U.S. patent application number 17/064206 was filed with the patent office on 2021-01-21 for graft materials for surgical breast procedures.
The applicant listed for this patent is LifeCell Corporation. Invention is credited to Nathaniel BACHRACH, Aaron M. BARERE, Melissa Richter BOWLEY, Evan J. FRIEDMAN.
Application Number | 20210015602 17/064206 |
Document ID | / |
Family ID | 1000005134977 |
Filed Date | 2021-01-21 |
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United States Patent
Application |
20210015602 |
Kind Code |
A1 |
BOWLEY; Melissa Richter ; et
al. |
January 21, 2021 |
GRAFT MATERIALS FOR SURGICAL BREAST PROCEDURES
Abstract
Graft materials and devices for surgical breast procedures may
include a sheet of biocompatible material and a plurality of
fenestrations distributed across a portion of the sheet of
biocompatible material. The sheet of biocompatible material can
have a first axis and a second axis coincident with the sheet of
biocompatible material. The sheet of biocompatible material can
also have a first edge that intersects the second axis and a second
edge that intersects the second axis. The first axis can be
orthogonal to the second axis. The plurality of fenestrations can
be distributed across a portion of the sheet of biocompatible
material closer to the first edge than the second edge. Other
apparatuses and methods are disclosed.
Inventors: |
BOWLEY; Melissa Richter;
(Newport, RI) ; BARERE; Aaron M.; (Hoboken,
NJ) ; FRIEDMAN; Evan J.; (Montvale, NJ) ;
BACHRACH; Nathaniel; (Clifton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LifeCell Corporation |
Branchburg |
NJ |
US |
|
|
Family ID: |
1000005134977 |
Appl. No.: |
17/064206 |
Filed: |
October 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15680666 |
Aug 18, 2017 |
10835370 |
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17064206 |
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14620667 |
Feb 12, 2015 |
10449034 |
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15680666 |
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12506839 |
Jul 21, 2009 |
8986377 |
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14620667 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/3637 20130101;
A61F 2210/0004 20130101; A61L 27/3695 20130101; A61L 27/362
20130101; A61F 2230/0008 20130101; A61F 2310/00365 20130101; A61F
2/0063 20130101; A61L 2430/04 20130101; A61L 27/3683 20130101; A61F
2/12 20130101; Y10T 29/49995 20150115 |
International
Class: |
A61F 2/12 20060101
A61F002/12; A61L 27/36 20060101 A61L027/36 |
Claims
1. A graft for surgical procedures, comprising: a sheet of
biocompatible material having a first axis, a second axis, a first
edge that intersects the second axis, and a second edge that
intersects the second axis; and a plurality of fenestrations
distributed across a portion of the sheet of biocompatible material
in a plurality of rows, each row forming an arcuate pattern.
2. The graft of claim 1, wherein each fenestration of the plurality
of fenestrations is linear.
3. The graft of claim 2, wherein each fenestration of the plurality
of fenestrations is parallel to the first axis.
4. The graft of claim 2, wherein each fenestration of the plurality
of fenestrations is parallel to the second axis.
5. The graft of claim 1, wherein each fenestration of the plurality
of fenestrations is circular.
6. The graft of claim 1, wherein at least one of the first edge and
the second edge has a convex curvature.
7. The graft of claim 6, wherein each fenestration of the plurality
of fenestrations are linear and parallel to the first edge.
8. The graft of claim 1, wherein the plurality of fenestrations
comprises: a first row of fenestrations having a first length; and
a second row of fenestrations having a second length; wherein the
second length is greater than the first length.
9. The graft of claim 1, wherein the plurality of fenestrations
comprises: a first row of fenestrations; and a second row of
fenestrations; wherein the first row of fenestrations includes a
greater number of fenestrations than the second row of
fenestrations.
10. The graft of claim 1, wherein the plurality of fenestrations
comprises: a first row of fenestrations; and a second row of
fenestrations; wherein the fenestrations of the first row of
fenestrations are offset from the fenestrations of the second row
of fenestrations.
11. A graft material, comprising: a sheet of a biocompatible
material configured to conform to a portion of a breast implant,
the sheet further comprising a first edge and a second edge,
wherein at least one of the first edge and the second edge is
curved; a first set of perforations through an upper portion of the
biocompatible material; and a second set of perforations through a
lower portion of the biocompatible material; wherein the first set
of perforations and the second set of perforations form an arcuate
pattern.
12. The graft material of claim 11, wherein each perforation of the
first set of perforations is parallel to the first edge and each
perforations of the second set of perforations is parallel to the
second edge.
13. The graft material of claim 11, wherein the first set of
perforations comprises a first group of slits of a first length and
the second set of perforations comprises a second group of slits of
a second length.
14. The graft material of claim 13, wherein the second length is
greater than the first length.
15. The graft material of claim 11, wherein the first set of
perforations has a first spacing distance between perforations that
is greater than a second spacing distance between perforations of
the second set of perforations.
16. The graft material of claim 11, wherein the first set of
perforations are offset from to the second set of perforations.
17. The graft material of claim 11, wherein each perforation of at
least one of the first set of perforations and the second set of
perforations are arcuate.
18. The graft material of claim 11, wherein each perforation of at
least one of the first set of perforations and the second set of
perforations are linear.
19. The graft material of claim 11, wherein each perforation of at
least one of the first set of perforations and the second set of
perforations are circular.
20. A medical implant, comprising: a sheet of biocompatible
material configured to conform to at least a portion of a breast
implant, the sheet of biocompatible material comprising: a
longitudinal axis, a vertical axis, a first edge and a second edge,
wherein the first edge and the second edge are parallel to the
longitudinal axis, and a third edge and a fourth edge, wherein the
third edge and the fourth edge are parallel to the vertical axis;
and a set of perforations positioned on the sheet of biocompatible
material, the set of perforations comprising: a first row of slits,
and a second row of slits; wherein the set of perforation form an
arcuate pattern across at least a portion of the sheet of
biocompatible material.
21. The medical implant of claim 20, wherein a distance along the
longitudinal axis of the sheet of biocompatible material is longer
than a distance along the vertical axis of the sheet of
biocompatible material.
22. The medical implant of claim 20, wherein slits of the first row
of slits are offset from slits of the second row of slits
23. The medical implant of claim 20, wherein the first row of slits
is parallel to the second row of slits.
24. The medical implant of claim 20, wherein the set of
perforations is adapted to permit expansion of portions of the
sheet of biocompatible material along the vertical axis.
25. The medical implant of claim 20, further comprising a first
breast implant.
26. The medical implant of claim 20, further comprising a first
breast implant, and wherein the set of perforations is adapted to
permit expansion of portions of the sheet of biocompatible material
around a surface of the first breast implant.
27. The medical implant of claim 20, wherein the set of
perforations comprises perforations that are irregularly spaced
apart.
28. The medical implant of claim 20, wherein the first row of slits
is separated from the second row of slits by a substantially
uniform separation distance.
29. The medical implant of claim 28, wherein the uniform separation
distance is between 0.1 millimeters and 20 millimeters.
30. The medical implant of claim 28, wherein the uniform separation
distance is between 2 millimeters and 6 millimeters.
31. The medical implant of claim 20, wherein the slits of at least
one of the first row of slits and the second row of slits have a
uniform length of between 0.1 millimeters and 20 millimeters.
32. The medical implant of claim 31, wherein the uniform length is
between 4 millimeters and 8 millimeters.
33. The medical implant of claim 20, wherein the sheet of
biocompatible material is substantially rectangular in shape.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/680,666, filed Aug. 18, 2017, entitled
"Graft Materials For Surgical Breast Procedures", which is a
continuation of U.S. patent application Ser. No. 14/620,667, filed
Feb. 12, 2015, entitled "Graft Materials For Surgical Breast
Procedures", which is a continuation of U.S. patent application
Ser. No. 12/506,839, now U.S. Pat. No. 8,986,377, filed Jul. 21,
2009, entitled "Graft Materials For Surgical Breast Procedures".
The entire content of the foregoing non-provisional application is
incorporated herein by reference.
[0002] The present disclosure relates to graft materials for
surgical breast or other plastic surgery procedures.
BACKGROUND
[0003] Graft materials can be used in a wide range of surgical
procedures to augment tissue or repair or correct tissue defects.
One application of graft materials is the field of cosmetic and
reconstructive surgical breast procedures, a field in which the
number of procedures performed each year continues to increase.
Some graft materials are typically provided to surgeons as a sheet
or sheet-like material, which the surgeon can cut to the desired
size and shape before implantation. Graft materials can be very
expensive and can pose challenges for attaining adequate
conformance to underlying features of the implantation site.
[0004] Accordingly, there is a need for improved graft
materials.
SUMMARY
[0005] According to certain embodiments, a graft material for
surgical breast procedures is disclosed that includes a sample of
biocompatible material with a first edge and a second edge. The
first edge has a convex portion that curves away from the second
edge, and the second edge has a convex portion that curves away
from the first edge.
[0006] According to certain embodiments, a graft material for
surgical breast procedures is disclosed that includes a sample of
biocompatible material with a set of perforations that form an
arcuate pattern across at least a portion of the sample of
biocompatible material.
[0007] According to certain embodiments, a method of making one or
more graft devices is disclosed. The method includes cutting one or
more samples from a sheet of biocompatible material such that the
samples are sized and shaped for conforming to a portion of a
surface of a breast implant.
DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a perspective view of one exemplary embodiment of
a graft material.
[0009] FIG. 2 is a perspective view of one exemplary embodiment of
a graft material.
[0010] FIG. 3 is a perspective view of one exemplary embodiment of
a graft material.
[0011] FIG. 4 is a perspective view of one exemplary embodiment of
a graft material.
[0012] FIG. 5 is a perspective view of one exemplary embodiment of
a graft material, illustrated in relation to a breast implant.
[0013] FIG. 6 is a perspective view of one exemplary embodiment of
a graft material.
[0014] FIG. 7 is a perspective view of one exemplary embodiment of
a graft material.
[0015] FIG. 8 is a perspective view of one exemplary embodiment of
a graft material.
[0016] FIG. 9 is a perspective view of one exemplary embodiment of
a graft material.
[0017] FIG. 10 is a perspective view of one exemplary embodiment of
a graft material.
[0018] FIG. 11 is a perspective view of one exemplary embodiment of
a graft material.
[0019] FIG. 12 is a perspective view of one exemplary embodiment of
a graft material.
[0020] FIG. 13 is a perspective view of one exemplary embodiment of
a graft material.
[0021] FIG. 14 is a detailed view of a set of perforations
consistent with one exemplary embodiment of a graft material.
DESCRIPTION OF CERTAIN EXEMPLARY EMBODIMENTS
[0022] Reference will now be made in detail to the present
embodiments (exemplary embodiments) of the invention, examples of
which are illustrated in the accompanying drawings. Wherever
possible, the same reference numbers will be used throughout the
drawings to refer to the same or like parts.
[0023] 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. Also,
terms such as "element" or "component" encompass both elements and
components comprising one unit and elements and components that
comprise more than one subunit, unless specifically stated
otherwise. Also, the use of the term "portion" may include part of
a moiety or the entire moiety.
[0024] 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.
[0025] The term "graft material," as used herein, generally refers
to a material such as, for example, tissue, processed tissue, or
synthetics that can be attached to or inserted into a bodily
part.
[0026] The terms "sheet" and "sheet-like," as used herein,
generally refer to a broad, relatively thin, surface or layer of a
material. Such sheets can, but may not, be relatively flexible, and
may be flat or uniform in thickness or may vary in thickness across
their surface.
[0027] The terms "breast implant" and "implant," as used herein,
generally refer to medical devices that are implanted either under
breast tissue or under the chest muscle for breast augmentation or
reconstruction. Such implants can include saline filled or silicone
gel implants, or other implants that provide volume for breast
augmentation.
[0028] The present disclosure relates to graft materials and
methods of using graft materials in breast or other plastic surgery
procedures. The graft materials can be used for tissue
augmentation, repair or regeneration of damaged tissue, and/or
correction of tissue defects. As such, the graft material and
methods discussed herein may be suitable for a wide range of
surgical applications. In various embodiments, the graft materials
and methods discussed herein may be suitable for various types of
surgical breast procedures, such as, for example, aesthetic surgery
associated with mastectomy or lumpectomy, breast reconstruction,
breast augmentation, breast enhancement, breast reduction,
mastopexy, and revisionary breast surgeries.
[0029] Various embodiments of graft materials discussed herein
include a sample of biocompatible material. In some embodiments, a
sample of biocompatible material may be a flat sheet or sheet-like
in form. A sample of biocompatible material may be a single layer
or may be multi-layered. In some embodiments, a sample of
biocompatible material may be a material that facilitates
revascularization and cell repopulation. For example, as further
described below, certain embodiments can include an acellular
tissue matrix ("ATM").
[0030] FIG. 1 provides a perspective view of one exemplary
embodiment of a graft material for surgical breast procedures. The
graft material may comprise a sample of biocompatible material 13a.
Sample of biocompatible material 13a can have a first edge 15a and
a second edge 17a. A portion of first edge 15a can be convex,
curving away from second edge 17a. Similarly, a portion of second
edge 17a can be convex, curving away from first edge 15a. As
depicted in FIG. 1, first edge 15a and second edge 17a may both be
substantially convex, thus making sample of biocompatible material
13a generally biconvex in shape.
[0031] In one exemplary embodiment, either or both first edge 15a
and second edge 17a may be substantially parabolicly curved. As
such, the curvature of each may be characterized, in part, by the
distance from the focus to the vertex of each parabola. For
example, as depicted in FIG. 1, first edge 15a and second edge 17a
may be substantially parabolicly curved, with the parabolic curve
of second edge 17a having a greater distance from its focus to its
vertex than that of first edge 15a. Furthermore, in certain
embodiments, sample of biocompatible material 13a may be implanted
across breast tissue of a patient such that first edge 15a is
positioned lateral and inferior to first edge 17a, and such that a
longitudinal axis y of sample of biocompatible material 13a is at
about a 45.degree. angle with respect to the transverse plane of
the patient.
[0032] First edge 15a and second edge 17a may join at an apex.
Depending on the needs of the procedure, the apex can be configured
in numerous shapes, such as, for example, a pointed apex 19a, as
depicted in FIG. 1, a rounded apex 19b, as depicted in FIG. 2, or a
squared apex 19c, as depicted in FIG. 3. Further, first edge 15a
and second edge 17a may be joined at more than one apex, and each
apex may be shaped differently. Similarly, sample of biocompatible
material 13a may be symmetrical, for example about an axis x, as
depicted in FIG. 1, or asymmetrical, such as 13b depicted in FIG.
4.
[0033] In some exemplary embodiments, the edges of a sample of
biocompatible material may have multiple portions with varying
degrees of curvature, including, for example, nonconvex, straight,
or concave portions, in addition to a convex portion. For example,
as shown in FIG. 4, a sample of biocompatible material 13b may have
a first edge 15b and a second edge 17b joined at a first apex 19d
and a second apex 19e. First edge 15b may have a nonconvex portion
29, and second edge 17b may have a nonconvex portion 31. The
nonconvex portions of first edge 15b and second edge 17b may
converge at the second apex 19e. In certain embodiments, sample of
biocompatible material 13b may be implanted across breast tissue of
a patient such that second apex 19e is positioned medial and
inferior to first apex 19d, and such that a longitudinal axis y of
sample of biocompatible material 13b is at about a 45.degree. angle
with respect to the transverse plane of the patient. Further, in
some embodiments, the nonconvex portions of first edge 15b and
second edge 17b may be substantially straight.
[0034] Since graft materials may be provided in sheet or sheet-like
forms, and the underlying features of the implantation site are
often rounded or irregularly shaped, it may be difficult to attain
adequate conformance between the graft material and the underlying
features. This can be challenging in surgical breast procedures,
where the desired outcome involves unique aesthetic and structural
demands. Specifically, it can be difficult to avoid undesired
pleating after implanting a sheet of graft material over a rounded
breast mound and/or breast implant. In some circumstances, pleating
may be undesirable because it may be perceptible by palpation
and/or it may negatively affect cell integration or infiltration.
Providing adequate support to maintain breast shape and projection
and to minimize or avoid eventual ptosis, or sagging, of the breast
can also be a challenge. In some embodiments, graft materials
incorporating edge configurations, as described herein, may improve
surface coverage and conformance to underlying anatomical features
when implanted in a patient.
[0035] In some exemplary embodiments, sample of biocompatible
material 13b may be specifically sized and shaped to conform to a
portion of a surface of a breast implant. For example, a specific
size and shape may be derived by modeling the lower pole of a
breast implant in its proper orientation with respect to gravity.
Accordingly, FIG. 5 shows a modeled Style 410 Anatomical Implant
(Allergan, Inc. (Santa Barbara, Calif.)) 21 in a vertical
orientation and a sample of biocompatible material 13b having a
shape produced by modeling biocompatible material covering 50% of
implant 21 such that sample of biocompatible material 13b may be
bordered by the inframammary fold, the lateral fold, and the
inferior edge of the pectoralis major muscle when implanted in a
patient. In some embodiments, tailoring the size and shape of the
graft material to a breast implant can provide better conformance
of the graft material to the implant and/or surrounding tissue and
may reduce the frequency of pleating.
[0036] Currently, graft material is typically provided to surgeons
as sheets or sheet-like devices, and the surgeon may cut the
material to the desired size and shape before implantation. While
providing flexibility to surgeons, this practice has several
drawbacks. Often, substantial amounts of the graft material can be
wasted. For example, surgeons may inaccurately estimate the size of
the device needed, either overestimating and disposing of the
unused portion of an unnecessarily large device, or underestimating
and necessitating the opening of a second packaged device. Such
waste can add substantial costs to procedures, as graft materials
are often very expensive and may be priced based on the amount of
material included. Furthermore, it may be difficult for surgeons to
accurately cut the material freehand into a specific optimum
shape.
[0037] In some embodiments, ready-to-use, off-the-shelf graft
materials can be made that are designed to conform to breast
implants of various specifications. For example, in some
embodiments, a sample of biocompatible material can be specifically
sized and shaped to conform to a particular type of breast implant,
such as, for example, gel or saline, round or anatomical/contour,
form-stable or nonform-stable, and smooth or textured implants.
Alternatively or additionally, a sample of biocompatible material
can be specifically sized and shaped to conform to breast implants
of a predetermined volume. For example, graft materials can be made
from a sample of biocompatible material sized and shaped
specifically for common breast implant volumes, such as, between
about 400 and about 550 cubic centimeters, between about 250 and
about 400 cubic centimeters, between about 250 and about 550 cubic
centimeters, or less than about 250 cubic centimeters. Further, a
sample of biocompatible material can be specifically shaped to
conform to breast implants of a particular profile, such as, for
example, samples of biocompatible material 13c and 13d, as shown in
FIGS. 6 and 7. Sample of biocompatible material 13c may be better
suited for a moderate profile implant while sample of biocompatible
material 13d may be better suited for a high profile implant.
Providing graft materials specifically sized and shaped for breast
implants of particular specifications (e.g., volume, surface area,
surface texture, material, profile, mechanical properties) may
remove some of the uncertainty associated with a surgeon attempting
to estimate the optimal size and shape of graft material needed for
a particular surgery. This in turn, may reduce the amount of graft
material that is sometimes wasted due to inaccurate estimates. This
may also reduce the need to perform trimming/resizing of the graft
material during surgery. Avoiding trimming/resizing during surgery
may reduce the duration of the surgery, which can be beneficial
both for the health of the patient and for reducing the cost of the
surgery.
[0038] In other exemplary embodiments, the sample of biocompatible
material can be slightly oversized relative to the modeled size and
shape. Slight oversizing can allow the graft material to
accommodate breast implants of different profiles. Additionally, an
identified size and shape can be slightly oversized in some
portions to make the graft material generally symmetrical, such as,
for example, sample of biocompatible material 13a. While this may
result in small excesses in material use, this could aid the
surgeon by making it unnecessary to identify a particular side that
must be positioned medially or laterally.
[0039] In some embodiments, the graft material described herein can
be used to assist in treating patients in whom complications
related to breast implants have arisen. Such complications can
include malposition (e.g., inframmary fold malposition, lateral
malposition, symmastia), stretch deformity, coverage issues (e.g.,
wrinkling and rippling), and capsular contraction. For example, in
some embodiments, the graft material described herein may be used
to help control the breast pocket size and location, act as an
"internal bra" to hold the implant in place, support fold repairs,
support the implant to reduce the pressure and tension on patient's
own tissue, and/or provide an additional layer for coverage of the
implant.
[0040] Exemplary embodiments may further include one or more sets
of perforations across at least a portion of the sample of
biocompatible material. Perforations can be formed in the sample of
biocompatible material by any suitable method, such as, for
example, die cutting, laser drilling, water jet cutting, skin graft
meshing, or manual incision (e.g., with a scalpel). In some
exemplary embodiments, such a set of perforations can be used to
improve the conformance of a sample of biocompatible material to
anatomical structures and/or a breast implant. For example, as
depicted in FIG. 8, set of perforations 23a may form an arcuate
pattern across sample of biocompatible material 13e. In some
exemplary embodiments, the arcuate pattern can improve conformance
of graft materials to rounded structures, such as, for example,
breast tissue. In certain embodiments, set of perforations 23a may
create a mesh pattern that enables separation and/or expansion of
portions of biocompatible material 13e such that portions of
biocompatible material 13e may be capable of covering larger
surface areas. In some exemplary embodiments, one or more sets of
perforations across at least a portion of the sample of
biocompatible material may also be used to modify the mechanical
properties of the sample of biocompatible and/or affect tissue
ingrowth.
[0041] In various embodiments, one or more sets of perforations can
be incorporated into graft material in numerous configurations
depending on the structure of the tissue on which the graft
material is to be implanted or type of breast implant being used.
For example, a set of perforations 23a can be included on samples
of biocompatible material of any desired shape, such as, for
example, semicircular (13e, 13f) (including semicircular with a
portion removed, as depicted in FIG. 9, to accommodate an
anatomical feature, such as, for example, the nipple-areola
complex), rectangular (13g), or customized to a breast implant
(13b), as described above in greater detail. The set of
perforations may be uniform or irregular in shape and spacing. A
set of perforations may include individual perforations that are
arcuate, individual perforations that are straight but arranged in
an arcuate pattern, or a combination of both, depending on the
features of the implantation surface. Individual perforations can
be formed as slits, circular apertures, or any other shape.
Furthermore, set of perforations 23a can be placed across an entire
surface of biocompatible material 13g, as depicted in FIG. 10, or
simply a portion of a surface of biocompatible material 13g, as
depicted in FIG. 11, in order to achieve desired conformance
characteristics across different portions of the sample of
biocompatible material 13g. Similarly, as depicted in FIG. 13,
multiple sets of perforations 23b, 23c can be included on a single
sample of biocompatible material to attain a desired variation of
conformance characteristics across the sample of biocompatible
material.
[0042] In some exemplary embodiments, as depicted in FIG. 14, a
uniform set of perforations may include a series of parallel slits
25. Each slit 25 may have a generally uniform length L, adjacent
slits may be separated longitudinally by a generally uniform gap
distance g, and adjacent parallel slits may be separated by a
generally uniform horizontal separation distance d. In some
exemplary embodiments, length L may be between about 0.1 and about
20 millimeters, gap distance g may be between about 0.1 and about
20 millimeters, and horizontal separation distance d may be between
about 0.1 and about 20 millimeters. Further, in some exemplary
embodiments, length L may be between about 4 and about 8
millimeters, gap distance g may be between about 2 and about 6
millimeters, and horizontal separation distance d may be between
about 2 and about 6 millimeters. In some exemplary embodiments,
adjacent parallel slits may be offset longitudinally with respect
to each other as depicted in FIG. 14. Such a configuration of a set
of parallel slits may provide improved conformance to a sample of
biocompatible material while still maintaining sufficient support
strength.
[0043] In some embodiments, the samples of biocompatible material
can comprise any suitable synthetic or biologic material, such as,
for example, medical-grade silicon, autologous or cadaveric tissue,
and/or biomatrices, such as, for example, ATM.
[0044] As used herein, ATM refers to a tissue-derived biomatrix
structure that can be made from any of a wide range of
collagen-containing tissues by removing all, or substantially all,
viable cells and all detectable subcellular components and/or
debris generated by killing cells. As used herein, an ATM lacking
"substantially all viable cells" is an ATM in which the
concentration of viable cells is less than 1% (e.g., less than:
0.1%; 0.01%; 0.001%; 0.0001%; 0.00001%; or 0.000001%) of that in
the tissue or organ from which the ATM was made.
[0045] ATM's that are suitable for use in the present disclosure
include those that contain, lack, or substantially lack, an
epithelial basement membrane. As used herein, an ATM that
"substantially lacks" an epithelial basement membrane is an
acellular tissue matrix containing less than 5% (e.g., less than:
3%; 2%; 1%; 0.5%; 0.25%; 0.1%; 0.01%; 0.001%; or even less than
0.0001%) of the epithelial basement membrane possessed by the
corresponding unprocessed tissue from which the acellular tissue
matrix was derived.
[0046] An epithelial basement membrane is a thin sheet of
extracellular material contiguous with the basilar aspect of
epithelial cells. Sheets of aggregated epithelial cells form an
epithelium. Thus, for example, the epithelium of skin is called the
epidermis, and the skin epithelial basement membrane lies between
the epidermis and the dermis. The epithelial basement membrane is a
specialized extracellular matrix that provides a barrier function
and an attachment surface for epithelial-like cells; however, it
does not contribute any significant structural or biomechanical
role to the underlying tissue (e.g., dermis). Components of
epithelial basement membranes include, for example, laminin,
collagen type VII, and nidogen. The temporal and spatial
organizations of the epithelial basement membrane distinguish it
from, e.g., the dermal extracellular matrix.
[0047] Accordingly, in some non-limiting embodiments, the ATMs
suitable for use in the present disclosure contain epithelial
basement membrane. In other non-limiting embodiments, ATM may lack
or substantially lack epithelial basement membrane.
[0048] ATM's suitable for use in the present disclosure may, for
example, retain certain biological functions, such as cell
recognition, cell binding, the ability to support cell spreading,
cell proliferation, cellular in-growth and cell differentiation.
Such functions may be provided, for example, by undenatured
collagenous proteins (e.g., type I collagen) and a variety of
non-collagenous molecules (e.g., proteins that serve as ligands for
either molecules such as integrin receptors, molecules with high
charge density such as glycosaminoglycans (e.g., hyaluronan) or
proteoglycans, or other adhesins). In some embodiments, the ATM's
may retain certain structural functions, including maintenance of
histological architecture and maintenance of the three-dimensional
array of the tissue's components. The ATM's described herein may
also, for example, exhibit desirable physical characteristics such
as strength, elasticity, and durability, defined porosity, and
retention of macromolecules.
[0049] ATMs suitable for use in the present disclosure may be
crosslinked or uncrosslinked.
[0050] The efficiency of the biological functions of an ATM can be
measured, for example, by the ability of the ATM to support cell
proliferation. In some embodiments of the present disclosure, the
ATM exhibits at least 50% (e.g., at least: 50%; 60%; 70%; 80%; 90%;
95%; 98%; 99%; 99.5%; 100%; or more than 100%) of that of the
native tissue or organ from which the ATM is made.
[0051] In some embodiments, the graft material is amenable to being
remodeled by infiltrating cells such as differentiated cells of the
relevant host tissue, stem cells such as mesenchymal stem cells, or
progenitor cells. This may be accomplished, for example, by forming
the grafted matrix material from tissue that is identical to the
surrounding host tissue, but such identity is not necessary.
[0052] Remodeling may be directed by the above-described ATM
components and signals from the surrounding host tissue (such as
cytokines, extracellular matrix components, biomechanical stimuli,
and bioelectrical stimuli). For example, the presence of
mesenchymal stem cells in the bone marrow and the peripheral
circulation has been documented in the literature and shown to
regenerate a variety of musculoskeletal tissues [Caplan (1991) J.
Orthop. Res. 9:641-650; Caplan (1994) Clin. Plast. Surg.
21:429-435; and Caplan et al. (1997) Clin Orthop. 342:254-269].
Additionally, the graft must provide some degree (greater than
threshold) of tensile and biomechanical strength during the
remodeling process.
[0053] ATM in accordance with the present disclosure may be
manufactured from a variety of source tissues. For example, ATM may
be produced from any collagen-containing soft tissue and muscular
skeleton (e.g., dermis, fascia, pericardium, dura, umbilical cords,
placentae, cardiac valves, ligaments, tendons, vascular tissue
(arteries and veins such as saphenous veins), neural connective
tissue, urinary bladder tissue, ureter tissue, or intestinal
tissue), as long as the above-described properties are retained by
the matrix. Moreover, the tissues in which ATM graft material are
placed may include any tissue that can be remodeled by invading or
infiltrating cells. Non-limiting examples of such tissues include
skeletal tissues such as bone, cartilage, ligaments, fascia, and
tendon. Other tissues in which any of the above grafts can be
placed include, for example, skin, gingiva, dura, myocardium,
vascular tissue, neural tissue, striated muscle, smooth muscle,
bladder wall, ureter tissue, intestine, and urethra tissue.
[0054] While an ATM may be made from one or more individuals of the
same species as the recipient of the ATM graft, this is not
necessarily the case. Thus, for example, an ATM may be made from
porcine tissue and implanted in a human patient. Species that can
serve as recipients of ATM and donors of tissues or organs for the
production of the ATM include, without limitation, humans, nonhuman
primates (e.g., monkeys, baboons, or chimpanzees), porcine, bovine,
horses, goats, sheep, dogs, cats, rabbits, guinea pigs, gerbils,
hamsters, rats, or mice. Of particular interest as donors are
animals (e.g., pigs) that have been genetically engineered to lack
the terminal .alpha.-galactose moiety. 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 all of
which are incorporated herein by reference in their entirety.
[0055] As an example of suitable porcine-derived tissue,
non-limiting mention is made of STRATTICE.TM., which is a porcine
dermal tissue produced by Lifecell Corporation (Branchburg, N.J.).
The tissue matrix may be derived from porcine skin by removing the
epidermis while leaving the dermal matrix substantially intact. In
some embodiments, the porcine-derived tissue matrix may facilitate
tissue ingrowth and remodeling with the patient's own cells. In
other embodiments, the material can include a collagenous matrix
derived from human cadaver skin (e.g. ALLODERM.RTM., Lifecell
Corporation (Branchburg, N.J.)) that has been processed to remove
both the epidermis and cells.
[0056] In some embodiments of the present disclosure, a freeze
dried ATM is produced from human dermis by the LifeCell Corporation
(Branchburg, N.J.) and marketed in the form of small sheets as
ALLODERM.RTM.. Such sheets are marketed by the LifeCell Corporation
as rectangular sheets with the dimensions of, for example, 1
cm.times.2 cm, 3 cm.times.7 cm, 4 cm.times.8 cm, 5 cm.times.10 cm,
4 cm.times.12 cm, and 6 cm.times.12 cm. The cryoprotectant used for
freezing and drying ALLODERM.RTM. is a solution of 35% maltodextrin
and 10 mM ethylenediaminetetraacetate (EDTA). Thus, the final dried
product contains about 60% by weight ATM and about 40% by weight
maltodextrin. The LifeCell Corporation also makes an analogous
product made from porcine dermis (designated XENODERM) having the
same proportions of ATM and maltodextrin as ALLODERM.RTM..
[0057] As an alternative to using such genetically engineered
animals as donors, appropriate tissues and organs can be treated,
before or after decellularization, with the enzyme
.alpha.-galactosidase, which removes terminal .alpha.-galactose
(.alpha.-gal) moieties from saccharide chains on, for example,
glycoproteins. Methods of treating tissue with
.alpha.-galactosidase to remove these moieties are described in,
for example, U.S. Pat. No. 6,331,319, the disclosure of which is
incorporated herein by reference in its entirety.
[0058] In an implementation, either before or after the soft tissue
cells are killed in the ATM, the collagen-containing material is
subjected to in vitro digestion of the collagen-containing material
with one or more glycosidases, and particularly galactosidases,
such as .alpha.-galactosidase. In particular, .alpha.-gal epitopes
are eliminated by enzymatic treatment with
.alpha.-galactosidases.
[0059] The N-acetylactosamine residues are epitopes that are
normally expressed on human and mammalian cells and thus are not
immunogenic. The in vitro digestion of the collagen-containing
material with glycosidases may be accomplished by various methods.
For example, the collagen-containing material can be soaked or
incubated in a buffer solution containing glycosidase.
Alternatively, a buffer solution containing the glycosidase can be
forced under pressure into the collagen-containing material via a
pulsatile lavage process.
[0060] 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 1.times.106-35.times.106 epitopes per
cell, 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).
[0061] Since non-primate mammals (e.g., pigs) produce .alpha.-gal
epitopes, xenotransplantation by injection 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, the substantial
elimination of .alpha.-gal epitopes from cells and from
extracellular components of the collagen-containing material, and
the prevention of reexpression 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.
[0062] ATMs suitable for use in the present disclosure may be
provided in various forms depending on the tissue or organ from
which it is derived, the nature of the recipient tissue or organ,
and the nature of the damage or defect in the recipient tissue or
organ. Thus, for example, a ATM derived from a heart valve can be
provided as a whole valve, as small sheets or strips, or as pieces
cut into any of a variety of shapes and/or sizes. The same concept
applies to ATM produced from any of the above-listed tissues and
organs. In some embodiments, the ATM is made from a recipient's own
collagen-based tissue.
[0063] ATM's suitable for use in the present disclosure can be
produced by a variety of methods, so long as their production
results in matrices with the above-described biological and
structural properties. As non-limiting examples of such production
methods, mention is made of the methods described in U.S. Pat. Nos.
4,865,871; 5,366,616, and 6,933,326, U.S. patent application
Publication Nos. US 2003/0035843 A1, and US 2005/0028228 A1, all of
which are incorporated herein by reference in their entirety.
[0064] In general, the steps involved in the production of an ATM
include harvesting the tissue from a donor (e.g., a human cadaver
or any of the above-listed mammals), chemical treatment so as to
stabilize the tissue and avoid biochemical and structural
degradation together with, or followed by, cell removal under
conditions which similarly preserve biological and structural
function. After thorough removal of dead and/or lysed cell
components that may cause inflammation as well as any
bioincompatible cell-removal agents, the matrix can be treated with
a cryopreservation agent and cryopreserved and, optionally, freeze
dried, again under conditions necessary to maintain the described
biological and structural properties of the matrix. After freeze
drying, the tissue can, optionally, be pulverized or micronized to
produce a particulate ATM under similar function-preserving
conditions. After cryopreservation or freeze-drying (and optionally
pulverization or micronization), the ATM can be thawed or
rehydrated, respectively. All steps are generally carried out under
aseptic, preferably sterile, conditions.
[0065] The initial 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 in some cases, a smooth muscle relaxant.
[0066] The tissue is then placed in a processing solution to remove
viable cells (e.g., epithelial cells, endothelial cells, smooth
muscle cells, and fibroblasts) from the structural matrix without
damaging the basement membrane complex or the biological and
structural integrity of the collagen matrix. The processing
solution may contain an appropriate buffer, salt, an antibiotic,
one or more detergents (e.g., Triton-x-100, 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. The tissue is then treated with a processing
solution containing active agents, and for a time period such that
the structural integrity of the matrix is maintained.
[0067] Alternatively, the tissue can be cryopreserved prior to
undergoing water replacement. If so, after decellularization, the
tissue is incubated in a cryopreservation solution. This solution
may contain at least one cryoprotectant to minimize ice crystal
damage to the structural matrix that could occur during freezing.
If the tissue is to be freeze dried, the solution may also contain
at least one dry-protective components, to minimize structural
damage during drying and may include a combination of an organic
solvent and water which undergoes neither expansion nor contraction
during freezing. The cryoprotective and dry-protective agents may
be the same. If the tissue is not going to be freeze dried, it can
be frozen by placing it (in a sterilized container) in a freezer at
about -80.degree. C., or by plunging it into sterile liquid
nitrogen, and then storing at a temperature below -160.degree. C.
until use. The tissue sample can be thawed prior to use by, for
example, immersing a sterile non-permeable vessel (see below)
containing the sample in a water bath at about 37.degree. C. or by
allowing the tissue to come to room temperature under ambient
conditions.
[0068] If the tissue is to be frozen and freeze dried, following
incubation in the cryopreservation solution, the tissue may be
packaged inside a sterile vessel that is permeable to water vapor
yet impermeable to bacteria, e.g., a water vapor permeable pouch or
glass vial. As a non-limiting example, one side of the pouch may
include medical grade porous TYVEK.RTM. membrane, a trademarked
product of DuPont Company of Wilmington, Del. This membrane is
porous to water vapor and impervious to bacteria and dust. The
TYVEK.RTM. membrane is heat sealed to an impermeable polyethylene
laminate sheet, leaving one side open, thus forming a two-sided
pouch. The open pouch is sterilized by irradiation prior to use.
The tissue is aseptically placed (through the open side) into the
sterile pouch. The open side is then aseptically heat sealed to
close the pouch. The packaged tissue is henceforth protected from
microbial contamination throughout subsequent processing steps.
[0069] The vessel containing the tissue is cooled to a low
temperature at a specified rate which is compatible with the
specific cryoprotectant formulation to minimize the freezing
damage. See U.S. Pat. No. 5,336,616 for non-limiting examples of
appropriate cooling protocols. The tissue is then dried at a low
temperature under vacuum conditions, such that water vapor is
removed sequentially from each ice crystal phase.
[0070] At the completion of the drying of the samples in the water
vapor permeable vessel, the vacuum of the freeze drying apparatus
is reversed with a dry inert gas such as nitrogen, helium or argon.
While being maintained in the same gaseous environment, the
semipermeable vessel is placed inside an impervious (i.e.,
impermeable to water vapor as well as microorganisms) vessel (e.g.,
a pouch) which is further sealed, e.g., by heat and/or pressure.
Where the tissue sample was frozen and dried in a glass vial, the
vial is sealed under vacuum with an appropriate inert stopper and
the vacuum of the drying apparatus reversed with an inert gas prior
to unloading. In either case, the final product is hermetically
sealed in an inert gaseous atmosphere.
[0071] After rehydration of the ATM (see below), histocompatible,
viable cells can be restored to the ATM to produce a permanently
accepted graft that may be remodeled by the host. In one
embodiment, histocompatible viable cells may be added to the
matrices by standard in vitro cell coculturing 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 ATM or by infusing or injecting cells
obtained from the recipient or histocompatible cells from another
donor into the ATM in situ.
[0072] The cell types chosen for reconstitution may depend on the
nature of the tissue or organ to which the ATM is being remodeled.
For example, the reconstitution of full-thickness skin with an ATM
often requires the restoration of epidermal cells or keratinocytes.
Thus, cells derived directly from the intended recipient can be
used to reconstitute an ATM and the resulting composition grafted
to the recipient in the form of a meshed split-skin graft.
Alternatively, cultured (autologous or allogeneic) cells can be
added to the ATM. Such cells can be, for example, grown under
standard tissue culture conditions and then added to the ATM. In
another embodiment, the cells can be grown in and/or on an ATM in
tissue culture. Cells grown in and/or on an ATM in tissue culture
can have been obtained directly from an appropriate donor (e.g.,
the intended recipient or an allogeneic donor) or they can have
been first grown in tissue culture in the absence of the ATM.
[0073] The endothelial cell is important for the reconstitution of
heart valves and vascular conduits. Such cells line the inner
surface of the tissue, and may be expanded in culture. Endothelial
cells may also be derived, for example, directly from the intended
recipient patient or from umbilical arteries or veins.
[0074] Other non-limiting examples of cells that may be used to
reconstitute the ATMs of the present disclosure include
fibroblasts, embryonic stem cells (ESC), adult or embryonic
mesenchymal stem cells (MSC), prochondroblasts, chondroblasts,
chondrocytes, pro-osteoblasts, osteocytes, osteoclasts, monocytes,
pro-cardiomyoblasts, pericytes, cardiomyoblasts, cardiomyocytes,
gingival epithelial cells, or periodontal ligament stem cells.
Naturally, the ATM can be repopulated with combinations of two more
(e.g., two, three, four, five, six, seven, eight, nine, or ten) of
these cell-types.
[0075] Reagents and methods for carrying out all the above steps
are known in the art. Suitable reagents and methods are described
in, for example, U.S. Pat. No. 5,336,616.
[0076] Other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and
practice of the invention disclosed herein. It is intended that the
specification and examples be considered as exemplary only, with a
true scope and spirit of the invention being indicated by the
following claims.
* * * * *