U.S. patent application number 13/727650 was filed with the patent office on 2013-05-09 for reinforced tissue graft.
This patent application is currently assigned to THE CLEVELAND CLINIC FOUNDATION. The applicant listed for this patent is The Cleveland Clinic Foundation. Invention is credited to Kathleen A. Derwin, Joseph P. Iannotti, Sambit Sahoo.
Application Number | 20130116799 13/727650 |
Document ID | / |
Family ID | 48224239 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116799 |
Kind Code |
A1 |
Derwin; Kathleen A. ; et
al. |
May 9, 2013 |
REINFORCED TISSUE GRAFT
Abstract
A biocompatible tissue graft includes a first layer of a
bioremodelable collageneous material, a second layer of
biocompatible synthetic or natural remodelable or substantially
remodelable material attached to the first layer; and at least one
fiber that is stitched in a reinforcing pattern in the first layer
and/or second layer to mitigate tearing and/or improve fixation
retention of the graft, and substantially maintain the improved
properties while one or more of the layers is remodeling.
Inventors: |
Derwin; Kathleen A.; (Shaker
Heights, OH) ; Iannotti; Joseph P.; (Strongsville,
OH) ; Sahoo; Sambit; (Cleveland, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Cleveland Clinic Foundation; |
Cleveland |
OH |
US |
|
|
Assignee: |
THE CLEVELAND CLINIC
FOUNDATION
Cleveland
OH
|
Family ID: |
48224239 |
Appl. No.: |
13/727650 |
Filed: |
December 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2011/042138 |
Jun 28, 2011 |
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13727650 |
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12934791 |
Sep 27, 2010 |
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PCT/US09/38570 |
Mar 27, 2009 |
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PCT/US2011/042138 |
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61359067 |
Jun 28, 2010 |
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61040066 |
Mar 27, 2008 |
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61720173 |
Oct 30, 2012 |
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Current U.S.
Class: |
623/23.72 |
Current CPC
Class: |
A61F 2/02 20130101; A61L
2420/08 20130101; A61L 27/3633 20130101; A61F 2/08 20130101; A61L
27/48 20130101; A61L 27/38 20130101; A61L 27/34 20130101; A61L
2420/04 20130101; A61F 2210/0076 20130101 |
Class at
Publication: |
623/23.72 |
International
Class: |
A61F 2/02 20060101
A61F002/02 |
Claims
1. A biocompatible tissue graft comprising: a first layer of a
bioremodelable collageneous material; a second layer of
biocompatible synthetic or natural remodelable or substantially
remodelable material attached to the first layer; and at least one
fiber that is stitched in a reinforcing pattern in the first layer
and/or second layer to mitigate tearing and/or improve fixation
retention of the layers, and substantially maintain the improved
properties while one or more of the layers is remodeling.
2. The tissue graft of claim 1, the first layer comprising
extracellular matrix and the at least one fiber reinforcing the
extracellular matrix.
3. The tissue graft of claim 2, the second layer comprising
extracellular matrix.
4. The tissue graft of claim 1, wherein the second layer comprising
a biocompatible substantially remodelable synthetic material.
5. The tissue graft of claim 4, wherein the second layer comprises
a mesh of synthetic material.
6. The tissue graft of claim 1, wherein the fiber comprises a
natural or synthetic material.
7. The tissue graft of claim 6, wherein the first layer comprises a
mammalian-derived or plant-based collagen material.
8. The tissue graft of claim 6, wherein the fiber is selected from
the group consisting of collagen, silk, sericin free silk, modified
silk fibroins, polyesters like PGA, PLA, polylactic-co-glycolic
acid (PLGA), polyethyleneglycol (PEG), polyhydroxyalkanoates (PHA),
polyethylene terephthalate (PET), polyethylene (PE), ultra-high
molecular weight polyethylene (UHMWPE), blends thereof, and
copolymers thereof.
9. The tissue graft of claim 6, wherein at least one of the first
layer, the second layer, and the fiber is modified to improve
adhesion between the layers and the fiber.
10. The tissue graft of claim 1, wherein the fibers are stitched
into the layers in a concentric pattern.
11. The tissue graft of claim 11, the at least one fiber having at
least one free end extending beyond a peripheral surface of the
tissue graft for securing the tissue graft to a host tissue.
12. The tissue graft of claim 2, wherein the extracellular matrix
is decellularized.
13. The tissue graft of claim 1, wherein at least one the first
layer or the second layer further comprises at least one
differentiated or progenitor cell.
14. The tissue graft of claim 1, wherein at least one of the first
layer or the second layer further comprises at least one
biologically active molecule selected from the group consisting of
drugs, sclerosing agents, enzymes, hormones, cytokines,
colony-stimulating factors, vaccine antigens, antibodies, clotting
factors, angiogenesis factors, regulatory proteins, transcription
factors, receptors, structural proteins, nucleic acid therapeutic
agents, and combinations thereof.
15. A biocompatible tissue graft comprising: a first layer of a
bioremodelable collageneous material; a second layer of
biocompatible synthetic or natural remodelable or substantially
remodelable material attached to the first layer; and at least one
fiber stitched in a reinforcing pattern in the first layer and/or
second layer to mitigate tearing of the graft, improve fixation
retention of the graft, and/or limit cyclic stretching of the
graft, and substantially maintain these properties following
partial enzymatic degradation of the graft while one or more of its
layers remodels, the at least one fiber having at least one free
end extending beyond a peripheral surface of the tissue graft for
securing the tissue graft to a host tissue.
16. The tissue graft of claim 15, wherein the at least one fiber
extends at a non-perpendicular angle to the peripheral surface of
the graft.
17. The tissue graft of claim 15, wherein the at least one fiber
extends beyond opposing peripheral surfaces of the graft.
18. The tissue graft of claim 15, wherein the at least one fiber
comprises a first fiber that extends beyond a first pair of
opposing peripheral surfaces and a second fiber that extends beyond
a second pair of opposing peripheral surfaces different from the
first pair.
19. The tissue graft of claim 15, wherein the fiber comprises a
biocompatible material that is bioresorbable, biodegradable, or
non-resorbable.
20. The tissue graft of claim 15, wherein at least one of the first
layer, the second layer, and the fiber is modified to improve
adhesion between the layers and the fiber.
21. The tissue graft of claim 15, wherein the at least one fiber is
stitched into at least one of the first layer or the second layer
in a cross-hatched configuration.
22. The tissue graft of claim 15, wherein the at least one fiber is
stitched into at least one of the first layer or second layer in a
concentric pattern.
23. The tissue graft of claim 15, wherein the at least one fiber is
stitched into at least one of the first layer or second layer in
multiple concentric patterns.
24. The tissue graft of claim 15, wherein the at least one fiber
comprises fibers stitched into at least one of the first layer or
second layer in a linear pattern.
25. The tissue graft of claim 15, wherein at least one of the first
layer and the second layer is decellularized.
26. The tissue graft of claim 15, wherein at least one the first
layer and the second layer further comprises at least one
differentiated or progenitor cell.
27. The tissue graft of claim 15, wherein at least one of the first
layer and the second layer further comprises at least one
biologically active molecule selected from the group consisting of
drugs, sclerosing agents, enzymes, hormones, cytokines,
colony-stimulating factors, vaccine antigens, antibodies, clotting
factors, angiogenesis factors, regulatory proteins, transcription
factors, receptors, structural proteins, nucleic acid therapeutic
agents, and combinations thereof.
28. The tissue graft of claim 15, the first layer comprising an
extracellular matrix and the at least one fiber reinforcing the
extracellular matrix.
29. The tissue graft of claim 28, the second layer comprising
extracellular matrix.
30. The tissue graft of claim 28, wherein the extracellular matrix
is decellularized.
31. The tissue graft of claim 15, wherein the second layer
comprising a biocompatible substantially remodelable synthetic
material.
32. The tissue graft of claim 31, wherein the second layer
comprises a mesh of synthetic material.
33. The tissue graft of claim 15, wherein the fiber comprises a
natural or synthetic material.
34. The tissue graft of claim 15, wherein the first layer comprises
a mammalian-derived or plant-based collagen material.
35. The tissue graft of claim 15, wherein the at least one fiber is
radio-opaque to allow the location, integrity, and/or deformation
of the tissue graft to be assessed in a living system.
Description
RELATED APPLICATIONS
[0001] This application is a Continuation-in-Part of International
Application No. PCT/US2011/042138, filed Jun. 28, 2011, which
claims priority from U.S. Provisional Application No. 61/359,067,
filed Jun. 28, 2010, this application is also a
Continuation-in-part of U.S. patent application Ser. No.
12/934,791, filed Sep. 27, 2010, which is a National phase filing
of PCT/US2009/038570, filed Mar. 27, 2009, which claims priority
from U.S. Provisional Application Ser. No. 61/040,066, filed Mar.
27, 2008, and also claims priority from U.S. Provisional
Application Ser. No. 61/720,173, filed Oct. 30, 2012, the subject
matter of which are incorporated herein by reference in their
entirety.
TECHNICAL FIELD
[0002] The present invention is directed to tissue grafts and, in
particular, is directed to a multilayered, reinforced tissue
graft.
BACKGROUND OF THE INVENTION
[0003] Researchers have experienced major challenges in designing
methods to repair abdominal wall defects that result from traumatic
injuries, surgical procedures (incisional hernias) or chronic
diseases. Currently available synthetic and biological grafts have
demonstrated only limited success. The graft should be
biocompatible, have adequate mechanical properties and should also
degrade at an appropriate rate to permit transition of function
from the graft to native fascia. While the use of synthetic meshes
has lowered incidence rates of incisional hernias to below 10%,
these repairs are still frequently complicated by infection,
visceral adhesion, extrusion and fistulation, and require
re-operation. Biological grafts derived from decellularized
tissues, such as dermis or small intestinal submucosa (SIS), have
shown greater success than synthetics. They are better
vascularized, less prone to be complicated by visceral adhesions,
and can be used in the presence of contaminated or infected fields.
While grafts derived from acellular dermis possess biomechanical
properties that are similar to abdominal wall fascia, and have
shown promise for hernia repair, they lose mechanical strength and
integrity after implantation, resulting in laxity, stretching and
poor suture retention, which in turn can lead to complications,
such as bulging, dehiscence, and hernia recurrence. The dermis
products are also commonly available in small sizes, and require
pre-operative suturing of multiple pieces to repair large hernia
defects.
SUMMARY
[0004] This application relates to a biocompatible tissue graft
that includes a first layer of a bioremodelable collageneous
material and a second layer of biocompatible synthetic or natural
remodelable, substantially remodelable, or non-remodelable material
attached to the first layer. The graft further includes at least
one fiber that is stitched in a reinforcing pattern in the first
layer and/or second layer to mitigate tearing and/or improve
fixation retention of the graft, and substantially maintain the
improved properties while one or more layers of the graft
remodels.
[0005] The first layer can include an extracellular matrix, and the
second layer can include an extracellular matrix, a biocompatible
substantially remodelable synthetic material, or a biocompatible
non-remodelable synthetic material.
[0006] The fiber can include a natural or synthetic material and be
stitched into at least one of the first layer and/or the second
layer in, for example, a cross-hatched configuration or a
concentric pattern. In one example, the first layer and the second
layer can be stitched together with the fiber. In some embodiments,
the fiber can be selected from the group consisting of collagen,
silk, sericin free silk, modified silk fibroins, polyesters like
PGA, PLA, polylactic-co-glycolic acid (PLGA), polyethyleneglycol
(PEG), polyhydroxyalkanoates (PHA), polyethylene terephthalate
(PET), polyethylene (PE), ultra-high molecular weight polyethylene
(UHMWPE), blends thereof, and copolymers thereof.
[0007] In an aspect of the application, the first layer and/or the
second layer can include extracellular matrix that is
decellularized. The first layer and/or the second layer can also be
seeded with at least one differentiated cell or progenitor cell.
The first layer and/or the second layer can further include at
least one biologically active molecule selected from the group
consisting of drugs, sclerosing agents, enzymes, hormones,
cytokines, colony-stimulating factors, vaccine antigens,
antibodies, clotting factors, angiogenesis factors, regulatory
proteins, transcription factors, receptors, structural proteins,
nucleic acid therapeutic agents, such as plasmids, vectors, siRNA,
and micro-RNA, and combinations thereof.
[0008] This application also relates to a method of constructing a
biocompatible tissue graft. The method includes providing an
extracellular matrix layer, providing a synthetic layer, attaching
the extracellular matrix layer to the synthetic layer, and
stitching at least one fiber into the layers in a reinforcement
pattern to mitigate tearing and/or improve fixation retention of
the graft, and substantially maintain the improved properties while
one or more layers of the graft remodels.
[0009] The method can further include providing a second
extracellular matrix layer and attaching the second extracellular
layer to the first extracellular layer and/or the synthetic layer.
The fiber can be stitched into the extracellular matrix layers and
the synthetic layer in a reinforcement pattern to mitigate tearing
and/or improve fixation retention of the graft, and substantially
maintain the improved properties while one or more layers of the
graft remodels.
[0010] In an aspect of the application, the second extracellular
matrix layer is provided only at one end of the tissue graft.
[0011] The fiber can include a natural or synthetic material and be
stitched into at least one of the first extracellular matrix layer,
the second extracellular matrix layer, and/or the synthetic layer
in, for example, a cross-hatched configuration or a concentric
pattern. The first extracellular matrix layer, the second
extracellular layer, and/or the synthetic layer can also be
stitched together with the fiber.
[0012] In another aspect of the application, the graft can have a
multilayer construction and include a first layer, a second layer,
and a third layer. The first layer, the second layer, or the third
layer can comprise at least one layer of an extracellular matrix
and at least one layer of a biocompatible substantially remodelable
synthetic material or biocompatible non-remodelable synthetic
material. The first layer, the second layer, and/or third layer can
be stitched together with a fiber. In one example, the first layer
and the second layer can be stitched together with the fiber. In
another example, the first layer, the second layer, and the third
layer can be stitched together with the fiber. The fiber can be
stitched into the extracellular matrix layer(s) and optionally the
synthetic layer(s) in a reinforcement pattern to mitigate tearing
and/or improve fixation retention of the graft, and substantially
maintain the improved properties while one or more layers of the
graft remodels.
[0013] In some embodiments, the fiber can be selected from the
group consisting of collagen, silk, sericin free silk, modified
silk fibroins, polyesters like PGA, PLA, polylactic-co-glycolic
acid (PLGA), polyethyleneglycol (PEG), polyhydroxyalkanoates (PHA),
polyethylene terephthalate (PET), polyethylene (PE), ultra-high
molecular weight polyethylene (UHMWPE), blends thereof, and
copolymers thereof.
[0014] An aspect of the application also relates to a biocompatible
tissue graft that includes a first layer of a bioremodelable
collageneous material. A second layer of biocompatible synthetic or
natural remodelable or substantially remodelable material is
attached to the first layer. At least one fiber is stitched in a
reinforcing pattern in the first layer and/or second layer to
mitigate tearing of the graft, improve the fixation retention of
the graft, and/or limit cyclic stretching of the graft and
substantially maintain these properties following partial enzymatic
degradation of the graft while one or more of its layers remodels.
The at least one fiber has at least one free end that extends
beyond a peripheral surface of the tissue graft for securing the
tissue graft to a host tissue.
[0015] The fiber can be formed from a biocompatible material and
have a high modulus of elasticity and failure load. Examples of
biocompatible materials that can be used to form the fiber include
silk, sericin-free silk, modified silk fibroin, polyesters, such as
poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(ethylene
glycol) (PEG), polyhydroxyalkanoates (PHA) and polyethylene
terephthalate (PET), medical grade polyethylene, such as
polyethylene (UHMWPE), blends thereof and copolymers thereof, as
well as other biocompatible materials that are typically used in
forming biocompatible fibers for in vivo medical applications. The
fiber can additionally be radio-opaque (e.g., by adding an
opacifier, such as barium sulfate or tantalum to the fiber).
[0016] Another aspect of the application relates to a method of
constructing a biocompatible tissue graft. The method includes
providing a tissue graft that includes a first layer of a
bioremodelable collageneous material and a second layer of
biocompatible synthetic or natural remodelable or substantially
remodelable material. At least one fiber is stitched into at least
one of the layers in a reinforcement pattern to mitigate tearing of
the graft, improve the fixation retention of the graft, and/or
limit cyclic stretching of the graft and substantially maintain
these properties following partial enzymatic degradation of the
graft while one or more of its layers remodels. The at least one
fiber can have a free end that extends beyond a peripheral surface
of the graft and is effective for securing the graft to a host
tissue.
[0017] A further aspect of the application relates to a method for
repairing tissue in a subject. The method includes providing a
tissue graft that includes a first layer of a bioremodelable
collageneous material, a second layer of biocompatible synthetic or
natural remodelable or substantially remodelable material attached
to the first layer, and at least one fiber stitched in a
reinforcing pattern in the first layer and/or second to mitigate
tearing of the graft, improve the fixation retention of the graft,
and/or limit cyclic stretching of the graft and substantially
maintain these properties following partial enzymatic degradation
of the graft while one or more of its layers remodels. The at least
one fiber having at least one free end extending beyond a
peripheral surface of the tissue graft for securing the tissue
graft to a host tissue. A free end of the at least one fiber that
extends beyond the peripheral surface of the graft is secured to
the tissue in the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The foregoing and other features and advantages of the
present invention will become apparent to those skilled in the art
to which the present invention relates upon reading the following
description with reference to the accompanying drawings, in
which:
[0019] FIG. 1 is schematic illustration of a multilayer tissue
graft having reinforcement means in accordance with an embodiment
of the present invention;
[0020] FIG. 2 is a top view of a multilayer tissue graft having a
reinforcement means in accordance with another embodiment of the
present invention;
[0021] FIG. 3A is a top view of a multilayer tissue graft having a
reinforcement means in accordance with yet another embodiment of
the present invention;
[0022] FIG. 3B is a top view of a multilayer tissue graft having a
reinforcement means in accordance with yet another embodiment of
the present invention;
[0023] FIG. 3C is a top view of a multilayer tissue graft having a
reinforcement means in accordance with yet another embodiment of
the present invention;
[0024] FIG. 4A is a schematic illustration of a multilayer tissue
graft having a reinforcement means in accordance with yet another
embodiment of the present invention;
[0025] FIG. 4B is a top view of a multilayer tissue graft having a
reinforcement means in accordance with yet another embodiment of
the present invention;
[0026] FIGS. 5-8 are schematic illustrations of multilayer tissue
grafts in accordance with yet another embodiment of the present
invention;
[0027] FIG. 9 is graph illustrating average load-displacement
curves of dermis, synthetic mesh, dermis layered against mesh and
stitched together using 6PLA/2PGA polymer braids;
[0028] FIG. 10 is a graph illustrating increased suture retention
load of dermis and mesh layers stitched together with 6PLA/2PGA
polymer braids, compared to dermis or synthetic mesh alone or
dermis and mesh layers unstitched;
[0029] FIG. 11A is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with yet another aspect
of the present invention;
[0030] FIG. 11B is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with yet another aspect
of the present invention;
[0031] FIG. 12A is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with an aspect of the
present invention;
[0032] FIG. 12B is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with another aspect of
the present invention;
[0033] FIG. 13 is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with another aspect of
the present invention;
[0034] FIG. 14 is a schematic illustration of a multilayer tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with yet another aspect
of the present invention;
[0035] FIG. 15 is a schematic illustration of a circular multilayer
tissue graft having a reinforcement means that extends beyond the
periphery of the tissue graft in accordance with yet another aspect
of the present invention;
[0036] FIG. 16A is a schematic illustration of a multilayer tissue
graft having reinforcement means that includes concentric and
linearly extending portions with free ends that extend beyond the
periphery of the tissue graft in accordance with yet another aspect
of the present invention;
[0037] FIG. 16B is a schematic illustration of another multilayer
tissue graft having reinforcement means that includes concentric
and linearly extending portions with free ends that extend beyond
the periphery of the tissue graft in accordance with yet another
aspect of the present invention;
[0038] FIG. 17 is a photograph illustrating a reinforced tissue
graft having a reinforcement means that extends beyond the
periphery of the tissue graft.
[0039] FIG. 18A is a photograph illustrating a rotator cuff repair
augmented with a reinforced tissue graft having a reinforcement
means that extends beyond the periphery of the tissue graft;
[0040] FIG. 18B is a photograph illustrating a rotator cuff repair
augmented with only a reinforcing fiber;
[0041] FIG. 19 is a graph illustrating the cyclic gap formation of
rotator cuff repairs without augmentation or augmented with a
reinforced tissue graft or a reinforcing fiber alone;
[0042] FIG. 20 is a graph illustrating the cyclic gap formation of
rotator cuff repairs without augmentation or augmented with
additional reinforced tissue grafts or reinforcing fibers alone;
and
[0043] FIG. 21 is a graph illustrating cumulative cyclic elongation
(CCE) curves of native and fiber-reinforced dermis patches before
and after enzymatic degradation.
DETAILED DESCRIPTION
[0044] The present invention is directed to biocompatible tissue
grafts and, in particular, is directed to a multilayered,
fiber-reinforced tissue graft with improved fixation retention,
suture retention, and biomechanical strength properties. The fiber
includes at least one free end that extends beyond the periphery of
the tissue graft for securing the graft to host tissue. The tissue
graft can be used to treat a tissue defect of a subject (e.g.,
human being), such as a musculoskeletal defect, or in
tendon-to-bone repairs (e.g., rotator cuff injury), or soft-tissue
repairs, such as the repair of lacerated muscles, muscle transfers,
or use in tendon reinforcement. The tissue graft may also be used
as a bridging material in a subject in the case where the gap
between a tendon and the associated bone is too large to repair
conventionally. The tissue graft can be incorporated between the
bone-tendon interface and fixed to the bone and tendon to repair a
gap or tear.
[0045] The term "biocompatible" as used herein refers to a material
that is substantially non-toxic in the in vivo environment of its
intended use, and that is not substantially rejected by the
patient's physiological system (i.e., is non-antigenic). This can
be gauged by the ability of a material to pass the biocompatibility
tests set forth in International Standards Organization (ISO)
Standard No. 10993 and/or the U.S. Pharmacopeia (USP) 23 and/or the
U.S. Food and Drug Administration (FDA) blue book memorandum No.
G95-1. Typically, these tests measure a material's toxicity,
infectivity, pyrogenicity, irritation potential, reactivity,
hemolytic activity, carcinogenicity and/or immunogenicity. A
biocompatible material, when introduced into a majority of
patients, will not cause an undesirably adverse, long-lived or
escalating biological reaction or response, and is distinguished
from a mild, transient inflammation, which typically accompanies
surgery or implantation of foreign objects into a living
organism.
[0046] The biocompatible tissue graft can be used as an overlay
(i.e., over or at the interface of the repair), an interpositional
(i.e., to fill a space between a tissue and its attachment), or an
underlay (i.e., under or at the interface of the repair). In one
example, the tissue graft can be applied over the bone-tendon
repair site and fixed to the bone and tendon to augment the repair.
In another example, the tissue graft can be used to repair an
abdominal wall injury site or abdominal wall hernia. Abdominal
hernias can be repaired by onlay, inlay, or underlay techniques,
where the graft is placed over, within, or under the defect in the
abdominal wall muscle. The underlay technique involves placing the
tissue graft beneath the abdominal musculature (underlying the
hernia defect and extending beyond it), and anchoring the edges of
the graft to the muscle using sutures.
[0047] In accordance with an aspect of the application, the
biocompatible tissue graft can include a first layer of
bioremodelable collagenous material and a second layer of
biocompatible resorbable or non-resorbable synthetic or natural
remodelable, substantially remodelable, or non-remodelable material
attached to the first layer. The first and second layers define a
peripheral surface of the tissue graft. At least one fiber is
stitched in a reinforcing pattern in the first layer, second layer,
or both the first layer and second layer to mitigate tearing of the
graft, improve the fixation retention of the graft, and/or limit
cyclic stretching of the graft and substantially maintain these
properties following partial enzymatic degradation of the graft
while one or more of its layers remodels. The at least one fiber
includes at least one free end that extends beyond the peripheral
surface for securing the tissue graft to a host tissue.
[0048] The terms "remodelable" and "bioremodelable" as used herein
refer to the ability of the material to be resorbed by the host and
replaced by host tissue (i.e., remodeled from one material to
another). Remodeling can occur in various microenvironments within
a body, including without limitation soft tissue, a sphincter
muscle region, body wall, tendon, ligament, bone and cardiovascular
tissues. Upon implantation of a remodelable material, cellular
infiltration and neovascularization are typically observed over a
period of about 5 days to about 6 months or longer, as the
remodelable material acts as a matrix for the ingrowth of adjacent
tissue with site-specific structural and functional properties. The
remodelable material may be completely or partially resorbed and
replaced by the host during this time period.
[0049] The term, "substantially remodelable" materials as used
herein include materials that are unlikely to be completely
resorbed and replaced by host tissue. These materials can permit
tissue ingrowth at a much slower rate than the rate of tissue
growth in the remodelable material. Tissue growth through the
substantially remodelable material is typically only observable
after sufficient periods of implantation in a body vessel that
permit substantial amounts of tissue growth in the remodelable
material.
[0050] By substantially maintaining "the improved properties while
one or more layers of the graft remodels", it is meant that the
improved fixation properties, such as suture retention properties,
are maintained or minimally decreased after implantation of the
graft in vivo due to, for example, collagenase digestion of the
remodelable or substantially remodelable layers, while the
remodelable or substantially remodelable layers of the graft are
resorbed by the host and replaced by host tissue and until the host
tissues have sufficient strength.
[0051] In some instances, the bioremodelable collagenous material
used to form the first layer can include at least one sheet of the
mammalian-derived ECM. The ECM can be derived from any mammalian
ECM, such as fascia, and in particular, fascia lata from humans.
The ECM can be derived from other connective tissue materials, such
as dermis as long as the ECM is biocompatible with the target site
or the tissue injury being treated in the subject or both. The ECM
can also be derived, for example, from other tissues and/or other
materials, such as collagen, skin, bone, articular cartilage,
meniscus, myocardium, periosteum, artery, vein, stomach, large
intestine, small intestine (such as SIS), peritoneum, mesothelium,
diaphragm, tendon, ligament, neural tissue, meninges, striated
muscle, smooth muscle, bladder, ureter, abdominal wall fascia, and
combinations thereof.
[0052] The ECM used to form the first layer may be obtained
directly from mammalian tissue (such as an autograft, allograft or
xenograft). These tissues may be obtained from patients at the time
of surgery or a commercial source, such as a tissue bank medical
device company. ECM obtained from tissue banks and other commercial
sources may be formed using proprietary processing techniques or
modified by additional processing techniques before it is used. In
one example, these techniques can be used to remove cells and other
potentially infectious agents from the ECM.
[0053] In other instances, the bioremodelable collagenous material
used to form the first layer can comprise a collagenous sheet that
is derived from a mammalian source or is plant-based. For example,
the collagenous sheet may constitute collagen that is derived from
the peritoneum of pigs (Kensey Nash ECM Surgical Patch manufactured
by Kensey Nash Corporation of Exton, Pa.). In another example, the
collagenous sheet may constitute collagen that is derived from the
Procollagen of plants and sold under the trade name COLLAGE RH
(manufactured by CollPlant of Ness-Ziona, Israel). The COLLAGE RH
may be formed by collecting Procollagen from plants and processing
it into pure, fibrin forming collagen.
[0054] In some instances, the second layer can be formed from a
bioremodelable collagenous material as described above, a
substantially remodelable synthetic or natural material, or a
non-remodelable synthetic material. In an aspect of the
application, the second layer, when attached to the first layer,
can structurally reinforce and/or mechanically enhance the first
layer and the tissue graft. For example, the second layer can
exhibit a construction that facilitates retention of the
reinforcing means in the tissue graft and thereby helps to enhance
and/or substantially maintain suture retention as the first layer
remodels and prevents relative movement between the first layer and
the second layer.
[0055] In some examples described herein, the second layer can
include a two-dimensional or three-dimensional fibrous matrix or
mesh construct, which may be shaped or formed for the particular
application. Typically, the mesh is a pliable material, such that
it has sufficient flexibility to be wrapped around the external
surface of a body passageway or cavity, or a portion thereof. The
mesh may be capable of providing support to the graft. In certain
aspects, the mesh may be adapted to release an amount of a
therapeutic agent.
[0056] Mesh materials may take a variety of forms. For example, the
mesh may be in a woven, knit, or non-woven form and may include
fibers or filaments that are randomly oriented relative to each
other or that are arranged in an ordered array or pattern. In one
aspect, the mesh may be in the form of a fabric, such as a knitted,
braided, crocheted, woven, non-woven (e.g., a melt-blown, wet-laid,
or electrospun) or webbed fabric. In one aspect, the mesh may
include a natural or synthetic biodegradable polymer that may be
formed into a knit mesh, a weave mesh, a sprayed mesh, a web mesh,
a braided mesh, a looped mesh, and the like. Preferably, the mesh
has intertwined threads that form a porous structure, which may be,
for example, knitted, woven, or webbed.
[0057] The structure and properties of the mesh used in the graft
can depend on the application and the desired mechanical (i.e.,
flexibility, tensile strength, and elasticity) and degradation
properties, and the desired loading and release characteristics for
selected therapeutic agent(s). The mesh should have mechanical
properties such that the graft can remain sufficiently strong until
the surrounding tissue has healed. Factors that affect the
flexibility and mechanical strength of the mesh include, for
example, the porosity, fabric thickness, fiber diameter, polymer
composition (e.g., type of monomers and initiators), process
conditions, and the additives that are used to prepare the
material.
[0058] Typically, the mesh possesses sufficient porosity to permit
the flow of fluids through the pores of the fiber network and to
facilitate tissue ingrowth. Generally, the interstices of the mesh
should be wide enough apart to allow light visible by eye, or
fluids, to pass through the pores. However, materials having a more
compact structure also may be used. The flow of fluid through the
interstices of the mesh may depend on a variety of factors,
including, for example, the stitch count or thread density. The
porosity of the mesh may be further tailored by, for example,
filling the interstices of the mesh with another material (e.g.,
particles or polymer) or by processing the mesh (e.g., by heating)
in order to reduce the pore size and to create non-fibrous areas.
Fluid flow through the mesh can vary depending on the properties of
the fluid, such as viscosity, hydrophilicity/hydrophobicity, ionic
concentration, temperature, elasticity, pseudoplasticity,
particulate content, and the like. In one example, the interstices
of the mesh can be large enough so as to not prevent the release of
impregnated or coated therapeutic agent(s) from the mesh, and the
interstices preferably do not prevent the exchange of tissue fluid
at the application site.
[0059] Mesh materials can also be sufficiently flexible so as to be
capable of conforming to the shape of an anatomical surface and/or
the first layer. In certain cases, the mesh material may be
sufficiently flexible so as to be capable of being wrapped around
all or a portion of the first layer and/or the external surface of
a body passageway or cavity. Flexible mesh materials are typically
in the form of flexible woven or knitted sheets having a thickness
ranging from about 25 microns to about 3000 microns; preferably
from about 50 to about 1000 microns. Mesh materials for use in the
practice of the invention typically range from about 100 to 400
microns in thickness.
[0060] In some instances, the second layer may be formed of any one
or combination of known biocompatible, synthetic or natural
materials, including polypropylene (PP), polyurethane (PU),
expanded polytetrafluoroethylene (ePTFE), polylactic acid (PLA),
polyglycolic acid (PGA), polycaprolactone (PCL), polydioxanone
(PDO), trimethylene carbonate (TMC), polyvinyl alcohol (PVA),
poly(ethylene oxide), poly(acrylic acid), poly(vinyl alcohol),
poly(N-isopropyl acrylamide), poly(vinyl pyrrolidone) (PVP), poly
(methacrylic acid), poly(p-styrene carboxylic acid),
poly(p-styrenesulfonic acid), poly(vinylsulfonicacid),
poly(ethyleneimine), poly(vinylamine), poly(anhydride), poly(HEMA),
polyhydroxybutyrate (PHB), silk, ECM materials, such as
decellularized SIS, UBM, muscle, fibronectin, fibrin, fibrinogen,
collagen, fibrillar and non-fibrillar collagen, adhesive
glycoproteins, proteoglycans (e.g., heparin sulfate, chondroitin
sulfate, dermatan sulfate), hyaluronan, secreted protein acidic and
rich in cysteine (SPARC), thrombospondins, tenacin, and cell
adhesion molecules (including integrins, vitronectin, fibronectin,
laminin, hyaluronic acid, elastin), proteins found in basement
membranes, and fibrosin), albumin, sodium alginate and derivatives,
chitosan and derivatives gelatin, starch, cellulose polymers (for
example methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate phthalate, cellulose acetate succinate,
hydroxypropylmethylcellulose phthalate), casein, dextran and
derivatives, polysaccharides, poly(orthoesters), polyesters,
poly(hydroxyvaleric acid), polydioxanone, poly(ethylene
terephthalate), poly(malic acid), poly(tartronic acid),
polyanhydrides, polyphosphazenes, poly(amino acids). These
compositions include copolymers of the above polymers as well as
blends and combinations of the above polymers.
[0061] In one example, the second layer is constructed of a
medical-grade polypropylene mesh fabric commercially available from
ATEX technologies, Inc. (Pinebluff, N.C.). In another example, the
second layer is constructed of a polylactic acid mesh (X-Repair)
available from Synthasome, Inc. (San Diego, Calif.).
[0062] The reinforcing means can include any structure or material
that is applied to the first layer and/or second layer, is capable
of mitigating tearing of the graft when the graft is fixed to
tissue being treated, is capable of increasing or improving the
fixation retention properties of the tissue graft beyond that which
is present in a first and second layers alone, and/or can limit the
cyclic stretching of the graft, and substantially maintain these
properties following partial enzymatic degradation of the graft
while one or more of its layers remodels. The fixation retention
properties can be tailored to increase the graft's ability to
remain secured to anatomic structures, such as bone and soft
tissues, when used to treat a tissue defect. The multilayer graft
may be secured to these anatomical structures by, for example,
weaving, screws, staples, sutures, pins, rods, other mechanical or
chemical fastening means or combinations thereof. For instance, the
graft may be secured to the treated tissue via different suture
configurations, such as, massive cuff, mattress stitching and
simple suture and different fixation techniques, such as, Synthes
screw or Biotenodesis screw fixation and suture anchors with a
Krakow stitch.
[0063] In one aspect of the invention, the reinforcing means can
include a thread or strands of fiber(s) that are stitched in a
reinforcement pattern in the tissue graft. Fiber stitched in a
reinforcement pattern can increase the fixation properties of the
tissue graft, which will result in a tissue graft having improved
mechanical properties for implantation and repair of anatomical
defects in a subject. The reinforcement pattern can include any
stitch pattern that mitigates tearing of the graft, improves the
fixation retention of the graft, and/or limits cyclic stretching of
the graft and substantially maintain these properties following
partial enzymatic degradation of the graft while one or more of its
layers remodels. For example, the stitch pattern can include one or
more generally concentric, peripheral or cross-hatched stitch
patterns.
[0064] The fiber can enhance the fixation retention, mitigate
tearing, and limit cyclic stretching of the tissue graft once
stitched into the graft. The fiber can be formed from a
biocompatible material that is bioresorbable, biodegradable, or
non-resorbable. The term bioresorbable is used herein to mean that
the material degrades into components, which may be resorbed by the
body and which may be further biodegradable. Biodegradable
materials are capable of being degraded by active biological
processes, such as enzymatic cleavage.
[0065] One example of a biocompatible material that can be used to
form the fiber is silk. The silk may include, for example,
sericin-free silk fibroin or silk-fibroin modified with a peptide
sequence that sequesters growth factors in vivo, such as disclosed
in U.S. Pat. No. 6,902,932, which is herein incorporated by
reference. The fibers can also be formed from biodegradable
polymers including poly(glycolic acid) (PGA), poly(lactic acid)
(PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol)
(PEG), blends thereof, and copolymers thereof. By way of example,
the reinforcing fiber may include a core of PGA surrounded by a
sheath of reinforced PLA fibers. The PGA and PLA may be obtained,
for example, from Concordia Fibers in Coventry, R.I. Other examples
of biocompatible polymers that can be used to form the fiber are
resorbable polyesters, such as polyhydroxyalkanoates (PHA), and
non-resorbable fibers, such as polyethylene terephthalate (PET) and
ultra-high molecular weight polyethylene (UHMWPE). The
biocompatible fibers can also be formed from mammalian collagen or
plant-based collagen such as COLLAGE RH. It will be appreciated
that the biocompatible fiber can be formed from other biocompatible
materials, such as other biocompatible materials that are typically
used in forming biocompatible fibers for in vivo medical
applications.
[0066] In another example, the biocompatible polymer used to form
the fibers may be radio-opaque to allow the location, integrity,
and/or deformation (e.g., contraction or distension) of the tissue
graft to be assessed in a living system. Such a radio-opaque fiber
will also mitigate tearing of the graft, improve the fixation
retention of the graft, and/or limit cyclic stretching of the graft
and substantially maintain these properties following partial
enzymatic degradation of the graft while one or more of its layers
remodels.
[0067] Regardless of the material used for the fiber of the
reinforcing means, the fiber should exhibit a high modulus of
elasticity and a failure load tailored to meet particular design
criterion corresponding with in vivo strength requirements of the
treated tissue. For example, reinforced patches used for the
treatment of large and massive rotator cuffs should exhibit failure
loads of greater than about 250 Newtons (N) at a time of
implantation, and greater than about 150 N after about one week of
implantation in vivo. Alternatively, reinforcing patches used for
the treatment of tissues experiencing lower natural loads may be
required to exhibit failure loads of about 30 N to about 50 N. As
another example, fiber reinforced layers used for the treatment of
ventral abdominal wall defects and hernias should exhibit burst
strengths greater than 50 N/cm, suture retention strengths greater
than 20 N, tear resistance greater than 20 N, and strain at 16 N/cm
load between about 10% and about 30%, at the time of implantation,
and substantially maintain these properties after implantation in
vivo until the host tissues have sufficient strength. It will be
understood, however, that the fibers, their stitch design (i.e.,
reinforcement pattern), or the particular first and second layers
can be tailored to produce failure loads of the fiber-reinforced
tissue graft commensurate in scale to any tissue treated within the
body.
[0068] In still other instances, at least one of the fibers, the
first layer, and the second layer (where applicable) can be
mechanically, chemically or biologically modified to enhance
adhesion between the fibers, the first layer, and the second layer
to further secure the first layer to the second layer and/or fibers
to the first layer and the second layer. This modification may
occur before or after attachment of the first layer to the second
layer as well as before or after the fibers are incorporated into
the first layer and the second layer. This modification may be
performed on a portion of or substantially all of the stitched
fibers or the first layer or the second layer or all three. During
loading of the tissue graft, the fibers may begin to displace
relative to the first layer and/or the second layer and may
ultimately completely slip out from the first layer and the second
layer and become the primary load bearing components of the
reinforced tissue construct. It therefore becomes desirable to
mitigate or prevent fiber slippage in order to ensure that usage
loads are borne by the entire graft and not just the fibers.
Adhesion characteristics of the fibers can be improved by ablation
via ultra-violet (UV) or infrared (IR) light, UV cross-linking or
chemical cross-linking, plasma etching, ion etching, coating the
fibers with microspheres, application of adhesives, such as
biocompatible synthetic adhesives, bioadhesives, or combinations
thereof. These treatments can likewise be performed on the first
layer and the second layer.
[0069] In another instance, the first layer and/or the second layer
can be seeded with a single type or a plurality of differentiated
cells or progenitor cells that become dispersed in the first layer
and/or second layer. Examples of differentiated cells are
fibroblasts, chondrocytes, osteoblasts, tenocytes, skeletal muscle
cells, smooth muscle cells, endothelial cells, and neural cells.
Examples of progenitor cells are bone marrow-derived progenitor
cells, adipose derived stem cells, hematopoietic stem cells,
endothelial progenitor cells, mesenchymal stem cells, multipotent
adult progenitor cells (MAPCs), embryonic stem cells, stromal
cells, and induced pluripotent stem cells. The differentiated and
progenitor cells can be autologous, allogeneic, xenogeneic or a
combination thereof. The differentiated and progenitor cells can
also be genetically modified. Genetically modified cells can
include cells that are transfected with an exogenous nucleic acid
and that express a polypeptide of interest including, for example,
a growth factor, a transcription factor, a cytokine, and/or a
recombinant protein.
[0070] The first layer and/or second layer of the multilayer graft
can additionally or optionally include at least one biologically
active molecule dispersed or seeded therein. Any desired
biologically active molecule can be selected for impregnating into
the ECM. For example, the biologically active molecule can include
antibiotics, sclerosing agents, enzymes, hormones, cytokines,
colony-stimulating factors, vaccine antigens, antibodies, clotting
factors, angiogenesis factors, regulatory proteins, transcription
factors, receptors, structural proteins, nucleic acid therapeutic
agents, such as plasmids, vectors, siRNA, and micro-RNA, and
combinations thereof. The biologically active molecule can be
chosen based on where the musculoskeletal graft is to be located in
the subject or the physiological requirements of the subject or
both. For example, if the musculoskeletal graft is used to repair a
tendon, the biologically active molecule which is seeded on or into
the ECM can be a growth factor such as IGF-I, TGF-.beta., VEGF,
bFGF, BMP or combinations thereof.
[0071] Optionally, a high-molecular weight (e.g., greater than
about 250 kDa) hyaluronic acid (HA) can be incorporated into the
multilayer tissue graft prior to, during, or after stitching of the
fibers into the first layer and/or the second layer. When
incorporated into the multilayer tissue graft, HA can potentially
inhibit the migration of inflammatory cells, induce the migration
of non-inflammatory cells, and promote angiogenesis, which would
promote integration of the tissue graft with the underlying host
tissues.
[0072] The high-molecular weight HA can be cross-linked within the
first layer and/or the second layer to mitigate diffusion of the HA
from the first layer and/or second layer. Cross-linked,
high-molecular-weight HA can be retained in the first layer and/or
second layer for extended periods in vitro. An example of a
cross-linked HA material that can be used in this application is
prepared by substituting tyramine moieties onto the HA chains and
then linking tyramines to form dityramine linkages between HA
chains, effectively cross-linking or gelling the HA into the first
layer and/or the second layer. Examples of dityramine-cross-linked
HA composition and chemistry are disclosed in U.S. Pat. Nos.
6,982,298 and 7,465,766 and U.S. Application Publications Nos.
2004/0147673 and 2005/0265959, which are herein incorporated by
reference in their entirety. The tyramine-substitution rate on the
HA molecules may be about five percent based on available
substitution sites as disclosed in the aforementioned
publications.
[0073] TS-HA can be impregnated into the first layer and/or the
second layer, and then immobilized within the first layer and/or
second layer by cross-linking of the tyramine adducts to form
dityramine linkages, thereby producing a cross-linked HA
macromolecular network. The TS-HA can be impregnated into the first
layer and/or second layer prior to or after stitching the first
layer and/or second layer. The TS-HA can be used to attach
fibronectin functional domains (FNfds) to the first layer and/or
second layer in order to further promote healing, cell migration,
and anti-inflammatory capabilities. FNfds possess the ability to
bind essential growth factors that influence cell recruitment and
proliferation (e.g., PDGF-BB and bFGF). The FNfds may, for example,
constitute fibronectin peptide "P-12" with a C-terminal tyrosine to
allow it to be cross-linked to TS-HA.
[0074] Optionally, tyramine-substituted gelatin (TS-gelatin) can be
immobilized within and on the surface of fascia ECM by
cross-linking of the tyramine adducts to form dityramine bridges.
The TS-gelatin can elicit a host macrophage response and thus
promote cellular infiltration and scaffold integration. (See for
example, U.S. Pat. Nos. 6,982,298 and 8,137,688, both of which are
incorporate by reference in their entirety).
[0075] Optionally, a high-molecular weight (e.g., greater than
about 250 kDa) hyaluronic acid (HA) can be incorporated into the
tissue graft prior to, during, or after stitching of the fibers
into the ECM. When incorporated into the tissue graft, HA can
potentially inhibit the migration of inflammatory cells, induce the
migration of non-inflammatory cells, and promote angiogenesis,
which would promote integration of the ECM with the underlying host
tissues.
[0076] The high-molecular weight HA can be cross-linked within the
ECM to mitigate diffusion of the HA from the ECM. Cross-linked,
high-molecular-weight HA can be retained in ECM for extended
periods in vitro. An example of a cross-linked HA material that can
be used in this application is prepared by substituting tyramine
moieties onto the HA chains and then linking tyramines to form
dityramine linkages between HA chains, effectively cross-linking or
gelling the HA into the ECM. Examples of dityramine-cross-linked HA
composition and chemistry are disclosed in U.S. Pat. Nos. 6,982,298
and 7,465,766 and U.S. Application Publications Nos. 2004/0147673
and 2005/0265959, which are herein incorporated by reference. The
tyramine-substitution rate on the HA molecules may be about five
percent based on available substitution sites as disclosed in the
aforementioned publications.
[0077] TS-HA can be impregnated into the ECM, and then immobilized
within ECM by cross-linking of the tyramine adducts to form
dityramine linkages, thereby producing a cross-linked HA
macromolecular network. The TS-HA can be impregnated into the ECM
prior to or after stitching the ECM. The TS-HA can be used to
attach fibronectin functional domains (FNfds) to the ECM in order
to further promote healing, cell migration, and anti-inflammatory
capabilities. FNfds possess the ability to bind essential growth
factors that influence cell recruitment and proliferation (e.g.,
PDGF-BB and bFGF). The FNfds may, for example, constitute
fibronectin peptide "P-12" with a C-terminal tyrosine to allow it
to be cross-linked to TS-HA.
[0078] One example of a multilayer tissue graft in accordance with
an aspect of the application is illustrated in FIG. 1. The tissue
graft 110 includes first and second layers 120 and 121 of
biocompatible material. Each of the first layer 120 and the second
layer 121 can include a bioremodelable collagenous material, e.g.,
an ECM layer, or a substantially remodelable or non-remodelable
synthetic or natural material. Reinforcing means 122 are provided
in the first and second layers 120 and 121 in a reinforcing
pattern.
[0079] The tissue graft 110 is illustrated as having a generally
rectangular strip shape (e.g., about 5 cm long by about 2 cm wide)
although the graft 110 can have other shapes, such as an elliptical
shape, a circular shape, a square shape, etc. (e.g., FIGS. 2-4).
The graft 110 includes a top surface 124 and a substantially
parallel bottom surface 126 spaced from the top surface. A first
side 128 and second side 130 connect the top surface 124 to the
bottom surface 126. The first and second sides 128, 130 extend
generally parallel to one another. The graft 110 further includes a
front surface 132 and rear surface 134 which connect the first side
128 to the second side 130. The front and rear surfaces 132, 134
extend generally parallel to one another. Each of the surfaces
124-134 is formed by the first layer 120 and the second layer
121.
[0080] The reinforcing means 122 can include at least one fiber
disposed or provided within the first layer 120 and/or the second
layer 121 by, for example, conventional stitching techniques. By
stitching, it is meant that at least one fiber of the reinforcing
means 122 is stitched into the first layer 120 and/or second layer
121 such that each stitch of the reinforcing means extends between
and through both the top surface 124 and the bottom surface 126 of
the first layer 120 and/or second layer 121 to securely fasten the
reinforcing means to the first layer and/or second layer.
[0081] The reinforcing means 122 may exhibit any reinforcement
configuration or pattern that increases the fixation properties of
the graft 110. One such configuration is illustrated in FIG. 1 in
which first and second fibers 140, 142 are stitched into the first
layer 120 and second layer 121 in geometrically concentric
configurations. Additionally or alternatively, the stitch lines of
the fibers can be placed further away from the edges of the graft
110 to delay, mitigate, or prevent slipping of the fibers 140, 142
within the first layer 120 and second layer 121. Although FIG. 1
illustrates two fibers in a geometrically concentric pattern 143,
it will be understood that more or fewer fibers can be stitched
into the first layer 120 and second layer 121 in a geometrically
concentric pattern. Additionally, it will be appreciated that
additional fibers can be stitched into the first layer 120 and/or
second layer 121 in other reinforcement patterns.
[0082] As shown in FIG. 1, the first fiber 140 can extend
substantially parallel to, and be spaced inwardly from, the
periphery of the graft 110. By way of example, the first fiber 140
can extend substantially parallel to the first and second sides
128, 130 and the front and rear surfaces 132, 134 of the graft 110
such that the first fiber exhibits a generally rectangular
configuration. The first fiber 140 can comprise a plurality of
interconnected stitches 141. The ends of the fiber 140 may be
stitched together (not shown) to form a continuous stitching
construction.
[0083] The second fiber 142 can extend substantially parallel to
the first fiber 140 and be disposed radially inward of the first
fiber within the graft 110. In this configuration, the first and
second fibers 140, 142 form a generally geometrically concentric
construction in a peripheral double pass orientation. The second
fiber 142 can comprise a plurality of interconnected stitches 145.
The second fiber can be substantially uniformly spaced inward from
the first fiber 140 by a gap indicated by "s.sub.1". The gap
s.sub.1 may be, for example, on the order of about 1 mm to about 3
mm (e.g., about 2 mm), although other spacing configurations will
be understood. It will be appreciated that although the gap s.sub.1
between the fibers 140 and 142 is substantially uniform, the gap
s.sub.1 may vary depending on reinforcement pattern in which the
fibers 140 and 142 are stitched. The ends of the second fiber 142,
like first fiber 140, may be stitched together (not shown) to form
a continuous stitching construction.
[0084] The first fiber 140 and the second fiber 142 can be stitched
in the graft so that the number of stitches per inch is, for
example, about 10 stitches per inch to about 20 stitches per inch
(e.g., about 15 stitches per inch). Generally, the more stitches
per inch, the greater the strength of the reinforcing means 122 and
the fixation retention properties of the tissue graft 110. In some
examples, however, it may be desirable to use less stitches per
inch to avoid excessive needle penetrations in the first layer 120
and/or second layer 121, which may potentially weaken the tissue
graft 110.
[0085] Other examples of concentric reinforcement stitch patterns
or configurations are illustrated in FIG. 1 and FIGS. 3A-3C. The
configurations in FIG. 2 and FIGS. 3A-3C are similar to the
configuration of FIG. 1, except that in FIG. 2 the graft 110 is
substantially circular and therefore the reinforcing means 122 is
provided in the graft in a generally circular configuration or
orientation. FIG. 2 illustrates one example of a graft 110 that
includes generally concentric reinforcement means 122 in a
peripheral double pass orientation. The reinforcement means 122
includes a first fiber 140 that comprises a plurality of
interconnected stitches 141 and a second fiber 142 that comprises a
plurality of interconnected stitches 145. The first fiber 140 can
extend substantially parallel to, and be spaced inwardly from, a
peripheral surface 133 of the graft 110 such that the first fiber
has a generally circular configuration. The second fiber 142 can
extend substantially parallel to the first fiber 140 and be
disposed radially inward of the first fiber within the graft 110.
In this configuration, the first and second fibers 140, 142 form a
generally concentric construction.
[0086] FIG. 3A illustrates another example of the reinforcing means
122 comprising two concentric patterns 143. Each concentric pattern
143 includes a first strand 140 that comprises a plurality of
interconnected stitches 141 and a second strand 142 that comprises
a plurality of interconnected stitches 145. Each first fiber 140
can extend substantially parallel to, and be spaced inwardly from,
a peripheral surface 133 of the graft 110 such that each first
fiber has a generally circular configuration. Each second fiber 142
can extend substantially parallel to the first fiber 140 and be
disposed radially inward of the first fiber within the graft 110.
In this configuration, each pair of first and second fibers 140,
142 form a generally concentric construction. Although the two
concentric patterns 143 are illustrated as being substantially
semi-circular, it will be understood that each concentric pattern
may exhibit alternative constructions such as, for example,
rectangular (e.g., in a two rectangle double pass orientation),
elliptical, triangular or combinations thereof within the spirit of
the present invention.
[0087] FIG. 3B illustrates another example of the reinforcing means
122 comprising three concentric patterns 143. Each concentric
pattern 143 comprises a first strand 140 comprising a plurality of
interconnected stitches 141 and a second strand 142 comprising a
plurality of interconnected stitches 145. Each first fiber 140 can
extend substantially parallel to, and be spaced inwardly from, a
peripheral surface 133 of the graft 110 such that each first fiber
has a generally circular configuration. Each second fiber 142 can
extend substantially parallel to the first fiber 140 and be
disposed radially inward of the first fiber within the graft 110.
In this configuration, each pair of first and second fibers 140,
142 form a generally concentric construction. It will be understood
that each concentric pattern may exhibit any constructions such as,
for example, rectangular (e.g., in a three rectangle double pass
orientation), elliptical, triangular, semi-circular, circular or
combinations thereof within the spirit of the present
invention.
[0088] FIG. 3C illustrates yet another example of a reinforcing
means 122 that includes a plurality of first strands 140, which
comprise a plurality of interconnected stitches 141 but without or
free of concentric second strands 142. In particular, the first
strands 140 may comprise four substantially parallel and elliptical
discrete first strands. Although the four first strands 140 are
illustrated as being substantially elliptical, it will be
understood that each first strands may exhibit alternative
constructions such as, for example, rectangular (e.g., in a four
rectangle single pass orientation), semi-circular, circular,
triangular or combinations thereof within the spirit of the present
invention. It will also be understood that one or more of the first
strands could have a geometrically concentric pattern with a second
strand within the spirit of the present invention.
[0089] FIG. 4A is a schematic illustration of a tissue graft 110
that includes a first layer 120, second layer 121, and a
reinforcing means 122 in accordance with another example of the
graft. The reinforcing means 122 includes a plurality of first
fibers 140 and a plurality of second fibers 142 stitched in a
cross-hatched pattern across the graft 110 and between the first
and second sides 128, 130 and the front and rear surfaces 132, 134.
Although FIG. 4A illustrates six first fibers 140 and eight second
fibers 142, it is understood that more or less of each fiber may be
utilized in accordance with the present invention. The first fibers
140 can extend in a first direction, indicated by "d.sub.1", across
the top surface 124 of the graft 110 from the first side 128 to the
second side 130. Each of the first fibers 140 can extend parallel
to one another and be spaced apart by a gap indicated by "s.sub.1".
The gap s.sub.1 may be, for example, on the order of about 1 mm to
about 3 mm, although other spacing configurations will be
understood. The gap s.sub.1 may be uniform or may vary between
first fibers 140.
[0090] The second fibers 142 can extend in a second direction,
indicated by "d.sub.2", across the top surface 124 of the graft 110
from the front surface 132 to the rear surface 134. The directions
"d.sub.1" and "d.sub.2" in which the first and second fibers 140,
142 extend may be configured such that the first fibers and the
second fibers are oriented perpendicular to each other. Each of the
second fibers 142 can extend parallel to one another and be spaced
apart by a gap indicated by "s.sub.2". The gap s.sub.2 may be, for
example, on the order of about 1 mm to about 3 mm, although the gap
can have other spacing configurations. The gap s.sub.2 may be
uniform or may vary between second fibers 142. The second fibers
142 are disposed in an overlying fashion relative to the first
fibers 140 such that the first fibers are disposed between the top
surface 124 of the graft 110 and the second fibers. The second
fibers 142, however, could alternatively be disposed between the
top surface 124 of the graft 110 and the first fibers 140.
[0091] FIG. 4B illustrates that the reinforcing means 122 comprises
a plurality of first fibers 140 and a plurality of second fibers
142 stitched in a cross-hatched pattern across the graft 110 and
between the first and second sides 128, 130 and the front and rear
surface 132, 134. Although FIG. 4B illustrates four first fibers
140 and four second fibers 142, it is understood that more or less
of each fiber may be utilized in accordance with the present
invention. Each of the first fibers 140 extends from the first side
128 to the second side 130 of the graft 110. Each of the second
fibers 142 extends from the front surface 132 to the rear surface
134 of the layer 120. The ends of the first fibers 140 and the ends
of the second fibers 142, respectively, may be stitched together
(not shown) to form a continuous stitching construction.
[0092] The second fibers 142 are disposed in an overlying fashion
relative to the first fibers 140 such that the first fibers are
disposed between the top surface 124 of the graft 110 and the
second fibers. The second fibers 142, however, could alternatively
be disposed between the top surface 124 of the graft 110 and the
first fibers 140. Although the first and second fibers 140, 142 are
illustrated as having a substantially rectangular shape (e.g., a
rectangular cross-hatch orientation), it will be understood that
the first fiber and/or the second fiber may exhibit alternative
constructions such as elliptical, semi-circular, circular,
triangular or combinations thereof within the spirit of the present
invention.
[0093] FIGS. 5-8 illustrate various tissue graft constructions 200,
300, 400, 500 having multiple layers in accordance with another
aspect of the present invention. In FIG. 5, the tissue graft 200
includes first and second layers 210, 220 of biocompatible
material. Each of the first layer 210 and the second layer 220 can
include a bioremodelable collagenous material (e.g., an ECM layer)
or a substantially remodelable or non-remodelable synthetic or
natural material. Reinforcing means 122 are provided in the first
and second layers 210, 220 in a reinforcing pattern as previously
described. As shown in FIG. 5, the reinforcing means 122 comprises
a plurality of first fibers 140 and a plurality of second fibers
142 stitched in a cross-hatched pattern across and through both
layers 210, 220 in order to mitigate tearing of the first and/or
second layers, improve fixation retention of the first and/or
second layers, and/or limit the cyclic stretching of the first
and/or second layers and substantially maintain these properties
following partial enzymatic degradation of the graft while one or
more of its layers remodels.
[0094] In FIG. 6, the tissue graft 300 includes first and second
layers 310, 320. The first layer 310 may constitute a
bioremodelable collagenous material (e.g., an ECM layer). The
second layer 320 is formed from at least two portions 322, 324 of
material that are each different than the material of the first
layer 310. Each portion 322, 324 of material may constitute a
bioremodelable collagenous material (e.g., an ECM layer) or a
substantially remodelable or non-remodelable synthetic or natural
material. The portions 322, 324 of material may collectively form a
second layer 320 that is the same size as the first layer 310 or a
different size. The portions 322, 324 of material of the second
layer 320 may abut one another or may be spaced from one another on
the first layer 310. As shown in FIG. 6, the portions 322, 324 of
material abut one another and are sized such that the first and
second layers 310, 320 have the same size and shape. Reinforcing
means 122 are provided in the first and second layers 310, 320 in a
reinforcing pattern as previously described. As shown in FIG. 6,
reinforcing means 122 comprises a plurality of first fibers 140 and
a plurality of second fibers 142 stitched in a cross-hatched
pattern across and through both layers 310, 320 in order to
mitigate tearing of the first and/or second layers, improve
fixation retention of the first and/or second layers, and/or limit
the cyclic stretching of the first and/or second layers and
substantially maintain these properties following partial enzymatic
degradation of the graft while one or more of its layers
remodels.
[0095] In FIG. 7, the tissue graft 400 includes first, second, and
third layers 410, 420, 430. Each of the first layer 410, the second
layer 420, and the third layer 430 may constitute a bioremodelable
collagenous material (e.g., an ECM layer) or a substantially
remodelable or non-remodelable synthetic or natural material. In
one instance, the second layer 420 comprises a synthetic layer
sandwiched between ECM layers 410, 430. The third layer 420 may be
sized and positioned to extend across only one end of the graft 400
overlying the first layer 410 or the second layer 420. In other
words, the third layer 430 only partially covers the first layer
410 or the second layer 420, thereby leaving the remainder of the
first layer or the second layer exposed. Reinforcing means 122 are
provided in the first, second, and third layers 410, 420, 430 in a
reinforcing pattern as previously described. As shown in FIG. 7,
the reinforcing means 122 comprises a plurality of first fibers 140
and a plurality of second fibers 142 stitched in a cross-hatched
pattern across and through all three layers 410, 420, 430 in order
to mitigate tearing of the first, second, and/or third layers,
improve fixation retention of the first, second, and/or third
layers, and/or limit the cyclic stretching of the first, second,
and/or third layers and substantially maintain these properties
following partial enzymatic degradation of the graft while one or
more of its layers remodels.
[0096] In FIG. 8, the tissue graft 500 includes first, second, and
third layers 510, 520, 530. Each of the first layer 510, the second
layer 520, and the third layer 530 may be a bioremodelable
collagenous material (e.g., an ECM layer) or a substantially
remodelable or non-remodelable synthetic or natural layer. In one
instance, the second layer 520 comprises a synthetic layer
sandwiched between ECM layers 510, 530. Unlike the graft 400 of
FIG. 7, however, the third layer 520 of the graft 500 of FIG. 8 is
sized and positioned to extend across the entire first layer 510 or
the second layer 520. Reinforcing means 122 are provided in the
first, second, and third layers 510, 520, 530 in a reinforcing
pattern as previously described. As shown in FIG. 8, the
reinforcing means 122 comprises a plurality of first fibers 140 and
a plurality of second fibers 142 stitched in a cross-hatched
pattern across and through all three layers 510, 520, 530 in order
to mitigate tearing of the first, second, and/or third layers,
improve fixation retention of the first, second, and/or third
layers, and/or limit the cyclic stretching of the first, second
and/or third layers and substantially maintain these properties
following partial enzymatic degradation of the graft while one or
more of its layers remodels.
[0097] In FIGS. 5-8, the layers forming the tissue grafts 200, 300,
400 or 500 may be bonded or secured to one another prior to
incorporating the reinforcing means 122 into the layers. The layers
may, for example, be laminated, vacuum pressed, lyobonded (i.e.,
bonding using the lyophlization process), heated, partially
cross-linked, etc. prior to incorporating the reinforcing means 122
into the layers. In such a case, the reinforcing means 122 not only
improves fixation retention in the grafts 200, 300, 400 or 500 but
also helps to minimize relative movement between layers of the
grafts. Alternatively, the layers may be simply placed overlying
one another prior to incorporating the reinforcing means 122 into
the layers. Furthermore, some layers or portions of layers of each
tissue graft 200, 300, 400 or 500 may be secured together prior to
incorporating the reinforcing means 122 while other portions or
layers of the tissue graft remain unsecured to other layers or
portions in accordance with the present invention.
[0098] In instances where the grafts 200, 300, 400 or 500 include
synthetic layers, the synthetic layers help to strengthen and
reinforce the graft and facilitate the incorporation of the
reinforcing means 122 into the graft. Those having ordinary skill
appreciate that although grafts formed from only two and three
layers are illustrated, the grafts may be formed from any number of
layers of bioremodelable collagenous material or substantially
remodelable or non-remodelable synthetic or natural material having
reinforcing means incorporated therein in accordance with the
present invention.
[0099] The tissue graft of the present invention can be used in
tissue engineering and musculoskeletal repair, such as rotator cuff
repair, but is not restricted to musculoskeletal applications. The
graft may be administered to a subject to mechanically and
biologically augment the repair. As discussed above, the tissue
graft can be used as overlay (i.e., over or at the interface of the
repair), an interpositional (i.e., to fill a space between a tissue
and its attachment), or an underlay (i.e., under or at the
interface of the repair). It will be appreciated that similar
methods and materials as described herein could also be adapted to
other tendon-to-bone repairs, soft-tissue repairs, such as the
repair of lacerated muscles, muscle transfers, spanning a large
muscle defect, or use in tendon reinforcement. These applications
require secure connections between the graft 110, 200, 300, 400 or
500 and the anatomical site. Fixation techniques to soft tissue
using conventional or novel suture methods, or the Pulvertaft weave
technique (M. Post, J Shoulder Elbow Surg 1995; 4:1-9) may be
utilized in accordance with the present invention.
[0100] Fixation techniques to bone using conventional or novel
suture methods, anchors, screws, plates, adhesives, staples or
tacks may be utilized in accordance with the present application.
The graft 110, 200, 300, 400 or 500 may also serve as a delivery
platform for the future investigation of any number of biologic
strategies aimed to enhance muscular skeletal repair (e.g., rotator
cuff healing). Furthermore, the graft 110, 200, 300, 400 or 500
could be effective for other needs in the field of surgical
reconstruction including soft-tissue repairs, such as the repair of
lacerated muscles, muscle transfers, abdominal wall reconstruction,
hernia repair, repair of compartment syndrome releases, tendon
reinforcement, or as a bridging material in a subject also be used
as a bridging material in a subject, such as where the gap between
a tendon and the associated bone is too large to repair
conventionally or in abdominal wall procedures with loss of tissue
domain.
[0101] The graft 110, 200, 300, 400, 500 may also serve as a
platform for the future investigation of any number of graft
strategies aimed to enhance muscular skeletal repair, e.g., rotator
cuff healing. Furthermore, the graft 110, 200, 300, 400, 500 could
be effective for other needs in the field of surgical
reconstruction, including ligament reconstruction, abdominal wall
repair, and tendon reconstruction in the setting of post-surgical
repair failure, trauma, and segmental defects.
[0102] The following examples are illustrative of the principles
and practice of this invention. Numerous additional embodiments
within the scope and spirit of the invention will become apparent
to those skilled in the art.
Example 1
[0103] This example shows stitching dermis and synthetic mesh
together using reinforcing fiber improves the mechanical properties
of the construct and mitigates tearing and/or improves fixation
retention of the layers compared to using either material alone or
both materials without stitching them together.
[0104] In this example, four groups were investigated: [0105] 1.
Dermis (native acellular dermis) [0106] 2. Mesh (synthetic UHMWPE
mesh) [0107] 3. Dermis layered against mesh (but not stitched)
[0108] 4. Dermis layered against mesh and stitched together using
6PLA/2PGA polymer braids.
[0109] Uniaxial suture retention tests were used to verify the
efficacy of stitching as a method to reinforce the two layers and
improve the mechanical properties of the construct by mitigating
tearing and/or improving fixation retention of the layers.
[0110] All human dermis grafts included allogeneic or xenogeneic
dermis. All 6PLA/2PGA braids used for reinforcing the layers were
obtained from Concordia Fibers, Coventry, R.I.
Uniaxial Suture Retention Test
[0111] A sample size (n=3-4) was used in each group. Each specimen
consisted of 1.5 cm wide.times.4.5 cm long strips of dermis and/or
mesh. Dermis and mesh layers were stitched using a 6PLA/2PGA
polymer braid (diameter: 400 um).
[0112] All specimens were hydrated for 30 minutes in saline
solution at 37.degree. C. A single simple suture loop of #2
FiberWire was applied using a reverse cutting needle, 7.5 mm from
one 1.5 cm wide edge; a template was used to assure uniformity in
the placement of the sutures. The suture loop was fixed on a hook
mounted on the cross head of a MTS 5543 table top system using a
100 lb load cell. The other end of the strip was clamped in 7.5
mm-deep clamps mounted on the MTS base. The specimen was stretched
at 30 mm/min and the mode of failure was recorded. The suture
retention load was defined as the maximum load attained by the
specimen.
[0113] The results of this test are illustrated in FIG. 9, FIG. 10
and Table 1. FIG. 9 (average load-displacement curves) shows that
compared to the other three groups, stitching the dermis and
synthetic mesh layers together increased toe-stiffness, made the
load-displacement curves more linear (increased toe:linear
stiffness ratio) and significantly increased suture retention
load.
TABLE-US-00001 TABLE 1 Summary of results from suture retention
tests of dermis, synthetic mesh, dermis and mesh layers unstitched
and dermis and mesh layers stitched together using 6PLA/2PGA
polymer braids. Like letters indicate a significant difference (P
< 0.05) between groups. Dermis + Mesh (Dermis + Mesh) Dermis (n
= 3) Mesh (n = 4) Unstitched (n = 3) Stitched (n = 3) Toe Stiffness
(N/mm) 0.6 .+-. 0.1.sup.a,b 0.3 .+-. 0.01.sup.a.c.d 0.7 .+-.
0.04.sup.c,e 1.7 .+-. 0.1.sup.b,d,e Linear Stiffness (N/mm) 8.3
.+-. 2.1.sup.a 9.3 .+-. 1.5 12.4 .+-. 3.0 13.7 .+-. 0.1.sup.a Toe:
Linear Stiffness Ratio (%) 7 .+-. 0.8.sup.a,b 3 .+-. 0.5.sup.a,c,d
6 .+-. 1.2.sup.c,e 12 .+-. 1.0.sup.b,c,e Suture Retention Load (N)
63.9 .+-. 13.3.sup.a,b,c 94.3 .+-. 6.3.sup.a,d,e 140.9 .+-.
12.9.sup.b,d,f 218.2 .+-. 14.3.sup.c,e,f
[0114] These data demonstrate that stitching dermis and synthetic
mesh together using reinforcing fiber improves the mechanical
properties of the construct and improves suture fixation retention
of the layers compared to using either material alone or both
materials without stitching them together.
Example 2
[0115] In this example, the biodegradable layer is stitched to a
synthetic mesh layer with a stitch pattern known to impart a suture
retention load to the construct that is greater than the suture
retention load of the dermis alone, the mesh alone, or dermis and
mesh that are not stitched together (Example 1). The biodegradable
layer could be, for example, ECM derived from human allogeneic or
xenogeneic dermis, the synthetic mesh could be made from
polypropylene and the stitching fiber could be a PLLA/PGA braid
obtained from Concordia Fibers, Coventry, R.I. In other
embodiments, the synthetic mesh and the stitching fiber could be
derived from other synthetic biomaterials with different
biodegradation profiles (such as UHMWPE, ePTFE, PLGA and PLLA) or
natural biomaterials (such as silk and collagen).
[0116] The stitched biodegradable and synthetic mesh layered
constructs are hydrated for 30 minutes in saline solution at
37.degree. C. A single simple suture loop of #2 FiberWire is
applied to each construct 7.5 mm from one end using a reverse
cutting needle. Samples are then incubated in 21 U/ml collagenase
type I solution at 37.degree. C. for 6 hours. Uniaxial suture
retention tests are performed using a MTS 5543 table top system
using a 100 lb load cell, where the suture retention load is
defined as the maximum load attained by the specimen.
[0117] The suture retention properties of the stitched
biodegradable and synthetic mesh layered construct are not
decreased after collagenase digestion whereas the suture retention
properties of the biodegradable layer with stitching but no
synthetic layer are decreased modestly and the suture retention
properties of the biodegradable layer alone are decreased
substantially. This example demonstrates how stitching the
biodegradable layer with fiber alone or in combination with a
synthetic mesh can potentially substantially maintain and/or
minimize the decrease in suture retention properties of the
construct while the ECM is remodeling.
[0118] FIGS. 11A-15 illustrate multilayer tissue grafts 700 in
accordance with yet another aspect of the present invention. The
tissue grafts 700 include first and second layers 120 and 121 of
biocompatible material. Each of the first layer 120 and the second
layer 121 can include a bioremodelable collagenous material, e.g.,
an ECM layer, or a substantially remodelable or non-remodelable
synthetic or natural material. Reinforcing means 122a are provided
in the first and second layers 120 and 121 in a reinforcing
pattern. The reinforcing means 122a of each tissue graft 700 are
similar to the reinforcing means 122 except that the reinforcing
means 122a includes one or more free end portions that extend
through and beyond the periphery of the tissue graft and are used
to secure the graft to the host tissue.
[0119] The graft 700 includes a top surface 124 and a substantially
parallel bottom surface 126 spaced from the top surface. A first
side 128 and second side 130 connect the top surface 124 to the
bottom surface 126. The first and second sides 128, 130 extend
generally parallel to one another. The graft 700 further includes a
front surface 132 and rear surface 134 which connect the first side
128 to the second side 130. The front and rear surfaces 132, 134
extend generally parallel to one another. Since there are multiple
layers 120, 121 in each graft 700, the peripheral surfaces 128-134
of the graft include portions of both the first layer 120 and the
second layer 121.
[0120] The reinforcing means 122a can include at least one fiber
disposed or provided within the first layer 120 and/or the second
layer 121 by, for example, conventional stitching techniques. By
stitching, it is meant that at least one fiber of the reinforcing
means 122a is stitched into the first layer 120 such that each
stitch of the reinforcing means extends through the top surface 124
of the graft 700 and a bottom surface 127 of the first layer 120
positioned between the layers 120, 121 to securely fasten the
reinforcing means to the first layer. Although the figures
illustrate the reinforcing means 122a extending only through the
first layer 120 it will be appreciated that the reinforcing means
may alternatively or additionally extend through the second layer
121 of the graft 700 in any of the multilayer embodiments of FIGS.
11A-16 in accordance with the present invention.
[0121] The reinforcing means 122a, constituting one first fiber 140
formed from stitches 145, is integrated into the first layer 120
such that free end portions 125, 129 of the first fiber extend
beyond one or more peripheral surfaces 128-134 of the graft 700. In
FIG. 11A, two portions 125 of the first fiber 140 extend through
the top and bottom surfaces 124, 127 and beyond the rear surface
134 of the graft 700 away from the first layer 120. Likewise, two
portions 129 of the first fiber 140 extend through the top and
bottom surfaces 124, 127 and beyond the front surface 132 of the
graft 700 away from the first layer. As shown, one of each free end
portion pair 125, 129 exits the graft 700 through the top surface
124 while the other of each free end portion pair extends between
the layers 120, 121 and exits the graft adjacent the respective
surface 132, 134. The portions 125, 129 thereafter extend beyond
the respective surface 132, 134 and are used to secure the graft
700 to the host tissue(s) using conventional fastening techniques.
It will be appreciated, however, that more or fewer (including
zero) portions 125, 129 of the fiber 140 may extend beyond the
respective surface 132, 134 of the graft 700 (not shown).
[0122] In FIG. 11B, a pair of spaced-apart first fibers 140 extends
the length of the first layer 120 and second layer 121. Each fiber
140 extends through the top surface 124 of the graft 700 and the
bottom surface 127 of the first layer 120. For each fiber 140, one
of each free end portion pair 125, 129 exits the graft 700 through
the top surface 124 while the other of each free end portion pair
extends between the layers 120, 121 and exits the graft adjacent
the respective surface 132, 134. The portions 125, 129 of each
first fiber 140 thereafter extend beyond the respective surfaces
132, 134. It will be appreciated, however, that more or fewer
(including zero) portions 125, 129 of each fiber 140 may extend
through the respective side 128, 130 of the graft 700 (not
shown).
[0123] Referring to FIGS. 12A and 12B, the graft 700 may further
include one or more second fibers 142 that extend transverse to and
intersect one first fiber 140 (FIG. 12A) or multiple first fibers
140 (FIG. 12B). The second fibers 142 may extend perpendicular to
the first fiber(s) 140 or may extend at an acute or obtuse angle
relative to the first fiber(s). In any case, the second fibers 142
extend through the top surface 124 of the graft 700 and the bottom
surface 127 of the first layer 120. Each second fiber 142 includes
one or more free end portions 147 that extend beyond the second
side 130 of the graft 700 and one or more free end portions 149
that extend beyond the first side 128 of the graft. For each second
fiber 142, one of each free end portion pair 125, 129 exits the
graft 700 through the top surface 124 while the other of each free
end portion pair extends between the layers 120, 121 and exits the
graft adjacent the respective side 128, 130. It will be appreciated
that more or fewer (including zero) portions 145, 147 of each
second fiber 142 may extend beyond the respective side 128, 130 of
the graft 700 (not shown).
[0124] Referring to FIGS. 13 and 14, the reinforcing means 122a
includes a plurality of second fibers 142 while the first fiber(s)
140 are omitted. The second fibers 142 extend through the top
surface 124 of the graft 700 and the bottom surface 127 of the
first layer 120. Each second fiber 142 includes portions 147 that
extend beyond the second side 130 and portions 149 that extend
beyond the first side 128. In FIG. 14, the second strands 142
extend transversely across the tissue graft 700 such that the
portions 145, 147 of each second strand extend beyond peripheral
surfaces of the tissue graft that do not oppose one another, e.g.,
the peripheral surfaces are adjacent to one another. In other
words, the portions 147, 149 of the second strands 142 do not
extend solely beyond the opposing first and second sides 128, 130.
Instead, the first portions 147 of the second strands 142 extend
through the top and bottom surfaces 124, 127 and exit the patch 120
at both the front surface 132 and the second side 130 and extend
beyond the front surface and the second side. Likewise, the second
portions 149 of the second strands 142 extend through the top and
bottom surfaces 124, 127 and exit the patch 120 at both the rear
surface 134 and the first side 128 and extend beyond the rear
surface and the first side. It will be appreciated that more or
fewer (including zero) portions 147, 149 of each second fiber 142
may extend beyond the respective surfaces 130, 132 and 128, 134 of
the graft 700 (not shown).
[0125] Although the grafts 700 in FIGS. 11A-14 are illustrated as
being rectangular or square, it will be appreciated that the graft
could alternatively be, for example, circular as shown in FIG. 15.
In such a case, the graft 700 has an arcuate peripheral surface
133. Each first fiber 140 extends through the top and bottom
surfaces 124, 127 and beyond the peripheral surface 133 at multiple
locations. The first fibers 140 may extend through or intersect at
the center of the circular graft 700 or may be spaced from the
center of the circular graft (not shown). Portions 125 of each
first fiber 140 extend beyond one side of the surface 133 relative
to the center of the graft 700 while portions 129 of each first
fiber extend beyond a different side of the surface relative to the
center. It will be appreciated that more or fewer (including zero)
portions 125, 129 of each first fiber 140 may extend beyond
different sides or portions of the surface 133 of the graft 700
(not shown).
[0126] The configuration of the reinforcement means 122a for the
multilayer graft 700 is not limited to those shown in FIGS. 11A-15.
The graft 700 may, for example, have reinforcing means 122a that
exhibit the concentric and/or cross-hatched configurations shown in
FIGS. 1-4B while including one or more free end portions that
extend beyond the periphery of the tissue graft. The reinforcing
means 122a may extend through any combination or number of layers
in the multilayer configurations of FIGS. 5-8. In all instances,
the reinforcement means 122a still includes at least one free end
that extends beyond at least one peripheral surface of the graft
700.
[0127] Another example of a tissue graft 800 in accordance with
another embodiment of the present invention is illustrated in FIGS.
16A-16B. The tissue graft 800 includes an ECM patch 120 and means
122 for reinforcing the patch. In the graft 800 of FIG. 16A the
reinforcing means 122 includes both a concentric pattern 143 of
first fibers 140 and linearly extending second fibers 142 with one
or more free end portions 147, 149 that extend through and beyond
the periphery of the graft. The linearly extending second fibers
142 traverse the concentric pattern 143 of first fibers 140
although one or more of the second fibers may alternatively be
spaced entirely from the concentric pattern (not shown). The
portions 147, 149 of the second fibers 142 may extend through and
beyond any combination of peripheral surfaces 124-134 of the graft
800.
[0128] FIG. 16B illustrates another example of reinforcing means
122 comprising two substantially concentric patterns 143 formed by
a pair of second fibers 142. More specifically, each second fiber
142 forms two substantially rectangular shapes that overlap one
another while both ends of the fiber extend linearly along the
patch towards the second side 130. Both the portions 147 and the
portions 149 of each second fiber 142 extend through the top
surface 124 and bottom surface 127 and beyond the same peripheral
surface 132, although the portions may extend through and beyond
any combination of peripheral surfaces 124-134 of the patch 120.
Although two patterns 143 are illustrated, it will be appreciated
that more or fewer patterns may be provided in the patch 120 in
accordance with the present invention.
[0129] The grafts 800 in FIGS. 16A-16B are illustrative and not
exhaustive examples of tissue grafts that may include both
concentric and linearly extending reinforcement means 122 with free
ends extending through and beyond peripheral surfaces of the graft
in accordance with the present invention. More specifically, tissue
grafts may be provided that include the concentric patterns 143 of
FIGS. 1-3B and/or the linearly extending cross-hatched pattern of
FIGS. 4A-4B.
Example 3
[0130] In this example, the tissue layer is reinforced with fiber
in a manner that strengthens and stiffens the tissue layer and is
also used for attachment to host tissues.
[0131] The tissue layer could be, for example, a 0.5.times.6 cm
strip of ECM derived from human fascia lata (Musculoskeletal
Transplant Foundation, Edison, N.J.) and the fiber could be a
UHMWPE braid (ForceFiber, TeleFlex Medical OEM, Kenosha, Wis.)
stitched in a single pass across the tissue layer (FIG. 17).
[0132] Two pairs of human cadaveric shoulders (mean age, 55.+-.9
years) were used in this study (Anatomy Gifts Registry, Glen
Burnie, Md. and ScienceCare, Aurora, Colo.). In each shoulder, the
supraspinatus was sharply released from the proximal humerus and
primarily repaired back to its insertion with anchors. For each
pair of shoulders, one repair was randomly assigned for
augmentation with a reinforced fascia strip (FIG. 18A) and the
other repair was augmented with the reinforcing fiber alone (FIG.
18B). The strips or fiber alone were passed through the tendon
repair approximately 1 cm medial to the repair suture line in a
mattress configuration and affixed to the humerus laterally with a
bone anchor. Repairs were subjected to cyclic mechanical loading of
5-180N at 0.25 Hz for 500 cycles. Repairs were tested in air, at
room temperature, and kept moist by intermittent spraying with
saline solution. Optical markers were used to monitor gap formation
across the repair during cyclic loading. Repair augmentation with
either the reinforcing fiber alone or the reinforced tissue strip
reduced cyclic gap formation compared to repairs with no
augmentation (FIG. 19). Repair augmentation with the reinforced
tissue strip reduced cyclic gap formation to a greater extent than
augmentation with the reinforcing fiber alone (FIG. 19).
[0133] Using a human cadaver model of rotator cuff repair, this
example demonstrates how repair augmentation reduces cyclic gap
formation and augmentation with a reinforced tissue strip is more
mechanically advantageous than augmentation with the reinforcing
fiber alone. Therefore, using the reinforced tissue strip, both the
tissue and the fiber have a biomechanical role in repair
augmentation. FIG. 20 compares the average gap formation for
alternative configurations for both the reinforced tissue strip and
the reinforcing fiber alone.
[0134] Although the results in the present example are limited to
tests conducted on a single layer tissue graft, it is expected that
constructing tissue grafts with multiple layers as described herein
will also yield advantageous cyclic gap formation reduction
results.
Example 4
[0135] In this example, the tissue layer is reinforced with fiber
in a manner that limits cyclic stretching of the tissue layer
following partial enzymatic degradation of the tissue. The tissue
layer could include, for example, a 5.times.5 cm patch of ECM
derived from human dermis (DermaMatrix, Musculoskeletal Transplant
Foundation, Edison, N.J.) and the fiber could be a #1 PLA/PGA braid
(6PLA sheath with 2PGA core, Concordia Medical, Coventry, R.I.)
stitched in a crosshatch pattern across the tissue layer. In other
embodiments, the tissue layer could include an allograft material
derived from other tissues, a xenograft material, a synthetic mesh
or multiple layers of combinations thereof, and the stitching fiber
could be derived from other synthetic biomaterials with different
biodegradation profiles (such as PP, UHMWPE, ePTFE, PLGA and PLLA)
or natural biomaterials (such as silk and collagen).
[0136] In this example, an in vitro accelerated enzymatic
degradation model (graft degradation in collagenase solution (21
U/ml) at 37.degree. C. for eight hours) was used to simulate in
vivo degradation of an ECM graft. Native and reinforced dermis
patches were mechanically tested before ("time-zero") and after
enzymatic degradation (n=6/group/condition) in a custom ball-burst
test setup with the patch fixed using eight peripheral mattress
suture loops of #2 FiberWire to the fixture. The patches were
preloaded to 10N and then cyclically loaded 10N-80N (the expected
physiologic load on a 5.times.5 cm abdominal wall patch) for 1000
cycles. The pretension elongation (PE), cyclic elongation (CE) and
cumulative CE (CCE=PE+CE) were measured for each cycle. All data
were analyzed by 2-way ANOVA and post hoc Tukey tests; p<0.05
was considered to be significant.
[0137] At time-zero, native and reinforced dermis patches underwent
similar (-21 mm, p=0.98) and significant (p<0.05) elongation (or
stretch) on cyclic loading elongation after 1000 cycles (FIG. 21
and Table 2). Enzymatic degradation resulted in significantly
higher rate and amount of elongation (28.4.+-.2.1 mm) in the native
dermis group compared to the reinforced group (25.0.+-.1.5 mm;
p<0.001). One patch in the enzyme-degraded native dermis group
failed during cyclic loading (at cycle 971).
TABLE-US-00002 TABLE 2 Cumulative elongation of native and
fiber-reinforced dermis patches after pretensioning and cyclic
loading (10-80N, 1000 cycles). Significant differences are
indicated by like letters. *One patch in the enzyme-degraded native
dermis group failed during cyclic loading (at cycle 971). Time Zero
(0 h) (n = 6) Collagenase (8 h) (n = 6) Fiber- Fiber- Native
reinforced Native reinforced Elongation (mm) Dermis Dermis Dermis
Dermis 10N Pretension 9.1 .+-. 0.8 8.9 .+-. 1.0 11.9 .+-. 1.3 11.3
.+-. 1.1 Cycle 1 16.6 .+-. 1.8 16.4 .+-. 1.0 19.0 .+-. 1.9 19.1
.+-. 1.1 Cycle 10 17.5 .+-. 1.9 17.5 .+-. 1.1 21.1 .+-. 2.2 20.8
.+-. 1.2 Cycle 100 19.0 .+-. 2.0 19.3 .+-. 1.2 24.5 .+-. 2.2 23.1
.+-. 1.3 Cycle 1000 .sup. 20.8 .+-. 2.1.sup.a .sup. 21.2 .+-.
1.2.sup.b 28.4 .+-. 2.1*.sup.a,c 25.1 .+-. 1.5.sup.b,c
[0138] Using an in vitro model of enzymatic degradation of ECM
grafts, this example demonstrates that dermis patches reinforced
with PLLA/PGA fiber limited the cyclic stretching of the grafts
after partial enzymatic degradation. Therefore, the presence of
reinforcing fiber is expected to limit stretching of the ECM graft
after surgical implantation such as in abdominal wall and hernia
repairs, and potentially improve repair outcomes by preventing
repair bulging and reherniation.
[0139] Although the results in the present example are limited to
tests conducted on a single layer tissue graft, it is expected that
constructing tissue grafts with multiple layers as described herein
will also yield advantageous, limited cyclic stretching behavior
following partial enzymatic degradation of the tissue.
[0140] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims. All
patents, publications and references cited in the foregoing
specification are herein incorporated by reference in their
entirety.
* * * * *