to the longitudinal axis of the intestine from which th~ segment I is rem~ved. The graft segment has generally parallel sides 32, 34 and oppoæite ends 36, 38. This segment 30 is wrapped about the achilles tendon as shown in Fig~ 7 to provide a double wrap or multilayered intermediate portion with the sides 32, 34 providing multiple layer opposit~ end portions for attachment to the enclo~ed tendon. The manner W093/05798 P~T/US921~N~7 7 ~
in which the graft ~s sutured to the tendon is illustrated in Fig. 6.
Fig. 8 shows the tubular segment of intestinal submucosa 40 folded back on itself to join i~s end portions 42, 44 to provide a first Gonnective portion 46 to be attached, for instance, to a ~irst bone and also to provide ;~
a bend indicated at 48 in the intermediate portion of the :~
segment 40 to provide a second connective portion to be attached to a second bone articulated with respect to the first bone. The segment arrangement in Fig. 8, therefore, illustrates a method of using a double segment or ~-~ multilayered segment of intestinal submucosa tis~ue in :
accordance with this invention~
Fig. g illustrates another method in whîch a segment 60 of intestinal submucosa is pulled within another tubular segment 62 of intestinal submucosa to provide a dual segment or double segment arrangement having greater strength.
Presently, it is believed that forming the ~:
present grafts to have the stratum co~pactum layer of the intestinal submucosa internally, at least in the intermediate portion, will promote graft vascularization, and tests have been made to establish this fact. It should be recognized, however, that having the stratum compactum on the exterior may function likewise to allow or even promote graft vascularization, and future tests may establi~h this fact. For instance, it will be appreciated that the arrangement shown in Figs. 5, 6 and 7, the ;~
' multiwrap arrangement, is such that the stratum co~pactum of the outer wrap is against the tunica submucosa of the inner wrap.
The grafts may be sterilized using some `~
convention~l sterilizat~on techniques including ~;
glutaraldehyde tanning with glutaraldehyde, formaldehyde `
~anning at acidic pH, propylene oxide treatment, gamma W093J~798 ~ 7 5 ~ PCT/US9~U~7 radiation, and peracetic acid sterilization. A .
sterilization technique which does not significantly weaken the mechanical strength and mechanical properties of the graft is preferably used. For instance, it is believed that strong gamma radiation may cause loss of strength in the graft material. Because one of the most attractive features of these intestinal submucosa grafts is the host-remodelling responses, it is desirable not to use a sterilization approach which will detract from that ~-property. .
It is presently believed that a suitable graft material should have a uniaxial longitudinal tensile strength of at least 3~5 MPa and a strain of no more than twenty percent with maximal load; a burst point of at least 300 mmHg for a specimen that is originally 100 microns thick and shaped in a tube of approximately 3 mm internal ~-diameter; and a porosity that is between 0.5 and 3.0 ml at 120 mmHg pressure per s~uare centimeter. As indicated ;~
above, it is presently believed that the most available 20 appropriate source for such intestinal submucosa graft may ~;
be the small intestine from 400 to 600 lb. sows which are harvested in slaughter houses. The tubular segments from `~
such sows typically have a diameter of about 10 mm to about 15 mm.
The graft material has a characteristic stress-strain relatio~ship. Because orthopedic application of the graft construct will most often involve stress upon the graft, it is desirable that the graft material be "pre- ~-;
conditioned" by controlled stretching prior to use as a connective tissue replacement.
One method of "pre-conditioning" involves application of a given load to the intestinal submucosa graft material for three to five cycles. Each cycle consists of applying a load of approximately two megapascals to the graft material for five seconds, W0 93/05798 PCr/US9210804?
.L i J 7 ~) a followed by a ten second relax~tion phase. It has been found that three to five cycles causes approximately twenty percent strain. The graft material does not retuxn to its original size; it remains in a "stretched" dimension.
To date, several studies have been ~ade that relate to orthopaedic applications of the type described above in connection with the drawings using intestinal submucosa harvested from sows~ These studies include fourteen dogs in which intestinal submucosa has been implanted as an anterior cruciate ligament, six dogs in which intestinal submucosa has been implanted as a medial ~-~' collateral l.igament and nine dogs in which intestinal submucosa has been used as an achilles tendon. In a separate single animal, intestinal submucosa has been used as a "fracture wrap." Some of these animals have been euthaniæed and the grafts harvested for e~aluation.
Results of three dogs with anterior cruciate ligament replacements have been evaluated to show tbat the tensile strength of the intestinal submucosa graft was at least seventy percent (70%) of the contralateral normal anterior cruciate ligament (ACL) by ten weeks post-surgery.
These evaluations show that the graft was approximately three times the thickness at ten weeks than it was at the time of the implantation, and it was well vascularized.
Th~ intestinal submucosa ACLs also become covered with synovium within two to three weeks and incorporate into the bone through the bone tunnels extremely rapidly and strongly. The longest survivors at this time are i approximately eight months and appear to be doing well.
Two dogæ with the intestinal mucosa medial collateral ligament have also been sacrificed to show aggressive fibroblastic ingrowth at one month post-surgery with synovial lining of the articular surface. The graft is attached firmly to the extra-articular aspect of the medial meniscus. There was almost complete restoration of W093/05798 PcT/uss2~ 7 7 ~ i~
-15- ~:
medial stability of the knee within four weeks of ~:
implantation. At this time, the remaining five dogs with intestinal submucosa medial collateral ligaments are clinically normal with no instability.
Three dogs with achilles tendon replacements with intestinal submucosa have been sacrificed. Of the thre~ ~:
groups of dogs, this group showed the most vi~i~le evidence of graft remodelling (probably because of location). The gra~ts thicken to the normal achilles tendon thickness within approximately ~our to six weeks and can support the normal weigh~ of the animal without a brac~ within one month. The remod~lled connective tissue shows extensive :~
vascularization and orientation of the collagen fibrils along the lines of stress. The only inflammation that was 15 pre~ent was represented by small accumulations of ~:
mononuclear cells near the suture material, just as would ;~
be seen in any surgical wound. The intestinal submucosa grafts appear to develop a peritenon that is synovialized and the boundary between the normal achilles and the ;~
20 intestinal submucosa graft was no longer recognizable with ~:
H&E stained histologic tissue sections by sixteen weeks post-surgery. Six dogs remain to be sacrificed in this group and the longest survivor is now approximately six months post-implant.
The bone tunnels with the encompassed intestinal ~:
submuco~a grafts have never been shown to be the weak point in tensile strength evaluations after sacrifice of dogs ~.
that have had the intestinal sub~ucosa ACL surgery. In "~
j addition, the test animals have not had:any infection problem with any of the orthopaedic applications to date.
.
other connective tissues, such as those involved in hernias `
and joint-dislocation injuries. It has been found that it is difficult to provide a tough, durable plastic material ~-;
which is suitable for long term connective tissue replacement. Plastic material~ can become infected and difficulties in treating such infections often lead to graft failure.
In accordance with the present invention ther~ is provided tissue graft constructs for orthopaedic and other surgical applications which in experiments to date have been shown to exhibit many of the desirable characteristics ~-~ important for optimal graft function.
The graft construct in accordance with this invention is prepared from a delaminated segment of intestinal tissue of a warm-blooded vertebrate, the segment comprising the tunica submucosa, the musculari~ mucosa and the stratum compactum of the tunica mucosa. The tunica submucosa, muscularis mucosa and stratum compactum are delaminated from the tunica muscularis and the lumina~
portion of the tunica mucosa of the segment of intestinal tis$ue. The resulting segment is a tubular, very tough, -;
fibrous, collagenous material which is fully described in U.S. Patents 4,902,508 issued February 20, 1990 and 4,956,178 issued September 11, l99o, which patents are expressly incorporated herein by reference-. In those patents, the tissue graft material is primarily described ~-in connection with vascular graft applications.
Intestinal submucosa graft material may be harvested from a biological source such as animals raised for meat production, including, for example, pigs, cattle and æheep or other warm-blooded vertebrates. Older sows having a weight between 400 and 600 lbs. have been found to be par~icularly good sources of graft material for use for this invention. A graft gegment removed ~rom ~uch an older 35 sow can have a tensile strength of up to 1700 psi in the ~;-W093/057~8 PCT/US92/~7 longitudinal direction of the intestine. Thus, ther~ i5 a ready source of intestinal submuc~sa ~raft material in slaughter houses around the country, ready to be harvested and utilized in accordance with the present invention.
The tri-layer întestinal segments used to form the graft constructs in accordance with this invention can be used in their delaminate tubular form or they can be cut longitudinally or laterally to form elongated tissue segments. In either form, such segments have an intermediate portion and opposite ~nd portions and opposite lateral portions which can be formed or surgical . attachment to existing physiological structures, us~ng :;~
surgically acceptable techniques.
An advantage of the intestinal submudosa graft formed ~or surgical repair in accordance with the present invention i~ its resistance to infection. ~he intestinal:~
~ubmucosa graft material, fully described in the aforesaid -~
patents, have high infection resistance, long shelf life and st~rage characteristics. It has been found that xenogeneic intestinal submucosa is compatible with hosts following implantation as vascular grafts, ligaments and tendons because of its basic composition. The intestinal submucosa connective tissue is apparently very similar among species. It is not recognized by the host's immune system as "foreign" and therefore is not reje~ted. Further the intestinal submucosa grafts appear to be extre~ely resistant to infection because of their trophic properties toward vascularization and toward endogenous tissues surgi~cally affixed or otherwise associated with the implant .
graft. In fact, most of the studies made with intestinal submueosa grafts to date have i~volved non-sterile grafts, and no infection problems have been encountered. Of :~
cour~e, appropriate sterilization technique~ acceptable to th~ Federal Drug Administration (FDA) may well be used to treat grafts in accoxdance with the present invention.
. .
W093/OS798 PCT/US92/08~7 ~
7~D :~`
It has been found tha unsterilized clean intestinal submucosa graft material can be kept at 4OC
(refrigerated) for at least one month without loss of gra~t performance. When the intestinal submucosa graft material is sterilized by known m thods, it will stay in good condition for at least two months at room temperature without any resultant loss in graft perfor2ance.
It has also been found that the grafts formed and used in accordance with this invention upon implantation undergo biological remodelling. They serve as a rapidly vascuIarized matrix for support and growth of new endogenous connective tissue. The graft material used in ~~ accordance with this invention has been found to be trophic for host tissues with which it is attached or otherwise a~sociated in its implanted environment. In multiple experiments the graft material has been found to be remodelled (resorbed and replaced with autogenous differentiated tissue) to assume the characterizing features of the tissue(s) with which it is associated at the site of implantation. In tendon and ligament replacement studies the graft appears to develop a surface ;
that is synovialized. Additionally, the boundaries between the graft and endogenous tissue are no longer discernible.
Indeed, where a single graft "sees" multiple i;~
25 microenvironments as implanted, it is differentially `~
remodeled along its length. Thus when used in cruciate ligament rep}acement experiments not only does the portion of th~ graft traversing the joint become vascularized and actually grow to look and function like the original ligament, but the portion of the graft in the femoral and tibial bone tunnels rapidly incorporates into and promotes development of the cortical and cancellous bone in those ~-`
tunnels. In fact, it has been found that after six months, it is not possible to identify the tunnels radiographically. It appears that intestinal submucosa , .
W093/05798 PCT/US92/~7 serves as a matrix for and stimulates bone regrowth (remodeling) within the tunnels~ The bone tunnels with the encompassed intestinal submucosa graft have never been shown to be a weak point in the tensile-strength evaluations after sacrifice of test dogs accomplished to date.
It is one object of the present invention, therefore, to provide graft constructs f oF use as connective tissue substitute, particularly as a substitute for ligaments and tendons. The graft is formed from a segment of intestinal tissue of a warm-blooded vertebrate.
The graft construct comprises the tunica submucosa, the muscularis mucosa and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portions of the tunica mucosa of the segment of intestinal tissue. The graft construct has a longitudinal dimension corresponding to the length of the segment of intestinal tissue and a ~ateral d.~mension proportioned to the diameter of the segment of intestinal tissue. For tendon and ligament replacement applications, the resulting segment is typically preconditioned by stretching longitudinally to a length longer than the length of the intestinal tissue segment from which it was 2S formed. For example, the segment is conditioned by suspending a weight from said segment, for a period of time sufficient to allow about ten to about twenty percent elongation of the tissue segment. Optionally, the graft I mat OE ial can be preconditioned by stretching in the lateral ~'!
dimension. (The graft material exhibits similar viscoelastic properties in the longitudinal and lateral di~ensions). The graft segment is then formed in a variety of shapes and configurations, for example, to serve as a liga-ent or tendon replacement or substitute or a p~tch for 35 a broken or severed tendon or ligament. Preferably, the 093/05798 PCT/US92/0~7 r~ ~3 segment is shaped and formed to have a layered or even a multilayered configuration with at least the opposite end portions and/or opposite lateral portions being formed to;~;
have multiple layers of the graft material to provide s reinforcement for attachment to physiological structures, including bone, tendon, ligament, cartilage and muscle. In a ligament replacement application, opposite ends are attached to first and second bones, respectively, the bones typically being articulated as in the case of a knee joint.
10 It is understood that ligaments serve as connective tis~ue~`
for bones, i.e., between articulated bones, while tendon~
~- serve as connective tissue to attach muscle to a bon~
When a segment of intestine is first harvested and delaminated as described above, it will be a tubular segment having an intermediate portion and opposite end portions. The end portions are then formed, ~anipulated or shaped to be attached, for example, to a bone structure in ~;~
a manner that will reduce the possibility o~ graft tearing at the point of attachment. Preferably it can be folded or .
partially everted to provide multiple layers for gripping, for example, with spiked washers or staples.
Alternatively, the segment may be folded back on itself to join the end portions to provide a first connective portion ~:
to be attached, for example, to a first bone and a bend in 25 the intermediate portion to provlde a second connective ~:
portion to be attache to a second bone articulated with respect to the first bone.
For example, one of the end portio~s may be adapted to be pulled through a tunnel in, for example, the ~
30 femur and attached thereto, while the other of the end :-portions may be adapted to be pulled through a tunnel in the tibia and attached thereto to pro~ide ~ substitute for the natural cruciate ligament, the segment~eing adapted to :
~e placed under tenslon between the tunnels to provide a WOg3/05798 PCT/US~2/~8~7 ~ :
ligament function, i.e., a tensioning and positioning function provided by a normal ligament.
The intestinal submucosa segment, which in its preferred embodiment consists essentially of the tunica submucosa, muscularis mucosa and stratum compactu~, has been found to have good mechanical strength characteristics in the same delaminated tubular form in which it is produced following the described delamination procedure.
It has been found that having the stratum compactum layer inside the tubular form in a tendon or ligament graft provides good trophic properties for va~cularization. It ~- is believed that grafts u~ed in accordance with the present invention with the intestinal segment inverted, i.e., with the stratum compactum on the outside will exhibit like functionality, but further testing is required to determine ~:
the vascularization characteristics with that structure ~:
utilized, for example, as a tendon or ligament graft~
Another object of the present invention is to provide a method for surgical repair of diseased or damaged 20 tissues connecting first and second tissue structures ~:
selected from the group consisting of bone, ligament, tendon, cartilage and muscle. The method comprises the step of attaching the first and second structures to .
opposite end portions or opposite lateral portions of a tissue graft construct ormed in accordance with the above described embodiments. The graft comprises the tunica sub~ucosa, the muscularis mucosa and t:e stratum compactum of a segment of intestinal tissue of a warm-blooded ;
vertebrate, said tunica submucosa, muscularis mucosa and ~tratum compactum being delaminated from the tunîca muscularis:and the luminal portion of the tunica mucosa of said intestina} tissue.
Because grafts used in orthopaedic applications :~
are typically pl~ced under tension in their ~urgical :`
installation, it may be preferable to combine two or even ~`
W093/05798 PCT/USg2/~N~7 ~
h~
-8- :
more tissue segments to provide a multi-ply (multi-layered) graft ~onstruct. It i5 another object of the present invention, therefore, to provide such grafts in which two or more intestinal segments are arranged ts have their end poxtions joined together with the joined end portions and/or lateral portions adapted to be attached to a bone, tendon, ligament or other physiological structure. One ;~
methcd for providing a double intestinal segment may be to pull one tubular segment internally within another segment to provide a double-walled tube, the joined ends of which can be attached, for example, to a bone, tendon or ~::
ligament. These doubled seg~ents will provide enhanced -~
tensile strength and resistance to stretching under tension.
- A further object of the present invention is tc ~:
provide such a graft in which one of said end portions is ~:
adapted to be pulled through a tunnel in, for example, the femur and attached thereto and the other of said end portion is adapted to be pulled throu~h a tunnel in the tibia and attached thereto to provide a substitute for the natural cruciate ligament, the segment being adapted to be placed under tension between the tunnels to provide a :~
ligament function. Similar procedures aan be employed to provide ligament function to other articulating bones.
Still a further object of the present invention is to provide an orthopaedic graft for use as connective tissue to hold f~actured bone pieces together and in proper~:
orientation in the body, the segment being formed to serve :~
I as a fracture wrap about segments of fractured bone and to be attached to the bone.
One other object of this invention is to provide a method for promoting the healin~ and/or regrowth of ~:`
diseased or da~aged tiæsue structures by surgically repairing such structures with a tissue graft construct prepared from a segment o~ intestinal submucosal tissue as ~093/0S798 PCT/US92/~N~7 ~
described above. The implanted graft construct is trophic toward vascularization and differentiated tissue growth and is essentially remodelled to assume the structural and functional characteristics of the repaired s~ructure.::.
Other objects and features of bhe present invention will become apparent as this descriptio~
pro~resses.
~, ~
Brief Description of the Drawinas Fig. 1 shows a lateral view of a knee With a graft in accordance with the present invention extending ~-~ through a tunnel through the tibia and wrapped over the top of a femur. . .
Fig. 2 shows an anterior view of the lèft 15 stifle showing the graft arrangement of Fig. 1. I
Fig. 3 shows an anterior view of the left stifle ~ `
with a graft in accordance with the present invention extending through tunnels in both the tibia and the femur with the end portions of the graft attached by screws and spiked washers in accordance with standard orthopaedic surgery practices.
Fig. 4 shows a medial view of the left stifle showing a graft in accordance with the present invention used as a medial collateral ligament replacement with opposite end portions of the graft attached-~y sutures to existing connective tissues.
Fig. 5 is a fragmentary view showing an achilles tendon with a graft placement in accordance with the ' present invention adapted to join a break in the tendon.
Fig. 6 is a frag~entary perspective view showing the graft of Fig. 5 being attached.
Fig. 7 is a sectional view showing how the graft is wrapped twice about the tendon in Figs. S and 6.
: ~ .
, w093/0~798 PCI/US92/08W?
~ L ;i 75 O
--10-- ,~
Fig. 8 shows a tubular section of the graft folded back on itsel~ to provide a double thickness of -~
intestinal sub~ucosa segment.
Fig. 9 is a fragmentary perspective view showin~
a graft segment pulled within another graft segment to provide a double-walled or tube-within-a-tube arrangement.
D~tailed Descri~tion of the In~en~iQa The intestinal submucosa graft of the prasent invention is harvested and delaminated in accorddnce with the description in the prior U.S. Patents 4,956,178 and 4,902,508. An intestinal submucosa segment is there~y obtained.
To date, of course, such grafts have been used only on test animals. The following description is based upon the experimental uses made or contemplated to date.
In Figs. 1 and 2, a femur is shown above the tibia with a lateral view in Pig. 1 and an anterior view of the left stifle in Fig. 2. As best seen in Fig. 2, a graft 10 is installed through a bone tunnel 12 in the tibia in a fashion well-known in orthopaedic surgery. The end portion `
of the graft 10 is attached as indicated at 14 by a spiked washer and screw arrangement to provide the connection to the tibia. The other end portion of the graft 10 is pulled up through the space between the condylar portions and wrapped over the lateral femoral condyle to be att~ched as indicated at 16 by another æpiked washer and screw arrangement. It will be appreciated that surgeonæ will I generally place such grafts under tension between connections 14, 16.
The arrangement shown in Figs. 1 and 2 may well be more adaptable for testing in dogs than it is for repair of human knees. Thus, Fig. 3 shows a likely human application of the graft 10 extending through aligned-tunnels 20, 22 in the femur and tibia with the opposite WOs3Jo5798 PCT/US92/~7 ~ i ~J~
ends of the graft lo being connected by teflon spiked washers and screws as indicated at 14 and 16. Such screws ;
and spiked washers may be replaced with spiked bone staples or any other type of soft-tissue-to-bone fixation devices commonly used in orthopaedic surgery. When the graft is pulled through the tunnels 20, 22 and placed under tension by the attachments indicated at 14, 16, the graft ~erves a ligament function between the femur and tibia. The graft ~
also apparently stimulates bone growth in the tunnels such ~-that the tunnels close in on the grafts to make connections which, after a period of time, do not have to be supplemented by the screw and washer arrangements. ~;~
Fig. 4 illustrates an intestinal submucosa gra~t `
10 used as a medial collateral ligament replacement attached by sutures to existing adjacent tissues. Thus lateral edg~s 23, 25 of the tubular gra~t 10 are sutured to the posterior oblique ligament 24 and the patellar tendon 26 while opposite ends 27, 29 of graft 10 are sutured to ligament/tendon tissues associated with the femur and `~
tibia, respective~y. The graft 10 is preferably placed under moderate tension~ As discussed above, the graft may -~
comprise one or more intestinal segments layered together to provide additional strength.
Figs. 5, 6 and 7 show how a segment of intestinal submucosa 30 may be shaped and formed to connect a broken or severed achilles tendon. The seqment 30 is shown as an elongated sheet, its longest dimension corresponding to the longitudinal axis of the intestine from which th~ segment I is rem~ved. The graft segment has generally parallel sides 32, 34 and oppoæite ends 36, 38. This segment 30 is wrapped about the achilles tendon as shown in Fig~ 7 to provide a double wrap or multilayered intermediate portion with the sides 32, 34 providing multiple layer opposit~ end portions for attachment to the enclo~ed tendon. The manner W093/05798 P~T/US921~N~7 7 ~
in which the graft ~s sutured to the tendon is illustrated in Fig. 6.
Fig. 8 shows the tubular segment of intestinal submucosa 40 folded back on itself to join i~s end portions 42, 44 to provide a first Gonnective portion 46 to be attached, for instance, to a ~irst bone and also to provide ;~
a bend indicated at 48 in the intermediate portion of the :~
segment 40 to provide a second connective portion to be attached to a second bone articulated with respect to the first bone. The segment arrangement in Fig. 8, therefore, illustrates a method of using a double segment or ~-~ multilayered segment of intestinal submucosa tis~ue in :
accordance with this invention~
Fig. g illustrates another method in whîch a segment 60 of intestinal submucosa is pulled within another tubular segment 62 of intestinal submucosa to provide a dual segment or double segment arrangement having greater strength.
Presently, it is believed that forming the ~:
present grafts to have the stratum co~pactum layer of the intestinal submucosa internally, at least in the intermediate portion, will promote graft vascularization, and tests have been made to establish this fact. It should be recognized, however, that having the stratum compactum on the exterior may function likewise to allow or even promote graft vascularization, and future tests may establi~h this fact. For instance, it will be appreciated that the arrangement shown in Figs. 5, 6 and 7, the ;~
' multiwrap arrangement, is such that the stratum co~pactum of the outer wrap is against the tunica submucosa of the inner wrap.
The grafts may be sterilized using some `~
convention~l sterilizat~on techniques including ~;
glutaraldehyde tanning with glutaraldehyde, formaldehyde `
~anning at acidic pH, propylene oxide treatment, gamma W093J~798 ~ 7 5 ~ PCT/US9~U~7 radiation, and peracetic acid sterilization. A .
sterilization technique which does not significantly weaken the mechanical strength and mechanical properties of the graft is preferably used. For instance, it is believed that strong gamma radiation may cause loss of strength in the graft material. Because one of the most attractive features of these intestinal submucosa grafts is the host-remodelling responses, it is desirable not to use a sterilization approach which will detract from that ~-property. .
It is presently believed that a suitable graft material should have a uniaxial longitudinal tensile strength of at least 3~5 MPa and a strain of no more than twenty percent with maximal load; a burst point of at least 300 mmHg for a specimen that is originally 100 microns thick and shaped in a tube of approximately 3 mm internal ~-diameter; and a porosity that is between 0.5 and 3.0 ml at 120 mmHg pressure per s~uare centimeter. As indicated ;~
above, it is presently believed that the most available 20 appropriate source for such intestinal submucosa graft may ~;
be the small intestine from 400 to 600 lb. sows which are harvested in slaughter houses. The tubular segments from `~
such sows typically have a diameter of about 10 mm to about 15 mm.
The graft material has a characteristic stress-strain relatio~ship. Because orthopedic application of the graft construct will most often involve stress upon the graft, it is desirable that the graft material be "pre- ~-;
conditioned" by controlled stretching prior to use as a connective tissue replacement.
One method of "pre-conditioning" involves application of a given load to the intestinal submucosa graft material for three to five cycles. Each cycle consists of applying a load of approximately two megapascals to the graft material for five seconds, W0 93/05798 PCr/US9210804?
.L i J 7 ~) a followed by a ten second relax~tion phase. It has been found that three to five cycles causes approximately twenty percent strain. The graft material does not retuxn to its original size; it remains in a "stretched" dimension.
To date, several studies have been ~ade that relate to orthopaedic applications of the type described above in connection with the drawings using intestinal submucosa harvested from sows~ These studies include fourteen dogs in which intestinal submucosa has been implanted as an anterior cruciate ligament, six dogs in which intestinal submucosa has been implanted as a medial ~-~' collateral l.igament and nine dogs in which intestinal submucosa has been used as an achilles tendon. In a separate single animal, intestinal submucosa has been used as a "fracture wrap." Some of these animals have been euthaniæed and the grafts harvested for e~aluation.
Results of three dogs with anterior cruciate ligament replacements have been evaluated to show tbat the tensile strength of the intestinal submucosa graft was at least seventy percent (70%) of the contralateral normal anterior cruciate ligament (ACL) by ten weeks post-surgery.
These evaluations show that the graft was approximately three times the thickness at ten weeks than it was at the time of the implantation, and it was well vascularized.
Th~ intestinal submucosa ACLs also become covered with synovium within two to three weeks and incorporate into the bone through the bone tunnels extremely rapidly and strongly. The longest survivors at this time are i approximately eight months and appear to be doing well.
Two dogæ with the intestinal mucosa medial collateral ligament have also been sacrificed to show aggressive fibroblastic ingrowth at one month post-surgery with synovial lining of the articular surface. The graft is attached firmly to the extra-articular aspect of the medial meniscus. There was almost complete restoration of W093/05798 PcT/uss2~ 7 7 ~ i~
-15- ~:
medial stability of the knee within four weeks of ~:
implantation. At this time, the remaining five dogs with intestinal submucosa medial collateral ligaments are clinically normal with no instability.
Three dogs with achilles tendon replacements with intestinal submucosa have been sacrificed. Of the thre~ ~:
groups of dogs, this group showed the most vi~i~le evidence of graft remodelling (probably because of location). The gra~ts thicken to the normal achilles tendon thickness within approximately ~our to six weeks and can support the normal weigh~ of the animal without a brac~ within one month. The remod~lled connective tissue shows extensive :~
vascularization and orientation of the collagen fibrils along the lines of stress. The only inflammation that was 15 pre~ent was represented by small accumulations of ~:
mononuclear cells near the suture material, just as would ;~
be seen in any surgical wound. The intestinal submucosa grafts appear to develop a peritenon that is synovialized and the boundary between the normal achilles and the ;~
20 intestinal submucosa graft was no longer recognizable with ~:
H&E stained histologic tissue sections by sixteen weeks post-surgery. Six dogs remain to be sacrificed in this group and the longest survivor is now approximately six months post-implant.
The bone tunnels with the encompassed intestinal ~:
submuco~a grafts have never been shown to be the weak point in tensile strength evaluations after sacrifice of dogs ~.
that have had the intestinal sub~ucosa ACL surgery. In "~
j addition, the test animals have not had:any infection problem with any of the orthopaedic applications to date.
.
Claims (13)
1. A tendon or ligament graft construct for use as connective tissue substitute, said graft formed from a segment of intestinal tissue of a warm-blooded vertebrate, said segment comprising the tunica submucosa, the muscularis mucosa, and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment of intestinal tissue, said graft construct having an intermediate portion and opposite end portions, said end portions being formed to present multiple segment layers for providing reinforcement for attachment of the graft construct to existing physiological structures, said graft construct further being conditioned for its use as a connective tissue substitute by stretching so that the graft construct is longer than the segment of intestinal tissue from which it is formed.
2. The graft construct of claim 1 conditioned by stretching so that it is about 10 to about 20 percent longer than the intestinal segment from which it was formed.
3. The graft construct of claim 1 in which said segment is folded back on itself to join said end portions to provide a first connective portion to be attached to a first physiological structure and a bend in said intermediate portion to provide a second connective portion to be attached to a second physiological structure.
4. The graft construct of claim 1 in which one of said end portions is adapted to be attached to a first bone and the other of said end portions is adapted to be attached to a second bone articulated with respect to said first bone, said construct being conditioned by stretching so that it is longer than the segment of intestinal tissue from which it was formed so that it can be placed under tension between said first and second bones to provide a ligament function.
5. A tendon or ligament graft for use as a connective tissue substitute in both ligament and tendon locations throughout the body, said graft comprising intestinal tissue of a warm-blooded vertebrate, said segment comprising the tunica submucosa, the muscularis mucosa and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment of intestinal tissue, said graft being formed to have an intermediate portion comprising multiple tissue segment layers, said intermediate portion terminating with opposite end portions, said end portions being formed for attachment to a bone, tendon or ligament, said graft further being conditioned for use as a tendon or ligament substitute by stretching so that the graft is longer than the segments of intestinal tissue from which it is formed.
6. The graft of claim 5 conditioned by stretching longitudinally so that it is about 10 to about 20 percent longer than the segment of intestinal tissue from which it was formed.
7. The graft of claim 5 conditioned by stretching laterally so that it is wider than the segment of intestinal tissue from which it was formed.
8. The graft of claim 5 in which said segment is cut and flattened out to provide an elongated sheet extending in the longitudinal direction of the intestine to have generally parallel sides and opposite ends, said sheet being rolled up about generally a cylindrical axis generally perpendicular to the longitudinal direction to provide said intermediate portion to enclose a tendon or ligament t said sides providing said opposite end portions to be attached to said enclosed tendon or ligament on opposite sides of a break or tear therein.
9. The graft of claim 8 in which said sheet is rolled up to have multilayers of said segment for enclosing a ligament or tendon.
10. The graft of claim 1 in which said graft is formed with at least two such segments, one pulled within the other to provide a double walled tubular structure with the adjacent end portions joined together.
11. A tendon or ligament graft material formed from a segment of intestinal tissue, said graft material comprising the tunica submucosa, the muscularis mucosa and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment of intestinal tissue, and said graft material initially having a longitudinal dimension corresponding to the length of the segment of intestinal tissue and a lateral dimension proportioned to the diameter of the segment of intestinal tissue, said tissue graft material being stretched longitudinally so that it is longer than the segment of intestinal tissue from which it was formed.
12. The tendon or ligament graft material of claim 11 stretched to a length about 10 to about 20%
longer than the segment of intestinal segment from which it was formed.
longer than the segment of intestinal segment from which it was formed.
13. The tendon or ligament graft material of claim 11 wherein the tissue graft material is also stretched laterally.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/764,818 US5281422A (en) | 1991-09-24 | 1991-09-24 | Graft for promoting autogenous tissue growth |
US764,818 | 1991-09-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2119750A1 true CA2119750A1 (en) | 1993-04-01 |
Family
ID=25071874
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002119750A Abandoned CA2119750A1 (en) | 1991-09-24 | 1992-09-21 | Graft for promoting autogenous tissue growth |
Country Status (10)
Country | Link |
---|---|
US (4) | US5281422A (en) |
EP (1) | EP0605581B1 (en) |
JP (1) | JP3544660B2 (en) |
AT (1) | ATE209926T1 (en) |
AU (1) | AU668520B2 (en) |
CA (1) | CA2119750A1 (en) |
DE (1) | DE69232266T2 (en) |
MX (1) | MX9205388A (en) |
NZ (1) | NZ244475A (en) |
WO (1) | WO1993005798A1 (en) |
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- 1992-09-21 DE DE69232266T patent/DE69232266T2/en not_active Expired - Lifetime
- 1992-09-21 EP EP92920627A patent/EP0605581B1/en not_active Expired - Lifetime
- 1992-09-21 AT AT92920627T patent/ATE209926T1/en not_active IP Right Cessation
- 1992-09-21 WO PCT/US1992/008047 patent/WO1993005798A1/en active IP Right Grant
- 1992-09-21 AU AU26511/92A patent/AU668520B2/en not_active Ceased
- 1992-09-21 JP JP50633493A patent/JP3544660B2/en not_active Expired - Lifetime
- 1992-09-23 MX MX9205388A patent/MX9205388A/en unknown
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AU2651192A (en) | 1993-04-27 |
DE69232266T2 (en) | 2002-08-14 |
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WO1993005798A1 (en) | 1993-04-01 |
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NZ244475A (en) | 1995-05-26 |
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