U.S. patent application number 09/911562 was filed with the patent office on 2001-11-22 for load-bearing osteoimplant, method for its manufacture and method of repairing bone using same.
Invention is credited to Boyce, Todd M., Manrique, Albert, Shimp, Lawrence A..
Application Number | 20010043940 09/911562 |
Document ID | / |
Family ID | 22972272 |
Filed Date | 2001-11-22 |
United States Patent
Application |
20010043940 |
Kind Code |
A1 |
Boyce, Todd M. ; et
al. |
November 22, 2001 |
Load-bearing osteoimplant, method for its manufacture and method of
repairing bone using same
Abstract
A load-bearing osteoimplant, method of making the osteoimplant
and method for repairing bone using the osteoimplant are provided.
The osteoimplant comprises a shaped, compressed composition of bone
particles. The osteoimplant possesses a bulk density of greater
than about 0.7 g/cm.sup.3 and a wet compressive strength of at
least about 3 MPa.
Inventors: |
Boyce, Todd M.; (Aberdeen,
NJ) ; Shimp, Lawrence A.; (Morganville, NJ) ;
Manrique, Albert; (Manalapan, NJ) |
Correspondence
Address: |
Peter G. Dilworth, Esq.
DILWORTH & BARRESE, LLP
333 Earle Ovington Blvd.
Uniondale
NY
11553
US
|
Family ID: |
22972272 |
Appl. No.: |
09/911562 |
Filed: |
July 24, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09911562 |
Jul 24, 2001 |
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09256447 |
Feb 23, 1999 |
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6294187 |
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Current U.S.
Class: |
424/423 ;
623/16.11 |
Current CPC
Class: |
A61L 27/3683 20130101;
A61F 2/28 20130101; A61L 27/3691 20130101; A61F 2002/30535
20130101; A61L 27/3645 20130101; A61L 27/3608 20130101; A61F 2/4644
20130101; A61L 27/3847 20130101; A61F 2250/0058 20130101; A61L
31/005 20130101; A61L 2430/02 20130101; A61F 2/32 20130101 |
Class at
Publication: |
424/423 ;
623/16.11 |
International
Class: |
A61F 002/28 |
Claims
What is claimed is:
1. A load-bearing osteoimplant comprising a shaped composition of
bone particles, wherein the osteoimplant possesses a bulk density
of greater than about 0.7 g/cm.sup.3 and a wet compressive strength
of at least about 3 MPa.
2. A load-bearing osteoimplant comprising a shaped composition of
bone particles, wherein the osteoimplant possesses a wet
compressive strength of at least about 3 MPa.
3. The osteoimplant of claim 1 or 2 wherein the bone particles are
selected from the group consisting of nondemineralized bone
particles, demineralized bone particles, and mixtures thereof.
4. The osteoimplant of claim 3 wherein the demineralized bone
particles are selected from the group consisting of superficially
demineralized, partially demineralized and fully demineralized bone
particles.
5. The osteoimplant of claim 3 wherein the demineralized bone
particles are fully demineralized.
6. The osteoimplant of claim 1 or 2 wherein the bone particles are
obtained from cortical, cancellous or cortico-cancellous bone of
autogenous, allogenic or xenogeneic origin.
7. The osteoimplant of claim 1 or 2 wherein the bone particles are
obtained from porcine or bovine bone.
8. The osteoimplant of claim 1 or 2 wherein the bone particles
comprise a mixture of nondemineralized bone particles and
demineralized bone particles.
9. The osteoimplant of claim 1 or 2 wherein the bone particles
comprise a mixture of partially demineralized bone particles and
fully demineralized bone particles.
10. The osteoimplant of claim 1 or 2 wherein the bone particles
further comprise nondemineralized bone particles.
11. The osteoimplant of claim 1 or 2 wherein at least about 60
weight percent of the bone particles are elongate.
12. The osteoimplant of claim 1 or 2 wherein at least about 90
weight percent of the bone particles are elongate.
13. The osteoimplant of claim 1 or 2 further comprising at least
one component selected from the group consisting of wetting agent,
binder, filler, fiber, surface active agent, bioactive substance
and biostatic/biocidal agent.
14. The osteoimplant of claim 1 or 2 further comprising one or more
components selected from the group consisting of water, organic
protic solvent, physiological saline liquid polyhydroxy compound
and mixture of water and liquid polyhydroxy compound.
15. The osteoimplant of claim 14 wherein the polyhydroxy compound
is selected from the group consisting of glycerol and glycerol
esters.
16. The osteoimplant of claim 1 or 2 further comprising a
biological adhesive.
17. The osteoimplant of claim 16 wherein the biological adhesive is
fibrin glue, fibrinogen thrombin, mussel adhesive protein, silk,
elastin, collagen, casein, gelatin, albumin, keratin, chitin or
chitosan.
18. The osteoimplant of claim 1 or 2 further comprising a
bioabsorbable polymer.
19. The osteoimplant of claim 18 wherein the bioabsorbable polymer
is selected from the group consisting of starches, polylactic acid,
polyglycolic acid, polylactic-co-glycolic acid, polydioxanone,
polycaprolactone, polycarbonates, polyorthoesters, polyamino acids,
polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly
(propylene glycol-co-fumaric acid), tyrosine-based polycarbonates,
tablet binders, polyvinylpyrollidone, cellulose, ethyl cellulose,
microcrystalline cellulose, and blends thereof.
20. The osteoimplant of claim 1 or 2 further comprising a
nonbioabsorbable polymer.
21. The osteoimplant of claim 20 wherein the nonbioabsorbable
polymer is selected from the group consisting of polyacrylate,
polymethyl methacrylate polytetrafluoroethylene, polyurethane, and
polyamide.
22. The osteoimplant of claim 1 or 2 further comprising a component
selected from the group consisting of calcium phosphates, calcium
salts, bone powder, graphite, pyrolytic carbon, bioglass,
bioceramic, and mixtures thereof.
23. The osteoimplant of claim 1 or 2 further comprising a surface
active agent selected from the group consisting of nonionic,
cationic, anionic, amphoteric surfactants, and mixtures
thereof.
24. The osteoimplant of claim 1 or 2 further comprising a component
selected from the group consisting of collagen, insoluble collagen
derivatives, and soluble solids and/or liquids dissolved therein;
antiviricides, antimicrobials and/or antibiotics selected from the
group consisting of erythromycin, bacitracin, neomycin, penicillin,
polymycin B, tetracyclines, biomycin, chloromycetin, streptomycins,
cefazolin, ampicillin, azactam, tobramycin, clindamycin and
gentamicin; biocidal/biostatic sugars selected from the group
consisting of dextran, glucose, amino acids, peptides; vitamins;
inorganic elements; co-factors for protein synthesis; hormones;
endocrine tissue or tissue fragments; synthesizers; enzymes
selected from the group consisting of collagenase, peptidases,
oxidases; polymer cell scaffolds with parenchymal cells; angiogenic
drugs and polymeric carriers containing such drugs; collagen
lattices; antigenic agents; cytoskeletal agents; cartilage
fragments; living cells selected from the group consisting of
chondrocytes, bone marrow cells, mesenchymal stem cells, natural
extracts, genetically engineered living cells or otherwise modified
living cells, DNA delivered by plasmid or viral vectors, and tissue
transplants; demineralized bone powder; autogenous tissues selected
from the group consisting of blood, serum, soft tissue, bone
marrow; bioadhesives, bone morphogenic proteins (BMPs);
osteoinductive factor (IFO); fibronectin (FN); endothelial cell
growth factor (ECGF); cementum attachment extracts (CAE);
ketanserin; human growth hormone (HGH); animal growth hormones;
epidermal growth factor (EGF); interleukin-1 (IL-1); human alpha
thrombin; transforming growth factor (TGF-beta); insulin-like
growth factor (IGF-1); platelet derived growth factors (PDGF);
fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament
chemotactic factor (PDLGF); somatotropin; bone digesters; antitumor
agents; immuno-suppressants; permeation enhancers; enamine
derivatives; alpha-keto aldehydes; and nucleic acids.
25. The osteoimplant of claim 1 or 2 further comprising a component
selected from the group consisting of transforming growth factor
(TGF-beta), insulin-like growth factor (IGF-1), somatotropin, basic
fibroblast growth factor (BFGF) and mixtures thereof.
26. The osteoimplant of claim 1 or 2 further comprising bone
morphogenetic protein (BMP).
27. The osteoimplant of claim 1 or 2 further comprising a component
selected from the group consisting of antibiotics, povidone, sugars
and mixtures thereof.
28. The osteoimplant of claim 13 wherein the bone particles
represent from about 5 to about 100 and the biocompatible component
represents from about 0 to about 95 weight percent of the
osteoimplant.
29. The osteoimplant of claim 8 wherein the weight ratio of
nondemineralized bone particles to demineralized bone particles
ranges from about 20:1 to about 1:20.
30. The osteoimplant of claim 9 wherein the weight ratio of
partially demineralized bone particles to fully demineralized bone
particles ranges from about 20:1 to about 1:20.
31. The osteoimplant of claim 1 or 2 wherein the bone particles are
crosslinked.
32. The osteoimplant of claim 1 or 2 further comprising at least
one macroporous hole.
33. The osteoimplant of claim 32 wherein the macroporous hole
contains therein an osteogenic material.
34. An intervertebral implant which comprises a shaped composition
of bone particles, wherein the composition possesses a bulk density
of greater than about 0.7 g/cm.sup.3 and a wet compressive strength
of at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
35. A spinal implant which comprises a shaped composition of bone
particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
36. An implant possessing the shape of a cylinder, wedge, plate,
threaded cylinder, fibular wedge, femoral strut or tibial strut
which comprises a shaped composition of bone particles, wherein the
composition possesses a bulk density of greater than about 0.7
g/cm.sup.3 and a wet compressive strength of at least about 3 MPa,
said implant being capable of initially bearing loads upon
implantation.
37. The osteoimplant of claim 36 further comprising at least one
macroporous hole.
38. The osteoimplant of claim 37 wherein the macroporous hole
contains therein an osteogenic material.
39. A bone plate which comprises a shaped composition of bone
particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said bone plate being capable of initially
bearing loads upon implantation.
40. A disk which comprises a shaped composition of bone particles,
wherein the composition possesses a bulk density of greater than
about 0.7 g/cm.sup.3 and a wet compressive strength of at least
about 3 MPa, said disk being capable of initially bearing loads
upon implantation.
41. A bone screw which comprises a shaped composition of bone
particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said bone screw being capable of initially
bearing loads upon implantation.
42. A femoral implant which comprises a shaped composition of bone
particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
43. An acetablular cup implant which comprises a shaped composition
of bone particles, wherein the composition possesses a bulk density
of greater than about 0.7 g/cm.sup.3 and a wet compressive strength
of at least about 3 MPa, said acetabular cup being capable of
initially bearing loads upon implantation.
44. A diaphyseal implant which comprises a shaped composition of
bone particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
45. An intercalary implant which comprises a shaped composition of
bone particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
46. An intramedullary implant which comprises a shaped composition
of bone particles, wherein the composition possesses a bulk density
of greater than about 0.7 g/cm.sup.3 and a wet compressive strength
of at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
47. A reinforcement rod implant which comprises a shaped
composition of s bone particles, wherein the composition possesses
a bulk density of greater than about 0.7 g/cm.sup.3 and a wet
compressive strength of at least about 3 MPa, said implant being
capable of initially bearing loads upon implantation.
48. A cranial bone implant which comprises a shaped composition of
bone particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
49. A maxillofacial implant which comprises a shaped composition of
bone particles, wherein the composition possesses a bulk density of
greater than about 0.7 g/cm.sup.3 and a wet compressive strength of
at least about 3 MPa, said implant being capable of initially
bearing loads upon implantation.
50. A method of repairing bone comprising implanting at a bone
repair site a load-bearing osteoimplant comprising a shaped
composition of bone particles, said osteoimplant possessing a bulk
density of greater than about 0.7 g/cm.sup.3.
51. The method of repairing bone of claim 50 selected from the
group consisting of the repair of simple and compound fractures and
non-unions, external and internal fixations, joint reconstructions,
arthrodesis, general arthroplasty, cup arthroplasty of the hip,
femoral and humeral head replacement, femoral head surface
replacement and total joint replacement, repairs of the vertebral
column, spinal fusion, internal fixation, tumor surgery, deficit
filling, discectomy, laminectomy, excision of spinal cord tumors,
anterior cervical and thoracic operations, repairs of spinal
injuries, scoliosis, lordosis and kyphosis treatments,
intermaxillary fixation of fractures, mentoplasty,
temporomandibular joint replacement, alveolar ridge augmentation
and reconstruction, onlay bone grafts, implant placement and
revision, and sinus lifts.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 09/256,447, filed Feb. 23, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to an osteoimplant for use in
the repair, replacement and/or augmentation of various portions of
animal or human skeletal systems, to a method for manufacturing the
osteoimplant and to a method of using the osteoimplant. More
particularly, this invention relates to an osteogenic osteoimplant
which provides mechanical or structural support to a bone repair
site.
BACKGROUND OF THE INVENTION
[0003] Shaped or cut bone segments have been used extensively to
solve various medical problems in human and animal orthopaedic
surgical practice, and their application has also extended to the
field of cosmetic and reconstructive surgery, dental reconstructive
surgery, and other medical fields involving surgery of hard
tissues. The use of autograft bone (where the patient provides the
source), allograft bone (where another individual of the same
species provides the source) or xenograft bone (where another
individual of a different species provides the source) is well
known in both human and veterinary medicine. In particular,
transplanted bone is known to provide support, promote healing,
fill bony cavities, separate bony elements (such as vertebral
bodies), promote fusion (where bones are induced to grow together
into a single, solid mass), or stabilize the sites of fractures.
More recently, processed bone has been developed into shapes for
use in new surgical applications, or as new materials for implants
that were historically made of non-biologically derived
materials.
[0004] Bone grafting applications are differentiated by the
requirements of the skeletal site. Certain applications require a
"structural graft" in which one role of the graft is to provide
mechanical or structural support to the site. Such grafts contain a
substantial portion of mineralized bone tissue to provide the
strength needed for loadbearing. The graft may also have beneficial
biological properties, such as incorporation into the skeleton,
osteoinduction, osteoconduction, or angiogenesis.
[0005] Structural grafts are conventionally made by processing, and
then cutting or otherwise shaping cortical bones collected for
transplant purposes. The range of bone grafts that might be thus
prepared is limited by the size and shape limitations of the bone
TISSUE from which the bone graft originated. Certain clinically
desirable shapes and sizes of grafts may thus be unattainable by
the cutting and shaping processes, due to the dimensional
limitations of the bone. For some shapes they may also be available
only in limited amounts, due to the large variations inherent in
the human or animal donor source populations.
[0006] Many structural allografts are never fully incorporated by
remodeling and replacement with host tissue due, in part, to the
difficulty with which the host's blood supply may penetrate
cortical bone, and partly to the poor osteoinductivity of
nondemineralized bone. To the extent that the implant is
incorporated and replaced by living host bone tissue, the body can
then recognize and repair damage, thus eliminating failure by
fatigue. In applications where the mechanical load-bearing
requirements of the graft are challenging, lack of replacement by
host bone tissue may compromise the graft by subjecting it to
repeated loading and cumulative unrepaired damage (mechanical
fatigue) within the implant material. Thus, it is highly desirable
that the graft have the capacity to support load initially, and be
capable of gradually transferring this load to the host bone tissue
as it remodels the implant.
SUMMARY OF THE INVENTION
[0007] It is an object of the present invention to provide an
osteoimplant possessing sufficient strength in a body fluid
environment to enable the osteoimplant to bear loads.
[0008] It is a further object of the present invention to provide a
load-bearing osteoimplant which contains pores or cavities which
permit the osteoimplant to be properly revascularized and
incorporated by the host.
[0009] It is yet a further object of the present invention to
provide a load-bearing osteoimplant which is osteogenic and thereby
promotes new host bone tissue formation within and around the
osteoimplant.
[0010] It is yet an even further object of the invention to provide
a load-bearing osteoimplant which supports load initially and is
capable of gradually transferring this load to the host bone tissue
as it remodels the osteoimplant.
[0011] It is yet an even further object of the invention to provide
a method for fabricating an osteoimplant which meets the foregoing
objectives.
[0012] It is yet an even further object of the present invention to
provide a method which enables the fabrication of osteoimplants of
any size and/or shape.
[0013] It is yet an even further object of the present invention to
provide a method for preparing osteoimplants which is not limited
by constraints imposed by the shape and size of the original bone
tissue from which the osteoimplants are derived.
[0014] These and further objects of the invention are obtained by a
load-bearing osteoimplant which comprises a shaped, compressed
composition of bone particles. The osteoimplant possesses a bulk
density of greater than about 0.7 g/cm.sup.3 and a wet compressive
strength of at least about 3 MPa. The osteoimplant of this
invention is fabricated by the method which comprises providing a
composition comprising bone particles optionally in combination
with one or more biocompatible components and applying compressive
force of greater than about 1000 psi to the composition to provide
a load-bearing osteoimplant.
[0015] The bone particles utilized in the fabrication of the
osteoimplant of this invention are selected from the group
consisting of nondemineralized bone particles, demineralized bone
particles, and combinations thereof. The bone particles are
remodeled and replaced by new host bone as incorporation of the
osteoimplant progresses in vivo. As described more filly
hereinbelow, bone particles can be fully demineralized by removing
substantially all of the inorganic mineral content of the bone
particles, can be partially demineralized by removing a significant
amount, but less than all, of the inorganic mineral content of the
bone particles, or can be only superficially demineralized by
removing a minor amount of the inorganic mineral content of the
bone particles.
[0016] The term "demineralized" as applied to the bone particles
utilized in the practice of the present invention is intended to
cover all bone particles which have had some portion of their
original mineral content removed by a demineralization process.
[0017] Nondemineralized bone particles provide strength to the
osteoimplant and allow it to initially support load. Demineralized
bone particles induce new bone formation at the site of the
demineralized bone and permit adjustment of the overall mechanical
properties of the osteoimplant. The osteoimplant of this invention
optionally includes additional biocompatible component(s) such as
wetting agents, biocompatible binders, fillers, fibers,
plasticizers, biostatic/biocidal agents, surface active agents,
bioactive agents, and the like.
[0018] The term "osteoimplant" herein is utilized in its broadest
sense and is not intended to be limited to any particular shapes,
sizes, configurations or applications.
[0019] The term "shaped" as applied to the osteoimplant herein
refers to a determined or regular form or configuration, in
contrast to an indeterminate or vague form or configuration (as in
the case of a limp or other solid mass of no special form) and is
characteristic of such materials as sheets, plates, disks, cores,
pins, screws, tubes, teeth, bones, portion of bone, wedges,
cylinders, threaded cylinders, and the like.
[0020] The phrase "wet compressive strength" as utilized herein
refers to the compressive strength of the osteoimplant after the
osteoimplant has been immersed in physiological saline (water
containing 0.9 g NaCl/100 ml water) for a minimum of 12 hours and a
maximum of 24 hours. Compressive strength is a well known
measurement of mechanical strength and is measured using the
procedure described herein.
[0021] The term "osteogenic" as applied to the osteoimplant of this
invention shall be understood as referring to the ability of the
osteoimplant to enhance or accelerate the ingrowth of new bone
tissue by one or more mechanisms such as osteogenesis,
osteoconduction and/or osteoinduction.
[0022] The term "incorporation" utilized herein refers to the
biological mechanism whereby host tissue gradually removes portions
of the osteoimplant of the invention and replaces those removed
portions with native host bone tissue while maintaining strength.
This phenomenon is also known in the scientific literature as
"creeping substitution". The term "incorporation" utilized herein
shall be understood as embracing what is known by those skilled in
the art as "creeping substitution".
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Various embodiments are described below with reference to
the drawings wherein:
[0024] FIGS. 1a-h show various configurations of an osteoimplant of
the present invention;
[0025] FIGS. 2a and 2b are views of a vertebrae and the
osteoimplant of the invention sized and shaped as a disc (FIG. 2a)
and threaded cylinder (FIG. 2b) for installation at an
intervertebral site;
[0026] FIG. 3 is a view of human cervical vertebrae showing an
osteoimplant of the invention affixed thereto as a cervical
plate;
[0027] FIG. 4 is a view of the human skull showing an osteoimplant
of the invention fashioned as a mandibular replacement;
[0028] FIG. 5 is a cross-sectional view of a human femur showing
implanted therein an osteoimplant fashioned as a femoral
implant;
[0029] FIGS. 6a and 6b show an embodiment of the osteoimplant of
the present invention configured and dimensioned as an acetabular
cup;
[0030] FIG. 7 is a view of a total hip replacement using the
femoral implant depicted in FIG. 5 and the acetabular cup depicted
in FIG. 6;
[0031] FIGS. 8a and 8b are views of a human radius and ulna showing
an osteoimplant of the invention fashioned as a diaphyseal plate
being implanted at a bone fracture site (FIG. 8a) and as an
intercalary implant implanted at a diaphyseal segment missing due
to trauma or tumor (FIG. 8b);
[0032] FIG. 9 is a view of a human femur and an osteoimplant of the
invention fashioned as an intramedullary rod positioned for
installation in the medullary canal of the femur;
[0033] FIG. 10 is a view of a femoral head and an osteoimplant of
the invention positioned for installation in a core decompression
site in the femoral head;
[0034] FIG. 11 is a view of a human skull and an osteoimplant of
the present invention positioned for implantation as a parietal
bone replacement;
[0035] FIGS. 12a and 12b show a cylindrical press-mold which can be
utilized in the fabrication of the osteoimplant of the
invention;
[0036] FIG. 13 shows a press which can be utilized in the
fabrication of the osteoimplant of the invention; and
[0037] FIG. 14 shows a press and heating apparatus which can be
utilized in the fabrication of the osteoimplant of the
invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] The load-bearing osteoimplant of the present invention is
produced by providing a composition comprising bone particles
optionally in combination with one or more biocompatible
components, and thereafter applying compressive force of at least
about 1000 psi to the composition to provide a load-bearing
osteoimplant. The osteoimplant fabricated in accordance with the
invention possesses a bulk density of at least about 0.7 g/cm.sup.3
and a wet compressive strength of at least about 3 MPa. In
accordance with further embodiments of the invention, the bone
particle-containing composition can be heated, lyophilized and/or
cross-linked either before, during or after the step of applying a
compressive force to the bone particle-containing composition.
[0039] The bone particles employed in the preparation of the bone
particle-containing composition can be obtained from cortical,
cancellous and/or corticocancellous bone which may be of
autogenous, allogenic and/or xenogeneic origin. Preferably, the
bone particles are obtained from cortical bone of allogenic origin.
Porcine and bovine bone are particularly advantageous types of
xenogeneic bone tissue which can be used individually or in
combination as sources for the bone particles. Particles are formed
by milling whole bone to produce fibers, chipping whole bone,
cutting whole bone, fracturing whole bone in liquid nitrogen, or
otherwise disintegrating the bone tissue. Particles can optionally
be sieved to produce those of a specific size.
[0040] The bone particles employed in the composition can be
powdered bone particles possessing a wide range of particle sizes
ranging from relatively fine powders to coarse grains and even
larger chips. Thus, e.g., powdered bone particles can range in
average particle size from about 0.05 to about 1.2 cm and
preferably from about 0.1 to about 1 cm and possess an average
median length to median thickness ratio of from about 1:1 to about
3:1. If desired, powdered bone particles can be graded into
different sizes to reduce or eliminate any less desirable size(s)
of particles which may be present.
[0041] Alternatively, or in combination with the aforementioned
bone powder, bone particles generally characterized as elongate and
possessing relatively high median length to median thickness ratios
can be utilized herein. Such elongate particles can be readily
obtained by any one of several methods, e.g., by milling or shaving
the surface of an entire bone or relatively large section of bone.
Employing a milling technique, one can obtain a mass of elongate
bone particles containing at least about 60 weight percent,
preferably at least about 70 weight percent, and most preferably at
least about 80 weight percent of elongate bone particles possessing
a median length of from about 2 to about 200 mm or more and
preferably from about 10 to about 100 mm, a median thickness of
from about 0.05 to about 2 mm, and preferably from about 0.2 to
about 1 mm and a median width of from about 1 mm to about 20 mm,
and preferably from about 2 to about 5 mm. These elongate bone
particles can possess a median length to median thickness ratio of
at least about 50:1 up to about 500:1 or more, and preferably from
about 50:1 to about 100:1, and a median length to median width
ratio of from about 10:1 and about 200: 1, and preferably from
about 50:1 to about 100:1. Another procedure for obtaining elongate
bone particles, particularly useful for pieces of bone of up to
about 100 mm in length, is the bone processing mill described in
commonly assigned U.S. Pat. No. 5,607,269. Use of this bone mill
results in the production of long, thin strips which quickly curl
lengthwise to provide tubular-like bone particles. If desired,
elongate bone particles can be graded into different sizes to
reduce or eliminate any less desirable size(s) of particles which
may be present. In overall appearance, elongate bone particles can
be described as filaments, fibers, threads, slender or narrow
strips, etc.
[0042] Preferably, at least about 60 weight percent, more
preferably at least about 75 weight percent, and most preferably at
least about 90 weight percent of the bone particles utilized in the
preparation of the bone particle-containing composition herein are
elongate. It has been observed that elongate bone particles provide
an osteoimplant possessing particularly good compressive
strength.
[0043] The bone particles are optionally demineralized in
accordance with known and conventional procedures in order to
reduce their inorganic mineral content. Demineralization methods
remove the inorganic mineral component of bone by employing acid
solutions. Such methods are well known in the art, see for example,
Reddi et al., Proc. Nat. Acad. Sci. 69, pp1601-1605 (1972),
incorporated herein by reference herein. The strength of the acid
solution, the shape of the bone particles and the duration of the
demineralization treatment will determine the extent of
demineralization. Reference in this regard may be made to
Lewandrowski et al., J. Biomed Materials Res, 31, pp 365-372
(1996), also incorporated herein by reference.
[0044] In a preferred demineralization procedure, the bone
particles are subjected to a defatting/disinfecting step which is
followed by an acid demineralization step. A preferred
defatting/disinfectant solution is an aqueous solution of ethanol,
the ethanol being a good solvent for lipids and the water being a
good hydrophilic carrier to enable the solution to penetrate more
deeply into the bone particles. The aqueous ethanol solution also
disinfects the bone by killing vegetative microorganisms and
viruses. Ordinarily, at least about 10 to about 40 percent by
weight of water (i.e., about 60 to about 90 weight percent of
defatting agent such as alcohol) should be present in the defatting
disinfecting solution to produce optimal lipid removal and
disinfection within the shortest period of time. The preferred
concentration range of the defatting solution is from about 60 to
about 85 weight percent alcohol and most preferably about 70 weight
percent alcohol. Following defatting, the bone particles are
immersed in acid over time to effect their demineralization. Acids
which can be employed in this step include inorganic acids such as
hydrochloric acid and organic acids such as peracetic acid. After
acid treatment, the demineralized bone particles are rinsed with
sterile water to remove residual amounts of acid and thereby raise
the pH. Where elongate bone particles are employed, some
entanglement of the wet demineralized bone particles will result.
The wet demineralized bone particles can then be immediately shaped
into any desired configuration or stored under aseptic conditions,
advantageously in a lyophilized state, for processing at a later
time. As an alternative to aseptic processing and storage, the
particles can be shaped into a desired configuration and sterilized
using known methods.
[0045] As utilized herein, the phrase "superficially demineralized"
as applied to the bone particles refers to bone particles
possessing at least about 90 weight percent of their original
inorganic mineral content. The phrase "partially demineralized" as
applied to the bone particles refers to bone particles possessing
from about 8 to about 90 weight percent of their original inorganic
mineral content, and the phrase "fully demineralized" as applied to
the bone particles refers to bone particles possessing less than
about 8, preferably less than about 1, weight percent of their
original inorganic mineral content. The unmodified term
"demineralized" as applied to the bone particles is intended to
cover any one or combination of the foregoing types of
demineralized bone particles.
[0046] Mixtures or combinations of one or more of the foregoing
types of bone particles can be employed. For example, one or more
of the foregoing types of demineralized bone particles can be
employed in combination with nondemineralized bone particles, i.e.,
bone particles that have not been subjected to a demineralization
process.
[0047] Nondemineralized bone particles possess an initial and
ongoing mechanical role, and later a biological role, in the
osteoimplant of this invention. Nondemineralized bone particles act
as a stiffener, providing strength to the osteoimplant and
enhancing its ability to support load. These bone particles also
play a biological role in bringing about new bone ingrowth by the
process known as osteoconduction. Thus, these bone particles are
gradually remodeled and replaced by new host bone as incorporation
of the osteoimplant progresses over time. The use of
nondemineralized bone particles is highly preferred, albeit not
essential, in the fabrication of the osteoimplant of the present
invention.
[0048] Demineralized bone particles likewise possess an initial and
ongoing mechanical role, and later a biological role, in the
osteoimplant of this invention. Superficial or partial
demineralization produces particles containing a mineralized core.
Particles of this type actually can contribute to the strength of
the osteoimplant, through their mineralized core. These particles
also play a biological role in bringing about new bone ingrowth by
the process known as osteoinduction. Full demineralization produces
particles in which nearly all of the mineral content has been
removed from the particles. Particles treated in this way do not
directly contribute to the strength of the osteoimplant; however,
they do contribute to the osteoinductivity of the osteoimplant and
provide a coherency or binding effect.
[0049] When prepared from bone particles that are almost
exclusively nondemineralized and/or superficially demineralized the
osteoimplant herein will tend to possess a fairly high compressive
strength, e.g., one approaching and even exceeding that of natural
bone. Accordingly, when an osteoimplant exhibiting a wet
compressive strength of on the order of from about 20 to about 200
MPa, is desired, a predominant amount of nondemineralized bone
particles and/or superficially demineralized bone particles can be
advantageously employed. In order to lower the compressive strength
of the osteoimplant, a quantity of partially or fully demineralized
bone particles can be employed in combination with nondemineralized
bone particles or superficially demineralized bone particles. Thus,
the use of various types of bone particles can be used to control
the overall mechanical and biological properties, i.e., the
strength, osteoconductivity and/or osteoinductivity, etc., of the
osteoimplant. The differential in compressive strength,
osteogenicity and other properties between partially and/or fully
demineralized bone particles on the one hand and non-demineralized
and/or superficially demineralized bone particles on the other hand
can be exploited. For example, nondemineralized and/or
superficially demineralized bone particles can be concentrated in
that region of the osteoimplant which will be directly subjected to
applied load upon implantation.
[0050] In one embodiment, where the composition is compressed in a
mold, e.g., a cylindrical press-mold, the walls of the mold can be
coated with a slurry or paste containing partially and/or fully
demineralized bone particles followed by addition of a slurry or
paste containing nondemineralized and/or superficially
demineralized bone particles (or vice versa) to provide an
osteoimplant which contains at least one discrete region, e.g., an
outer surface, composed of partially and/or fully demineralized
bone particles and at least one discrete region, e.g., a core,
composed of nondemineralized and/or superficially demineralized
bone particles.
[0051] The amount of each individual type of bone particle employed
can vary widely depending on the mechanical and biological
properties desired. Thus, e.g., the weight ratio of
nondemineralized to demineralized bone particles can broadly range
from about 20:1 to about 1:20 and the weight ratio of superficially
and/or partially demineralized bone particles to fully
demineralized bone particles can broadly range from about 20:1 to
about 1:20. Suitable amounts can be readily determined by those
skilled in the art on a case-by-case basis by routine
experimentation.
[0052] If desired, the bone particles can be modified in one or
more ways, e.g., their protein content can be augmented or modified
as described in U.S. Pat. Nos. 4,743,259 and 4,902,296, the
contents of which are incorporated by reference herein.
[0053] The bone particle-containing composition fabricated in
accordance with this disclosure will typically possess a bone
particle content ranging from about 5 to about 100 weight percent,
preferably from about 40 to about 99 weight percent, and more
preferably from about 50 to about 95 weight percent, based on the
weight of the entire composition calculated prior to compression of
the composition.
[0054] The bone particles can be combined with one or more
biocompatible components such as wetting agents, biocompatible
binders, fillers, fibers, plasticizers, biostatic/biocidal agents,
surface active agents, bioactive agents, and the like, prior to,
during, or after compressing the bone particle-containing
composition. One or more of such components can be combined with
the bone particles by any suitable means, e.g., by soaking or
immersing the bone particles in a solution or dispersion of the
desired component, by physically admixing the bone particles and
the desired component, and the like.
[0055] Suitable wetting agents include biocompatible liquids such
as water, organic protic solvent, aqueous solution such as
physiological saline, concentrated saline solutions, sugar
solutions, ionic solutions of any kind, and liquid polyhydroxy
compounds such as glycerol and glycerol esters, and mixtures
thereof. The use of wetting agents in general is preferred in the
practice of the present invention, as they improve handling of bone
particles. When employed, wetting agents will typically represent
from about 20 to about 80 weight percent of the bone
particle-containing composition, calculated prior to compression of
the composition. Certain wetting agents such as water can be
advantageously removed from the osteoimplant, e.g., by heating and
lyophilizing the osteoimplant.
[0056] Suitable biocompatible binders include biological adhesives
such as fibrin glue, fibrinogen, thrombin, mussel adhesive protein,
silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin
or chitosan; cyanoacrylates; epoxy-based compounds; dental resin
sealants; bioactive glass ceramics (such as apatite-wollastonite),
dental resin cements; glass ionomer cements (such as Ionocap.RTM.
and Inocem.RTM. available from lonos Medizinische Produkte GmbH,
Greisberg, Germany); gelatin-resorcinol-formaldehyde glues;
collagen-based glues; cellulosics such as ethyl cellulose;
bioabsorbable polymers such as starches, polylactic acid,
polyglycolic acid, polylactic-co-glycolic acid, polydioxanone,
polycaprolactone, polycarbonates, polyorthoesters, polyamino acids,
polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly
(propylene glycol-co-fumaric acid), tyrosine-based polycarbonates,
pharmaceutical tablet binders (such as Eudragit.RTM. binders
available from Huls America, Inc.), polyvinylpyrrolidone,
cellulose, ethyl cellulose, micro-crystalline cellulose and blends
thereof; starch ethylenevinyl alcohols, polycyanoacrylates;
polyphosphazenes; nonbioabsorbable polymers such as polyacrylate,
polymethyl methacrylate, polytetrafluoroethylene, polyurethane and
polyamide; etc. Preferred binders are polyhydroxybutyrate,
polyhydroxyvalerate and tyrosine-based polycarbonates. When
employed, binders will typically represent from about 5 to about 70
weight percent of the bone particle-containing composition,
calculated prior to compression of the composition.
[0057] The use of biocompatible binder as biocompatible component
is particularly preferred in the practice of the present invention.
Biocompatible binder acts as a matrix which binds the bone
particles, thus providing coherency in a fluid environment and also
improving the mechanical strength of the osteoimplant.
[0058] Suitable fillers include graphite, pyrolytic carbon,
bioceramics, bone powder, demineralized bone powder, anorganic bone
(i.e., bone mineral only, with the organic constituents removed),
dentin tooth enamel, aragonite, calcite, nacre, amorphous calcium
phosphate, hydroxyapatite, tricalcium phosphate, Bioglass.RTM. and
other calcium phosphate materials, calcium salts, etc. Preferred
fillers are demineralized bone powder and hydroxyapatite. When
employed, filler will typically represent from about 5 to about 80
weight percent of the bone particle-containing composition,
calculated prior to compression of the composition.
[0059] Suitable fibers include carbon fibers, collagen fibers,
tendon or ligament derived fibers, keratin, cellulose,
hydroxyapatite and other calcium phosphate fibers. When employed,
fiber will typically represent from about 5 to about 75 weight
percent of the bone particle-containing composition, calculated
prior to compression of the composition.
[0060] Suitable plasticizers include liquid polyhydroxy compounds
such as glycerol, monoacetin, diacetin, etc. Glycerol and aqueous
solutions of glycerol are preferred. When employed, plasticizer
will typically represent from about 20 to about 80 weight percent
of the bone particle-containing composition, calculated prior to
compression of the composition.
[0061] Suitable biostatic/biocidal agents include antibiotics such
as erythromycin, bacitracin, neomycin, penicillin, polymycin B,
tetracyclines, biomycin, chloromycetin, and streptomycins,
cefazolin, ampicillin, azactam, tobramycin, clindamycin and
gentamicin, povidone, sugars, mucopolysaccharides, etc. Preferred
biostatic/biocidal agents are antibiotics. When employed,
biostatic/biocidal agent will typically represent from about 10 to
about 95 weight percent of the bone particle-containing
composition, calculated prior to compression of the
composition.
[0062] Suitable surface active agents include the biocompatible
nonionic, cationic, anionic and amphoteric surfactants. Preferred
surface active agents are the nonionic surfactants. When employed,
surface active agent will typically represent from about 1 to about
80 weight percent of the bone particle-containing composition,
calculated prior to compression of the composition.
[0063] Any of a variety of bioactive substances can be incorporated
in, or associated with, the bone particles. Thus, one or more
bioactive substances can be combined with the bone particles by
soaking or immersing the bone particles in a solution or dispersion
of the desired bioactive substance(s). Bioactive substances include
physiologically or pharmacologically active substances that act
locally or systemically in the host.
[0064] Bioactive substances which can be readily combined with the
bone particles include, e.g., collagen, insoluble collagen
derivatives, etc., and soluble solids and/or liquids dissolved
therein; antiviricides, particularly those effective against HIV
and hepatitis; antimicrobials and/or antibiotics such as
erythromycin, bacitracin, neomycin, penicillin, polymycin B,
tetracyclines, biomycin, chloromycetin, and streptomycins,
cefazolin, ampicillin, azactam, tobramycin, clindamycin and
gentamicin, etc.; biocidal/biostatic sugars such as dextran,
glucose, etc.; amino acids; peptides; vitamins; inorganic elements;
co-factors for protein synthesis; hormones; endocrine tissue or
tissue fragments; synthesizers; enzymes such as collagenase,
peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal
cells; angiogenic agents and polymeric carriers containing such
agents; collagen lattices; antigenic agents; cytoskeletal agents;
cartilage fragments; living cells such as chondrocytes, bone marrow
cells, mesenchymal stem cells, natural extracts, genetically
engineered living cells or otherwise modified living cells; DNA
delivered by plasmid or viral vectors; tissue transplants;
demineralized bone powder; autogenous tissues such as blood, serum,
soft tissue, bone marrow, etc.; bioadhesives, bone morphogenic
proteins (BMPs); osteoinductive factor; fibronectin (FN);
endothelial cell growth factor (ECGF); cementum attachment extracts
(CAE); ketanserin; human growth hormone (HGH); animal growth
hormones; epidermal growth factor (EGF); interleukin-1 (IL-1);
human alpha thrombin; transforming growth factor (TGF-beta);
insulin-like growth factor (IGF-1); platelet derived growth factors
(PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal
ligament chemotactic factor (PDLGF); somatotropin; bone digestors;
antitumor agents; immuno-suppressants; permeation enhancers, e.g.,
fatty acid esters such as laureate, myristate and stearate
monoesters of polyethylene glycol, enamine derivatives, alpha-keto
aldehydes, etc.; and nucleic acids. Preferred bioactive substances
are currently bone morphogenic proteins and DNA delivered by
plasmid or viral vector. When employed, bioactive substance will
typically represent from about 0.1 to about 20 weight percent of
the bone particle-containing composition, calculated prior to
compression of the composition.
[0065] It will be understood by those skilled in the art that the
foregoing biocompatible components are not intended to be
exhaustive and that other biocompatible components may be admixed
with bone particles within the practice of the present
invention.
[0066] The total amount of such optionally added biocompatible
substances will typically range from about 0 to about 95,
preferably from about 1 to about 60, more preferably from about 5
to about 50, weight percent of the bone particle-containing
composition, based on the weight of the entire composition prior to
compression of the composition, with optimum levels being readily
determined in a specific case by routine experimentation.
[0067] One method of fabricating the bone particle-containing
composition which can be advantageously utilized herein involves
wetting a quantity of bone particles, of which at least about 60
weight percent preferably constitute elongate bone particles, with
a wetting agent as described above to form a composition having the
consistency of a slurry or paste. Optionally, the wetting agent can
comprise dissolved or admixed therein one or more biocompatible
substances such as biocompatible binders, fillers, plasticizers,
biostatic/biocidal agents, surface active agents, bioactive
substances, etc., as previously described.
[0068] Preferred wetting agents for forming the slurry or paste of
bone particles include water, liquid polyhydroxy compounds and
their esters, and polyhydroxy compounds in combination with water
and/or surface active agents, e.g., the Pluronics.RTM. series of
nonionic surfactants. Water is the most preferred wetting agent for
utilization herein. The preferred polyhydroxy compounds possess up
to about 12 carbon atoms and, where their esters are concerned, are
preferably the monoesters and diesters. Specific polyhydroxy
compounds of the foregoing type include glycerol and its monoesters
and diesters derived from low molecular weight carboxylic acids,
e.g., monoacetin and diacetin (respectively, glycerol monoacetate
and glycerol diacetate), ethylene glycol, diethylene glycol,
triethylene glycol, 1,2-propanediol, trimethylolethane,
trimethylolpropane, pentaerythritol, sorbitol, and the like. Of
these, glycerol is especially preferred as it improves the handling
characteristics of the bone particles wetted therewith and is
biocompatible and easily metabolized. Mixtures of polyhydroxy
compounds or esters, e.g., sorbitol dissolved in glycerol, glycerol
combined with monoacetin and/or diacetin, etc., are also useful.
Where elongate bone particles are employed, some entanglement of
the wet bone particles will result. Preferably, excess liquid can
be removed from the slurry or paste, e.g., by applying the slurry
or paste to a form such as a flat sheet, mesh screen or
three-dimensional mold and draining away excess liquid.
[0069] Where, in a particular composition, the bone particles have
a tendency to quickly or prematurely separate or to otherwise
settle out from the slurry or paste such that application of a
fairly homogeneous composition is rendered difficult or
inconvenient, it can be advantageous to include within the
composition a substance whose thixotropic characteristics prevent
or reduce this tendency. Thus, e.g., where the wetting agent is
water and/or glycerol and separation of bone particles occurs to an
excessive extent where a particular application is concerned, a
thickener such as a solution of polyvinyl alcohol,
polyvinylpyrrolidone, cellulosic ester such as hydroxypropyl
methylcellulose, carboxy methylcellulose, pectin, xanthan gum,
food-grade texturizing agent, gelatin, dextran, collagen, starch,
hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide,
polyelectrolyte such as polyacrylic acid salt, hydrogels, chitosan,
other materials that can suspend particles, etc., can be combined
with the wetting agent in an amount sufficient to significantly
improve the suspension-keeping characteristics of the
composition.
[0070] After production of the bone particle-containing
composition, the composition is subjected to a compressive force of
at least about 1,000 psi to produce the osteoimplant of this
invention. Typically, compressive forces of from about 2,500 to
about 60,000 psi can be employed with particularly good effect,
with compressive forces of from about 2,500 to about 20,000 psi
presently being preferred. The compression step will typically be
conducted for a period of time ranging from about 0.1 to about 180
hours, preferably from about 4 to about 72 hours. The resulting
osteoimplant possesses a bulk density (measured by dividing the
weight of the osteoimplant by its volume) of at least about 0.7
g/cm.sup.3, preferably at least about 1.0 g/cm.sup.3. After being
immersed in physiological saline for 12-24 hours, the osteoimplant
of this invention possesses a wet compressive strength (as measured
by the method described hereinbelow) of at least about 3 MPa.
Typically, the wet compressive strength of the osteoimplant
substantially exceeds 3 MPa. In most cases (and especially where a
predominant amount of nondemineralized elongate bone particles are
utilized in the fabrication of the osteoimplant), the inventors
have found that wet compressive strength normally exceeds about 15
MPa and typically ranges from about 15 to about 100 MPA. The wet
compressive strength of the osteoimplant of this invention allows
the osteoimplant to provide significant mechanical or structural
support to a bone repair site in a body fluid environment over an
extended period of time in vivo.
[0071] To effect compression of the composition, the composition
can be placed in a mold possessing any suitable or desired shape or
configuration and compressed in a press, e.g., a Carver.RTM. manual
press.
[0072] FIGS. 12a and 12b depict a cylindrical press-mold 10 which
is suitable for use in the present invention. Mold 10 consists of
three parts, a hollow cylinder 12, an end cap 14 and a plunger 16.
Mold 10 is assembled by placing hollow cylinder 10 on top of end
cap 12. The interior of hollow cylinder 12 is then filled with the
bone particle-containing composition described herein, shown at 18.
Thereafter, plunger 16 is placed on top of cylinder 10 which has
been filled with bone particle-containing composition 18. As shown
best in FIG. 12b, bone particle-containing composition 18 is filled
to a height inside cylinder 12 which results in plunger 16 coming
to a rest on composition 18 instead of cylinder 12. As shown in
FIG. 13, mold 10 is placed inside a manual hydraulic press,
generally depicted at 20. Press 20 is equipped with two plates 22
and 24. Plate 24 remains stationary while plate 22 moves in an
upward direction as indicated by the arrow in FIG. 13. Movement of
plate 22 is hydraulically controlled by means of a handle or other
means (not shown) which is operated by the user. As plate 22 moves
upward, plunger 16 is forced against plate 24 and moves downward to
apply compressive force against composition 18 inside mold 10.
[0073] The osteoimplant produced by the method of this invention
can be described as a hard, chalk-like material. The osteoimplant
may possess tiny pores or cavities which permit the osteoimplant to
be properly revascularized and incorporated by the host. It can be
easily shaped or machined into any of a wide variety of
configurations. In accordance with a preferred embodiment, the
osteoimplant is provided with macroporosity, i.e., holes, which
enhance blood flow through the osteoimplant or can be filled with a
medically useful substance (such as Grafton.RTM. putty available
from Osteotech Inc., Eatontown, N.J.). Such macroporosity can be
provided, e.g., by drilling or by using a mold which possesses
spikes therein.
[0074] Before, during or after application of compressive force to
the bone particle-containing composition, the composition can be
subjected to an additional operation selected from heating,
lyophilizing and cross-linking to further enhance the mechanical
and/or biological properties of the osteoimplant. Incorporation of
biocompatible component(s), if any, to the composition can precede
or come after the step(s) of subjecting the composition to such
additional operation(s).
[0075] In accordance with a preferred embodiment, the composition
is heated during or after the compression step. The composition can
be heated at a suitable temperature, e.g., one ranging from about
30.degree. to about 70.degree. C., preferably from about 40.degree.
to about 50.degree. C., for 1 to 72 hours preferably 24 to 48
hours. A presently preferred mode of heating involves placing the
bone particle-containing composition in a mold and immersing the
mold in a heated biocompatible liquid, e.g., water, glycerol,
solution of glycerol and water, ionic solutions of any kind,
saline, concentrated saline, etc., such that the liquid can
communicate with the composition being compressed. Concentrated
saline is preferred. The composition inside the mold is compressed
to provide an osteoimplant in accordance with the present
invention. As shown in FIG. 13, mold 10 is placed in container 30
which is filled with biocompatible liquid 32. Surrounding container
30 is a heat tape 34 which contains electric heating elements (not
shown) which are controlled by an electrostat (not shown). By
raising the temperature of biocompatible liquid 32, heat is
transferred to the composition (not shown) inside mold 10. As plate
22 moves upward, plunger 16 is compressed against plate 24 and
exerts downward compressive force against the composition. While
not wishing to be bound by theory, it is believed that
biocompatible liquid 32 actually enters mold 10 through seams
formed by the connection between end cap 14 and cylinder 12 and
contacts the composition. It has been discovered that this mode of
heating provides osteoimplants possessing particularly good
strength characteristics.
[0076] The osteoimplant can be lyophilized, advantageously after
the bone particle-containing composition has been compressed in
accordance with this disclosure, under conditions that are well
known in the art, e.g., a shelf temperature of from about
-20.degree. to about -55.degree. C., a vacuum of from about 150 to
about 100 mTorr for a period of time ranging from about 4 to about
48 hours.
[0077] Crosslinking can be performed in order to improve the
strength of the osteoimplant. Crosslinking of the bone
particle-containing composition can be effected by a variety of
known methods including chemical reaction, the application of
energy such as radiant energy, which includes irradiation by UV
light or microwave energy, drying and/or heating and dye-mediated
photo-oxidation; dehydrothermal treatment in which water is slowly
removed while the bone particles are subjected to a vacuum; and,
enzymatic treatment to form chemical linkages at any
collagen-collagen interface. The preferred method of forming
chemical linkages is by chemical reaction.
[0078] Chemical crosslinking agents include those that contain
bifinctional or multifunctional reactive groups, and which react
with surface-exposed collagen of adjacent bone particles within the
bone particle-containing composition. By reacting with multiple
functional groups on the same or different collagen molecules, the
chemical crosslinking agent increases the mechanical strength of
the osteoimplant.
[0079] Chemical crosslinking involves exposing the bone particles
presenting surface-exposed collagen to the chemical crosslinking
agent, either by contacting bone particles with a solution of the
chemical crosslinking agent, or by exposing bone particles to the
vapors of the chemical crosslinking agent under conditions
appropriate for the particular type of crosslinking reaction. For
example, the osteoimplant of this invention can be immersed in a
solution of cross-linking agent for a period of time sufficient to
allow complete penetration of the solution into the osteoimplant.
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. The resulting osteoimplant is then washed to remove all
leachable traces of the chemical.
[0080] Suitable chemical crosslinking 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 phenolic 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 other heterobifunctional crosslinking
agents; hexamethylene diisocyante; sugars, including glucose, will
also crosslink collagen.
[0081] Glutaraldehyde crosslinked biomaterials have a tendency to
over-calcify in the body. In this situation, should it be deemed
necessary, calcification-controlling agents can be used with
aldehyde crosslinking agents. These calcification-controlling
agents include dimethyl sulfoxide (DMSO), surfactants,
diphosphonates, aminooleic acid, and metallic ions, for example
ions of iron and aluminum. The concentrations of these
calcification-controlling agents can be determined by routine
experimentation by those skilled in the art.
[0082] When enzymatic 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.
[0083] 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 crosslinks 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 crosslink surface-exposed collagen.
[0084] 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 bone particles. 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.
[0085] The resulting osteoimplant can assume a determined or
regular form or configuration such as a sheet, plate, disk, cone,
pin, screw, tube, tooth, tooth root, bone or portion of bone, wedge
or portion of wedge, cylinder, threaded cylinder (dowel), to name
but a few. Of course, the osteoimplant can be machined or shaped by
any suitable mechanical shaping means. Computerized modeling can,
for example, be employed to provide an intricately-shaped
osteoimplant which is custom-fitted to the bone repair site with
great precision. In a preferred embodiment, the osteoimplant
possesses the configuration of a threaded cylinder (dowel).
[0086] It will be understood that combinations of one or more of
the foregoing operations can be employed, e.g., heating followed by
lyophilizing; cross-linking followed by heating, etc.
[0087] The osteoimplant herein is applied at a bone repair site,
e.g., one resulting from injury, defect brought about during the
course of surgery, infection, malignancy or developmental
malformation, which requires mechanical support. The osteoimplant
can be utilized in a wide variety of orthopaedic, periodontal,
neurosurgical and oral and maxillofacial surgical procedures such
as the repair of simple and compound fractures and non-unions,
external and internal fixations, joint reconstructions such as
arthrodesis, general arthroplasty, cup arthroplasty of the hip,
femoral and humeral head replacement, femoral head surface
replacement and total joint replacement, repairs of the vertebral
column including spinal fusion and internal fixation, tumor
surgery, e.g., deficit filling, discectomy, laminectomy, excision
of spinal cord tumors, anterior cervical and thoracic operations,
repairs of spinal injuries, scoliosis, lordosis and kyphosis
treatments, intermaxillary fixation of fractures, mentoplasty,
temporomandibular joint replacement, alveolar ridge augmentation
and reconstruction, onlay bone grafts, implant placement and
revision, sinus lifts, etc. Specific bones which can be repaired or
replaced with the bone-derived implant herein include the ethmoid,
frontal, nasal, occipital, parietal, temporal, mandible, maxilla,
zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra,
sacrum, rib, sternum, clavicle, scapula, humerus, radius, ulna,
carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis,
femur, tibia, fibula, patella, calcaneus, tarsal and metatarsal
bones. The osteoimplant can be implanted at the bone repair site,
if desired, using any suitable affixation means, e.g., sutures,
staples, bioadhesives, and the like.
[0088] Referring now to the drawings, FIGS. 1a-h depict various
embodiments of an osteoimplant according to the present invention
configured and dimensioned in the shape of a cylinder 40, wedge 50,
plate 60, threaded cylinder (dowel) 70, fibular wedge 62, femoral
struts 64, 66 and tibial strut 68. In accordance with a preferred
embodiment, cylinder 20 and wedge 30 are provided with
macroporosity, namely holes. 42 and 52, respectively, which have
been drilled into cylinder 40 and wedge 50. Macroporosity promotes
blood flow through the osteoimplant and enhances and accelerates
the incorporation of the osteoimplant by the host. Furthermore,
macroporous holes 42 and 52 can be advantageously filled with an
osteogenic material, e.g., Grafton.RTM. putty available from
Osteotech, Inc., Eastontown, N.J.
[0089] In FIG. 2a, osteoimplant 80 is configured and dimensioned as
a disk to be inserted into the intervertebral fibrocartilage site
82 on the anterior side of vertebral column 84. In FIG. 2b,
osteoimplant 70 is configured and dimensioned as a threaded
cylinder (as depicted in FIG. 1d) to be inserted into the
intervertebral site 72 on the anterior side of vertebral column
84.
[0090] In FIG. 3, the osteoimplant of the invention is configured
and dimensioned as a cervical plate 90 and is shown affixed to
cervical vertebrae 94, 96 by bone screws 92. In accordance with a
preferred embodiment, bone screws 92 form yet another embodiment of
the osteoimplant of the present invention.
[0091] In FIG. 4, the osteoimplant 100 of the invention is sized
and shaped to form the mandible of skull 102.
[0092] In FIG. 5, the osteoimplant 110 of the invention is sized
and shaped as a femoral implant. Osteoimplant 110 comprises head
112 which is attached to ball 114. Ball 114 is fabricated from
plastic or metal and is affixed to osteoimplant 110 by any suitable
means, e.g, screw 116. Osteoimplant is inserted into intramedullary
canal 118 of femur 120.
[0093] In FIG. 6a and b, the osteoimplant 130 of the invention is
sized and shaped as an acetabular cup which is configured and
dimensioned to receive plastic or metallic liner 132.
[0094] In FIG. 7, a total hip replacement with the osteoimplant 110
depicted in FIG. 5 and the osteoimplant 130 of FIGS. 6a and 6b is
depicted.
[0095] In FIG. 8a, the osteoimplant 140 of the invention is sized
and shaped as a diaphyseal implant and is shown being implanted via
bone screws 142 on a fracture 144 along the diaphyseal segment of a
human radius 146. Optionally, and preferably, screws 142 can be
fabricated from compressed bone particles in accordance with this
disclosure.
[0096] In FIG. 8b, osteoimplant 180 of the invention is sized and
shaped as an intercalary implant and is shown already implanted at
a diaphyseal segment of human radius 146 that is missing due to
trauma or tumor.
[0097] In FIG. 9, the osteoimplant 150 of the invention is sized
and shaped as an intramedullary rod for insertion into the
medullary canal 154 of femur 152.
[0098] In FIG. 10, osteoimplant 186 is sized and shaped as a
reinforcement rod for insertion into a core decompression site 184
formed by drilling a hole into femoral head 182.
[0099] In FIG. 11, osteoimplant 160 is sized and shaped to form
part of the parietal bone 162 for skull 164. Osteoimplant 160
promotes fusion with parietal bone 88.
[0100] The present invention is intended to embrace all such
devices which are constructed as the osteoimplant of the present
invention and the attendant uses of such devices.
[0101] It will also be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
[0102] The following examples illustrate the practice of this
invention.
[0103] Wet Compressive Strength
[0104] Wet compressive strength of the osteoimplant of this
invention is measured using the following method:
[0105] Initial density is determined by measuring specimen
dimensions with a caliper to determine volume, and then weighing
the specimen on a laboratory balance. The specimen is then placed
in a container with 0.9% NaCl solution at room temperature for
12-24 hours. After the hydration period, the specimen is measured
again to determine dimensions, and dimensions are recorded. The
specimen is then centered on a compression platen (MTS 643.10A-01)
in a servohydraulic testing system (MTS 858 Bionix). The top platen
is lowered onto the specimen until a compressive preload of 0.1 kN
is achieved. The system displacement transducer is then zeroed (MTS
358.10), defining zero displacement as the displacement associated
initially with 0.1 kN preload. Using system software (MTS 790.90
Testworks for Teststar), the specimen is loaded in the displacement
mode, using a ramp compressive load of 0.5 mm/s, until an endpoint
of 4 mm displacement is achieved. After the 4 mm displacement is
achieved, the loading is stopped automatically, and the specimen is
unloaded. During testing, load (from the system load cell MTS
661.20E-03) and displacement data are collected every 0.05 sec.
EXAMPLE 1
[0106] Elongate bone particles were prepared using a milling
machine. Half of the volume of the particles was fully
demineralized using two charges of 0.6N HCl acid. The
nondemineralized and the fully demineralized particles were then
combined together in an aqueous solution containing glycerol and
allowed to soak for 4-12 hours at room temperature. The particles
were then removed from the solution by straining, and placed into a
28 mm diameter cylindrical press-mold while still moist. The
particles were pressed to 10,000 psi for 15 minutes. The resulting
compressed pellet was heated in situ in an oven for 4 hours at
45.degree. C. The osteoimplant was then frozen in a -70.degree. C.
freezer (1.5 hours), and freeze-dried overnight, after which it was
removed from the mold. The bulk density of the osteoimplant
produced was 1.34 g/cm.sup.3. The height of the osteoimplant was 29
mm. The wet compressive strength of the osteoimplant exceeded 3
MPa.
EXAMPLE 2
[0107] The procedure of Example 1 was used except the ratio of
fully demineralized to nondemineralized bone particles was 2:1, the
pellet was heated in situ in an oven for 4 hours at 40.degree. C.
and the pressure was 2,500 psi. The resulting compressed pellet was
cut into two portions and each portion was treated with
crosslinking agent: 10% neutral buffered formalin (both dipped and
in vapor phase) and 4% Denacol EX313 (a polyepoxy-ether compound
available from Nagase America Corp., New York, N.Y.), respectively.
In each case, the resulting osteoimplant swelled a little and
became stiff, and resistant to manual pressure. The bulk density of
the osteoimplant produced was 1.2 g/cm.sup.3. The wet compressive
strength of the osteoimplant exceeded 3 MPa.
EXAMPLE 3
[0108] The procedure of Example 1 was followed except that all of
the particles were partially demineralized by using 225 ml of 0.6N
HCl and allowing the acid to react to depletion. Additionally, the
mold was hexagonal in configuration (with each side of the hexagon
measuring 18 mm). After completing the freeze-drying step, the
resulting osteoimplant was placed in a bath of 10% neutral buffered
formalin and the exposed collagen of the partially demineralized
bone particles was allowed to cross-link for 48 hours. The
resulting dry osteoimplant was tested mechanically and was found to
possess a dry compressive strength of about 85 MPa. The bulk
density of the osteoimplant was 1.05 g/cm.sup.3.
EXAMPLE 4
[0109] The procedure of Example 3 was repeated and the resulting
osteoimplant was immersed in physiological saline for 12-24 hours
and was found to possess an ultimate wet compressive strength of
about 45 MPa. The bulk density of the osteoimplant was 1.05
g/cm.sup.3.
EXAMPLE 5
[0110] Elongate bone particles were prepared using a milling
machine. The nondemineralized particles were then combined with
ethyl cellulose (3:2 ratio by weight), and covered with 70% ethanol
for 30 minutes, with stirring. The elongate bone particles were
then removed from the solution by straining, and placed into a
press-mold while still moist. The elongate bone particles were
pressed to 10,000 psi for 15 minutes. The resulting compressed
pellet was heated in situ in an oven for 4 hours at 45.degree. C.
The implant was then frozen in a -70.degree. C. freezer
(overnight), and freeze-dried, after which it was removed from the
mold. The osteoimplant was immersed in physiological saline
overnight and was found to possess a wet compressive strength of 20
MPa.
EXAMPLE 6
[0111] Bone particles were prepared by using a block plane on the
periosteal surface of cortical bone. Half of the volume of the bone
particles was filly demineralized using two changes of 0.6N HCl
acid. The mineralized (25 g) and the demineralized particles (25 g
based on original weight) were then combined together in a 70%
ethanol solution with 20 g ethyl cellulose. This mixture was
stirred for 30 minutes at room temperature. The particles were then
removed form the solution by straining, and placed into a
cylindrical press-mold while still moist. The particles were
pressed to 18,000 psi for 10 minutes. The resulting compressed
pellet was heated in situ in an oven for 4 hours at 45.degree. C.
The implant was then frozen in a -70.degree. C. freezer (1.5
hours), and freeze-dried overnight, after which it was removed from
the mold. The dry compressive strength of the osteoimplant was 6.5
MPa and the wet compressive strength of the osteoimplant was 4.0
MPa.
EXAMPLE 7
[0112] Elongate bone particles were prepared using a milling
machine (30 g). An equivalent amount by weight of cortical bone
chips were also prepared by grinding in a bone mill. Chips were
sieved between screens having dimensions between 4.0 mm and 1.8 mm.
The elongate particles and the chips were then combined together in
a container with 70% Ethanol (1 liter) and ethyl cellulose (20 g).
The components were mixed together thoroughly and allowed to soak
for 30 minutes at room temperature. The mixture was then removed
from the excess solution by straining, and placed into a press-mold
while still moist. The particles were pressed to 10,000 psi for 10
minutes. The resulting compressed pellet was heated in situ in an
oven for 4 hours at 45.degree. C. The implant was then frozen in a
-70.degree. C. freezer (1.5 hours), and freeze-dried overnight,
after which it was removed from the mold. The wet compressive
strength of the osteoimplant exceeded 3 MPa.
EXAMPLE 8
[0113] Twenty grams of elongate bone particles were produced by
milling from diaphyseal bone. The nondemineralized elongate bone
particles were mixed with 10 grams dry ethyl cellulose. To this
mixture, 150 ml of 95% ethanol was added, and the mixture was
stirred for 30 minutes. The fluid was then drained off, and 20 ml
of elongate bone particles was measured out and placed in a
cylindrical press-mold. The elongate bone particles were pressed
for 10 minutes at 56,000 psi. After pressing, the pellet, still in
its mold, was placed in an oven at 45.degree. C. for 4 hours, and
then in a -70.degree. C. freezer overnight. The pellet was
freeze-dried for about 3 days. The resulting osteoimplant (10 mm
dia. by 9.1 mm high cylinder) was then re-hydrated overnight in
physiological saline (water containing 0.9 g NaCl/100 ml water).
The wet compressive strength of the osteoimplant was 31.9 MPa.
EXAMPLE 9
[0114] Elongate bone particles were produced by milling from
diaphyseal bone. These elongate bone particles were then partially
demineralized using 14 ml of 0.6 HCl acid solution. The acid was
allowed to react to exhaustion (pH.about.7). The partially
demineralized elongate bone particles were then washed in water,
and placed into a 13 mm cylindrical press-mold. The filled mold was
placed in a heated water bath made by surrounding an open-topped
metal flask with a heating strip. The water was heated continuously
to 70.degree. C. during the pressing process. The bone particles
were pressed at 120,000 psi for 3 days. The pellet produced was
placed in a -70.degree. C. freezer for 1 hour, then freeze-dried
for 24 hours. The resulting osteoimplant had a bulk density of 1.9
g/cm.sup.3. This osteoimplant was rehydrated overnight in
physiological saline, and then tested for wet compressive strength.
The resulting wet compressive strength was 56.4 MPa.
EXAMPLE 10
[0115] An osteoimplant was prepared as in Example 9, except that
the bone particles used were 100-500 .mu.m powder, superficially
demineralized with 0.6N HCl. The mold size was 10 mm diameter for
this example. The resulting osteoimplant had a bulk density of 1.9
g/cm.sup.3 and a wet compressive strength of 17.6 MPa.
EXAMPLE 11
[0116] An osteoimplant was prepared as in Example 9, except that
the elongate bone particles were pressed in a 10 mm diameter mold
for 24 hours at 40.degree. C. The resulting osteoimplant had a bulk
density of 1.8 g/cm.sup.3, and a wet compressive strength of 41.6
MPa.
EXAMPLE 12
[0117] An osteoimplant was prepared as in Example 9, except that
the elongate bone particles were placed in a 50% aqueous solution
of glycerol and were pressed in a 10 mm diameter mold surrounded by
heated 50% aqueous solution of glycerol at 40.degree. C. The
implant was pressed to 40,000 psi for 24 hours. The resulting
osteoimplant had a bulk density of 1.6 g/cm.sup.3, and a wet
compressive strength of 12.5 MPa.
* * * * *