U.S. patent application number 14/543234 was filed with the patent office on 2015-08-06 for thin bendable bone plate for bone deficit repair and method of preparation.
The applicant listed for this patent is Theodore Malinin. Invention is credited to Theodore Malinin.
Application Number | 20150216665 14/543234 |
Document ID | / |
Family ID | 51870073 |
Filed Date | 2015-08-06 |
United States Patent
Application |
20150216665 |
Kind Code |
A1 |
Malinin; Theodore |
August 6, 2015 |
THIN BENDABLE BONE PLATE FOR BONE DEFICIT REPAIR AND METHOD OF
PREPARATION
Abstract
A flexible, bendable organic decalcified or partially
decalcified bone, cortical or cancellous, adapted for use in
augmentation or repair of animal skeletal structures comprising a
continuous plate or sheet of natural bone, as well as dermis is
described. The thickness, flexibility and tensile strength of the
construct is such as to allow it to be shaped and contoured without
damage to it. The composition is ultimately remodeled by the body,
thus obviating the need for additional surgical intervention. The
clinical indications for the use of the invented construct are
many, but are particularly prominent in dentistry, oral and
maxillofacial surgery and implantology. It is particularly useful
in the maxillary sinus augmentation. A unique new method, different
from previously described methods for the preparation of the
disclosed constructs, is described.
Inventors: |
Malinin; Theodore; (Miami,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Malinin; Theodore |
Miami |
FL |
US |
|
|
Family ID: |
51870073 |
Appl. No.: |
14/543234 |
Filed: |
November 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14173495 |
Feb 5, 2014 |
8888823 |
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14543234 |
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Current U.S.
Class: |
623/23.63 ;
83/14 |
Current CPC
Class: |
A61L 2430/02 20130101;
Y10T 83/0405 20150401; A61B 2017/00526 20130101; A61L 31/005
20130101; A61B 17/8085 20130101; A61L 31/146 20130101 |
International
Class: |
A61F 2/28 20060101
A61F002/28 |
Claims
1-36. (canceled)
37. A flexible organic bone plate comprising a sheet of partially
or fully decalcified natural bone, wherein the thickness of the
sheet is 3.0 millimeters or less, and wherein the sheet contains a
plurality of irregular perforations with serrated edges.
38. The flexible organic bone plate of claim 37, further comprising
channels radiating out from the plurality of irregular
perforations.
39. The flexible organic bone plate of claim 37, wherein the
plurality of irregular perforations vary in size and shape.
40. The flexible organic bone plate of claim 37, wherein the
plurality of irregular perforations comprise cross-sectional areas
defining stellate, quadrangular, triangular or hexagonal shapes, or
a mixture thereof.
41. The flexible organic bone of claim 37, wherein the thickness of
the sheet is between 0.045 millimeters and 3.0 millimeters.
42. The flexible organic bone plate of claim 37, wherein the bone
plate is adapted for use in augmentation or repair of animal
skeletal structures.
43. The flexible organic bone plate of claim 37, wherein the
natural bone is from a mammal.
44. The flexible organic bone plate of claim 43, wherein the mammal
is a human.
45. The flexible organic bone plate of claim 37, wherein the
irregular perforations with serrated edges are configured to
facilitate ingrowth of cells and vasculature from preexisting
sources of cartilage or bone tissue at a faster rate compared to a
bone sheet of similar thickness having regular perforations without
serrated edges.
46. The flexible organic bone plate of claim 37, wherein the bone
plate is freeze-dried or hypothermically dehydrated.
47. A process for the production of an organic bone plate having a
predetermined thickness comprising: (i) decalcifying, either
partially or completely, a bone which has been harvested from a
bone donor; and (ii) cutting the bone after the decalcifying into
one or more sheets having a thickness of 3.0 mm or less.
48. The process of claim 47, further comprising harvesting the bone
from the bone donor.
49. The process of claim 48, wherein the bone donor is a
vertebrate.
50. The process of claim 49, wherein the vertebrate is a human.
51. The process of claim 47, further comprising processing the bone
to remove substantially all blood and lipid residue prior to the
decalcifying.
52. The process of claim 47, wherein the decalcifying comprises
contacting the bone with EDTA, citric acid, hydrochloric acid, or
combinations thereof.
53. The process of claim 52, wherein the decalcifying comprises
contacting the bone with citric acid.
54. The process of claim 52, wherein the decalcifying comprises
contacting the bone with EDTA and citric acid.
55. The process of claim 52, wherein the decalcifying comprises
contacting the bone with EDTA, citric acid, and hydrochloric
acid.
56. The process of claim 47, further comprising creating a
plurality of perforations on either the bone after the decalcifying
or the one or more sheets of the bone after the cutting.
57. The process of claim 56, wherein the plurality of perforations
are created by punching, burring, drilling, or lasering the
sheet.
58. The process of claim 56, wherein the plurality of perforations
comprise one or more irregular perforations with serrated
edges.
59. The process of claim 58, where the one or more irregular
perforations include channels radiating therefrom.
60. The process of claim 56, wherein the plurality of perforations
comprise one or more round perforations.
61. A method for the in vivo repair or replacement of a section of
an animal skeletal system comprising: affixing, to the section of
the animal skeletal system, a flexible organic bone plate
comprising a sheet of partially or fully decalcified natural bone
having a thickness of 3.0 millimeters or less, wherein the sheet
comprises a plurality of irregular perforations having serrated
edges defined therein.
62. The method of claim 61, wherein the plurality of irregular
perforations having serrated edges are configured to facilitate
ingrowth of cells and vasculature from preexisting sources of
cartilage or bone tissue at a faster rate compared to a bone sheet
of similar thickness having regular perforations without serrated
edges.
63. The method of claim 61, wherein the plurality of irregular
perforations include channels radiating therefrom.
64. A flexible organic bone plate comprising a sheet of partially
or fully decalcified natural bone, wherein the flexible organic
plate is obtained by the process of: (i) decalcifying, either
partially or completely, a bone from a bone donor; (ii) cutting the
decalcified bone from step (i) into one or more sheets of
decalcified bone having a thickness of 3.0 mm or less using a sharp
blade; and (iii) creating a plurality of perforations on the one or
more decalcified bone sheets of step (ii).
65. The flexible organic bone plate of claim 64, wherein the
plurality of perforations comprise one or more round
perforations.
66. The flexible organic bone plate of claim 64, wherein the
plurality of perforations comprise one or more irregular
perforations.
67. The flexible organic bone plate of claim 64, wherein the
plurality of perforations comprise one or more irregular
perforations with serrated edges.
68. The flexible organic bone plate of claim 67, wherein the
irregular perforations comprise a cross-sectional area that defines
a stellate, quadrangular, triangular or hexagonal shape.
69. The flexible organic bone plate of claim 67, wherein the
process further comprises creating channels radiating out from the
irregular perforations.
70. The flexible organic bone plate of claim 64, wherein the
perforations are created by punching, burring or lasering the one
or more decalcified bone sheets.
71. The flexible organic bone plate of claim 64, wherein the
process further comprises harvesting the bone from the bone
donor.
72. The flexible organic bone plate of claim 64, wherein the
decalcifying comprises contacting the bone with EDTA, citric acid,
hydrochloric acid, or combinations thereof.
Description
FIELD OF INVENTION
[0001] The present invention relates to the preparation of
allogeneic, xenogeneic and autologous implants for use in the
repair or replacement of portions of the human skeletal system,
particularly those formed by membranous ossification. In
particular, it is directed toward the use in surgical procedures
such as mandibular augmentation, sinus elevation, guided tissue
regeneration, closure of nasal oral fistula, closure of the cranial
defects and related procedures. The invention discloses implants
which cause induction of bone regeneration, as well as the process
for making the same.
BACKGROUND
[0002] Mammalia bone is made up of matrix in which are encased
immature cells as well as osteocytes. The organic portion of the
matrix is composed of collagen, polymucosaccarides, osseous
channels and related compounds and structures. The inorganic
portion of the bone which contributes to the characteristic harness
of the bone is hydroxyapatite, a form of calcium phosphate.
[0003] If the inorganic component is partially or completely
removed, the remaining organic bone matrix can be transplanted into
an animal and will reform new bone. No adverse effects are
typically associated with such transplantation. The rate of
reformation and degree of successful outcomes is variable, however,
as each bone has its own requirements for healing, immobilization,
and bone grafting. Thus there is a need for improved implants.
SUMMARY OF THE INVENTION
[0004] In one aspect, a flexible organic bone plate comprises a
continuous sheet of partially or fully decalcified natural bone.
The thickness of the sheet may be 1.5 millimeters or less. The
sheet may contain a plurality of irregular perforations with
serrated edges. In one embodiment, channels radiate out from the
plurality of irregular perforations. The plurality of irregular
perforations may vary in size and shape. In one embodiment, the
plurality of irregular perforations comprise cross-sectional areas
defining stellate, quadrangular, triangular or hexagonal shapes, or
a mixture thereof. In one embodiment, the thickness of the sheet is
between 0.045 millimeters and 1.5 millimeters. In some embodiments,
the bone plate is adapted for use in augmentation or repair of
animal skeletal structures. The natural bone may be from a mammal.
In one embodiment, the mammal is a human. The irregular
perforations with serrated edges may be configured to facilitate
ingrowth of cells and vasculature from preexisting sources of
cartilage or bone tissue at a faster rate compared to a bone sheet
of similar thickness having regular perforations without serrated
edges. In some embodiments, the bone plate is free-dried.
[0005] In another aspect, a process for the production of an
organic bone plate having a predetermined thickness comprises
decalcifying, either partially or completely, a bone which has been
harvested from a bone donor and cutting the bone after the
decalcifying into one or more sheets having a thickness 1.5 mm or
less. The process may further include harvesting the bone from the
bone donor. The bone donor may be a vertebrate, for example. In one
embodiment, the vertebrate is a human. The process may further
comprise processing the bone to remove substantially all blood and
lipid residue prior to the decalcifying. In one embodiment, the
decalcifying comprises contacting the bone with EDTA, citric acid,
hydrochloric acid, or combinations thereof. In one such embodiment,
the decalcifying comprises contacting the bone with citric acid. In
another such embodiment, the decalcifying comprises contacting the
bone with EDTA and citric acid. In yet another such embodiment, the
decalcifying comprises contacting the bone with EDTA, citric acid,
and hydrochloric acid. The process may further comprise creating a
plurality of irregular perforations having serrated edges on either
the bone after the decalcifying or the one or more sheets of the
bone after the cutting. In one embodiment, the plurality of
perforations are created by punching, burring, drilling, or
lasering the sheet. The plurality of perforations may further
include channels radiating therefrom. In one embodiment, the
plurality of perforations comprise one or more perforations having
a cross-sectional area that defines a stellate, quadrangular,
triangular or hexagonal shape. In one embodiment, the cutting
comprises utilizing a sharp blade to cut the bone.
[0006] In yet another aspect, a method for the in vivo repair or
replacement of a section of an animal skeletal system comprises
affixing, to the section of the animal skeletal system, a flexible
organic bone plate comprising a continuous sheet of partially or
fully decalcified natural bone having a thickness of 1.5
millimeters or less, wherein the continuous sheet comprises a
plurality of irregular perforations having serrated edges defined
therein configured to facilitate ingrowth of cells and vasculature
from preexisting sources of cartilage or bone tissue at a faster
rate compared to a bone sheet of similar thickness having regular
perforations without serrated edges. In one embodiment, the one or
more irregular perforations having a cross-sectional area defining
a stellate, quadrangular, triangular or hexagonal shape. The
plurality of irregular perforations may include channels radiating
therefrom.
[0007] In still yet another aspect, a flexible organic bone plate
comprises a continuous sheet of partially or fully decalcified
natural bone. The flexible organic plate is obtained by the process
of: (i) decalcifying, either partially or completely, a bone from a
bone donor; (ii) cutting the decalcified bone from step (i) into
one or more sheets of decalcified bone having a thickness of 1.5 mm
or less using a sharp blade; and (iii) creating a plurality of
irregular perforations having serrated edges on the one or more
decalcified bone sheets of step (ii). The irregular perforations
may be created by punching, burring or lasering the one or more
decalcified bone sheets. The irregular perforations may further
comprise a cross-sectional area that defines astellate,
quadrangular, triangular or hexagonal shape. In one embodiment, the
process further comprises harvesting the bone from the bone donor.
In a further embodiment, the process further comprises creating
channels radiating out from the irregular perforations. In one
embodiment, the decalcifying comprises contacting the bone with
EDTA, citric acid, hydrochloric acid, or combinations thereof In
one such embodiment, the decalcifying comprises contacting the bone
with citric acid. In another such embodiment, the decalcifying
comprises contacting the bone with EDTA and citric acid. In yet
another such embodiment, the decalcifying comprises contacting the
bone with EDTA and hydrochloric acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1. Decalcified bendable cortical bone plate with round
perforations according to various embodiments.
[0009] FIG. 2. Device for producing round holes in decalcified bone
plates or membranes or for making perforations in freeze-dried
dermis or other membranous structures according to various
embodiments. The shape of the perforations can be altered by
changing the shape of tubes used to produce the holes.
[0010] FIG. 3. Decalcified cancellous bone plate. Trebeculae serve
as perforations. These plates are prepared from endosteum according
to various embodiments.
[0011] FIG. 4. Irregular perforations in freeze-dried dermis
according to various embodiments,
[0012] FIG. 5. Decalcified cortical bone being cut with a sharp
blade in a Steddy-Riggs sectioning device according to various
embodiments.
[0013] FIG. 6. Close-up view of decalcified cortical bone cut with
a sharp blade according to various embodiments.
[0014] FIG. 7. Decalcified cortical bone plate 0.85 mm in thickness
before it is perforated according to various embodiments.
[0015] FIG. 8. Microscopic section of a decalcified freeze-dried
flexible cortical bone plate four weeks post-implantation into an
experimental animal according to various embodiments. The
perforation in the center has been replaced with vascularized
mesenchymal tissue of the host. Bone matrix contains
osteoprogenitor cells of the host.
[0016] FIGS. 9a-9d: Decalcified bone plates showing irregular
perforations according to various embodiments. FIG. 9(a)
illustrates quadrangular perforations. FIG. 9(b) illustrated
irregular perforations with channels (black arrows) extending
therefrom. FIG. 9(c) illustrates stellate perforations. FIG. 9(d)
illustrates regular round perforations for comparison.
[0017] FIGS. 10a-10d illustrate the flexible, bendable, malleable
bone plate according to various embodiments. FIGS. 10(a) to 10(c)
illustrate the flexibility of the decalcified bone plate. FIG.
10(d) illustrates that the bone plate will return to its original
shape when straightened out after bending.
[0018] FIG. 11 illustrates the bone plate of the prior art which is
rigid and stiff thus allowing it to be bent only to a small
degree.
[0019] FIG. 12 illustrates a comparison of the bone plate depicted
in FIGS. 10a-10d and the prior art bone plate depicted in FIG.
11.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Described herein are bone plates (sometimes referred to as
membranes) and variants thereof. Also described herein are methods
and devices for producing bone plates and variants thereof.
[0021] While the bone plates of the present disclosure may be
referred to as simply bone plates, it is understood that the bone
plates comprise organic bone plates, such that a desirable portion
of the organic component of the bone has been retained and a
significant portion of the inorganic component of the bone has been
removed, e.g., completely or partially removed. For example,
according to various embodiments, the inorganic portion of the bone
may be decalcified by contacting the bone with citric acid,
ethylene diamine tetraacetic acid (EDTA), and weak hydrochloric
acid. In various embodiments, the contacting of the bone with
citric acid is configured such that the citric acid demineralizes
the bone slowly and gently to thereby avoid complications, such as
destruction of the bone matrix, encountered with the use of strong
hydrochloric acid.
[0022] As described herein, the completely or partially decalcified
bone matrix is preferably sliced into thin sheets. The thin sheets
are flexible while retaining tensile strength such that they may be
manipulated to desired conformations. Such sheets or membranes
further retain many biologic properties related to osteogenesis.
According to the present disclosure, such sheets may be prepared
using methods that avoid limitations that may be associated with
conventional preparation techniques that, for example, require
precutting un-decalcified sheets with an expensive diamond saw
blade or conventional microtome intended for making sections for
histological examination. Rather, the present disclosure described
cutting bone decalcified with citric acid or by other methods with
a sharp thin blade. As will become more clear below, the methods of
the present disclosure may therefore prepare bone plates in which
beneficial proteins associated with the bone may be retained to a
greater degree due to the avoidance of contacting the bone with
strong acid and creating excessive heat when sectioning the bone,
e.g., prior to decalcification or with a saw or conventional
microtome knife.
[0023] According to various embodiments, a bone plate comprises
organic bone formed in a continuous sheet of partially or fully
decalcified natural bone. The bone plate may further include one or
more artificial perforations defined therein. For example, FIG. 1
depicts decalcified bone comprising flexible or bendable
characteristics comprising cortical bone plate having round
perforations produced by the device depicted in FIG. 2. Such a
device may be used for producing round holes, or as described
below, irregular holes in decalcified bone plates or membranes or
for making perforations in freeze-dried dermis or other membranous
structures according to various embodiments. For example, according
to various embodiments, the shape of the perforations may be
altered by changing the shape of tubes used to produce the holes or
perforations.
[0024] According to various embodiments, the perforations
preferably define irregular rather than round cross-sectional
areas, which may be further defined by uneven edges. FIG. 3 depicts
another embodiment of a decalcified cancellous bone plate prepared
from endosteum according to various embodiments. In this
embodiment, trebeculae serve as perforations. In certain
embodiments, the bone plate comprises one or more artificial
perforations having uneven edges that define irregular
cross-sectional areas. In further embodiments, the uneven edges
comprise serrated edges from which slits (or channels) may further
radiate in different directions to thereby form a series of canals
radiating from the senated edges of the irregular perforations, as
shown in FIG. 4 and FIG. 9b.
[0025] According to various embodiments, a method of preparing the
bone plate comprises creating perforations by punching, burring,
lasering or otherwise forming the perforations on the bone using,
for example, a punch, burring or perforating implement, laser, or
similar devices. For example, in some embodiments, a device
comprising a plurality of perforating members defining one or more
perforation shapes, such as a round perforation shape as
illustrated in FIG. 2 or an irregular shape, may be used to form
perforations on the bone, preferably in bone that has been
decalcified. In certain embodiments, the slits forming the canals
radiating from the perforations on the surfaces of the construct
may be formed thereon by stationary drills, blades, saws, laser or
similar devices.
[0026] It is noted that, according to various embodiments, the bone
plate according to the present disclosure may be employed as
allografts, autografts, or xenografts in transplantation
procedures. For example, the bone plates or variants thereof,
comprising irregular perforations defined by serrated or uneven
edges having canals radiating therefrom, as herein described, may
beneficially facilitate ingrowth of the cells and vasculature from
the host bed into which the construct is implanted. Such ingrowth
may include ingrowth which is accelerated compared to bone plates
having conventional round perforations with even edges. According
to various embodiments, density or number of perforations may be
varied or consistent.
[0027] In various embodiments, the bone plate as described above
may be further characterized by flexibility. For example, the bone
plate may comprise flexibility such that it may bend or flex. In
some embodiments, flexibility may comprise malleability, such that
the bone plate may be bendable while retaining its tensile strength
into a desired form, shape, or suitable conformation. In one
embodiment, flexibility comprises a degree of elasticity or
reversible deformation as a result of application and removal of
stress, e.g., shear, tensile, or compressive stress. For example,
the bone plate may be flexibly bent or strained into a bent or
folded conformation. Upon removal of the stress, the bone plate may
then retain a portion of its pre-stress form. In the above
embodiments or another embodiment, the flexibility of the bone
plate may comprise the ability to be shaped or formed into
sequential first, second, or third conformations upon application
of sequential stresses configured to transition the bone plate into
such sequential conformations. Thus, in one embodiment, the bone
plate comprises a flexible continuous sheet of partially or fully
decalcified natural bone. The thickness of the sheet, for example,
may be 1.5 millimeters or less. In one embodiment, the sheet
comprises a plurality of irregular perforations with serrated edges
as described above.
[0028] In various embodiments, the bone plate may be freeze-dried
and thus comprise a freeze-dried organic bone plate comprising a
continuous sheet of partially or fully decalcified natural bone,
wherein the thickness of the sheet is 1.5 millimeters or less and
wherein the sheet contains a plurality of irregular perforations
with serrated edges having canals radiating therefrom. As described
above, the bone plate according to the present disclosure is also
flexible.
[0029] As introduced above, in certain embodiments, the bone plate
comprises channels radiating out from the serrated edges of the
irregular perforations, such as is set forth in FIG. 9b. Such
irregular perforations may vary in shape and size. For example, the
irregular perforations may comprise stellate, quadrangular,
triangular or hexagonal perforations, or mixtures thereof. This
list, however, is non-limiting. Such irregular perforations with
serrated edges may be configured to facilitate ingrowth of cells
and vasculature from preexisting sources of cartilage or bone
tissue at a faster rate when compared to a bone sheet of similar
thickness having regular perforations without serrated edges.
[0030] As introduced above, the bone plate may comprise a
continuous sheet of partially or fully decalcified natural bone. In
various embodiments, the thickness of the sheet is between 0.45
millimeters and 1.5 millimeters. In an embodiment, the thickness of
the sheet may be between 0.045 to 1.0 millimeters, 1.0 millimeters
to 1.5 millimeters, 0.75-1.25 millimeters and so forth. For
example, in one embodiment, the thickness of the sheet may be
between about 1.25 millimeters to about 3.0 millimeters or thicker.
Such ranges are used as shorthand for describing each and every
value that is in that range. Any value within the range can be
selected as the terminus of the range.
[0031] In an embodiment, the natural bone is from a mammal,
including a human. In an embodiment, the bone is cancellous bone.
In another embodiment, the bone is cortical bone.
[0032] In any of the above embodiments, the bone plate is adapted
for use in augmentation or repair of animal skeletal
structures.
[0033] The flexible organic bone plate described herein exhibits
superior flexibility over those of the prior art. For example, as
shown in FIG. 10C, the bone plate may be bent without fracturing.
The bone plate may be formed into bent or folded conformations as
shown in FIGS. 10A and 10B. The bone plate may also return to its
original shape when straightened out, as showing in FIG. 10D.
[0034] Also provided are methods for making flexible organic bone
plates which comprise a continuous sheet of partially or fully
decalcified natural bone. This optionally includes excising an
entire bone or part of a bone from a bone donor. In various
embodiments, the donor can be either human (allogeneic) and animal
(xenogeneic). A harvested or excised bone may be processed
immediately or preserved according to any known preservation method
including freezing, freeze-drying, hypothermic dehydration,
chemical dehydration, immersion in a chemical solutions, etc.
Partial or complete decalcification is carried out on thin bone
plates, strips or other configurations. Decalcification can be
carried out by exposing bone to citric acid, ethylene diamine
tetraacetic acid (EDTA) and weak hydrochloric acid, or by other
methods
[0035] A method of producing a flexible organic bone plate comprise
decalcifying the bone, as described herein, and subsequently
cutting the decalcified bone with a sharp blade. This process is
further illustrated in FIGS. 5-7. FIG. 5 shows flexible decalcified
bone positioned between two plastic plates bone plates of a
Stadie-Riggs tissue slicer. A sharp blade is positioned between the
two plastic plates and is slidable to section the bone, as
illustrated in FIG. 6, into thin sheets of desired thickness, an
example of which is provide in FIG. 7. Such thin sheets of
decalcified bone made by this process support growth of human cells
in vivo as set forth in FIG. 8 and produce osteogenesis in
experimental animals. In addition, the serrated perforations with
radial channels improve and facilitate the osteogenesis process.
This method avoids the need to cut un-decalcified bone with a
diamond saw blade, or a conventional microtome. By first
decalcifying the bone, using, for example, citric acid or any other
method disclosed herein, the decalcified bone can be cut with a
sharp blade rather than a saw or conventional microtome knife. Thus
it avoids the use of an expensive precision saw and diamond blade.
Sectioning of bone with a bone saw creates heat which deactivates
some proteins, despite the use of irrigation during the process.
The method of the present invention, by decalcifying first and then
cutting with a sharp blade, does not create heat and avoids the
deactivation of proteins.
[0036] Thus, in one embodiment, the invention can comprise a
process for the production of an organic bone plate having a
predetermined thickness comprising: (i) decalcifying, either
partially or completely, a bone which has been harvested from a
bone donor; and (ii) cutting the decalcified bone from step (i)
into sheets having a thickness of 1.5 mm or less.
[0037] Also provided is a flexible perforated organic bone plate
comprising a continuous sheet of partially or fully decalcified
natural bone, wherein the flexible perforated organic plate matrix
is obtained by the process of described herein. For example, in an
embodiment the process comprises: (i) decalcifying, either
partially or completely, an entire or part of a bone from a bone
donor; (ii) cutting the decalcified bone from step (i) into sheets
having a thickness of 1.5 mm or less using a sharp blade; and (iii)
creating a plurality of irregular perforations with serrated edges
on the decalcified bone sheet of step (ii).
[0038] The present invention provides for decalcifying the bone
with citric acid, ethylene diamine tetraacetic acid (EDTA) and weak
hydrochloric acid. Citric acid decalcifies bone slowly and gently
and avoids the complications, such as complete destruction of the
bone matrix, encountered with strong hydrochloric acid. Citric acid
does not produce deleterious effects on humans. Bone decalcified
with citric acid, EDTA, or combinations thereof, with or without
and hydrochloric acid can be cut with a sharp blade. For example,
the decalcified bone can be placed between two rigid plates, e.g.,
rigid plastic or metal plates, and cut with a sharp blade.
Alternatively, bone can be rigidly held in a vice or other device
and cut by guided blades, for example. The thickness of the
preparations, for example, as shown in FIG. 1, so obtained varies
between 0.45 mm to 1.5 mm.
[0039] Thus, in an embodiment, the decalcification of the bone in
step (i) comprises decalcifying the bone with EDTA, citric acid,
hydrochloric acid, or combinations thereof or by other decalcifying
methods. In an embodiment, the bone is decalcified with citric
acid. In another embodiment, the bone is decalcified with EDTA and
citric acid. In a further embodiment, the bone is decalcified with
citric acid, EDTA and weak hydrochloric acid. In various
embodiments, decalcifying bone as herein disclosed avoids
over-decalcification of the bone thereby improving flexibility of
the bone preparation compared to bone preparations prepared by
conventional methods.
[0040] In a further embodiment, the method comprises cutting the
decalcified bone with a sharp blade. As used herein, sharp blade
includes, but is not limited to thin flexible blades such as those
manufactured by Lipshaw, scalpels, thin knife blades, wires, or
laser devices. According to various embodiments, a sharp blade does
not include a bone saw or conventional microtome.
[0041] In one embodiment, preparing the bone plate further
comprises creating a plurality of irregular perforations having
serrated edges on or through the bone sheet after either
decalcifying the bone or cutting the decalcified bone. In certain
embodiments, the irregular perforations are created by punching,
burring, drilling, or lasering the sheet. In some embodiments, the
plurality of irregular perforations include channels radiating
therefrom. In one embodiment, the plurality of irregular
perforations comprise perforations having cross-sectional areas
defining stellate, quadrangular, triangular, or hexagonal shapes,
or combinations thereof. It is to be appreciated, however, that the
cross-sectional area of the irregular perforations may define
additional geometric shapes as well as non-geometric shapes.
[0042] In one embodiment, the process further comprises harvesting
a bone from a donor, which may include a defined unit of bone or
part of a defined unit of bone excised from the bone donor. In
various embodiments, harvesting a bone may comprise excising bone
from a donor bone, which may include a defined unit of bone or a
part of a defined unit of bone harvested from a bone donor. In
certain embodiments, the bone donor is a vertebrate. In one
embodiment, for example, the vertebrate is a human. Methods for
harvesting a bone, or part of a bone, from a bone donor are known
in the art, e.g., as described in Malinin, T. & Temple, H. T.
(2013). Musculoskeletal Tissue Transplantation and Tissue Banking.
New Delhi, India: Jaypee Brothers Medical Pub., the contents of
which are here incorporated by reference in its entirety. Common
donor sites from which donor bone may be harvested include, but are
not limited to, the ilium, tibia, fibula, and ribs. In addition,
the bone may be harvested from the mandible of the vertebrate. In
an embodiment, the bone is cancellous bone. In another embodiment,
the bone is cortical bone.
[0043] In some embodiments, the process further comprises
processing the harvested bone to remove substantially all blood and
lipid residue prior to the decalcification of the harvested bone.
Such processing methods are known in the art, e.g., as described in
Malinin, T. & Temple, H. T. (2013). Musculoskeletal Tissue
Transplantation and Tissue Banking. New Delhi, India: Jaypee
Brothers Medical Pub.
[0044] In a further embodiment, the process comprises freeze drying
the resulting organic bone plate. Methods for preparing freeze
dried sections of decalcified bone are known in the art, such as
those described in Malinin, T. I. (1992). Acquisition and banking
of bone allografts. In Habal M B, Reddi A H (Eds.), Bone grafts and
bone substitutes (pp. 206-233). Philadelphia, Pa.: W.B. Saunders
Co., which is hereby incorporated by reference in its entirety.
[0045] According to various embodiments, the bone plate of the
present disclosure may be employed in surgical procedures such as
mandibular augmentation, sinus elevation, guided tissue
regeneration, closure of nasal oral fistula, closure of cranial
defects, among others. The bone plate prepared and comprising the
characteristic features as herein described may comprise a
construct suitable for use as an implant configured to beneficially
promote induction of bone regeneration superior to certain
conventional constructs prepared by more expensive or complex
methods.
[0046] In various embodiments, a method for the in vivo repair or
replacement of a section of an animal skeletal system is disclosed.
The method may comprise affixing to the section a flexible
perforated organic bone plate comprising a continuous sheet of
partially or fully decalcified natural bone, as described herein.
In one embodiment, the bone plate contains a plurality of irregular
perforations with serrated edges, such as, for example, stellate,
quadrangular, triangular or hexagonal perforations. In a further
embodiment, the plurality of irregular perforations contains
channels radiating therefrom and the surface can be scored in a
gull wing or similar pattern.
[0047] In view of the above description and examples below, one of
ordinary skill in the art will be able to practice the invention as
claimed without undue experimentation. The foregoing will be better
understood with reference to the following examples that detail
certain embodiments of the invention. All references made to these
examples are for the purposes of illustration and not limitation.
The following examples should not be considered exhaustive or
exclusive, but merely illustrative.
EXAMPLES
Example 1
Excision and Preparation of a Donor Bone
[0048] The bone was excised under aseptic conditions from cadaver
bone. The bone was washed and the periosteum was removed. The bone
marrow was removed with metal brushes and the medullary cavity was
washed out with copious irrigation. Microbiological studies were
conducted to assure sterility and laboratory tests were performed
on the donor.
Example 2
Preparation of Freeze-Dried, Decalcified, Flexible Bone Plates From
Donor Bone
[0049] The bone prepared in Example 1 was wrapped and quick frozen
by placement it into vapor phase of liquid nitrogen. After all
microbiological studies to assure sterility were completed, and
laboratory reports on the donor received, the bone was placed on a
pre-cooled shelf (-40.degree. C.) of a freeze-dryer and the vacuum
pump turned on. The chamber of the freeze-dryer was maintained at
100 millitorr of vacuum, and the condenser at -70.degree. C. The
freeze-drying cycle was 14 days. During the last two days of the
cycle the shelf temperature was brought up to 25.degree. C. The
bone was removed from the freeze-dryer following the freeze-drying
cycle and was sectioned into 3 individual plates. These bone plates
were placed into 10% v/w solution of citric acid for 48 hours and
then transferred to solutions of 5% v/w of EDTA and finally into
10.5N HCl for 48 hours in each. Following removal of the bone
plates from the HCl solution, the bone plates where cut in a
Stadie-Riggs tissue slicer, as shown in FIGS. 5 & 6.
Perforations in decalcified bone were made with specially prepared
punches.
Example 3
Implantation of Freeze-Dried, Decalcified, Flexible Bone Plates
into an Experimental Animal
[0050] Freeze-dried, decalcified, flexible bone plates with round
perforations prepared at described in Examples 1 and 2 where
implanted intramuscularly into athymic rats. The animals were
sacrificed at 2, 4, and 6 weeks post-implantation and implants
removed with surrounding soft tissues. The implants and surrounding
soft tissue were x-rayed, photographed and fixed in 10% formalin in
Earle's balanced salt solution. Paraffin embedded tissues were
section on rotary microtomes at 5-6 microns, and stained with
hematoxylin and eosin and "special stains" as needed.
* * * * *