U.S. patent application number 16/566220 was filed with the patent office on 2020-01-02 for abdominal wall treatment devices.
The applicant listed for this patent is LifeCell Corporation. Invention is credited to Aaron Barere, Eric Stevenson, Wendell Sun.
Application Number | 20200000472 16/566220 |
Document ID | / |
Family ID | 43838024 |
Filed Date | 2020-01-02 |
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United States Patent
Application |
20200000472 |
Kind Code |
A1 |
Stevenson; Eric ; et
al. |
January 2, 2020 |
ABDOMINAL WALL TREATMENT DEVICES
Abstract
Devices and methods for treating or repairing openings in an
body wall are provided. The devices and methods can include
acellular tissue matrices. The tissue matrices can be positioned
within the abdominal opening and can be used to close the
opening.
Inventors: |
Stevenson; Eric; (San
Antonio, TX) ; Sun; Wendell; (Warrington, PA)
; Barere; Aaron; (Hoboken, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LifeCell Corporation |
Madison |
NJ |
US |
|
|
Family ID: |
43838024 |
Appl. No.: |
16/566220 |
Filed: |
September 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13029487 |
Feb 17, 2011 |
10448951 |
|
|
16566220 |
|
|
|
|
61306006 |
Feb 19, 2010 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2017/00004
20130101; A61B 17/085 20130101; A61B 17/08 20130101; A61F
2013/00451 20130101 |
International
Class: |
A61B 17/08 20060101
A61B017/08 |
Claims
1. An abdominal or fascia treatment device, comprising: a sheet of
acellular tissue matrix, wherein the sheet of acellular tissue
matrix includes an elongated opening and, on opposite sides of the
opening, multiple reinforced holes for receiving sutures.
2. The device of claim 1, wherein the holes include two or more
rows of holes positioned on each side of the elongated opening.
3. The device of claim 1, wherein the sheet comprises two or more
pieces of acellular tissue matrix.
4. The device of claim 1, wherein the acellular tissue matrix is a
dermal acellular tissue matrix.
5. The device of claim 4, wherein the dermal tissue matrix is a
human tissue matrix.
6. The device of claim 4, wherein the dermal tissue matrix is a
porcine tissue matrix.
7. The device of claim 1, wherein the reinforced holes include an
adhesive.
8. The device of claim 7, wherein the adhesive comprises a
cyanoacrylate adhesive.
9. The device of claim 7, wherein the adhesive comprises
fibrin.
10. The device of claim 1, wherein rims or edges of the holes are
crosslinked.
11. The device of claim 1, wherein the elongated opening extends
across a portion of a center of the sheet of acellular tissue
matrix and is configured to provide access to a body cavity in an
open configuration and close the body cavity in a closed
configuration.
12. A method of treating an abdominal or fascia defect, comprising:
positioning a sheet of acellular tissue matrix in or on a defect in
a body cavity, wherein the sheet of acellular tissue matrix
includes an elongated opening and, on opposite sides of the
opening, multiple rows of reinforced holes for receiving sutures;
and securing the acellular tissue matrix to tissue surrounding a
peripheral border of the defect to close the defect.
13. The method of claim 12, wherein the reinforced holes include an
adhesive.
14. The method of claim 13, wherein the adhesive comprises a
cyanoacrylate adhesive.
15. The method of claim 14, wherein the adhesive comprises
fibrin.
16. The method of claim 12, wherein the acellular tissue matrix is
secured by attaching at least one first suture to a first row of
reinforced holes.
17. The method of claim 16, further comprising attaching at least
one second suture to a second row of reinforced holes.
18. The method of claim 17, wherein the at least one first suture
is removed after attaching the at least one second suture.
19. The method of claim 12, wherein the sheet comprises two or more
pieces of acellular tissue matrix.
20. The method of claim 12, wherein rims or edges of the holes are
crosslinked.
21. The method of claim 12, further comprising: closing the
elongated opening with at least one suture attached to at least one
row of reinforced holes.
22. The method of claim 21, further comprising: removing the at
least one suture to open the elongated opening; and accessing the
abdominal cavity through the elongated opening.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 13/029,487 filed Feb. 17, 2011, which claims priority under 35
U.S.C. .sctn. 119 to U.S. Provisional Application No. 61/306,006,
which was filed on Feb. 19, 2010.
[0002] The present disclosure relates to devices and methods for
treating or repairing openings in body cavities, including
abdominal openings.
[0003] There are various situations in which it may be very
difficult or impossible for surgeons to close abdominal incisions.
For example, after trauma or with certain diseases, the abdominal
viscera may swell, making it very difficult to return the abdominal
contents to the abdomen after creating a relatively large incision.
In addition, for very large (e.g., obese) patients, or for patients
who have lost a portion of their abdominal wall due, for example,
to prior surgical resection or trauma, it can be difficult or
impossible to close the abdominal wall completely. However, various
devices and methods for closing abdominal incisions have had
certain disadvantages.
[0004] In addition, for certain surgeries, it may be necessary to
access the abdominal cavity multiple times. However, it is
generally undesirable to make multiple incisions at the same
location while a primary incision is still healing. Further,
closing an incision that has been accessed multiple times can lead
to increased risk of infection, and often, such incisions are
closed by secondary approximation, which can be unpleasant for the
patient.
[0005] Accordingly, there is a need for improved devices for
closing abdominal incisions or incisions or defects in fascia.
[0006] An abdominal or fascia treatment device is provided. The
device may comprise a first synthetic polymeric material and an
acellular tissue matrix attached to a peripheral border of the
synthetic polymeric material such that the acellular tissue matrix
can be secured to tissues surrounding an opening in a body cavity
to close the body cavity without attaching the first synthetic
polymeric material to tissue.
[0007] A method of treating an abdominal or fascia opening is
provided. The method may comprise positioning a synthetic polymeric
material in the opening, wherein the synthetic polymeric material
is attached to an acellular tissue matrix along a peripheral border
of the synthetic polymeric material. The method further comprises
securing the acellular tissue matrix to tissues surrounding a
peripheral border of the abdominal opening to close the
opening.
[0008] An abdominal or fascia treatment device is provided. The
device may comprise a sheet of acellular tissue matrix, wherein the
sheet includes an elongated opening, and on opposite sides of the
opening, multiple reinforced holes for receiving sutures.
BRIEF DESCRIPTION OF DRAWINGS
[0009] FIG. 1 illustrates a device and method for treating
abdominal openings, according to certain embodiments.
[0010] FIG. 2 illustrates a device for treating abdominal openings,
according to certain embodiments.
[0011] FIG. 3 illustrates a device for treating abdominal openings,
according to certain embodiments.
[0012] FIG. 4 illustrates the device of FIG. 3, as it may be used
for treating abdominal openings, according to certain
embodiments.
[0013] FIGS. 5A-5D are cross sectional views of the device of FIG.
2, according to various exemplary embodiments.
[0014] FIG. 6 illustrates a perspective view of the device of FIG.
2, according to certain embodiments.
DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0015] In this application, the use of the singular includes the
plural unless specifically stated otherwise. In this application,
the use of "or" means "and/or" unless stated otherwise.
Furthermore, the use of the term "including", as well as other
forms, such as "includes" and "included", is not limiting.
[0016] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
this application, including but not limited to patents, patent
applications, articles, books, and treatises, are hereby expressly
incorporated by reference in their entirety for any purpose.
[0017] The term "acellular tissue matrix," as used herein, refers
generally to any tissue matrix that is substantially free of cells
and other antigenic material. Skin, parts of skin (e.g., dermis),
and other tissues such as blood vessels, heart valves, fascia and
nerve connective tissue may be used to create acellular matrices
within the scope of the present disclosure.
[0018] The term "abdominal defect," as used herein refers generally
to a disruption in the abdominal wall. The disruption can include a
hole that passes through the entire abdominal wall, such as an
incision through the wall, or can include an incision or defect in
one or more layers of the abdominal wall, such as the skin and
subcutaneous fat.
[0019] FIG. 1 illustrates a device and method for treating
abdominal openings, according to certain embodiments. According to
certain embodiments, the device 100 can be used to close an
abdominal defect 140, including, for example, an incision created
by surgery. As shown in FIG. 1, the device 100 can assist in
closure of a midline incision, or can be used to assist in closure
of other incisions (e.g., more laterally positioned incisions,
transverse incisions, or oblique incisions).
[0020] As described further below, the device 100 can include one
or more sheets of material 110, 120 that can be used to connect
opposing edges of a wound, surgical incision, or other abdominal
defect 140. For example, when the existing fascia or other tissue
surrounding the defect 140 is insufficient, for whatever reason,
the device 100 can provide additional material to allow tissues
(e.g., fascia) surrounding a defect 140 to be connected and to
cover the entire defect 140. In certain embodiments, the device 100
can be used to cover the defect 140 temporarily until a final
closure is desired or possible. For example, if final closure is
not possible due to swelling of abdominal contents, the device 100
can be used to close the abdomen until swelling abates. In
addition, the device 100, can provide an access site to allow
multiple surgeries. In addition, the device 100 can be adjusted
during two or more surgeries to allow more normal surgical closure,
as described further below.
[0021] In certain embodiments, the sheets 110, 120 of the device
100 include a biologic material, including an acellular tissue
matrix, such as a dermal acellular tissue matrix. In addition, in
certain embodiments, the sheets 110, 120 further include a
synthetic polymeric material that is attached to the acellular
tissue matrix. Various embodiments of the device 100, are described
with reference to FIGS. 2-5D below (labeled 200, 300).
[0022] FIG. 2 illustrates a device 200 for treating abdominal
defects, according to certain embodiments. In certain embodiments,
the device 200 includes a first synthetic polymeric material 210
and an acellular tissue matrix 220 attached to an entire peripheral
border 230 of the synthetic polymeric material 210. In use, the
acellular tissue matrix 220 can be secured to tissues surrounding a
defect 140 in a body cavity to close the body cavity (e.g., the
abdomen) without attaching the first synthetic polymeric material
to tissue. For example, when an abdominal incision is formed
(either midline or at another location), it may be difficult to
close the incision completely. This may be due to swelling of
abdominal contents, large patient size, and/or loss of tissue due
to prior surgery, trauma or disease. In addition, in some cases, it
may be desirable to access the surgical site again, e.g., to
perform additional surgeries. The device 200 can assist in closure
of an incision or other defect and can be used to re-access the
surgical site and/or to close the defect after problems that
prevented normal closure abate (e.g., swelling diminishes or
subsequent surgical steps are complete).
[0023] As used herein, the term "synthetic polymeric material"
includes any polymeric material sheet produced by man, either from
a chemical reaction, or by assembling a natural material to produce
a sheet. For example, polymers produced by man can include,
polyethylenes or polyamides. Materials produced by assembling a
natural material can include, for example, sheets produced from
silk.
[0024] During initial implantation, the synthetic polymeric
material 210 with an acellular tissue matrix 220 attached to its
peripheral border 230 to form a joint 235 (see FIGS. 5A-5D) is
positioned in the defect in the abdominal wall. Next, the acellular
tissue matrix is attached to tissues surrounding a peripheral
border of the abdominal defect to close the defect. Generally, for
a midline incision, the acellular tissue matrix 220 will be secured
to abdominal fascia (e.g., the rectus sheath), thereby acting as an
extension of the rectus sheath, which is normally used to close
midline abdominal incisions. The acellular tissue matrix can be
attached to the tissues using typical sutures, surgical staples, or
clips, or other suitable connecting mechanisms, as are known in the
art. In certain embodiments, the acellular tissue matrix 220 can be
connected by passing sutures through the acellular tissue matrix
220. In certain embodiments, the sutures can be passed through
preformed openings 295, which may be reinforced (or openings 360,
as shown in FIG. 3).
[0025] Various materials can be used to produce the synthetic
polymeric material 210 and acellular tissue matrix 220
(collectively "materials"). Generally, both materials should be
sterile or asceptic and should possess suitable biomechanical
properties to prevent rupture or tearing during use. In addition,
in some embodiments, the mechanical properties of the materials are
compatible to provide even stress distributions relative to the
different materials to prevent failure, as described in more detail
below. In addition, the synthetic material should be generally
inert or biologically compatible to prevent undue inflammation.
Suitable synthetic materials can include, for example,
GORE-TEX.RTM. (or other polytetrafluroethylene materials),
MARLEX.RTM. (high density polyethylene), or prolene. In certain
embodiments, the synthetic materials can include synthetic,
resorbable materials over part or all of their dimensions. In
addition, the materials may be coated with therapeutic agents,
(e.g., anti-adhesive coatings, antimicrobials, etc.).
[0026] The acellular tissue matrix can be selected to provide a
variety of different biological and mechanical properties. For
example, the acellular tissue matrix can be selected to allow
tissue ingrowth and remodeling to allow regeneration of tissue
normally found at the site where the matrix is implanted. For
example, the acellular tissue matrix, when implanted on or into
fascia, may be selected to allow regeneration of the fascia without
excessive fibrosis or scar formation. In addition, the acellular
tissue matrix should not elicit an excessive inflammatory reaction
and should ultimately be remodeled to produce tissue similar to the
original host tissue. In certain embodiments, the acellular tissue
matrix can include ALLODERM.RTM. or Strattice.TM., which are human
and porcine acellular dermal matrices respectively. Alternatively,
other suitable acellular tissue matrices can be used, as described
further below.
[0027] Generally, both the synthetic polymeric material 210 and
acellular tissue matrix 220 should possess mechanical properties
such that the materials will not fail (i.e., rupture or tear)
during use. In addition, the materials should have sufficient
flexibility and elasticity to be handled by a surgeon when
implanted, to be shaped to allow coverage of underlying structures,
and to allow stretching during patient movement to provide even
stress distribution to adjacent tissues without tearing. It will be
understood that these properties can be varied by altering the
general material properties (e.g., tensile strength and elastic
properties), as well as the structural characteristics of the
materials (e.g., thickness). In certain embodiments, the materials
will have been selected such that the materials can withstand a
tensile force of at least 20 N without failure. In some
embodiments, the materials can withstand a minimum force per unit
width, such as at least 20 N/cm, at least 24 N/cm, or higher,
depending on the patient. In addition, in certain embodiments, the
materials are selected to allow retention of sutures. In some
embodiments, the materials have a suture retention strength of at
least 20 N.
[0028] In certain embodiments, the materials 210, 220 may be
selected and sized such that, during use, the stress distribution
across the materials remains relatively even. For example, in
various embodiments, the synthetic polymeric material 210 and the
acellular tissue matrix 220 can be selected such that the ultimate
tensile strength and/or elastic properties over typical operating
ranges are relatively equal, or within a certain range of one
another. In addition, the mechanical properties of the joint 235
between the synthetic polymeric material 210 and acellular tissue
matrix 220 can be similarly matched with those of the synthetic
polymeric material 210 and/or acellular tissue matrix 220. For
example, in certain embodiments, the ultimate strength of the
synthetic polymeric material 210 differs from the ultimate strength
of the acellular tissue matrix 220 by less than 20%, less than 15%,
less than 10%, less than 5%, or any value between those
percentages. In certain embodiments, the elastic modulus of the
synthetic polymeric material 210 differs from the elastic modulus
of the acellular tissue matrix 220 by less than 20%, less than 15%,
less than 10%, less than 5%, or any value between those
percentages.
[0029] The synthetic polymeric material 210 and acellular tissue
matrix 220 can be attached to one another using a number of devices
or techniques. For example, the materials 210, 220 may be connected
using various sutures, staples, tacks, or adhesives including
permanent sutures, such as prolene sutures. The materials 210, 220
can be connected to one another in a number of configurations.
FIGS. 5A-5D are cross sectional views of the device of FIG. 2,
according to various exemplary embodiments. As illustrated, the
materials can be attached at an end-to-end joint 235 (FIG. 5A), by
an overlapping joint 235' (FIG. 5B), with the synthetic material
210 forming a bifurcated pocket joint 235'' (FIG. 5C), or with the
acellular tissue matrix forming a bifurcated pocket joint 235'''
(FIG. 5D).
[0030] In certain embodiments, the materials can be attached by
weaving one or both of the materials to the other. For example,
FIG. 6 illustrates an acellular tissue matrix 220 that is attach to
a woven synthetic material 211 at a joint 250. In other
embodiments, the biologic material 220 can be woven, or both
materials 220, 211 are woven to produce a joint 250 with sufficient
mechanical properties to prevent failure during use, while allowing
relatively even stress distribution.
[0031] As described above, the acellular tissue matrix 220 can be
secured to tissues surrounding a defect 140 in a body cavity to
close the defect without attaching the first synthetic polymeric
material to tissue. In this way, the acellular tissue matrix 220,
which is selected to allow tissue ingrowth and remodeling, is the
only material (other than sutures or other connecting devices) that
is connected, attached, and/or anchored to the tissue. Further,
after attachment, the fascia or other tissue can begin ingrowth and
remodeling.
[0032] In addition, as noted above, in some embodiments, it may be
desirable to access a surgical site/incision multiple times, and/or
to ultimately close the incision permanently after completion of
subsequent treatments or after changes in a patient's condition
(e.g., diminished swelling of abdominal contents). Accordingly, in
some embodiments, the synthetic polymeric material can include an
opening 240 or can be cut, without cutting adjacent tissue, to
allow repeated access. The opening 240 can then be resealed with
sutures 260 or other devices. In some embodiments, part of the
synthetic polymeric material (delimited by oval 250) can be
removed, and the synthetic polymeric material 210 can be shortened
to provide additional tension on the incision margins or to remove
excess or contaminated materials.
[0033] In some cases, it may be desirable to completely remove the
synthetic polymeric material 210 while leaving the acellular tissue
matrix 220 attached to tissues. For example, the synthetic
polymeric material 210 may be removed at a later time, e.g., after
swelling has diminished or subsequent surgeries have been
completed, and the acellular tissue matrix 220 can be left attached
to the tissues surrounding the peripheral border of the abdominal
defect. In addition, the abdominal defect can then be closed after
removing the synthetic polymeric material 210 by attaching
remaining portions of the acellular tissue matrix 220 to one
another using sutures, staples, or other surgical means. In various
embodiments, the acellular tissue matrix 220 will bolster the
fascia or other tissue around the defect to prevent reopening or
dehiscence. In addition, the acellular tissue matrix can provide
additional tissue in cases where there is insufficient tissue
present for normal fascia closure.
[0034] In some embodiments, as described above, the acellular
tissue matrix 220 can include openings 295, and the openings can be
used to receive sutures for closing the abdominal opening. In some
embodiments, the openings 295 can be reinforced, as described
further below.
[0035] In certain embodiments devices for treating abdominal
defects which do not include a synthetic polymeric material in a
sheet are provided, as described above. Such devices may include
only an acellular tissue matrix, but may be useful for closing
certain incisions in the presence of the above noted challenges
(e.g., swelling, insufficient tissue, need to access surgical sites
multiple times). FIG. 3 illustrates a device 300 for treating
abdominal defects, according to certain embodiments. The device 300
comprises a sheet 310 of acellular tissue matrix, wherein the sheet
310 includes an elongated opening 340, and on opposite sides of the
opening 340 multiple holes 360 for receiving sutures, and wherein
the multiple holes 360 are reinforced. The device 300 can be
secured to wound margins (e.g., via fascia using sutures), and the
reinforced holes 360 can receive sutures that provide tension to
the device 300 and wound margins to close the wound or
incision.
[0036] In some cases, the opening 340 can be reopened, for example,
to perform a subsequent operation, clean a wound/abdominal site, or
for any other purpose. In addition, in some cases, the device 300
can have multiple sets of reinforced holes 360, to allow the device
to be sutured with at varying distances, for example, to provide
increasing tension to wound margins, or to remove excess material.
For example, in some embodiments, the preformed holes 360 include
two or more rows 365, 367 of holes positioned on each side of the
elongated opening 340, and sutures can be placed through holes at
selected distances apart. For example, as shown in FIG. 4, sutures
may initially be attached through a first row of holes 365 nearest
the opening 340, to close an incision. However, later, as swelling
of abdominal viscera decreases, or as tissues stretch, a surgeon
may add additional sutures or replace the sutures, passing the
sutures through openings 367. In this way, the wound or incision
margins can be pulled closer together as the sutures are tightened
or shortened.
[0037] As shown in FIGS. 3 and 4, the device 300 can include a
single sheet of material. However, in some embodiments, two or more
pieces of acellular tissue matrix 310 may be used. For example, the
device of FIG. 3 can be divided into two pieces along a line
extending from line 370 to produce two pieces of material. The two
pieces can be implanted on opposite sides of a wound or incision
and sutured in place to close the wound or incision, as described
above.
[0038] The openings 360 (and 295) can be reinforced in a number of
ways. In some embodiments, the openings 360 can be reinforced using
a biocompatible adhesive placed around the rim or edge of the
openings 360. Suitable adhesives include, for example, fibrin glue,
cyanoacrylate-based tissue adhesives (e.g., DERMABOND.RTM.), and
chitosan tissue adhesives. In some embodiments, the rim or edges of
the openings 360 can be crosslinked to increase their strength and
prevent tearing (e.g., using chemical or radiation induced
cross-linking).
Suitable Acellular Tissue Matrices
[0039] As noted above, the term "acellular tissue matrix," as used
herein, refers generally to any tissue matrix that is substantially
free of cells and other antigenic material. Skin, parts of skin
(e.g., dermis), and other tissues such as blood vessels, heart
valves, fascia and nerve connective tissue may be used to create
acellular matrices within the scope of the present disclosure.
[0040] In general, the steps involved in the production of an
acellular tissue matrix include harvesting the tissue from a donor
(e.g., a human cadaver or animal source) and cell removal under
conditions that preserve biological and structural function. In
certain embodiments, the process includes chemical treatment to
stabilize the tissue and avoid biochemical and structural
degradation together with or before cell removal. In various
embodiments, the stabilizing solution arrests and prevents osmotic,
hypoxic, autolytic, and proteolytic degradation, protects against
microbial contamination, and reduces mechanical damage that can
occur with tissues that contain, for example, smooth muscle
components (e.g., blood vessels). The stabilizing solution may
contain an appropriate buffer, one or more antioxidants, one or
more oncotic agents, one or more antibiotics, one or more protease
inhibitors, and/or one or more smooth muscle relaxants.
[0041] The tissue is then placed in a decellularization solution to
remove viable cells (e.g., epithelial cells, endothelial cells,
smooth muscle cells, and fibroblasts) from the structural matrix
without damaging the biological and structural integrity of the
collagen matrix. The decellularization solution may contain an
appropriate buffer, salt, an antibiotic, one or more detergents
(e.g., TRITON X-100.TM., sodium deoxycholate, polyoxyethylene (20)
sorbitan mono-oleate), one or more agents to prevent cross-linking,
one or more protease inhibitors, and/or one or more enzymes. In
some embodiments, the decellularization solution comprises 1%
TRITON X-100.TM. in RPMI media with Gentamicin and 25 mM EDTA
(ethylenediaminetetraacetic acid). In some embodiments, the tissue
is incubated in the decellularization solution overnight at
37.degree. C. with gentle shaking at 90 rpm. In certain
embodiments, additional detergents may be used to remove fat from
the tissue sample. For example, in some embodiments, 2% sodium
deoxycholate is added to the decellularization solution.
[0042] After the decellularization process, the tissue sample is
washed thoroughly with saline. In some exemplary embodiments, e.g.,
when xenogenic material is used, the decellularized tissue is then
treated overnight at room temperature with a deoxyribonuclease
(DNase) solution. In some embodiments, the tissue sample is treated
with a DNase solution prepared in DNase buffer (20 mM HEPES
(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 20 mM CaCl2
and 20 mM MgCl2). Optionally, an antibiotic solution (e.g.,
Gentamicin) may be added to the DNase solution. Any suitable buffer
can be used as long as the buffer provides suitable DNase
activity.
[0043] While an acellular tissue matrix may be made from one or
more individuals of the same species as the recipient of the
acellular tissue matrix graft, this is not necessarily the case.
Thus, for example, an acellular tissue matrix may be made from
porcine tissue and implanted in a human patient. Species that can
serve as recipients of acellular tissue matrix and donors of
tissues or organs for the production of the acellular tissue matrix
include, without limitation, mammals, such as humans, nonhuman
primates (e.g., monkeys, baboons, or chimpanzees), pigs, cows,
horses, goats, sheep, dogs, cats, rabbits, guinea pigs, gerbils,
hamsters, rats, or mice.
[0044] Elimination of the .alpha.-gal epitopes from the
collagen-containing material may diminish the immune response
against the collagen-containing material. The .alpha.-gal epitope
is expressed in non-primate mammals and in New World monkeys
(monkeys of South America) as well as on macromolecules such as
proteoglycans of the extracellular components. U. Galili et al., J.
Biol. Chem. 263: 17755 (1988). This epitope is absent in Old World
primates (monkeys of Asia and Africa and apes) and humans, however.
Id. Anti-gal antibodies are produced in humans and primates as a
result of an immune response to .alpha.-gal epitope carbohydrate
structures on gastrointestinal bacteria. U. Galili et al., Infect.
Immun. 56: 1730 (1988); R. M. Hamadeh et al., J. Clin. Invest. 89:
1223 (1992).
[0045] Since non-primate mammals (e.g., pigs) produce .alpha.-gal
epitopes, xenotransplantation of collagen-containing material from
these mammals into primates often results in rejection because of
primate anti-Gal binding to these epitopes on the
collagen-containing material. The binding results in the
destruction of the collagen-containing material by complement
fixation and by antibody dependent cell cytotoxicity. U. Galili et
al., Immunology Today 14: 480 (1993); M. Sandrin et al., Proc.
Natl. Acad. Sci. USA 90: 11391 (1993); H. Good et al., Transplant.
Proc. 24: 559 (1992); B. H. Collins et al., J. Immunol. 154: 5500
(1995). Furthermore, xenotransplantation results in major
activation of the immune system to produce increased amounts of
high affinity anti-gal antibodies. Accordingly, in some
embodiments, when animals that produce .alpha.-gal epitopes are
used as the tissue source, the substantial elimination of
.alpha.-gal epitopes from cells and from extracellular components
of the collagen-containing material, and the prevention of
re-expression of cellular .alpha.-gal epitopes can diminish the
immune response against the collagen-containing material associated
with anti-gal antibody binding to .alpha.-gal epitopes.
[0046] To remove .alpha.-gal epitopes, after washing the tissue
thoroughly with saline to remove the DNase solution, the tissue
sample may be subjected to one or more enzymatic treatments to
remove certain immunogenic antigens, if present in the sample. In
some embodiments, the tissue sample may be treated with an
.alpha.-galactosidase enzyme to eliminate .alpha.-gal epitopes if
present in the tissue. In some embodiments, the tissue sample is
treated with .alpha.-galactosidase at a concentration of 300 U/L
prepared in 100 mM phosphate buffer at pH 6.0 In other embodiments,
the concentration of .alpha.-galactosidase is increased to 400 U/L
for adequate removal of the .alpha.-gal epitopes from the harvested
tissue. Any suitable enzyme concentration and buffer can be used as
long as sufficient removal of antigens is achieved.
[0047] Alternatively, rather than treating the tissue with enzymes,
animals that have been genetically modified to lack one or more
antigenic epitopes may be selected as the tissue source. For
example, animals (e.g., pigs) that have been genetically engineered
to lack the terminal .alpha.-galactose moiety can be selected as
the tissue source. For descriptions of appropriate animals see
co-pending U.S. application Ser. No. 10/896,594 and U.S. Pat. No.
6,166,288, the disclosures of which are incorporated herein by
reference in their entirety. In addition, certain exemplary methods
of processing tissues to produce acellular matrices with or without
reduced amounts of or lacking alpha-1,3-galactose moieties, are
described in Xu, Hui. et al., "A Porcine-Derived Acellular Dermal
Scaffold that Supports Soft Tissue Regeneration: Removal of
Terminal Galactose-.alpha.-(1,3)-Galactose and Retention of Matrix
Structure," Tissue Engineering, Vol. 15, 1-13 (2009), which is
incorporated by reference in its entirety.
[0048] After the acellular tissue matrix is formed,
histocompatible, viable cells may optionally be seeded in the
acellular tissue matrix to produce a graft that may be further
remodeled by the host. In some embodiments, histocompatible viable
cells may be added to the matrices by standard in vitro cell
co-culturing techniques prior to transplantation, or by in vivo
repopulation following transplantation. In vivo repopulation can be
by the recipient's own cells migrating into the acellular tissue
matrix or by infusing or injecting cells obtained from the
recipient or histocompatible cells from another donor into the
acellular tissue matrix in situ. Various cell types can be used,
including embryonic stem cells, adult stem cells (e.g. mesenchymal
stem cells), and/or neuronal cells. In various embodiments, the
cells can be directly applied to the inner portion of the acellular
tissue matrix just before or after implantation. In certain
embodiments, the cells can be placed within the acellular tissue
matrix to be implanted, and cultured prior to implantation.
* * * * *