U.S. patent application number 11/007679 was filed with the patent office on 2005-06-02 for soft and calcified tissue implants.
This patent application is currently assigned to Regeneration Technologies, Inc.. Invention is credited to Buskirk, Dayna, Gross, James M., Scurti, Gina, Seid, Chris, Wironen, John F..
Application Number | 20050119744 11/007679 |
Document ID | / |
Family ID | 25478229 |
Filed Date | 2005-06-02 |
United States Patent
Application |
20050119744 |
Kind Code |
A1 |
Buskirk, Dayna ; et
al. |
June 2, 2005 |
Soft and calcified tissue implants
Abstract
Disclosed herein is processed dermis graft for use in orthopedic
surgical procedures. Specifically exemplified herein is a processed
dermis graft comprising one or more bone blocks having a groove cut
into the surface thereof, wherein said groove is sufficient to
accommodate a fixation screw. Also disclosed is a method of
processing dermis that results in a dermis derived implant suitable
to replace a tendon or ligament in a recipient in need thereof.
Other compositions and applications of a dermis derived implant,
and methods of manufacture and use, are disclosed.
Inventors: |
Buskirk, Dayna; (Alachua,
FL) ; Seid, Chris; (Alachua, FL) ; Wironen,
John F.; (Alachua, FL) ; Gross, James M.;
(Alachua, FL) ; Scurti, Gina; (Alachua,
FL) |
Correspondence
Address: |
MCANDREWS HELD & MALLOY, LTD
500 WEST MADISON STREET
SUITE 3400
CHICAGO
IL
60661
|
Assignee: |
Regeneration Technologies,
Inc.
|
Family ID: |
25478229 |
Appl. No.: |
11/007679 |
Filed: |
December 8, 2004 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11007679 |
Dec 8, 2004 |
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09942537 |
Aug 29, 2001 |
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09942537 |
Aug 29, 2001 |
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09481319 |
Jan 11, 2000 |
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6497726 |
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09942537 |
Aug 29, 2001 |
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09750192 |
Dec 28, 2000 |
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09942537 |
Aug 29, 2001 |
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09782594 |
Feb 12, 2001 |
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60181622 |
Feb 10, 2000 |
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Current U.S.
Class: |
623/13.17 ;
623/13.11; 623/13.14; 623/15.12; 623/23.72 |
Current CPC
Class: |
A61F 2002/2817 20130101;
A61F 2002/30113 20130101; A61F 2002/30224 20130101; A61F 2002/3028
20130101; A61B 17/8645 20130101; A61F 2/447 20130101; A61F
2002/30179 20130101; A61F 2002/30492 20130101; A61F 2002/30904
20130101; A61F 2220/0025 20130101; A61F 2230/0082 20130101; A61F
2310/00976 20130101; A61B 17/1637 20130101; A61F 2/0811 20130101;
A61L 27/3641 20130101; A61F 2/4644 20130101; A61F 2002/30057
20130101; A61F 2002/30975 20130101; A61F 2310/0097 20130101; A61F
2002/30062 20130101; A61F 2002/30329 20130101; A61F 2230/0058
20130101; A61F 2002/2835 20130101; A61F 2002/3085 20130101; A61F
2230/0006 20130101; A61L 27/3687 20130101; A61F 2/08 20130101; A61F
2/446 20130101; A61F 2002/30235 20130101; A61F 2002/30599 20130101;
A61F 2002/30962 20130101; A61F 2310/00383 20130101; A61F 2/3094
20130101; A61F 2220/0033 20130101; A61L 27/3608 20130101; A61L
2430/02 20130101; A61F 2002/2839 20130101; A61L 24/0005 20130101;
A61L 27/365 20130101; A61F 2002/30225 20130101; A61L 31/005
20130101; A61F 2230/0015 20130101; A61F 2002/30785 20130101; A61F
2310/00293 20130101; A61F 2002/30059 20130101; A61F 2/28 20130101;
A61F 2002/30131 20130101; A61F 2220/005 20130101; A61L 27/3691
20130101; A61B 17/1671 20130101; A61F 2002/30266 20130101; A61F
2002/30795 20130101; A61F 2310/00365 20130101; A61F 2002/30261
20130101; A61F 2230/0019 20130101; A61F 2230/0063 20130101; A61F
2002/30387 20130101; A61F 2002/4649 20130101; A61L 27/3658
20130101; A61F 2002/30448 20130101; A61F 2002/30563 20130101; A61L
2430/34 20130101; A61F 2230/0069 20130101; A61F 2250/0063 20130101;
A61F 2002/30677 20130101; A61F 2002/30153 20130101; A61L 27/3645
20130101; A61L 27/3604 20130101; A61F 2/442 20130101; A61F
2002/30383 20130101; A61F 2002/30133 20130101; A61F 2002/30354
20130101; A61F 2002/30957 20130101; A61F 2210/0004 20130101; A61L
2430/40 20130101; A61L 2/0082 20130101; A61L 27/3683 20130101; A61F
2230/0013 20130101 |
Class at
Publication: |
623/013.17 ;
623/023.72; 623/013.11; 623/013.14; 623/015.12 |
International
Class: |
A61F 002/08 |
Claims
1. A method of calcifying a section of soft tissue, dermis,
pericardium, fascia, woven soft tissue, urinary bladder membrane
(UBM), or small intestine submucosa (SIS) implant material
comprising contacting a section of said implant material with a
calcium solution to form a treated section, and thereafter
contacting said treated section with a phosphate solution.
2. The method of claim 1, wherein said calcium solution is a
saturated calcium hydroxide, and said phosphate solution is
phosphate buffer adjusted to approximately pH 7.0.
3. A method of calcifying implant material comprising the steps of:
a) contacting said implant material with a viral inactivating
agent; b) contacting said implant material with a decellularizing
agent; c) contacting said implant material with a saturated calcium
hydroxide solution; and d) contacting said implant material treated
by step c with a phosphate solution.
4. The method of claim 3 wherein said viral inactivating agent
comprises, benzalkonium chloride; said decellularizing agent
comprises a solution comprising, by weight, about 1 percent TWEEN
20 and about 0.5 percent hydrogen peroxide; and wherein said method
further optionally comprises sonicating said implant material
during step b.
5. A calcified section of implant material made according to the
method of claim 3.
6-35. (canceled)
36. A method of preparing a soft tissue graft comprising: a)
decellularizing a section of soft tissue; b) layering said
decellularized section of soft tissue around a mandrel to form a
layered shape of a desired thickness; and c) treating a part of
said layered shape with a cross-linking agent to cause said soft
tissue to adhere together.
37. The method of claim 36, additionally comprising removing said
mandrel to provide a cohesive shape of crosslinked tissue
layers.
38. The method of claim 36, additionally comprising drying said
section of soft tissue after said decellularizing step, after said
treating step, or after both said steps, wherein said drying is
performed by contacting said section of soft tissue with alcohol,
heat drying, vacuum drying, freeze drying or a combination
thereof.
39. The method of claim 36, additionally comprising a virus
inactivating step comprising contacting said section of soft tissue
with a virus inactivating agent, comprising benzalkonium chloride,
calcium hydroxide, sodium hydroxide or hydrogen peroxide, or a
combination thereof.
40. The method of claim 36, wherein said treating to adhere is
accomplished by immersing said section of soft tissue in a gelatin
solution.
41. The method of claim 36, wherein said decellularizing is by
immersing said section of soft tissue in a solution comprising, by
weight, about 0.5 percent or more TWEEN 20 and about 0.5 percent or
more hydrogen peroxide.
42. The method of claim 36, additionally comprising applying
pressure to said layered shape of soft tissue.
43. The method of claim 36 wherein said soft tissue comprises
dermis, fascia, pericardium, woven soft tissue, urinary bladder
membrane, peritoneum, or SIS.
44. A soft tissue graft produced by the method of claim 36.
45. A method of preparing a soft tissue graft comprising: a)
decellularizing and virally inactivating a section of soft tissue;
and b) subjecting all or a portion of said decellularized and
virally inactivated soft tissue to a cross-linking treatment.
46. The method of claim 45, wherein said cross-linking treatment
comprises contacting said decellularized and virally inactivated
soft tissue with glutaraldehyde, formaldehyde or another mono- or
dialdehydes; glycerol polyglycidyl ethers, polyethylene glycol
diglycidyl ethers or other polyepoxy and diepoxy glycidyl ethers;
titanium dioxide, chromium dioxide, aluminum dioxide, zirconium
salt; an organic tannin or other phenylic oxides derived from
plants; chemicals for esterification of carboxyl groups followed by
reaction with hydrazide to form activated acyl azide
functionalities in the collagen; dicyclohexyl carbodiimide or a
derivative thereof; heterobifunctional crosslinking agents;
hexamethylene diisocyante; or one or more sugars.
47. The method of claim 46, wherein said cross-linking treatment
comprises contact with transglutaminase.
48. A method of preparing a soft tissue graft comprising: a)
decellularizing a section of soft tissue comprising a first end and
a second end; b) layering said section of soft tissue around a
mandrel to form a layered shape of a desired thickness; and c)
contacting said first end, second end or both of said layered shape
of soft tissue with a hardening treatment.
49. The method of claim 48, wherein said hardening treatment
comprises calcification.
50. The method of claim 49, wherein said calcification comprises
contacting a section of said soft tissue with a calcium solution to
form a treated section, and thereafter contacting said treated
section with a phosphate solution.
51. The method of claim 50, wherein said calcium solution is
saturated calcium hydroxide, and said phosphate solution is a
phosphate buffer adjusted to approximately pH 7.0.
52. The method of claim 48, wherein said section of soft tissue is
comprised of dermis, fascia, pericardium, woven soft tissue,
urinary bladder membrane, peritoneum, or SIS.
53. A soft tissue graft produced by the method of claim 48.
54. A method of preparing a dermis derived graft comprising: a)
obtaining a section of dermis tissue comprising a first end and a
second end; and b) attaching a bone block to either said first end
or said second end or both.
55. The method of claim 54, wherein said attaching is by chemical
annealing, chemical adhesive, suturing, pinning to, or wrapping and
tying the processed dermis around said bone block.
56. A dermis derived graft produced by the method of claim 54.
57. A method of conducting orthopedic surgery on an animal
comprising: obtaining a dermis derived bone-ended graft, said graft
comprising processed dermis comprising a first end and a second
end, and a first bone block affixable to said first end, to said
second end, or to both said ends; and attaching said first bone
block to a desired position in an animal in need thereof with a
fixation screw.
58. The method of claim 57, wherein said first bone block is
pre-shaped into a dowel, and wherein said bone block has a groove
suitable for accommodating the fixation screw.
59. The method of claim 58, wherein said first bone block of said
first end of said dermis is a different size than a second bone
block attached to said second end of said dermis.
60. The method of claim 57, where in said attaching step, said
first bone block is attached to at least one bone of the animal.
mammalian patient host
61. The method of claim 60, wherein the said bone of the animal is
selected from the group of bones consisting of patella, femur and
tibia.
62-74. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 60/296,530, filed on Jun. 6, 2001, and a continuation of U.S.
application Ser. No. 09/481,319, filed on Jan. 11, 2000, and a
continuation of U.S. application Ser. No. 09/750,192, filed Dec.
28, 2000, and a continuation of U.S. application Ser. No.
09/782,594, filed Feb. 12, 2001, which itself is a continuation of
U.S. application Ser. No. 60/181,622. The benefit of priority under
35 USC 119, 120 is claimed for the foregoing applications, and are
also incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Orthopedic medicine is increasingly becoming aware of the
vast potential and advantages of using grafts made from allograft
bone to treat and repair spinal and common joint injuries, such as
Anterior Cruciate Ligament (ACL) or Posterior Cruciate Ligament
(PCL) tears. In the case of injuries involves surgically
reconnecting the torn portions of a damaged ligament. However, this
technique is often not possible, especially when the damage to the
ligament is extensive. The recent utilization of bone/tendon grafts
has dramatically improved the results of joint repair in cases of
severe trauma. Even in cases of extensive damage to the joint
ligaments, orthopedic surgeons have been able to achieve 100
percent range of motion and stability using donor bone/tendon
grafts.
[0003] Despite these realized advantages, there have been some
difficulties encountered with utilizing bone/tendon grafts. For
example, surgical procedures involving transplantation and fixation
of these grafts can be tedious and lengthy. Currently,
bone/tendon/bone grafts must be specifically shaped for the
recipient during surgery, which can require thirty minutes to over
an hour of time. Further, surgeons must establish a means of
attaching the graft, which also takes up valuable surgery time.
[0004] Another difficulty associated with using allograft implants,
such as bone/tendon grafts, is that there is only a limited supply
of source tissue. As a result, patients often have to settle for
inferior surgical procedures simply based on the lack of
availability of tissue. Accordingly, there is a need in the art for
the development of implants that implement unrealized sources of
tissue.
SUMMARY OF THE INVENTION
[0005] One aspect of the subject invention concerns methods of
production and compositions for a novel dermis-derived graft (DDG)
that facilitates an easier and more efficient surgery for
reconstructing ligaments in a joint. While the embodiments herein
exemplify the use of dermis tissue, it is understood that other
tissue types can be adapted for use in accord with the teachings
herein. Specifically, other soft tissues can be used such as
ligament, tendon, muscle, dura, pericardium, fascia, and
peritoneum, as well as demineralized bone. Tissues can be derived
from allogenic, autogenic, or xenogenic sources. Alternatively
synthetic materials may be used alone or in combination with
natural materials. In one embodiment, the subject invention
pertains to a DDG that comprises a section of processed dermis that
is rolled to a cylindrical shape, and two bone blocks positioned at
opposite ends of the rolled dermis, wherein the bone blocks are
pre-shaped for uniform and consistent alignment into a recipient
bone.
[0006] In a specific aspect, the subject invention pertains to a
dermis derived bone-ended graft useful in orthopedic surgery
comprising one or more bone blocks, and processed dermis attached
to said one or more bone blocks; wherein said one or more bone
blocks is cut to provide a groove sufficient to accommodate a
fixation screw. Alternatively, the subject invention pertains to a
dermis derived bone-ended graft useful in orthopedic surgery
comprising one or more bone blocks and processed dermis attached to
said one or more bone blocks, wherein said one or more bone blocks
is pre-shaped into a dowel.
[0007] Another aspect of the invention regards a process for
calcification of all or part of a dermis implant. Comparative data
are provided that show the relative performance of processed dermis
implants in laboratory rats, in which dermis implants had been
calcified prior to implantation.
[0008] Another aspect of the invention regards the calcification of
all or part of a tissue selected from: soft tissue; pericardium;
fascia; woven soft tissue (as from skeletal muscle); urinary
bladder membrane (UBM); and SIS.
[0009] Another aspect of the invention is the use of processed
dermis as a replacement or as auxiliary support for the Anterior
Longitudinal Ligament (ALL), and for use as a Spinal Tension Band
(STB) or other type of tension band. For the ALL and STB, the
dermis is formed into a shape that spans the anterior of at least
two vertebrae (for an ALL support structure) or at least four
vertebrae (for an STB), and the ends are affixed to a part of the
vertebrae. The preferred attachment points for an STB are at the
spinous processes of the adjacent vertebrae. This minimizes
movement of (and thereby reduces degradation of) of the vertebrae
adjacent to the vertebrae that are being fused. Such adjacent
vertebrae are known to undergo excessive wear due to the lack of
motion of the adjacent fused vertebrae. The ALL- and STB-type DDGs
provide tensioning to help prevent excessive back bending due to
the partial or total functional loss of the ALL owing to surgery or
traumatic injury. As disclosed herein, the ends of dermis for such
use preferably are calcified, and starting materials other than
dermis may be used for such applications.
[0010] Preferably, the dermis is processed according to a method
that preserves the dermis basement membrane. A process known to
accomplish this is the subject of U.S. Patent Application Ser. No.
60/296,530, which is incorporated by reference. In yet another
aspect, the subject invention pertains to a method of conducting
orthopedic surgery on an animal comprising obtaining a dermis
derived bone-ended graft, said graft comprising processed dermis
having two ends, and one or more bone blocks attached to said
processed dermis, wherein at least one of said one or more bone
blocks has a groove suitable for accommodating a fixation
screw.
[0011] An alternative aspect of the invention pertains to an
implant comprising a bone block and processed dermis, wherein the
bone block comprises a groove for accommodating a fixation
screw.
[0012] These and other advantageous aspects of the subject
invention are described in further detail below.
DETAILED DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows diagrams depicting different shapes and
constructions of an implant in accordance with the subject
invention. FIG. 1A shows a bone-tendon-bone type implant. FIGS.
1B-E represent an implant comprising a specific assembled bone
block.
[0014] FIG. 2 is a diagram depicting implant embodiments in accord
with the teachings herein.
[0015] FIG. 3 depicts a first embodiment FIG. 3A and depicts a
second embodiment FIG. 3B of an anterior longitudinal replacement
for limiting motion between adjacent vertebrae to be fused.
[0016] FIG. 4 depicts a band for limiting the motion and reducing
the degradation of vertebrae juxtaposed to vertebrae undergoing
spinal fusion (i.e., as a spinal tension band) or for being affixed
to any other anatomical structures to minimize motion of such
structures in relation to each other.
[0017] FIG. 5 shows plan and perspective views of a bone fixation
plug that compresses the soft tissue graft component of the implant
as the plug is being tightened into a hole.
DETAILED DISCLOSURE OF THE INVENTION
[0018] The present invention uses processed dermis as a material
for implants which can be used as replacement or reinforcing
tendons, ligaments, and the like. Particular features of the
methods and the products of the present invention provide for a
dermis-based implant that remodels into a `new` replacement tendon
or ligament. The present invention also discloses a process for the
calcification of dermis and other tissues, including soft tissue,
pericardium, fascia, woven soft tissue (as from skeletal muscle),
urinary bladder membrane (UBM), and SIS. These collectively are
referred to as "implant material," and when processed, as
"processed implant material." The bone that is used in this
application, for instance to comprise bone blocks, may be selected
from cortical, cancellous, cortico-cancellous, or demineralized
bone, obtained from human or xenograft sources. Optionally,
synthetic material may be incorporated in combination with such
bone. Also, bone blocks may be comprised of two or more segments
assembled together in a assembled allograft implant. The
construction and use of assembled allograft implants is disclosed
more fully in U.S. patent application Ser. No. 09/782,594, which is
incorporated by reference.
[0019] Other features provide for implants fabricated for specific
applications, such as to supplement or replace the anterior
longitudinal ligament of the spine. Methods of initial preparation
and production of dermis implants, and of specific production for
use as ALL- and STB-type implants are also disclosed.
[0020] I. Preparation of Dermis Derived Graft Material
[0021] For the purposes of this disclosure, the term "tendon",
unless otherwise indicated, is taken to mean flexible fibrous
connective tissue that attaches muscle to bone. In the context of
bone/tendon/bone grafts, tendon can refer to the fibrous connective
tissue that connects the patella to the femur and tibia. The term
"ligament" is taken to mean the more general term of any fibrous
structure connecting one body part to another, and more
particularly to flexible, e fibrous connective tissue that connects
bone to bone or holds organs in place. Also, the term "processed
dermis" is taken to mean dermis that has been processed by the
initial processing described herein, or another method of
decellularizing dermis, and by the secondary process described
herein, in which the initially processed dermis is formed into an
implant. A dermis derived graft (DDG) is synonymous with a dermis
derived implant, and these terms are defined to indicate a graft or
implant substantially comprised of processed dermis.
[0022] The term "processed dermis" as used herein is intended in a
broad sense and refers to fibrous connective tissue for use in
grafts derived from dermis of a donor, or from dermis cultured in
vitro. The preferred initial processing is that described in U.S.
Patent Application Ser. No. 60/296,530, which is incorporated by
reference. The initial processing provides a decellularized dermis
sample that retains the structural functionality of the basement
membrane. This results in superior structural and functional
properties of the final dermis derived implant.
[0023] Basic steps of a preferred initial processing method are
summarized as follows:
[0024] 1. Contacting the donor dermis with a viral inactivating
agent that includes benzalkonium chloride; and
[0025] 2. Contacting the dermis with one or more decellularizing
agents, for instance about 0.5 percent Tween 20 and about 0.5
percent hydrogen peroxide.
[0026] Additional possible steps include contacting the dermis with
calcium hydroxide (to aid in virus inactivation), with a chelating
agent, for instance EDTA, sonicating the dermis during such
treatments, and drying the dermis, such as by freeze-drying.
[0027] Preferably, a method in accordance with U.S. Patent
Application No. 60/296,530 is used for initial preparation of the
dermis. For example, dermis is selected that is at least 0.7 mm
thick, and is free of epidermis, muscle, fat, hair, scars, moles,
debris and tattoos. The dermis is cut to a desired size, and is
soaked in 1 M NaCl. Thereafter the dermis is soaked in a 1%
solution of benzalkonium chloride at 2-6 degrees Centigrade for
1-24 hours to reduce microbial load. Then the dermis is immersed in
a solution of 1% Tween 20 and 0.5% hydrogen peroxide, and is
sonicated for approximately 15 minutes at room temperature,
stirring at least once per minute. Preferably, microbial load is
further reduced by soaking in saturated calcium hydroxide solution
while sonicating for approximately 15 minutes. The dermis is rinsed
in purified water to remove the calcium hydroxide, Thereafter the
calcium in the dermis is chelated with EDTA by soaking in a 0.1%
EDTA solution for about 15 minutes, and stirring or sonicating.
After two rinses to remove the EDTA, the dermis pH is neutralized
with buffer. Then purified water rinses remove the buffer. Drying
is begun with soaking in 70% isopropanol, and is completed with
freeze-drying. In general, the volume of solution to dermis is at
least tenfold. This or similar initial processing provides dermis
ready for further specific processing of the present invention.
[0028] In one specific, detailed initial processing procedure, the
following steps are used:
[0029] 1. Wash dermis obtained from donor(s) in sodium
monophosphate buffer, pH=7.0, and transfer to a bottle containing a
one percent BZK (benzalkonium chloride) solution. Store by
freezing.
[0030] 2. Thaw dermis and transfer to a 1 Molar NaCl solution and
incubate overnight at room temperature. This separates the
epidermis.
[0031] 3. Remove the epidermis and rinse dermis in sterile
deionized water. Cut into desired sizes as needed.
[0032] 4. Place dermis into a 0.5% hydrogen peroxide solution and
sonicate for 15 minutes at room temperature. All dermis must be
covered with the solution during this step.
[0033] 5. Transfer the dermis to a solution (in excess relative to
the dermis sample) of any of the following: 0.5% Tween-20; 0.5%
sodium dodecyl sulfate; 1.0% Triton X-100. Then sonicate for 15
minutes at room temperature.
[0034] 6. Transfer dermis to an excess solution (relative to dermis
sample) of saturated, filtered CaOH. Then sonicate for 15 minutes
at room temperature.
[0035] 7. Rinse twice with de-ionized water, then transfer to an
approximately 0.1% EDTA solution, let soak for 15 minutes, then
rinse twice with de-ionized water.
[0036] 8. Rinse dermis sample(s) in an excess solution of sodium
monophosphate buffer (pH=7.0) three times, for five minutes each
time.
[0037] 9. Rinse dermis sample(s) in sterile deionized water.
[0038] 10. Transfer dermis sample(s) to an excess of 70% isopropyl
alcohol for 15 minutes to dehydrate the dermis (do not
sonicate).
[0039] 11. Package dermis, or cut to size (if not already cut), and
package for lyophilization.
[0040] 12. Lyophilize the sample(s).
[0041] 13. Treat dermis with a low dose of gamma radiation.
[0042] After initial processing, in certain applications the dermis
is further processed to form, as described in section III, implant
structures suitable for use as a tendon or ligament. Alternately,
the dermis is used for other types of implants, including those
referred to in section IV below.
[0043] The major component of the processed dermis is collagen. A
cross linking step may be added in the initial processing, or in
the subsequent processing where the implant is being formed or
shaped (such as in section II), to cross link collagen molecules.
Cross linking approaches have been described in a previous
application for a moldable bone paste, U.S. application Ser. No.
09/750,192, which is incorporated by reference, and is described
here for the present application.
[0044] Typical chemical cross-linking agents used in accord with
this invention include those that contain bifunctional or
multifunctional reactive groups, and which react with collagen of
the processed dermis. By reacting with multiple functional groups
on the same or different collagen molecules, the chemical
cross-linking agent increases the mechanical strength of the
implant.
[0045] The cross-linking step of the subject embodiment involves
treatment of the dermis to a treatment sufficient to effectuate
chemical linkages between adjacent molecules. Typically, such
linkages are between adjacent collagen molecules exposed on the
surface of the dermis. Crosslinking conditions include an
appropriate pH and temperature, and times ranging from minutes to
days, depending upon the level of crosslinking desired, and the
activity of the chemical crosslinking agent. Preferably, the
implant is then washed to remove all leachable traces of the
chemical.
[0046] Suitable chemical cross linking agents include mono- and
dialdehydes, including glutaraldehyde and formaldehyde; polyepoxy
compounds such as glycerol polyglycidyl ethers, polyethylene glycol
diglycidyl ethers and other polyepoxy and diepoxy glycidyl ethers;
tanning agents including polyvalent metallic oxides such as
titanium dioxide, chromium dioxide, aluminum dioxide, zirconium
salt, as well as organic tannins and other phenylic oxides derived
from plants; chemicals for esterification or carboxyl groups
followed by reaction with hydrazide to form activated acyl azide
functionalities in the collagen; dicyclohexyl carbodiimide and its
derivatives as well as heterobifunctional crosslinking agents;
hexamethylene diisocyante; sugars, including glucose, will also
cross link collagen.
[0047] It is known that certain chemical cross-linking agents,
e.g., glutaraldehyde, have a propensity to exceed desired
calcification of cross-linked, implanted biomaterials. In order to
control this calcification, certain agents can be added into the
composition of the subject embodiment, such as dimethyl sulfoxide
(DMSO), surfactants, diphosphonates, aminooleic acid, and metallic
ions, for example ions of iron and aluminum. The concentrations of
these calcification-tempering agents can be determined y routine
experimentation by those skilled in the art.
[0048] When enzymatic cross-linking treatment is employed, useful
enzymes include those known in the art which are capable of
catalyzing crosslinking reactions on proteins or peptides,
preferably collagen molecules, e.g., transglutaminase as described
in Jurgensen et al., The Journal of Bone and Joint Surgery,
79-a(2), 185-193 (1997), herein incorporated by reference.
[0049] Formation of chemical linkages can also be accomplished by
the application of energy. One way to form chemical linkages by
application of energy is to use methods known to form highly
reactive oxygen ions generated from atmospheric gas, which in turn,
promote oxygen cross links between surface-exposed collagen. Such
methods include using energy in the form of ultraviolet light,
microwave energy and the like. Another method utilizing the
application of energy is a process known as dye-mediated
photo-oxidation in which a chemical dye under the action of visible
light is used to cross link surface-exposed collagen.
[0050] Another method for the formation of chemical linkages is by
dehydrothermal treatment which uses combined heat and the slow
removal of water, preferably under vacuum, to achieve crosslinking
of collagen in the processed dermis. The process involves
chemically combining a hydroxy group from a functional group of one
collagen molecule and a hydrogen ion from a functional group of
another collagen molecule reacting to form water which is then
removed resulting in the formation of a bond between the collagen
molecules.
[0051] II. Preparation of Calcified Dermis Derived Implant
[0052] It has been learned that the ends, other sections of, or an
entire piece of the processed dermis, may be calcified by the
following process. By modifying the twelve-step method shown above,
such that the contacting with calcium hydroxide solution is
followed immediately by the phosphate buffer solution, calcium is
deposited onto (or precipitates onto) the dermis. Approaches to
calcifying the dermis sample include contacting with the phosphate
buffer slowly, as by changing out the solution in which the dermis
section is held, or rapidly, as by moving the dermis section from a
vessel containing the calcium hydroxide to a vessel containing
phosphate buffer. The preferred pH of the phosphate buffer is in
the range of 6.8 to 7.2 pH units. While not being bound to a
particular theory, the change in pH is believed to cause a
precipitation of calcium onto the processed dermis. The deposited
calcium adds rigidity to the section. It has been observed that
calcification will not occur appreciably if the EDTA solution is
used between the calcium hydroxide step and the phosphate buffer
step. The following evaluation illustrates one use of calcified
dermis prepared according to this invention.
[0053] Evaluation of Initially Prepared Dermis in Animal Model
[0054] Samples of dermis were prepared using the twelve-step method
described in section I, varying the type and amount of detergent
agent, as shown in the table of results.
[0055] Thereafter, the dermis so prepared was implanted and
evaluated as described below.
[0056] A. Sample Preparation for Implantation
[0057] 1.) Lyophilized dermis was cut (aseptically) into
approximately 1.times.1 cm implants, weighed before hydration
(pre-implantation dry weight), and rehydrated with sterile saline
containing antibiotics.
[0058] 2.) Samples were implanted (4 per rat) into Athyrnic nude
rat model following SOP# with modification: only one suture was
used to hold the implant in place.
[0059] 3.) Implants were recovered at 3, 6, and 12 week
post-implantation (2 week samples per donor/per treatment/per time
point--total of 6 for each treatment/time point) 1-2 were kept for
historical analysis and 4-5 were removed, lyophilized to determine
dry-weight post-implantation (to determine percent loss of tissue
after in vivo exposure).
[0060] B. Animal Surgeries
[0061] 1.) Surgeries were performed as follows: Animals were
anesthetized via intramuscular injection (thigh or gluteus muscle)
of ketamine (100 mg/k) and Xylazine (15 mg/kg). Sterile technique
was used and surgery was performed in a class 100 hood. Alcohol and
providone iodine were applied to the abdomen of the animal. An
incision was made parallel to the midline of the abdomen from just
below the tip of the sternum to just above the navel. The skin is
dissected away from the underlying muscle on either side of the
abdomen. The muscle is isolated and a 0.5.times.0.5 cm area of
fascia was scored from the muscle until the muscle bled, one are in
each quadrant of the abdomen. A 1.times.1 cm piece of dermis was
sutured to the muscle over the area that was previously scored,
with two corners of the dermis sutured in to place with
non-absorbable 30 prolyene suture. The skin was closed with wound
clips in a continuous line. Providone iodine is reapplied to the
wound and the animal is returned to its' cage. according to (Rat
Assay Osteoinductivity Surgery) with the following exceptions:
[0062] 2.) At 3, 6, and 12 weeks, animals were sacrificed according
to a humane procedure.
[0063] 3.) The skin was shaved on the stomach using a disposable
razor or hair clippers.
[0064] 4.) The muscle flap with the overlying skin was removed.
[0065] 5.) The entire muscle flap was photographed for macroscopic
observation.
[0066] 6.) Implant material was removed (6 per time point for each
test sample), and placed in labeled sterile petri dishes for
drying. If implants were difficult to remove, the entire muscle
flap was removed and the implant was carefully excised using
scalpels in the lab. Before dissection, each implant site was
photographed for documentation purposes.
[0067] 7.) 3 implants of each sample at each time point was
prepared for histological processing. (H&E staining)
[0068] C. Results and Discussion
1 Dry Implant Dry Explant Implant Group Weight Weight % Change 1Fa
40 SDS .0225 .0542 +140.9% 1Ed .0218 .0469 +115.1% 1Bd .0236 .0259
+9.7% 1Gd 40 Triton .0121 .0352 +190.9% 1He .0126 .0404 +220.6% 2Ad
.0086 .0271 +215.1% 1Db 40 Tween .0073 .0231 +216.4% 2Fe .0091
.0309 +239.6% 1Fe .0073 .0289 +295.9% 2Eb 41 SDS .0148 .0370 +150%
1Eb .0107 .0342 +219.6% 1Cb .0104 .0342 +228.8% 2Ee 41 Triton .0068
.0272 +300% 1Gb .0080 .0282 +243.9% 2Be .0077 .0304 +294.8% 2Da 41
Tween .0075 .0239 +218.7% 2Ca .0071 .0241 +239.4% 2Aa .0079 .0282
+257% 2Fb 42 SDS .0062 .0207 +233.9% 1Db .0073 .0231 +216.4% 1Ee
.0079 .0242 +206.3% 1Bd 42 Triton .0096 .0585 +509.4% 1Ce .0111
.0332 +199.1% 1Aa .0099 .0322 +225.3% 2Fa 42 Tween .0129 .0446
+245.7% 1Fb .0093 .0290 +211.8% 1Dd .0155 .0555 +258.1%
[0069] Explants appeared to have calcified during the first
four-week period to a low degree. X-Ray analysis confirmed the
presence of calcified matrix. This is postulated to be due to
neutralization of the CaOH treatment with buffer which resulted in
the precipitation of calcium phosphate on the tissue. When
calcification of the dermis is not desired, the dermis can be
thoroughly washed with sterile water and EDTA prior to
neutralization with buffer.
[0070] These results show an increased level of bone deposition
that is believed related to the initial levels of calcification
described in this section. In vivo the implants became much less
pliable compared to implants processed in a standard,
non-calcifying manner. The inventors believe that in some
applications, some forms of calcified, processed dermis implants
could form bone. This is based on the fact that both demineralized
bone (which forms bone as an implant) and acellular dermis are
comprised of primarily Type I collagen.
[0071] In addition, growth and other factors, as are known in the
art and administered to suit the purpose of the particular
application, are added to the implant. For example, prior to
assembly or after assembly, the graft materials are soaked,
infused, impregnated, coated or otherwise treated with bone
morphogenetic proteins (BMP's), antibiotics, growth factors
(including angiogenic growth factors), nucleic acids, peptides, and
the like.
[0072] It is noted that all or part of other tissue samples,
whether allograft, xenograft or autograft, may be calcified in
accordance with the present invention. Examples of such tissues
include: soft tissue; pericardium; fascia; woven soft tissue (as
from skeletal muscle); urinary bladder membrane (UBM); and SIS.
Accordingly, where the term DDG is used in regard to calcification,
it is appreciated that these tissue types may be substituted for
the dermis tissue. Variations in the duration of a particular step,
and other modifications of the above described processes, may be
required to optimize the process for each such tissue. However,
such modifications are within the scope of reasonable
experimentation having the above process as guidance.
[0073] III. Production of Dermis-Derived and Other Types of
Tendon/Ligament-Type Implants
[0074] Dermis processed as described above, or as processed by
other methods, can be fabricated into an implant that substitutes
for or replaces a tendon or ligament in a recipient in need
thereof. The dermis derived implant may be used as a scaffold for
tendon and ligament regeneration, a locus for remodeling that is
superior to other implant choices (e.g., demineralized ligament,
urinary bladder matrix, small intestine submucosa). While not being
bound to a particular theory, this is believed due to the presence
of a collagen structure that is less labile to enzymatic
degradation than other implant choices, and to the presence of the
basement membrane. However, it is understood that other materials
may be utilized in accord with the teachings herein, including but
not limited to, demineralized bone (partially or fully), ligaments,
tendons, peritoneum, urinary bladder matrix, dura mater, and
muscle, from allograft and xenograft sources.
[0075] The following embodiments of implants and their production
are meant to be illustrative, and not limiting. It is noted that
for the following embodiments, the processed dermis is a material
suited for remodeling by the recipient's body into a `new` tendon
or ligament.
[0076] Thus, one aspect of the present invention is processing
dermis for specific use as a tendon implant. For example, a section
of dermis initially processed by the method described in section I
is reconstituted by soaking in a 5% gelatin solution for two
minutes. The section is rolled around a wooden swab to establish a
desired thickness and mass for the intended application. One end,
approximately .+-.2 inch, of the rolled dermis is immersed in a
saturated calcium hydroxide solution, and this is sonicated for 10
minutes. The dermis is soaked in 50 mM phosphate buffer for 10
minutes, and soaked in acetone for 30 minutes for initial drying.
Drying is continued with placement in a drying oven set to
approximately 60 degrees Centigrade for two hours.
[0077] Following the above procedure, in one trial it was observed
that the layers of the dermis, upon subsequent reconstitution,
slightly separated in some places.
[0078] In a subsequent trial, the dermis was soaked in gelatin as
above, rolled around the swab mandrel and secured with suture
material. Then this was wrapped in a paper towel and rolled under
pressure. This was frozen, and then freeze-dried. The step of
soaking in acetone was excluded. The dermis so processed was more
difficult to separate compared to the first trial's samples. It was
determined in animal trials that the implant only needs to hold
together during surgery because proper fixation at the ends will
ensure that the implant functions.
[0079] Typical embodiments of dermis-derived tendons and ligaments
comprise a main intermediate section of processed dermis and two
ends for attachment of the implant to desired body parts of a
recipient. In one embodiment, one or more soft tissue screws are
used to attach each end to a desired body part. In another
embodiment, one or both ends are fixed in a substance (for
instance, alpha-BSM, hydroxyapatite, calcium sulfate) which hardens
the end(s) and allows the use of a hard tissue interference screw
for attachment to the recipient's body part. This is described in
section II. Alternately, as described below, the ends are attached
to pieces of bone that are suited for subsequent attachment to the
recipient's body part.
[0080] In addition to the above basic steps, the dermis may be
cross linked, such as by the methods and agents described in
section 1. Alternately, or in addition, an appropriate
biocompatible adhesive may be added to attach the outer flap to the
immediately underlying layer. Alternately, or in addition, the
dermis is held together and on the swab (or other mandrel-like
device) with string, twine, suture material, or other wrapping.
Pressure is applied as needed to help hold the rolled layers
together. Layering the dermis provides additional strength, and
cross linking the layers further adds to the strength.
[0081] In addition, growth and other factors, as are known in the
art and administered to suit the purpose of the particular
application, are added to the implant. For example, prior to
assembly or after assembly, the graft materials are soaked,
infused, impregnated, coated or otherwise treated with antibiotics,
growth factors (including angiogenic growth factors), nucleic
acids, peptides, and the like.
[0082] Regarding the use of pieces of bones at one or more ends of
the processed dermis, referring to FIG. 1A, there is shown an
embodiment directed to a DDG 100 comprising a first bone block 110
and a second bone block 120 interconnected by processed dermis 130,
in which the bone blocks have been pre-shaped into dowels.
[0083] To facilitate placement of a fixation screw, dowels are
preferably machined down the length of the bone block to form
radius cuts 115, 125. The radius cuts 115, 125 aid in the
attachment of the graft to recipient bone because they provide a
groove to position a fixation screw, which results in increased
surface area at the contact between the bone block and the screw.
The radius cuts 115, 125 provide the additional advantage of
increasing the pull out loads of the bone block, as well as filling
of dead space in tunnel.
[0084] Fixation methods known in the art can be used in accord with
the principles of the subject invention, which include, but are not
limited to, staples, buttons, screw and washer, interference
screws, and self-taping screws. In a preferred embodiment, fixation
is accomplished by interference screws and/or self-tapping screws.
In an even more preferred embodiment, the radius cuts 115, 125
contain a thread profile 135 that matches the thread profile of the
fixation screw, thereby further increasing the stability of
fixation.
[0085] Referring to FIG. 1B-C, another embodiment directed to an
implant 150 that employs a bone block, 151 that comprises a `tee-`
or `cross-` shaped profile. The bone block is comprised of two
interlocking substantially planar pieces, 151a and 151b, that
comprise a slot 163 and slip together to present four fins, 152a-d,
that radiate from a center point, 154. The substantially planar
segments comprise a slot 163 that defines a slotted section 165 and
a body section 166. The preferred length of the bone block, 151, is
approximately 2.5 mm, and the preferred diameter may range from
approximately 2.0 to 12.0 mm.
[0086] Processed soft tissue is attached to the bone blocks by
various conventional means known to those skilled in the art, as
described below. In addition, the processed soft tissue is attached
by wrapping through holes made in the fins, 152a-d, of the bone
block 151. As shown in FIG. 1D, the processed soft tissue 153 also
can be passed into one channel and out a second channel and then
fastened to form a loop (as by sutures, tying, etc.). In a
preferred embodiment (shown in FIG. 1C), two separate flexible
bands 161 and 162 (natural, e.g., dermis or synthetic) are looped
over the top of the bone block 151, wherein one band 162 contacts
fins 152a and c, and the second band 161 contacts fins 152b and d.
When the bone block 151 is positioned into a channel, such as a
tunnel formed in a patient's bone during surgery, the two bands
looped over the bone block 151 are compressed against the fins
152a-d and thereby secured into place. Alternatively, the ends of
the fins can comprise teeth or are otherwise irregular to further
prevent slippage of the bands.
[0087] To fasten the tee-shaped bone block to the bone of a
recipient in need of an implant, a round hole is drilled into the
site of placement. The bone block is inserted to the desired depth,
and at least one interference screw, 157 (FIG. 1F) is placed along
side the bone block 151 and is tightened to set compress the bone
block against the wall of the hole in the recipient's bone.
[0088] It is well recognized that many other shapes of bone blocks,
as known or conceived by one of ordinary skill in the art, will
serve the purpose of attachment in the present invention. For
instance, a bone block with three, rather than four fins, in
profile, can be used.
[0089] Referring now to FIG. 2, three different embodiments of the
subject DDGs are shown. FIG. 2A shows an embodiment that comprises
a basic configuration of the subject DDGs. Bone blocks 210 and 220
are in a pre-shaped dowel form with no groove thereon, and are
connected by processed dermis 100. FIG. 2B shows another version of
the DDG, wherein the bone blocks are pre-shaped into dowels with
tapered ends. Bone block 212 is a dowel that has a proximal tapered
region 216 in relation to processed dermis 200, and bone block 214
is pre-shaped into a dowel that has a distal tapered region 218 in
relation to processed dermis 200. FIG. 2C illustrates a preferred
version of the invention, which has a bone block 230 with a
proximal tapered region 239 and a groove 238 positioned on the bone
block 230. This version also comprises a second bone block 234 with
a distal tapered region and a groove 236 positioned on bone block
234 as well. The embodiments shown in FIGS. 2B-C are tapered such
that implantation into a pre-formed tunnel in recipient bone is
preferred to occur in the direction of the arrow.
[0090] In an alternative embodiment, the subject invention is
directed to an implant having at least one bone block portion and
at least one processed dermis section, wherein the bone block
portion comprises a groove on its exterior. Once the bone blocks
are extracted, they are machined into a dowel or other desired
shape. In a specific embodiment, the dowel is machined into
dimensions suitable for various surgical procedures. The machining
is preferably conducted on a graduated die, a grinding wheel, a
core cutter, a lathe, or machining tools that are specifically
designed and adapted for this purpose. Preferred dimensions of the
diameter for the dowels include 9 mm, 10 mm, 11 mm, and 12 mm.
Reproducibility of the product dimensions is an important feature
for the successful use of such grafts in the clinical setting.
[0091] The bone ends, whether in the shape of a dowel, other shapes
described herein, or shapes known to those skilled in the art, are
attached to the processed dermis by means such as chemical
annealing, chemical adhesive, suturing (optionally through drilled
holes in the bone), pinning to, or wrapping and tying the processed
dermis around the bone ends (and optionally applying a suitable
adhesive). When the attachment means includes use of tying the
processed dermis to a bone end, the bone end optionally has grooves
transverse to the long axis of the assembly which may receive the
windings of the wrapping line (suture material or other suitable
line). Furthermore, a block may be used that comprises an assembled
block formed from two or more individual segments fastened
together. The block made be made from cortical, cancellous bone
segments, or both that are obtained from allogenic, autogenic, or
xenogenic sources. The bone segments may be mineralized, or
partially or fully demineralized. Furthermore, the block may be
made from synthetic segments or a combination of bone and synthetic
segments. Synthetic materials contemplated for use herein include,
but are not limited to, stainless steel, titanium, cobalt
chromium-molybdenum alloy, and a plastic of one or more members
selected from the group consisting of nylon, polycarbonate,
polypropylene, polyacetal, polyethylene oxide and its copolymers,
polyvinylpyrolidone, polyacrylates, polyesters, polysulfone,
polylactide, poly(L-lactide) (PLLA), poly(D,L-lactide) (PLA),
poly(glycolide) (PGA), poly(L-lactide-co-D,L-Lactide) (PLLA/PLA),
poly(L-lactide-co-glycolide) (PLA/PGA),
poly(glocolide-co-trimethylene carbonate) (PGA/PTMC), polydioxanone
(PDS), polycaprolactone (PCL), polyhydroxybutyrate (PHBT),
poly(phosphazenes), poly(D,L-lactide-co-capro- lactone) (PLA/PCL),
poly(glycolide-co-caprolactone) (PGA/PCL), poly(phosphase ester),
polyanhydrides, polyvinyl alcohol, hydrophilic polyurethanes, and a
combination of one or more bioabsorbable polymers. Copending U.S.
application Ser. No. 09/782,594 is incorporated herein by reference
for disclosure on assembled implants.
[0092] Another shape of bone block is shown in FIG. 5. A two-part
bone fixation plug, or screw, 501, has a first half, 502 and a
second half, 503, that fit together. Each half, 502 and 503, has an
outer surface, 520 and 521, respectively, that comprises
approximately half of a generally conical shape. Each half, 502 and
503, has an inner mating surface, 522 and 523, respectively, whose
surface generally matches the other side's inner mating surface so
as to form, when joined together or in close proximity, a
substantially conical surface on the outer surface. The shape of
the inner mating surfaces may be curvilinear, flat, or a
combination, or may comprise ridges, grooves, teeth or some other
irregular shape to aid in gripping the soft tissue placed thereon.
In a preferred embodiment the inner mating surfaces are
substantially flat.
[0093] One or both of the inner mating surfaces 522 and 523 have
one or more protrusions for alignment that, upon mating of the
halves 502 and 503, enter matching voids or holes to align the
joining together of the halves, 502 and 503. As shown in FIG. 5,
the protrusions may be in the form of pins 524 from a first half,
502, that enter counterposed holes 525 in a second half, 503. The
end section, 504, of a processed soft tissue, 505, such as dermis,
is positioned between the inner mating surfaces, 522 and 523. The
ends 530,531 of the plug, 501, preferably have driver hole formed
therein to receive a driving tool when the two halves 502,503 are
brought together; for instance, a shallow hexagonal cavity for a
hex (Allen) wrench, a lateral or `tee` slot for a screwdriver, the
outer border shaped hexagonally to receive an open end wrench or
socket, or other means known to those of ordinary skill in the
art.
[0094] The plug, 501, has threads, 508, on the generally conical
outer surfaces, 520 and 521. The threads of the first half, 502,
and the second half, 503, of the plug, 501, are generally of the
same size and are designed to approximately meet when the halves
are joined together. When the halves, 502 and 503, are joined
together, the plug, 501, is threaded into a sized hole in a bone of
a recipient in need of an implant. As the plug passes farther into
the hole, the inner mating surfaces, 522 and 523, are compressed
closer together, and these compress against the soft tissue end,
504. This fastens the soft tissue, 505, to the bone block.
[0095] It is noted that various means to control the compression by
and contact with the inner mating surfaces onto the soft tissue
end, 504, can be effectuated. For instance, spacers or nub on the
inner mating surfaces, preferably spaced peripherally to where the
soft tissue end contacts, can stop the travel of the inner mating
surfaces to provide a sufficient level of compression without
crushing the soft tissue end, 504. Grooves or ridges on one or both
of the inner mating surfaces, 522 and 523, can provide extra
friction and pressure to avoid slippage. These can be alone or in
combination with the peripheral spacers or nubs. Other designs can
be implemented, where the basic goal is to compress a soft tissue
graft component of the implant as the plug is being tightened into
a hole, so the soft tissue component is attached to, or locked into
the plug. For instance, the soft tissue end, 504, may have a
thicker bitter end, and this may fit into a depression in one or
both inner mating surfaces, so that upon compression this thicker
end would be unable to slip through the narrower space between the
rest of the flat surfaces. In another embodiment, the end, 504, of
the soft tissue, 505, passes entirely through both inner mating
surfaces of the plug, 501, so it extends beyond the ends, 530 and
531, of the plug, 501. The end of the implant material, 504, may be
thickened so it abuts to the end surface 530, of the plug, 501, or
it may be later adjusted and fastened, such as by suturing or tying
in a knot.
[0096] As shown in FIG. 5E, a variation of this embodiment is to
insert the fixation plug, with the long portion of tissue 505
preceding the plug, into a hole 537 that passes entirely through a
bone 526 of a recipient. A tapered hole may be used, so the soft
tissue component passes from a hole that is relatively small in
comparison to the opening into which the fixation plug is
tightened. As the plug 501 comprising the two halves 502 and 503 is
secured into the hole 537 they compress and secure the soft tissue
505.
[0097] The above discussion regards the joining of one end of a
section of implant material, such as processed dermis, with a bone
plug having various characteristics. It is recognized that when a
bone-tendon-bone or similar implant is made, it typically has a
bone plug at both ends of the flexible implant material that
functions as a tendon matrix. A particular bone-tendon-bone or
similar implant may use the same type of bone plug at both ends, or
may use different types of bone plugs at each end, depending on the
structural requirements of the recipient, the availability of
implant parts, and other factors. Also, although the example in
this section regarded processed dermis, it is recognized, as
disclosed in the preceding section, that tissues other than dermis
may be processed and used for bone-tendon-bone and similar
implants.
[0098] Finally, as noted above, the bone that is used to construct
bone blocks may be selected from cortical, cancellous,
cortico-cancellous, or demineralized bone, obtained from human or
xenograft sources. Optionally, synthetic material may be
incorporated in combination with such bone. Also, bone blocks may
be comprised of two or more segments assembled together in a
assembled allograft implant.
[0099] IV. Implants for Augmenting or Replacing the Spinal Anterior
Longitudinal Ligament (ALL) and Other Uses
[0100] In another aspect of the invention, a processed dermis
implant (DDG) is used to augment or replace the function of the
anterior longitudinal ligament (ALL), such as after a surgery that
partially or completely severs the ALL (such as during insertion of
disc replacement implants or prostheses), or after other damage
(e.g., trauma) to the ALL. Preferably, the DDG is calcified at the
ends to allow use of stronger means of attachment. It is noted
that, depending on the nature of the surgery, a disc
replacement/spinal fusion operation may access the vertebrae by
partially or completely severing the ALL. Without a fully
functional ALL, there is a risk of damage to the spine from
excessive backward bending in that the intact ALL tensions the
anterior span of the spine. Also, the DDG stabilizes the motion of
the segment anteriorly. This is more conducive to spinal
fusion.
[0101] An additional advantage of a DDG produced according to the
method of this invention, for the application of augmenting or
replacing a partially or completely severed ALL, is that is may
block and thereby prevent the expulsion of interbody grafts. Such
DDGs are preferably affixed to the vertebral bodies with screws,
pins, staples or anchors of various types known in the art or
heretofore developed. The attachment means preferably are well
secured and with means to minimize the possibility that the
attachment means will loosen, as such loosening in the vertebral
area, rich with blood vessels and nerves, can be extremely
dangerous and potentially leads to death. One embodiment uses bone
screws which are applied with a bone paste to accelerate bone
growth onto the bone screws.
[0102] As a result of placing a DDG to span two adjacent vertebrae,
lumber extension is reduced, thereby providing a more stable
environment to promote fusion. In FIG. 3, there is provided one
embodiment 300 of the DDG ALL implant according to this invention.
This implant 300 is prepared from processed dermis which has been
folded to provide sufficient strength. A top portion, 310, and a
bottom portion, 320, are prefereably fully mineralized, or
partially mineralized, as by calcification. Also, the
mineralization may be restricted to the surface layer(s) to modify
the stress-fracture behavior of the implant. The top portion 310
and the bottom portion 320 each have a series of holes 305 by means
of which the DDG implant is affixed to a superior vertebra V1 and
an inferior vertebra V2. The intermediate section, 330, is
processed to maintain a desired degree of flexibility while
maintaining sufficient tensional strength. In this fashion, while
permitting a slight amount of motion, the DDG implant substantially
restricts motion at the vertebral segment spanned by the DDG
implant. Also shown in outline is a pair of interbody implants 340
inserted between superior vertebra V1 and inferior vertebra V2. In
FIG. 3B, there is shown a further embodiment of the DDG implant of
this invention which is identical in all respects to the implant
shown in FIG. 3A, but wherein this embodiment has an enlarged upper
segment 310' and lower segment 320' for affixation to the vertebrae
V1 and V2. It will be appreciated that the precise shape of the DDG
implant is not critical. Furthermore, the DDG implant may span more
than two vertebrae. In one preferred embodiment the DDG implant is
20 to 30 mm wide and 3 mm thick, and has one aperture in each of
its four corners.
[0103] In yet a further embodiment of the DDG implant of this
invention, there is provided a spinal tension band, STB. Typically,
in spinal fusions, the motion segment adjacent to the fused segment
(the juxtaposed discs) have been found to rapidly degrade. This
degradation appears to be due to the hyper motion at these levels,
due to the decreased motion at the fused segments. The STB of this
invention assists in preventing this degradation and can avoid the
need for further surgery, by spanning the fused segments and
attaching to the juxtaposed vertebral body at the spinous process
thereof. The STB may be used in any region of the spine, but is
typically most useful for spanning fusions at two, three, or more
levels. The STB of this invention replaces or augments use of
flexible stainless steel, titanium cables, elastomeric or polymeric
synthetic materials currently in use. Accordingly, known techniques
for attaching such devices to the spinous processes may be used, or
the STB may be affixed to juxtaposed vertebral bodies in a fashion
analogous to that described above for the DDG implant to augment or
replace the ALL function.
[0104] In FIG. 4, there is disclosed one embodiment of the STB 400
of this invention. As can be seen, the STB 400 is affixed to a
superior vertebra, VA, and an inferior vertebra, VB, each of which
are juxtaposed to a vertebra V1 and V2, which are being fused to
each other by means of interbody fusion devices IB1 and 1B2.
Intermediate portion 410 is dermis processed to maintain a desired
level of flexibility and strength, while the top portion 420 and
the bottom portion 430 are preferably in a mineralized or partially
demineralized state. Affixation means 425 and 435 are provided for
fixation of the STB to the juxtaposed vertebrae VA and VB,
respectively. Those skilled in the art will appreciate that this
embodiment of the invention may be applied to any other anatomical
structure to minimize motion of such structures in relation to each
other. For example, the tension band of this invention may be
utilized outside of the spinal context, for example for the repair
of a split sternum in a sternotomy. Also, the tension band of this
invention is used for spanning a bone fracture site. In this
application, one or more tension bands are attached to attachment
sites on both sides of the fracture.
[0105] It is further appreciated that other implant substances may
be processed and utilized for an implant to augment or replace an
ALL or as an STB or other tension band. Among the implant materials
that may be used are: segmentally demineralized bone; fascia,
pericardium; ligaments; tendons (including as processed as
described above, herein); ligaments; muscle; dura; xenograft
demineralized bone; xenograft segmentally demineralized bone;
calcified implant materials made from soft tissue, fascia,
pericardium, UBM, SIS, or woven soft tissue (skeletal muscle); or
any combination of these implant substances, and optionally in
combination with biocompatible synthetic materials. Further, as
appropriate these may be attached to bone pieces (human or
xenograft), for instance when the bone pieces provide a preferred
means of affixation to the bone or other part of the recipient.
[0106] It also is noted that strip size variations are recognized
and are within the scope of this invention. For instance, wide or
narrow strips comprising the ALL, STB, or tension band implants may
be used. Also, strips each comprising a layering of dermis, or
other allograft tissues such as those listed above, may be used at
one or two levels (e.g., one internal to the other), and the
implants may be used for the cervical, thoracic, or lumbar regions
of the spine. Further, the implants described in this invention may
be used to augment or replace the posterior longitudinal ligament
for procedures where this ligament is in need of augmenting or
replacing.
[0107] Those skilled in the art will appreciate that the graft may
be an autograft, allograft, or xenograft. Xenograft implants may
further require treatments to minimize the level of antigenic
agents and/or potentially pathogenic agents present in the graft.
Techniques now known, or those which are later developed, for
preparing tissue such that it is suitable for and not rejected by
the recipient are incorporated herein. In cases where the graft is
an allograft, a donor is preferably screened for a wide variety of
communicable diseases and pathogens, including human
immunodeficiency virus, cytomegalovirus hepatitis B, hepatitis C
and several other pathogens. These tests may be conducted by any of
a number of means conventional in the art, including, but not
limited to, ELISA assays, PCR assays, or hemagglutination. Such
testing follows the requirements of the following associations: (a)
American Association of Tissue Banks. Technical Manual for Tissue
Banking, Technical Manual-Musculoskeletal Tissues, pages M19-M20;
(b) The Food and Drug Administration, Interim Rule, Federal
Register, Vol. 58, No. 238, Tuesday, December 14, Rules and
Regulations, 65517, D. Infectious Disease Testing and Donor
Screening; (c) MMWR, Vol.43, No. RR-8, Guidelines for Preventing
Transmission of Human Immunodeficiency Virus Through
Transplantation of Human Tissue and Organs, pages 4-7; (d) Florida
Administrative Weekly, Vol. 10, No.34, Aug. 21, 1992,
59A-1.001-014, 59A-1.005(12)(c), F.A.C., (12)(a)-(h), 59A-1.005(15,
F.A.C., (4) (a)-(8). In addition to a battery of standard
biochemical assays, the donor, or their next of kin can be
interviewed to ascertain whether the donor engaged in any of a
number of high risk behaviors such as having multiple sexual
partners, suffering from hemophilia, engaging in intravenous drug
use etc. Once a donor has been ascertained to be acceptable, the
tissue for obtaining the DDGs as described above are recovered and
cleaned.
[0108] The teachings of all patents and publications cited
throughout this specification are incorporated by reference in
their entirety to the extent not inconsistent with the teachings
herein.
[0109] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and the scope of the
appended claims.
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