U.S. patent number RE46,275 [Application Number 14/196,317] was granted by the patent office on 2017-01-17 for nanocrystalline apatites and composites, prostheses incorporating them, and method for their production.
This patent grant is currently assigned to Massachusetts Institute of Technology. The grantee listed for this patent is Massachusetts Institute of Technology. Invention is credited to Edward S. Ahn, Atsushi Nakahira, Jackie Y. Ying.
United States Patent |
RE46,275 |
Ying , et al. |
January 17, 2017 |
Nanocrystalline apatites and composites, prostheses incorporating
them, and method for their production
Abstract
Methods for synthesis of nanocrystalline apatites are presented,
as well as a series of specific reaction parameters that can be
adjusted to tailor, in specific ways, properties in the recovered
product. Particulate apatite compositions having average crystal
size of less than 150 nm are provided. Products also can have a
surface area of at least 40 m.sup.2/g and can be of high density.
Hydroxyapatite material is investigated in particular detail.
Compositions of the invention can be used as prosthetic implants
and coatings for prosthetic implants.
Inventors: |
Ying; Jackie Y. (Singapore,
SG), Ahn; Edward S. (Dover, MA), Nakahira;
Atsushi (Kyoto, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology |
Cambridge |
MA |
US |
|
|
Assignee: |
Massachusetts Institute of
Technology (Cambridge, MA)
|
Family
ID: |
42583528 |
Appl.
No.: |
14/196,317 |
Filed: |
March 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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13536924 |
Jun 28, 2012 |
RE44820 |
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12749299 |
Mar 29, 2010 |
RE43661 |
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10863863 |
Jun 7, 2004 |
RE41584 |
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10044801 |
Jan 11, 2002 |
RE39196 |
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60035535 |
Jan 16, 1997 |
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Reissue of: |
09007930 |
Jan 16, 1998 |
6013591 |
Jan 11, 2000 |
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Reissue of: |
09007930 |
Jan 16, 1998 |
6013591 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C04B
35/645 (20130101); C04B 35/447 (20130101); C01B
25/32 (20130101); A61L 27/12 (20130101); C04B
35/6262 (20130101); A61L 27/32 (20130101); C04B
35/62675 (20130101); C03C 4/0007 (20130101); C04B
35/117 (20130101); C03C 4/0007 (20130101); C03C
14/00 (20130101); C04B 35/62675 (20130101); A61L
27/12 (20130101); B82Y 30/00 (20130101); C01B
25/32 (20130101); A61L 27/32 (20130101); C04B
35/645 (20130101); C03C 4/0021 (20130101); C04B
35/6262 (20130101); C04B 35/447 (20130101); A61F
2/30767 (20130101); C04B 35/46 (20130101); C04B
35/488 (20130101); B82Y 30/00 (20130101); C04B
35/488 (20130101); C03C 14/00 (20130101); C04B
35/46 (20130101); A61F 2310/00796 (20130101); C04B
2235/77 (20130101); C04B 2235/5409 (20130101); C04B
2235/6562 (20130101); C04B 2235/785 (20130101); C04B
2235/3217 (20130101); C04B 2235/608 (20130101); C04B
2235/3225 (20130101); C04B 2235/656 (20130101); C04B
2235/3232 (20130101); C04B 2235/80 (20130101); C04B
2235/3246 (20130101); C04B 2235/9653 (20130101); A61F
2/30767 (20130101); C04B 2235/668 (20130101); C04B
2235/3212 (20130101); C04B 2235/5454 (20130101); A61F
2310/00239 (20130101); C04B 2235/5445 (20130101); C04B
2235/6567 (20130101); Y10S 977/776 (20130101); C04B
2235/3225 (20130101); C04B 2235/3246 (20130101); C04B
2235/549 (20130101); C04B 2235/3212 (20130101); C04B
2235/96 (20130101); C04B 2235/6567 (20130101); C04B
2235/656 (20130101); C04B 2235/668 (20130101); C04B
2235/3217 (20130101); C04B 2235/3232 (20130101); C04B
2235/80 (20130101); A61F 2310/00239 (20130101); A61L
2400/12 (20130101); C04B 2235/3244 (20130101); C04B
2235/5445 (20130101); A61F 2310/00796 (20130101); C04B
2235/9653 (20130101); C04B 2235/608 (20130101); C04B
2235/6562 (20130101); C04B 2235/5454 (20130101); Y10S
977/776 (20130101); C04B 2235/5409 (20130101); A61F
2310/00293 (20130101); C04B 2235/77 (20130101); C04B
2235/785 (20130101); A61L 2400/12 (20130101); F16C
2240/64 (20130101); C04B 2235/3244 (20130101); A61F
2310/00293 (20130101); C04B 2235/549 (20130101); C04B
2235/96 (20130101) |
Current International
Class: |
A61L
27/12 (20060101); A61F 2/30 (20060101); A61L
27/32 (20060101); C04B 35/447 (20060101); C03C
14/00 (20060101); C03C 4/00 (20060101); B82Y
30/00 (20110101); C04B 35/626 (20060101); C04B
35/645 (20060101); C04B 35/46 (20060101); C04B
35/488 (20060101); C01B 25/32 (20060101) |
Field of
Search: |
;501/1 ;106/35
;423/311,422,423 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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4175212 |
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Jun 1992 |
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JP |
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4331719 |
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Nov 1992 |
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JP |
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Other References
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.
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applicant .
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Obtained by Mechanochemical Treatment" The Ceramic Society of
Japan, 97(5): 554-558 (1989). cited by applicant .
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cited by applicant .
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Mechano-Chemical Method and Their Sintering," Journal of the
European Ceramic Society, 16: 429-436 (1996). cited by applicant
.
Uematsu, et al., "Transparent Hydroxyapatite Prepared by Hot
Isotactic Pressing of Filter Cake," J. American Ceramic Society,
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Ceramics," Biomaterials 21 (2000) 1803-1810. cited by applicant
.
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Biomaterials 20 (1999) 1221-1227. cited by applicant .
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Stablized Zirconia Plate in the Presence of Water Vapor" The
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applicant .
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Calcium Metaphosphate and Tetracalcium Phosphate" The Ceramic
Society of Japan, 99(3): 211-214 (1991). cited by applicant .
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Mechanochmical Reaction" The Ceramic Society of Japan, 99(2):
150-152 (1991). cited by applicant .
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Geological Institute. Dictionary of Geological Terms. Published
1984. 3.sup.rd Edition: p. 4. cited by applicant .
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Society. Physical Review E. Jul. 19, 2005. 72 (011605):1-15. DOI:
10.1103/PhysRevE.72.011605. cited by applicant .
M. Jarcho, et al., "Hydroxylapatite Synthesis and Characterization
in Dense Polycrystalline Form", J. of Materials Science, 11, pp.
2027-2035 (1976), no month. cited by applicant .
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for Prosthetic Applications", J. of Materials Science, 16, pp.
809-812 (1981), no month. cited by applicant.
|
Primary Examiner: McKane; Elizabeth
Attorney, Agent or Firm: Wolf, Greenfield & Sacks,
P.C.
Parent Case Text
RELATED APPLICATION
.[.This non-provisional application claims the benefit under Title
35, U.S.C. .sctn.119(e) of co-pending U.S. provisional application
serial No. 60/035,535, filed Jan. 16, 1997, entitled
"Nanocrystalline Apatites and Composites, Prostheses Incorporating
Them, and Method for Their Production" by Jackie Y. Ying et al.,
incorporated herein by reference..]. .Iadd.This application is a
continuation re-issue of application Ser. No. 13/536,924, filed
Jun. 28, 2012 now U.S. Pat. No. Re. 44,820, which is a continuation
re-issue of U.S. Pat. No. Re. 43,661, issued Sep. 18, 2012, filed
as application Ser. No. 12/749,299, filed Mar. 29, 2010, which is a
continuation re-issue of U.S. Pat. No. Re. 41,584, issued Aug. 24,
2010, filed as application Ser. No. 10/863,863, filed Jun. 7, 2004,
which is a continuation re-issue of U.S. Pat. No. Re. 39,196,
issued Jul. 18, 2006, filed as application Ser. No. 10/044,801 on
Jan. 11, 2002, which is a reissue of U.S. Pat. No. 6,013,591,
issued Jan. 11, 2000, entitled NANOCRYSTALLINE APATITES AND
COMPOSITES, PROSTHESES INCORPORATING THEM, AND METHOD FOR THEIR
PRODUCTION, filed as application Ser. No. 09/007,930 on Jan. 16,
1998, which claims priority to U.S. provisional application Ser.
No. 60/035,535, filed Jan. 16, 1997, all of which are incorporated
herein by reference..Iaddend.
.Iadd.Notice: More than one reissue application has been filed for
the reissue of U.S. Pat. No. 6,013,591. The reissue applications
are patent application Ser. Nos. 10/044,801 filed Jan. 11, 2002,
10/863,863 filed Jun. 7, 2004, which is a continuation re-issue of
patent application Ser. No. 10/044,801; Ser. No. 12/749,299 filed
Mar. 29, 2010, which is a continuation re-issue of patent
application Ser. No. 10/863,863; Ser. No. 13/536,924 filed Jun. 28,
2012, which is a continuation re-issue of patent application Ser.
No. 12/749,299; and the instant application which is a continuation
re-issue of patent application Ser. No. 13/536,924..Iaddend.
Claims
What is claimed is:
.[.1. A composition, comprising particulate apatite having an
average apatite crystal size of less than 100 nm, wherein the
crystal is spherical..].
.[.2. The composition of claim 1 comprising particulate apatite
having an average apatite crystal size of less than 50 nm..].
.[.3. The composition of claim 1 comprising particulate apatite
having an average apatite crystal size of less than 30 nm..].
.[.4. The composition of claim 1 comprising particulate apatite
having an average apatite crystal size of less than 20 nm..].
.[.5. A composition as in claim 1 wherein the particulate apatite
is densified..].
.[.6. The composition of claim 1 comprising apatite having an
average particle size of less than 1 .mu.m..].
.[.7. The composition of claim 1 comprising apatite having an
average particle size of less than 0.5 .mu.m..].
.[.8. The composition of claim 1 comprising apatite having an
average particle size of less than 0.25 .mu.m..].
.[.9. A composition comprising particulate apatite having a surface
area of at least 40 m.sup.2/g and a spherical crystal..].
.[.10. The composition of claim 7 comprising particulate apatite
having a surface area of at least 100 m.sup.2/g..].
.[.11. The composition of claim 9 comprising particulate apatite
having a surface area of at least 150 m.sup.2/g..].
.[.12. The composition of claim 9 that undergoes apatite phase
decomposition of less than 10% when exposed to conditions of at
least 1000.degree. C. for at least 2 hours..].
.[.13. The composition of claim 12 that undergoes apatite phase
decomposition of less than 5% when exposed to conditions of at
least 1000.degree. C. for at least 2 hours..].
.[.14. The composition of claim 12 that undergoes apatite phase
decomposition of less than 3% when exposed to conditions of at
least 1000.degree. C. for at least 2 hours..].
.[.15. The composition of claim 12 that undergoes apatite phase
decomposition of less than 10% when exposed to conditions of at
least 1100.degree. C. for at least 2 hours..].
.[.16. The composition of claim 12 that undergoes apatite phase
decomposition of less than 5% when exposed to conditions of at
least 1100.degree. C. for at least 2 hours..].
.[.17. The composition of claim 12 that undergoes apatite phase
decomposition of less than 3% when exposed to conditions of at
least 1100.degree. C. for at least 2 hours..].
.[.18. The composition of claim 12 that undergoes apatite phase
decomposition of less than 10% when exposed to conditions of at
least 1200.degree. C. for at least 2 hours..].
.[.19. The composition of claim 12 that undergoes apatite phase
decomposition of less than 5% when exposed to conditions of at
least 1200.degree. C. for at least 2 hours..].
.[.20. The composition of claim 12 that undergoes apatite phase
decomposition of less than 3% when exposed to conditions of at
least 1200.degree. C. for at least 2 hours..].
.[.21. The composition of claim 12 that undergoes apatite phase
decomposition of less than 10% when exposed to conditions of at
least 1300.degree. C. for at least 2 hours..].
.[.22. The composition of claim 12 that undergoes apatite phase
decomposition of less than 5% when exposed to conditions of at
least 1300.degree. C. for at least 2 hours..].
.[.23. The composition of claim 12 that undergoes apatite phase
decomposition of less than 3% when exposed to conditions of at
least 1300.degree. C. for at least 2 hours..].
.[.24. An article having a dimension of at least 0.5 cm made up of
the composition of claim 1..].
.[.25. The article of claim 24 wherein the particulate apatite is
consolidated..].
.[.26. The article of claim 24, formed into the shape of a
prosthesis..].
.[.27. The article of claim 24 that is a prosthesis..].
.[.28. The article of claim 24 comprising an exterior coating on a
prosthesis..].
.[.29. The article of claim 28 comprising an exterior coating, on a
prosthesis, of at least 0.5 micron in thickness..].
.[.30. The article of claim 24 having a theoretical density of at
least 90%..].
.[.31. The article of claim 24 having a theoretical density of at
least 95%..].
.[.32. The article of claim 24 having a theoretical density of at
least 98%..].
.[.33. An article having a dimension of at least 0.5 cm made up of
the composition of claim 9..].
.[.34. The article of claim 33 having a porosity of at least
20%..].
.[.35. The article of claim 33 having a porosity of at least
30%..].
.[.36. The article of claim 33 having a porosity of at least
50%..].
.[.37. The article of claim 33 having a porosity of at least
75%..].
.[.38. The densified article of claim 33 having compressive
strength of at least about 150 MPa..].
.[.39. The densified article of claim 38, having a density of at
least about 98%..].
.[.40. The densified article of claim 33 having compressive
strength of at least about 500 MPa..].
.[.41. The densified article of claim 33 having compressive
strength of at least about 700 MPa..].
.[.42. The densified article of claim 38, having a density of at
least about 90%..].
.[.43. The densified article of claim 38, having a density of at
least about 95%..].
.[.44. The article of claim 24 that is a part of a
prosthesis..].
.Iadd.45. A composition comprising particulate apatite, said
particulate apatite having an average apatite crystal size of less
than 100 nm, a crystal aspect ratio ranging from spherical to about
2.9:1, and a surface area of at least about 40
m.sup.2/g..Iaddend.
.Iadd.46. A composition comprising particulate apatite, said
particulate apatite having a crystal aspect ratio ranging from
spherical to about 2.9:1 and an average particle size small enough
that the composition can be sintered to a density of at least 98%
at a temperature of less than about 1100.degree. C..Iaddend.
.Iadd.47. The composition of claim 45, wherein the particulate
apatite has a surface area greater than 60 m.sup.2/g..Iaddend.
.Iadd.48. The composition of claim 45, wherein the particulate
apatite has a surface area greater than 100 m.sup.2/g..Iaddend.
.Iadd.49. The composition of claim 45, wherein the particulate
apatite has an average particle size of less than 1
.mu.m..Iaddend.
.Iadd.50. The composition of claim 45, wherein the particulate
apatite has an average apatite particle size of less than 0.5
microns..Iaddend.
.Iadd.51. The composition of claim 45, wherein the particulate
apatite is consolidated..Iaddend.
.Iadd.52. The composition of claim 45, wherein the composition can
be sintered to a density of at least 98% at a temperature of less
than about 1100.degree. C..Iaddend.
.Iadd.53. The composition of claim 46, wherein the particulate
apatite has an average particle size of less than 1
.mu.m..Iaddend.
.Iadd.54. The composition of claim 46, wherein the particulate
apatite has an average apatite particle size of less than 0.5
microns..Iaddend.
.Iadd.55. The composition of claim 46, wherein the average apatite
crystal size is less than 250 nm..Iaddend.
.Iadd.56. The composition of claim 46, wherein the average apatite
crystal size is less than 100 nm..Iaddend.
.Iadd.57. The composition of claim 46, wherein the particulate
apatite has a surface area greater than 40 m.sup.2/g..Iaddend.
.Iadd.58. The composition of claim 46, wherein the particulate
apatite has a surface area greater than 60 m.sup.2/g..Iaddend.
.Iadd.59. The composition of claim 46, wherein the particulate
apatite has a surface area greater than 100 m.sup.2/g..Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates generally to bioceramics and more
particularly to a class of apatite materials and composites
incorporating these materials that are useful as prostheses, or
coatings for prosthesis, and methods for production of these
materials.
BACKGROUND OF THE INVENTION
Biomaterials are a class of functional materials designed to
interact with and become incorporated into the human body for uses
such as prostheses. Unlike products obtained through
bioengineering, the manufacture of biomaterials rarely requires
cellular processing or a biological intermediary.
There is a need for biomimetic structures friendly to body
chemistry and physiology. Goals for these biomaterials are that
they possess mechanical stability for hardness, compressive
strength, flexural strength, and wear resistance, controlled
microstructure to develop functional gradients, controlled
interfacial properties to maintain structural integrity in
physiological conditions, and well-understood surface chemistry
tailored to provide appropriate adhesion properties, chemical
resistance, long implant life, and patient comfort.
A wide variety of biomaterials exist such as biocompatible polymers
and bioceramics. Biocompatible polymers include biodegradable
polymers for use in providing structural support to organs and
other body parts, drug delivery, and the like, and
non-biodegradable polymers such as polymer prosthesis. For example,
hip joint replacements typically make use of non-biodegradable
polymers. The technique typically requires a traumatic in vivo
polymerization reaction within the cup of a hip joint, and the use
of a metal ball joint within the cup which can result in stress
shielding (described below), causing bone dissolution. Uneven wear
rates between the metal ball joint and the polymer sockets can
cause the polymer to disintegrate within the body causing even more
rapid dissolution. As a result, the interface between the metal
ball joint and bone often loosens over time causing the patient
great discomfort. The result is that hip joint replacement using
current state-of-the-art technology may have to be performed more
than once in a patient.
Bioceramics have found widespread use in periodontic and orthopedic
applications as well as oral, plastic, and ear, nose, and throat
surgery. Common materials for bioceramics are alumina, zirconia,
calcium phosphate based ceramics, and glass-ceramics. Bioceramics
can be categorized according to their in vivo interaction,
typically as bioinert, bioactive, and resorbable bioceramics.
Various types of bioceramics undergo fixation within the body
according to different processes. Some processes are generally more
favorable than others, but in many cases a bioceramic material that
undergoes fixation within the body via one advantageous interaction
may be associated with other disadvantages.
Bioinert bioceramics include single crystal and polycrystalline
alumina and zirconia, and are characterized as such because the
body encapsulates the ceramics with fibrous tissue as a natural
mechanism in recognition of the inert ceramic as a foreign object,
and tissue growth associated with this reaction is used to
mechanically fix the ceramic article in the body. In dense alumina
and zirconia, the tissue grows into surface irregularities. In
porous polycrystalline alumina, zirconia, etc., tissue grows into
the pores.
Resorbable bioceramics include tricalcium phosphate, calcium
sulfate, and calcium phosphate salt based bioceramics. They are
used to replace damaged tissue and to eventually be resorbed such
that host tissue surrounding an implant made of the resorbable
ceramic eventually replaces the implant.
Bioactive bioceramics include hydroxyapatite bioceramics, glass,
and glass-ceramics. A "bioactive" material is one that elicits a
specific biological response at its surface which results in the
formation of a bond with tissue. Thus, bioactive materials undergo
chemical reactions in the body, but only at their surfaces. These
chemical reactions lead to chemical and biological bonding to
tissue at the interface between tissue and a bioactive implant,
rather than mere ingrowth of tissue into pores of the implant which
provide mechanical fixation. A characteristic of bioactive ceramic
articles is the formation of a hydroxycarbonate apatite (HCA) layer
on the surface of the article. The degree of bioactivity is
measured in terms of the rate of formation of HCA, bonding,
strength, and thickness of the bonding layer as well as cellular
activity.
Although many ceramic compositions have been tested as implants to
repair various parts of the body, few have achieved human clinical
application. Problems associated with ceramic implants typically
involve the lack of a stable interface with connective tissue, or a
lack of matching of the mechanical behavior of the implant with the
tissue to be replaced, or both (L. L. Hench, "Bioceramics: from
Concept to Clinic", J. Am. Ceram. Soc., 74, 1487-1510 (1991)). In
the case of bioinert bioceramic materials, only a mechanical
interlock is obtained, and if the mechanical fixation between the
surrounding tissue and implant is not strong enough, then loosening
of the bioceramic can occur causing necrosis of the surrounding
tissue along with total implant failure. For example, when alumina
or zirconia implants are implanted with a tight mechanical fit
within the body and movement does not occur at the interface with
tissue, they are clinically successful. However, if movement
occurs, the fibrous capsule surrounding the implant can grow to
become several hundred microns thick and the implant can loosen,
leading to clinical failure.
Problems long associated with resorbable bioceramics are the
maintenance of strength, stability of the interface, and matching
of the resorption rate to the regeneration rate of the host tissue.
Furthermore, the constituents of resorbable biomaterials must be
metabolically acceptable since large quantities of material must be
digested by cells. This imposes a severe limitation on these
compositions.
The success of bioceramic implants depends upon properties of
strength, fatigue resistance, fracture toughness, and the like.
These properties are reported to be a function of grain size and
purity, but strength typically decreases as grain size increases.
High temperature sintering of .beta.-tricalcium phosphate results
typically in micron scale grains (Akao, et al., "Dense
Polycrystalline .beta.-tricalcium Phosphate for Prosthetic
Applications", J. Mat. Sci., 17, 343-346 (1982)). It has been
reported that an increase in the average grain size of
polycrystalline .alpha.-Al.sub.2O.sub.3 to greater than 7 microns
can decrease mechanical properties by about 20% (Hench J. Am.
Ceram. Soc., referenced above). Additionally, as strength is
increased, porosity typically decreases according to prior art
liquid phase and solid state sintering techniques (Hench, et al.,
Ed., Introduction to Bioceramics, Chapter 1, pages 17-20
(1993)).
One problem associated with hard tissue prosthesis, for example,
artificial bones or bone portions, is "stress shielding". This
phenomenon results when a prosthesis of relatively high Young's
modulus, such as alumina, is used as an implant against bone. The
higher modulus of elasticity of the implant results in its carrying
nearly all the load. This prevents the bone from being loaded, a
requirement for bone to remain healthy and strong. That is, stress
shielding weakens bone in the region where a load applied to the
bone is lowest or in compression. Bone that is unloaded or loaded
in compression undergoes a biological change that leads to bone
resorption. The elastic modulus of cortical bone ranges between 7
and 25 GPa, which is 10 to 50 times lower than that of alumina. The
modulus of cancellous bone is significantly lower than that of
cortical bone. The modulus of elasticity of a variety of materials
used for load bearing implants is compared with the modulus values
of cortical bone and cancerous bone in Hench, et al., Ed.
Introduction to Bioceramics, referenced above.
Hydroxyapatite, Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, is an
attractive and widely utilized bioceramic material for orthopedic
and dental implants because it closely resembles native tooth and
bone crystal structure. Though hydroxyapatite is the most common
bioceramic, applications for its use have been limited by its
processability and architectural design conceptualization.
Conventional processing lacks compositional purity and homogeneity.
Because hydroxyapatite is difficult to sinter, dense hydroxyapatite
structures for dental implants and low wear orthopedic applications
typically have been obtained by high-temperature and/or
high-pressure sintering with glassy sintering aids which frequently
induce decomposition to undesirable phases with poor mechanical
stability and poor chemical resistance to physiological conditions.
Thus, conventionally-formed hydroxyapatite necessitates expensive
processing and compromises structural integrity due to the presence
of secondary phases. Existing methods require high forming and
machining costs to obtain products with complex shapes.
Furthermore, typical conventional hydroxyapatite decomposes above
1250.degree. C. This results in a material with poor mechanical
stability and poor chemical resistance.
Jarcho, et al., in "Hydroxyapatite Synthesis and Characterization
in Dense Polycrystalline Form", J. Mater. Sci., 11, 2027-2035
(1976)), describe a process for forming dense polycrystalline
hydroxyapatite that is "substantially stronger than other
hydroxyapatite materials", and that elicits "an excellent
biological response when implanted in bone" (p. 2027). A
precipitation method was used and material of average grain size of
from about 150-700 nm recovered. However, Jarcho, et al. report low
volume fraction of pores, and report considerable grain growth
during sintering even at firing temperatures of 1000.degree. C.
Jarcho, et al. achieved 99% density in some cases, but using a
technique that can be impractical for forming desired shapes. M.
Akao, et al., in "Mechanical Properties of Sintered Hydroxyapatite
for Prosthetic Applications", J. Mater. Sci., 16, 809-812 (1981),
report the compressive flexural torsional and dynamic torsional
strengths of polycrystalline hydroxyapatite sintered at
1300.degree. C. for three hours and, compare the mechanical
properties of the product with those of cortical bone, dentine, and
enamel. The compressive strength of the sintered hydroxy apatite
was approximately 3-6 times as strong as that of cortical bone.
There is much room for improvement in the use of hydroxyapatite as
implants. As reported by Hench et al., "Bioceramics: from concept
to clinic", American Ceramic Society Bulletin 72, 4, 93-98 (1993),
"Because (hydroxyapatite) implants have low reliability under
tensile load, such calcium phosphate bioceramics can only be used
as powders, or as small, unloaded implants such as in the middle
ear, dental implants with reinforcing metal posts, coatings on
metal implants, low-loaded porous implants where bone growth acts
as a reinforcing phase, and as the bioactive phase in a composite."
(p. 97). Hench, J. Am. Ceram Soc. (1991; referenced above) reports
that hydroxyapatite has been used as a coating on porous metal
surfaces for fixation of orthopedic prostheses, in particular, that
hydroxyapatite powder in the pores of porous, coated-metal implants
would significantly affect the rate and vitality of bone ingrowth
into the pores. It is reported that many investigators have
explored this technique, with plasma spray coating of implants
generally being preferred. Hench reports, however, that long term
animal studies and clinical trials of load-bearing dental and
orthopedic prostheses suggest that the hydroxyapatite coatings may
degrade or come off (p. 1504). Thus, the creation of new forms of
hydroxyapatite having improved mechanical properties would have
significant use, but the results of prior art attempts have been
disappointing.
Recently, attention has been focused on nanocrystalline or
nanocomposite materials for mechanical, optical and catalytic
applications. By designing materials from the cluster level,
crystallite building blocks of less than 10 nm are possible,
through which unique size-dependent properties such as quantum
confinement effect and superparamagnetism can be obtained. Various
nanocrystalline ceramics for structural applications have been
especially rigorously investigated in the 1990's. R. Siegel
discusses nanophase metals and ceramics in "Recent Progress in
Nanophase Materials", in Processing and Properties of
Nanocrystalline Materials, C. Suryanarayana, et al., Ed., The
Minerals, Metals & Materials Society (1996), noting that while
many methods exist for the synthesis of nanostructured materials,
including chemical or physical vapor deposition, gas condensation,
chemical precipitation, aerosol reactions, and biological
templating, synthesis and processing methods for creating tailored
nanostructures are sorely needed, especially techniques that allow
careful control of surface and interface chemistry and that can
lead to adherent surface coatings or well-consolidated bulk
materials. It is noted that in the case of normally soft metals,
decreasing grain sizes of the metal below a critical length scale
(less than about 50 nm) for the sources of dislocations in the
metal increases the metal's strength. It is noted that clusters of
metals, intermetallic compounds, and ceramics have been
consolidated to form ultrafine-grained polycrystals that have
mechanical properties remarkably different and improved relative to
their conventional coarse-grained counterpart. Nanophase copper and
palladium, assembled from clusters with diameters in the range of
5-7 nm, are noted for having hardness and yield strength values up
to 500% greater than in conventionally-produced metal. It is also
noted that ceramics and conventionally brittle intermetallics can
be rendered ductile by being synthesized from clusters with sizes
below about 15 nm, the ductility resulting from the increased ease
with which the ultrafine grains can slide by one another in
"grain-boundary sliding." However, synthesis of nanocrystalline or
nanocomposite materials is difficult. Significant effort has been
put into such synthesis and it is likely that in many or most
attempts particle sizes on the nanometer scale are not recovered
due to agglomeration. A delicate balance of synthetic parameters
typically must be elucidated in connection with a particular set of
materials.
In an article entitled, "New Nanocomposite Structural Ceramics", by
Niihara, et al., the synthesis and characterization of micro- and
nanocomposite structural ceramics is reported. A variety of
ceramics including Al.sub.2O.sub.3/SiC,
Al.sub.2O.sub.3/Si.sub.3N.sub.4, and the like were investigated.
Nanocomposites including intra- and intergranular nanocomposites
and nano/nanocomposites demonstrated improvement of mechanical
properties and/or machinability and superplasticity.
While hydroxyapatite is used widely, and a hydroxyapatite
formulation having mechanical and morphological properties
advantageous for prostheses would be very useful, attempts to date
have failed to produce reliable structural hydroxyapatite implants.
Accordingly, it is an object of the invention to provide relatively
simple techniques for synthesizing nanocrystalline apatite
materials having structural and morphological properties useful for
structural implants. In particular, it is an object to provide
synthesis techniques that produce densified, nanocrystalline
material under mild conditions including relatively low sintering
temperature, reducing or eliminating decomposition and minimizing
cost. It is another object to obtain apatite materials having
enhanced mechanical and chemical resistance by maintaining an
ultrafine microstructure in sintering through suppression of grain
growth.
SUMMARY OF THE INVENTION
The present invention provides a set of compositions, articles, and
methods involving apatite materials of particularly small crystal
size and/or particle size that can be readily formed into a variety
of products.
By carefully controlling processing parameters affecting the
molecular and structural development of hydroxyapatite such as
precursor type, precursor concentration, addition rate of
precursors, aging time, reaction and aging temperature, and pH
during synthesis, as well as by controlling parameters affecting
the agglomeration of ceramic particles such as washing and drying
of the as-synthesized gel, a loosely agglomerated nanocrystalline
hydroxyapatite powder is obtained. By minimizing particle size,
packing and densification is enhanced resulting in the fabrication
of densified nanocrystalline hydroxyapatite by using a simple
pressureless sintering process at relatively low sintering
temperatures. By reducing crystallite size, ceramics become more
ductile as the volume fraction of grain boundaries increases
allowing grain boundary sliding. Nanostructured hydroxyapatite also
allows superplastic net-shape forming for inexpensive production.
Furthermore, by achieving smaller crystallite sizes, defect size is
reduced. With minimized flaw sizes, nanocrystalline hydroxyapatite
is densified with minimal or no sintering additives at
substantially lower temperatures and demonstrates improved strength
compared to the conventional polycrystalline hydroxyapatite. Thus,
nanocrystalline hydroxyapatite possesses greater reliability and
better mechanical properties compared to conventional
hydroxyapatite with a coarser microstructure. Additionally,
hydroxyapatite can be structurally reinforced by nanocomposite
processing such as incorporating nanocrystalline zirconia into
hydroxyapatite. Additionally, carbonate icons be substituted for
phosphate ions in hydroxyapatite to yield carbonate apatite, both
Type A and Type B.
Using wet chemical processing as the basis, synthetic approaches to
obtain a variety of products: hydroxyapatite, carbonate apatite,
and fluoroapatite in the form of nanocrystalline dense structures
as well as high surface area powders and coatings are developed by
controlling the morphology, size, and reactivity of the
precipitated particles. These novel materials possess high chemical
purity and phase homogeneity with tailored mechanical strength and
biocompatibility. A wet chemical approach is used because it is
versatile, simple, and easy to control, in terms of both the
preparative reactions and the characteristics of the reaction
product. Furthermore, the synthesis conditions of the wet chemical
approach can be tailored to physiological conditions for biomimetic
processing. When synthesized at low temperatures and at ambient
pressures in an aqueous solution resembling physiological fluid, a
bioactive hydroxyapatite stable in the body is produced.
In order to manipulate the processing of nanocrystalline
hydroxyapatite, important processing parameters were identified.
Parameters affecting the molecular and structural development, and
chemistry of hydroxyapatite such as reaction and aging temperature,
aging time, addition rate of Ca(NO.sub.3).sub.2 to the basic
(NH.sub.4).sub.2HPO.sub.4 solution, NH.sub.4OH concentration during
chemical precipitation, and precursor concentration were examined.
Parameters affecting the agglomeration and densification of ceramic
particles such as grinding method, calcination temperature, and
sintering temperature were also investigated. By reducing
crystallite size, ceramics are toughened as the volume fraction of
grain boundaries increases allowing grain boundary sliding.
Furthermore, by achieving smaller crystallite sizes, defect size
are reduced. By minimizing particle size, packing and densification
can be enhanced.
In one aspect, the invention provides a composition including
particulate apatite having an average apatite crystal size of less
than 250 nm. In another embodiment, the invention provides an
apatite composition having a surface area of at least 40
m.sup.2/g.
The invention provides, according to another aspect, a method that
involves precipitating apatite from a solvent as an apatite
precipitate, removing the solvent from the apatite precipitate, and
recovering the precipitate, particulate apatite. In the method, the
recovered particulate apatite has an average crystal size of less
than 150 nm.
The invention also provides a method of calcining nanocrystalline
apatite at a temperature of less than 1000.degree. C. and
recovering a nanostructured apatite product having a BET surface
area of at least 40 m.sup.2/g and a crystal size of less than 500
nm.
In another aspect the invention provides a particulate apatite
composition having an average crystal size small enough that the
composition can be sintered to a theoretical density of at least
90% by pressureless sintering. In another aspect, a method is
provided comprising sintering a composition comprising an apatite
to a theoretical density of at least 90% by pressureless
sintering.
The invention also provides a method involving precipitating
crystalline apatite from solution. The crystalline apatite has an
average crystallite size of less than 250 nm and a BET surface area
of at least 40 m.sup.2/g. The precipitation is carried out under
conditions, including temperature, in which, at a temperature at
least 20.degree. C. different from the precipitating temperature
and under identical conditions other than temperature, crystalline
apatite is precipitated having an average crystallite size of
greater than 250 nm and a BET surface area of less than 40
m.sup.2/g.
The invention also provides a method involving sintering a quantity
of apatite powder at a temperature of at least 900.degree. C. while
allowing apatite phase decomposition of less than 10% in the
material.
The invention also provides a composition comprising
nanocrystalline apatite that has a theoretical density of at least
90% and an average grain size of less than one micron.
A method of the invention, in another embodiment, involves
precipitating apatite from a solvent as an apatite precipitate.
Solvent is removed from the apatite precipitate, and the
precipitate, particulate apatite is recovered having an average
particle size of less than 1 micron.
The invention also provides a method that involves calcining
nanocrystalline apatite at a temperature of less than 1000.degree.
C. and recovering a nanostructured apatite product having a BET
surface area of at least 40 m.sup.2/g and an average particle size
of less than 1 micron.
The invention also includes a method involving sintering apatite in
the absence of any sintering additives.
The invention also provides a composition including particulate
apatite having a surface area of at least 40 m.sup.2/g.
A method is provided in accordance with the invention that involves
precipitating a particulate apatite from solution having a
crystallite size of less than 250 nm and a BET surface area of at
least 40 m.sup.2/g under conditions including temperature in which,
at a temperature at least 20.degree. different from the
precipitating temperature and under identical conditions other than
temperature, particulate apatite is precipitated having an average
crystallite size of greater than 250 nm and a BET surface area of
less than 40 m.sup.2/g.
Other advantages, novel features, and objects of the invention will
become apparent from the following detailed description of the
invention when considered in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a series of x-ray diffraction (XRD) patterns of a variety
of hydroxyapatite samples involving different preparation
treatments;
FIG. 2 is a series of Fourier Transform infrared (PA-FTIR) spectra
of nanocrystalline hydroxyapatite as synthesized and after a series
of treatment steps;
FIG. 3 is a series of XRD patterns of nanocrystalline
hydroxyapatite after a series of treatment steps as in the material
identified in FIG. 2;
FIG. 4 is a series of XRD patterns of comparative, conventional,
commercially-available hydroxyapatite as received and after a
series of treatment steps;
FIG. 5 is an XRD pattern of nanocrystalline hydroxyapatite after
calcination; and
FIG. 6 is an PA-FTIR spectrum of the nanocrystalline hydroxyapatite
sample for which the XRD pattern is provided in FIG. 5.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods for synthesis of
nanostructured apatites, and selection criteria for process
conditions and steps for carrying out related methods, that result
in better microstructural control and design on the nanometer
scale, phase uniformity on the molecular level, enhanced sintering
behavior, greater mechanical reliability, and superplastic net
shape forming. Because of exceptional microstructural control, flaw
sizes are reduced which improve densification and mechanical
reliability, and ultrafine domain sizes are obtained which increase
ductility and superplasticity.
Nanocrystalline apatites are provided in accordance with the
invention that possess greater reliability, better mechanical
properties, and enhanced bioactivity compared to conventional
hydroxyapatite with a micron scale microstructure. With minimized
flaw sizes, nanocrystalline apatites of the invention are densified
without additives at substantially lower temperatures and
demonstrate unusual strength and ductility compared to the
conventional polycrystalline hydroxyapatite. The nanostructured
apatites not only provide superior mechanical properties but also
offer the potential for superplastic net-shape forming for
inexpensive rapid prototyping. Additionally, apatites can be
structurally reinforced by nanocomposite processing involving
incorporation of species such as zirconia into apatites.
The invention involves production of nanometer-sized compact
resulting from a pressureless sintering process at relatively low
sintering temperatures compared to temperatures used in known
methods of producing micron-sized hydroxyapatite. A wet chemical
approach is used in synthesis of preferred compositions leading to
the advantages that compositional homogeneity is provided and the
method is versatile and easy to control both in terms of the
preparative reactions and character of the reaction product. The
processing can be tailored for different applications such as
densified apatites, coatings, cements, and composites by
controlling the morphology, size, reactivity of the precipitated
particles, and adjusting their composition.
Apatite compositions of the invention are preferably of
nanocrystalline size. Crystal size typically governs bulk
properties in an article, with smaller crystal sizes being
advantageous for purposes of the invention. Minimization of
particle size, by minimizing crystal size, makes densification of
particles easier because smaller particles can re-arrange and pack
more readily and have a greater driving force for densification.
Accordingly, it is a goal of the invention to provide
nanocrystalline apatite powder having an average particle size that
approaches the average crystal size of the material. The invention
involves, in preferred embodiments, a wet chemical approach in
which nanocrystals are precipitated and in which the individual
crystals define individual particles, followed by recovery of
powder in which the crystals are agglomerated to a minimal extent,
and further processing involving densification resulting in
materials with useful properties.
The invention provides a method of forming ceramic material that is
applicable to a wide variety of materials, including apatitic
materials (apatites) such as fluoroapatites and exemplified by
hydroxyapatite and carbonate apatite (Type A and Type B). Preferred
bioceramics are represented by the general formula
M.sub.10.sup.2+(ZO.sub.y.sup.3-).sub.6X.sup.2-, where M=Ca, Ba, Sr,
Mg, Pb, Cd, etc. where M can be substituted with Na and/or K and
consequently the formula can be substituted with an appropriate
number of vacancies and/or anions, as known by one of ordinary
skill in the art; ZO.sub.y=PO.sub.4, AsO.sub.4, VO.sub.4, etc.
where ZO.sub.y can be substituted with SiO.sub.4, SO.sub.4,
CO.sub.3, BO.sub.3, etc. to balance a total charge of cations, as
known by one of ordinary skill in the art; and X=F.sub.2,
(OH).sub.2, Cl.sub.2, Br.sub.2, I.sub.2, O, CO.sub.3 etc. A
preferred set of compounds are those that form hexagonally-packed
crystals. Calcium-based apatites such as hydroxyapatite are
particularly preferred. One set of preferred apatites include
calcium phosphate apatites such as Ca.sub.5(PO.sub.4,
CO.sub.3F).sub.3R; Ca.sub.5(PO.sub.4CO.sub.3OH)OH;
Ca.sub.5(PO.sub.4).sub.3Cl; Ca.sub.5(PO.sub.4).sub.3F;
Ca.sub.5(PO.sub.4).sub.3OH; Ca.sub.10(PO.sub.4).sub.6 CO.sub.3;
Ca.sub.10(PO.sub.4).sub.6O; and non-calcium phosphate apatites such
as Ba.sub.5(PO.sub.4).sub.3Cl, (Sr,Ce).sub.5(PO.sub.4).sub.3OH,
(Ce,Ca).sub.5(PO.sub.4).sub.3(OH,F),
(Y,Ca).sub.5(PO.sub.4).sub.3(OH,F),
Na.sub.3Pb.sub.2(SO.sub.4).sub.3Cl,
Na.sub.3Ca.sub.2(SO.sub.4).sub.3OH,
Ca.sub.5[SiO.sub.4,PO.sub.4,SO.sub.4].sub.3(Cl,F),
Pb.sub.5(AsO.sub.4).sub.3Cl, (Ca,Sr).sub.5[AsO.sub.4,
PO.sub.4].sub.3OH, Pb.sub.5(AsO.sub.4).sub.3Cl,
Ca.sub.5[SiO.sub.4,PO.sub.4,SO.sub.4].sub.3(F,OH,Cl),
Pb.sub.3Ca.sub.2(AsO.sub.4).sub.3Cl, Ca.sub.5[SiO.sub.4,
PO.sub.4,SO.sub.4].sub.3(OH,F,Cl), Ca.sub.5(AsO.sub.4).sub.3OH,
Pb.sub.5(AsO.sub.4).sub.3Cl,
(Ba,Ca,Pb).sub.5[AsO.sub.4,PO.sub.4].sub.3Cl,
Pb.sub.5(PO.sub.4).sub.3Cl, Sr.sub.5(PO.sub.4).sub.3(OH,F),
Ca.sub.5(AsO.sub.4).sub.3F, Ca.sub.5[AsO.sub.4,PO.sub.4].sub.3Cl,
Pb.sub.5(VO.sub.4)Cl.
The invention also involves formation of nanocrystalline composites
including one or more apatites with other auxiliary additives
including ceramics, metals, and alloys. Ceramics preferred for use
in composites include alumina, zirconia, titania, silicon carbide,
silicon nitrides and other structural ceramics. Metals such as Ti,
Al, Ni, W, Fe, Mo, Co, Zr, V, and other structural metals and
alloys are useful. Preferably the structural additive also is
nanocrystalline. The structural attitude should be selected to
strengthen the composite. The auxiliary non-apatite structural
component can form a major or minor component, with the overall
composite having at least 10% apatite, preferably at least 20%
apatite, more preferably at least 50% apatite. Composites can be
formed by mixture of two or more component powders, suspension of
one or more components in a solution in which one or more other
components are dissolved followed by precipitation of one or more
solution components, or precipitation from solution of at least two
components simultaneously or nearly simultaneously. The latter
technique is preferred. Zirconia and alumina are used
advantageously in compositions when toughening of a composition is
desired. Compositions can be formulated based on mechanical
properties desired. For example, if a secondary phase is "pinned"
at grain boundaries, that is, forms an intergranular phase,
ultra-fine particle size may be maintained by preventing fusion of
particles of the first phase, which aids densification and
strengthens the material. Secondary phases that form within primary
phase grains can deflect cracks, that is, prevent crack propagation
within the primary phase, strengthening the material. Where a
composite is formed, it is typically best if the various components
are of approximately similar particle size.
A variety of simple screening tests can be used to select
bioceramics that have a very high probability of forming
nanocrystalline compositions in accordance with the invention. One
simple test involves forming a solution of a candidate species, or
reactants that can form a candidate species, precipitating the
candidate species from a solution, and determining particle and
crystal size of the resulting suspension using light-scattering
measurements. The precipitate can be removed from solution, and XRD
or microscopy such as SEM or TEM can be used to determine particle
and crystal size. In this manner, for example, a large number of
candidate species can be screened by simultaneously precipitating
the species from a series of solutions and performing
light-scattering measurements on each resulting suspension.
Following this screening test, resulting precipitate can be used in
accordance with the invention of the method described in greater
detail below.
It has generally been relatively straightforward to make porous
ceramic articles, but significantly more difficult to make dense
ceramic articles. The invention provides material that can be
easily densified into dense, strong material that can be used for
load-bearing implants where strength is required, such as ball
joints for hips, crowns for teeth, etc.
In the prior art, densification for strengthening typically has
necessitated temperatures at which a particular material tends to
decompose, potentially reducing biocompatibility and causing the
material to degrade and reducing mechanical properties. The prior
art generally teaches that, alternatively, a glassy phase (a
"sintering aid," known) can be added which becomes highly viscous
and flows freely during sintering but results in an interfacial
glassy phase that weakens an article formed thereby.
The ability to readily densify the bioceramic material of the
invention indicates that the material is of a quality that can make
it very useful for uses that do not necessarily require density.
That is, densification can be a screening test for a particularly
useful composition, and many compositions of the invention are
referred to as densifiable under certain conditions but need not
necessarily be densified. The very small particle size of the
invention allows formation of very dense articles.
As such, the compositions of the invention are easily formable
without expensive machining because of their small crystal and
particle size. Because of the small particle size of the
compositions of the invention, sintering can take place at low
temperatures, eliminating or minimizing decomposition. The
compositions can be sintered to a high theoretical density without
"sintering aids" which are known, such as glasses and glassy
oxides. The compositions of the invention can be densified without
external pressure at low temperature for short periods of time, for
example no more than 2 hours, preferably no more than 1 hour, and
more preferably no more than 30 minutes.
The invention can also be used to make relatively porous material
for use in high-surface-area, flowable materials such as cement for
teeth, cement for cranial surgery, and the like. In some cases,
porosity can be tailored for a particular purpose such as for bone
ingrowth where pores of approximately 200 microns may be
desirable.
The compositions of the invention can be used as coatings. For
example, thermal spray coatings, liquid-based coatings, vapor-phase
coatings, coatings via wet chemical methods, and the like known in
the art can benefit from the composition of the invention as the
very small particle size results in higher-quality and
better-adherent coatings. Porous coatings can be made by admixing
an organic species with the bioceramic, forming the coating, and
burning out the organic material. Similarly, self-assembled
surfactants can be used to form very small pores, as described in
co-pending, commonly-owned U.S. Pat. application Ser. No.
08/415,695 of Ying, et al., now abandoned, incorporated herein by
reference. For larger pore articles, a polymer can be admixed with
the bioceramic crystalline powder and burned out after
solidification.
The bioceramic material of the invention having very small crystal
sizes make it ideal for powders or coatings, and for use with
bones. The crystal size of healthy bone is approximately 20-30 nm,
and bioceramic material having similar crystal size will be better
compatible with bone as a result. In particular, the invention
provides compositions including particulate material, preferably
apatite, having an average crystal size of less than 250 nm
according to preferred embodiments. Preferably, the crystal size is
less than 150 nm, more preferably less than 100 nm, more preferably
less than 50 nm, more preferably less than 30 nm, and more
preferably still less than 20 nm. In accordance with another set of
preferred embodiments, the invention provides bioceramic material
having a small average particle size, in particular an average
particle size of less than 1 .mu.m, preferably having an average
particle size of less than 0.5 .mu.m, more preferably still an
average particle size of less than 0.25 .mu.m. Any combination of
preferred particle size and preferred crystal size can define a
preferable combination of the invention, for example an average
crystal size of less than 150 nm and an average particle size of
less than 1 .mu.m, etc.
The composition of the invention is particulate ceramic material,
preferably apatite, that has a high surface area. In one set of
embodiments the surface area is at least 40 m.sup.2/g, preferably
at least 60 m.sup.2/g, more preferably at least 100 m.sup.2/g, more
preferably still at least 150 m.sup.2/g. The composition of the
invention is particularly robust and resistant to phase
decomposition. Apatite compositions of the invention, alone or as
part of a composite including an auxiliary structural additive,
preferably undergoe apatite phase decomposition of less than 10%
when exposed to conditions of at least 1000.degree. C. for at least
2 hours. More preferably a composition undergoes apatite phase
decomposition of less than 5%, and more preferably less than 3%
under these conditions. In another set of embodiments, the
composition undergoes apatite phase decomposition of less than 10%
when exposed to conditions of at least 1100.degree. C. for at least
2 hours, preferably less than 5% and more preferably less than 3%
under these conditions. In another set of embodiments apatite phase
decomposition of less than 10% is realized when the composition is
exposed to conditions of at least 1200.degree. C. for at least 2
hours, and apatite phase decomposition is preferably less than 5%
and more preferably less than 3% under these conditions. In another
set of embodiments, one exposed to conditions of at least
1300.degree. C. for at least 2 hours such compositions undergo
apatite phase decomposition of less than 10%, preferably less than
5%, and more preferable less than 3%.
The invention provides articles having a dimension of at least 0.5
cm made of any of the above-described or other compositions of the
invention. The article preferably is a densified nanocrystalline
apatite article where "densified" is defined as having undergone a
densification step to create a self-supporting particle and,
preferably, densified to a theoretical density of at least 75%. The
article can be formed into the shape of a prosthesis, or can define
at least part of a prosthesis such as an exterior coating on a
prosthesis. When used as an exterior coating on a prosthesis, the
article is at least 0.5 .mu.m thick in at least one region, and the
dimension of at least 0.5 cm is a lateral dimension relative to the
article coated. The theoretical density of articles of the
invention preferably is at least 90%, more preferably at least 95%,
and more preferably still at least 98%. Porous articles can be
provided in accordance with the invention, for example for
stimulating bone ingrowth, and where porosity is desired articles
having a porosity of at least 20% are preferred, more preferably
the porosity is at least 30%, more preferably at least 50%, and
more preferably still at least 75%.
"Densified" as used in accordance with the invention also can be
defined in terms of the compressive strength of the article, with
densified particles of the invention preferably having a
compressive strength of at least about 150 MPa. More preferably the
compressive strength of articles of the invention is at least about
500 MPa, more preferably still at least about 700 MPa.
The compositions of the invention can be provided as consolidated
particulate apatite, where "consolidated" is meant to define a
collection of apatite particles that forms a self-supporting
structure. Apatite can be consolidated by providing particulate
apatite in a press and compressing the apatite to form an article.
The consolidated particulate apatite can be dense, or porous.
In all compositions, articles, and methods of the invention,
preferred compositions, articles, and products of methods is
hydroxyapatite, optionally in combination with an auxiliary
structural additive to define a composite article.
In order to produce nanocrystalline apatites having properties
tailored for a particular application, a series of processing
parameters are provided in accordance with the invention that
affect the molecular and structural development and chemistry of
apatites, such as aging temperature, aging time, addition rate of
reactants (such as addition rate of Ca(NO.sub.3).sub.2 to basic
(NH.sub.4).sub.2HPO.sub.4 solution in hydroxyapatite production),
NH.sub.4OH concentration during chemical precipitation, and
precursor concentration. Parameters affecting the agglomeration and
densification of ceramic particles such as grinding method,
calcination temperature, and sintering temperature also are
provided. By reducing crystallite size, ceramics are toughened as
the volume fraction of grain boundaries increases allowing grain
boundary sliding. Furthermore, by achieving smaller crystallite
sizes, defect size is reduced. By minimizing particle size, packing
and densification are enhanced.
In one set of embodiments the method in the invention involves
precipitating apatite from a solvent by adding a calcium salt to a
phosphate source. Suitable calcium salts and phosphate sources
would be recognized by those of ordinary skill in the art after
reading the present disclosure. In one embodiment apatite is
precipitated from a solvent containing a calcium salt in a
concentration of less than 1 M, preferably less than 0.5 M, and
more preferably from about 0.16 M to about 2.1 M. Preferred methods
include precipitating apatite from a solvent containing a calcium
salt and phosphate source in a molar ratio of about 10:6. A
separate set of embodiments involves mixing a calcium source and a
phosphate source in any way.
Rates of addition of calcium source to phosphate source are
advantageous in many circumstances. Preferred rates are addition of
calcium source to phosphate source at a rate of less than about
0.010 mols calcium source per minute, preferably less than about
0.007 mols/minute, more preferably still less than about 0.005
mols/minute. A preferred calcium source is CaNO.sub.3, and a
preferred phosphate source is [NH.sub.4].sub.2PO.sub.4.
pH has been found to be an important parameter in many
circumstances, and apatite is preferably precipitated from a
solvent at a pH of from about 7 to about 14, more preferably from
about 11 to about 13. Apatite crystals are precipitated having a
crystal size according to preferred embodiments described above,
and precipitated particulate apatite having surface areas as
described above, in particular preferably at least 40 m.sup.2/g, 60
m.sup.2/g more preferably at least 100 m.sup.2/g, and more
preferably still at least 150 m.sup.2/g, are recovered. It has also
been found that wet grinding the resulting precipitate from the
precipitation step of the invention is advantageous.
The apatite product precipitated in accordance with the invention
is preferably aged at a temperature of between about -25.degree. C.
and above 100.degree. C., more preferably between about 10.degree.
C. and about 50.degree. C., and more preferably still approximately
room temperature, i.e. about 20.degree. C. The apatite is
preferably aged for at least one minute.
The invention involves calcining nanocrystalline apatite, in a
preferred set of embodiments, under a set of conditions that allow
recovery of apatite product that is particularly pure and robust as
described above. In preferred embodiments the recovered apatite
product is of a nature such that it can be sintered at mild
conditions of temperature less than 1100.degree. C., yet results in
a product having a theoretical density of at least 95% and a grain
size of less than 225 nanometers. Most preferred are products which
can be sintered at a temperature of less than 1000.degree. C.
resulting in a product having a theoretical density of at least
98%, and a nanostructured apatite product recovered preferably has
an BET surface area of at least 40 m.sup.2/g and a crystal size of
less than 250 nm.
As noted above, the invention involves a sintering technique using
compositions of the invention that results in very low
decomposition. Pressureless sintering preferably takes place at a
temperature of no more than 1100.degree. C. for a period of time of
no more than 2 hours, more preferably no more than 1000.degree. C.
for this period of time, and more preferably still no more than
900.degree. C. for 2 hours. Apatite phase decomposition of less
than 10% occurs in this sintering step, preferably decomposition of
less than 5%, preferably less than 3%. Sintering can be carried out
in the absence of sintering aids. Such additives are known, and are
mentioned above. Pressureless sintering is preferred and is
possible because of the unique nature of the compositions of the
invention. In particular, the average crystal size of particulate
apatite of the invention is small enough that the composition can
be sintered to a theoretical density of at least 90% by
pressureless sintering, preferably at least 95%, and more
preferably still at least 98% by pressureless sintering, in each
case at a grain size preferably of less than 225 nanometers, at a
temperature of no more than 1200.degree. C. in one set of
embodiments, more preferably no more than 1100.degree. C., more
preferably no more than 1000.degree. C., and more preferably still
the pressureless sintering to a theoretical density of 90%, 95%, or
preferably 98% is carried out at a temperature of no more than
900.degree. C. The pressureless sintering steps can be carried out
to result in a densified apatite product having undergone
decomposition of less than 10%, more preferably less than 5% and
more preferably still less than 3%.
Another aspect of the invention involved techniques for colloidal
and hot pressing of apatites. Hot pressing is a form of
pressure-assisted sintering where by a pressure is applied
uniaxially to a powder contained within the die during sintering
under a vacuum. The pressure-assisted sintering allows for more
rapid densification and a lower sintering temperature. However,
because the hot pressing occurs under a vacuum, the decomposition
reaction of hydroxyapatite is favored, necessitating a lower
sintering temperature to prevent decomposition. Colloidal pressing
(wet pressing) is a process by which a stabilized sol of
hydroxyapatite is uniaxially pressed in a die. A stabilized sol of
material is defined as a suspension of particles which do not
undergo sedimentation appreciably over time. Frits within the die
allow the solvent to escape as the die is pressurized while
trapping the solid particles. Once enough solvent is removed to
obtain a solid pellet, the pellet is removed and is carefully dried
to prevent drying stresses from cracking the pellet. After fully
drying the pellet, the pellet is CIPed and undergoes normal
pressureless sintering. By avoiding a dry powder phase, colloidal
pressing prevents the agglomeration associated with working with a
dry powder and benefits from the lubrication effects of the solvent
during pressing, which allow the particles in solution to rearrange
into the densest packing. The present invention provides synthesis
conditions for successful hot pressing and colloidal pressing.
As mentioned, all of the compositions and articles of the invention
can include an auxiliary structural additive, and methods of the
invention can involve formation of apatite material including
auxiliary structural additive. The auxiliary structural additive
can be a metal oxide, preferably selected from among zirconia,
titania, and alumina, and/or any combination of these alone or with
other known structural additives, defining a composite. The
auxiliary structural additive can be added in an amount of from
about 1 to about 50% by volume, preferably from about 15 to about
35% by volume. The additive can be nanocrystalline to form a
"nano/nano" composite. In methods of the invention involving
precipitation, apatite can be precipitated from a solvent
containing, in suspension, an auxiliary structural additive, or
apatite can be provided in suspension in a solvent from which is
precipitated the auxiliary structural additive or, preferably, the
apatite and auxiliary structural additive or additives are
co-precipitated essentially simultaneously. Nanocrystalline apatite
can be calcined in the presence of auxiliary structural additive
and a nanostructured apatite product recovered. Similarly,
sintering of the nanocrystalline apatite in the presence of the
auxiliary structural additive is advantageous. Alternatively,
apatite powder can be independently recovered and auxiliary
structural additive independently provided (rather than
precipitation from a common solvent or suspension), and admixed and
sintered.
Using apatite synthesis via the wet chemistry route provided in the
invention, a variety of useful applications are realized. First,
nanocrystalline apatite powders are provided. Furthermore, since
the nanocrystalline apatites of the invention have superior
sinterability, they can be easily developed into dental and
orthopedic implants requiring densified hydroxyapatite parts.
Composites provided in the invention, such as zirconia-toughened
apatites possess even better mechanical strength than pure apatites
and have the potential as material of choice for load-bearing
applications. Also, since densified apatites are provided that are
thermally stable up to 1300.degree. C., they can be used in high
temperature applications. The chemical precipitation process of the
invention can also be modified to provide a variety of other novel
products such as coatings, cements, nanocrystalline carbonate
apatites as artificial bone crystals, and nanocrystalline
fluoroapatite for dental applications.
As mentioned above, the invention also involves the substitution of
carbonate for hydroxide in processing resulting in Type A carbonate
apatite and substitution of carbonate for phosphate in processing
resulting in Type B carbonate apatite. In its broadest sense, the
invention according to this aspect involves processing conditions,
for carbonate apatite, according to the preferred ranges of
temperature, pH, aging time, and other parameters listed above as
important to the invention in connection with hydroxyapatite. In
addition, for the carbonate apatite embodiment, carbonate source,
method of carbonate introduction, temperature, aging time, and pH
are important, especially for carbonate apatite. Products made
according to these methods also are a part of the invention.
The function and advantage of these and other embodiments of the
present invention will be more fully understood from the examples
below. The following examples are intended to illustrate the
benefits of the present invention, but do not exemplify the full
scope of the invention.
EXAMPLE 1.
Synthesis and Characterization of Nanocrystalline
Hydroxyapatite
A nanocrystalline hydroxyapatite powder was successfully
synthesized that allowed pressureless sintering without glassy
sintering aids at a remarkably low temperature of 1100.degree. C.
for 2 hours or less, resulting in a material that was >98%
dense.
A series of experiments were conducted to determine the feasibility
of synthesizing nanocrystalline hydroxyapatite and to determine the
optimal pH, aging temperature, aging time, and heat treatment where
the optimal hydroxyapatite is the sample that possesses the highest
green and sintered densities. Reagant grade
Ca(NO.sub.3).sub.2.4H.sub.2O and (NH.sub.4).sub.2HPO.sub.4 were
used as starting materials. Aqueous solutions of
(NH.sub.4).sub.2HPO.sub.4 (NHP) and Ca(NO.sub.3).sub.2 (CaN) were
prepared such that the Ca:P ratio was 10:6. 0.300 M
(NH.sub.4).sub.2HPO.sub.4 and 0.500 M Ca(NO.sub.3).sub.2 as well as
0.100 M (NH.sub.4).sub.2HPO.sub.4 and 0.167 M Ca(NO.sub.3).sub.2
were prepared. These solutions were mixed with a magnetic stirrer.
The pH of the NH.sub.4).sub.2HPO.sub.4 aqueous solution was varied
by adding concentrated NH.sub.4OH. 300 ml of a 0.500 M solution of
Ca(NO.sub.3).sub.2 was added to 300 ml of 0.300 M aqueous
(NH.sub.4).sub.2HPO.sub.4, or 900 ml of a 0.167 M solution of
Ca(NO.sub.3).sub.2 was added to 900 ml of 0.100 M aqueous
(NH.sub.4).sub.2HPO.sub.4 solution at a rate from 2 ml/min to 48
ml/min; the number of moles of precursors was constant in both set
of reactions. The combined solution was magnetically stirred for 12
or 100 hours and aged at 0.degree. C., room temperature, or
70.degree. C., The white precipitate was collected by
centrifugation at 1500 rpm for 15 minutes. After decanting, the
precipitate was redispersed in a distilled water and NH.sub.4OH
solution by magnetically stirring for 20 minutes; this procedure
was repeated two more times with decreasing amounts of NH.sub.4OH
and a fourth and final time with ethanol. The gel was air dried at
room temperature for 24 hours and then dried in a 150.degree. C.
oven for an additional 24 hours. The gel was then finely ground
with an alumina mortar and pestle. Instead of air drying the gel,
the gel was also wet ground. Wet grinding is a procedure by which a
gel is ground in a heated mortar and pestle until the gel becomes a
fine powder. The ground powders we re then heat treated in air at
550.degree. C., 700.degree. C. and 900.degree. C. with a heating
rate of 10.degree. C./min, and a dwell time of 2 hours.
Pressureless Sintering
The hydroxyapatite powders heat treated at 550.degree. C. in air
were sieved and ground to a mesh size of 230. The powders were
uniaxially pressed in stainless steel dies at 150 MPa. Pellets were
produced using an 8 mm diameter die. From 0.15 g of sample, these
compacted pellets were then cold isostatically pressed (CIPed) at
300 MPa in oil for 3 minutes. After CIPing the pellets were
sintered in air atmosphere by normal pressureless sintering.
Pressureless sintering was done at 1100.degree. C. for 2 hours with
a heating rate of 5.degree. C./min. Sintering was also performed at
1000.degree. C., 1100.degree. C., 1200.degree. C., 1300.degree. C.
with a heating rate of 5.degree. C./min.
Characterization and Evaluation
Nano-hydroxyapatite powder calcined at 550.degree. C. were
characterized by photoacoustic Fourier-transform infrared
spectroscopy (PA-FTIR) on a Biorad Digilab spectrometer and by
X-ray powder diffraction (XRD) on a Siemens D5000 diffractometer
(45kV-40mA, Cu-K.alpha.). The XRD pattern was analyzed using a
Scherrer's analysis of the (002) peak which corresponds to a
d-spacing of 3.44 .ANG. to determine the XRD crystallite size. The
BET surface area and pore size distribution of nano-hydroxyapatite
powder after a 550.degree. C. heat treatment were evaluated with
nitrogen adsorption analysis (Micromeritics ASAP2000). Densities of
the green and sintered pellets were measured geometrically and by
Archimedes method using water, respectively. The theoretical
density was assumed to be 3.16 g/cc. Densified and sintered HAP
pellets were characterized by XRD.
EXAMPLE 2
Determination of Optimal Conditions--Calcination, and Comparison
With Commercially-Available Hydroxyapatite Powder
One sample of nanocrystalline hydroxyapatite from Example 1 (Trial
2) was heat-treated in air at 550.degree. C., 700.degree. C., and
900.degree. C. for 2 hours in order to investigate the effect of
calcination temperature on the microstructure of hydroxyapatite;
Trial 2 synthesis conditions are presented in Table 1. The XRD
patterns of the as-synthesized hydroxyapatite at various
calcination temperatures (FIG. 1) indicated that the sample heat
treated at 550.degree. C. had better crystallinity than the
precursor gel prior to the heat treatment, although the peaks were
still quite broad. The heat treatment at 700.degree. C. gave
increased crystallinity compared to the sample treated at only
550.degree. C. and was composed of only hydroxyapatite. Even after
calcination at 900.degree. C., the sample was found to be composed
of only hydroxyapatite. The XRD patterns of the as-received
conventional hydroxyapatite powders (Aldrich) (FIG. 1(b)) showed
the presence of CaHPO.sub.4.2H.sub.2O (brushite) and
Ca.sub.3(PO.sub.4).sub.2 (beta-tricalcium phosphate or .beta.-TCP).
By 700.degree. C., this material contained substantial amount of
Ca.sub.3(PO.sub.4).sub.2 while our nanocrystalline material gave
only a pure hydroxyapatite phase.
TABLE-US-00001 TABLE 1 Trial 2 Synthesis Conditions Aging
Ca(NO.sub.3).sub.2 CaN NHP Time Rxn/Aging Addition Rate Grinding
Concentration Amount Concentration Amount NH.sub.4OH Trial (hr)
Temp (.degree. C.) (ml/min) Method (M) (ml) (M) (ml) Amount (ml) 2
12 25 15 Wet 0.500 300 0.300 300 30
The effect of calcination in air on the molecular structure of the
nanocrystalline hydroxyapatite powder was studied with PA-FTIR. The
FTIR spectrum in FIG. 2 of the nanocrystalline hydroxyapatite
powder calcined at 550.degree. C. was similar to that of the
as-synthesized hydroxyapatite precursor gel, although the peak at
875 cm.sup.-1 associated with HPO.sub.4.sup.2- was reduced. The
PO.sub.4.sup.3- peaks near 1030-1090 cm.sup.-1 and at 560-600 cm-1
also became more well-resolved after calcination indicating that
the hydroxyapatite structure became more defined. With increasing
temperature, the broad band at 3000-3400 cm.sup.-1 became less
prominent as water was removed. The peak intensities of
CO.sub.3.sup.2- around 1400 cm.sup.-1 and H.sub.2O at 1630
cm.sup.-1 were substantially reduced.
The surface areas of nano-hydroxyapatite powder after calcination
at various temperatures are summarized in Table 2. Hydroxyapatite
calcined at 550.degree. C. has a high BET surface area of 107.5
m.sup.2/g, compared to 39.5 m.sup.2/g for the as-received
conventional hydroxyapatite powder (Aldrich). The increase in
calcination temperature decreased the surface area of
nano-hydroxyapatite powder. Thus, the optimal calcination
temperature for the pure nano-hydroxyapatite powder is 550.degree.
C. because phase homogeneity and high surface area are retained
while volatiles are removed by this calcination temperature making
the powder ideal for compaction.
TABLE-US-00002 TABLE 2 XRD Crystallite Size and BET Surface Area of
Hydroxyapatite from TEM Observation and XRD Analysis Calcination
Temperature XRD Crystallite Size BET Surface Area (.degree. C.)
(nm) (m.sup.2/g) as-synthesized 40.0 226.6 550 40.0 107.5 700 75
42.5 900 >100 9.3 Aldrich (as-received) 92 39.5
EXAMPLE 3
Determination of Optimal Conditions--Sintering, and Comparison with
Commercially-Available Hydroxyapatite Powder
The Trial 2 hydroxyapatite calcined at 550.degree. C. in air was
CIPed and sintered at 1000.degree. C., 1100.degree. C.,
1200.degree. C. and 1300.degree. C. in air. Conventional
hydroxyapatite is known to be stable up to 1360.degree. C. (K. De
Groot, C. P. A. T. Klein, J. G. C. Wolker, and J. De
Blieck-Hogervorst, "Chemistry of Calcium Phosphate Bioceramics,"
Handbook of Bioactive Ceramics: Calcium Phosphate and
Hydroxyapatite Ceramics, Vol 2, pp. 3-15, Edited by T. Yamamuro, L.
L. Hench, and J. Wilson, CRC. Press, Boca Raton, 1990). The
decomposition reaction is
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2.fwdarw.3Ca.sub.3(PO.sub.4).sub.2+CaO+-
H.sub.2O and begins at 1200.degree. C. (K. Kamiya, T. Yoko, K.
Tanaka, Y. Fujiyama, "Growth of Fibrous Hydroxyapatite in Gel
System," J. Mater. Sci., 24, 827-832, 1989). It has been reported
that even below 1200.degree. C. the loss of OH.sup.- may occur (K.
R. Venkatachari, D. Huang, S. P. Ostrander, W. Schulze, and G. C.
Stangle, "Preparation of Nanocrystalline Yttria Stabilized
Zirconia" J. Mater. Res., 10,756-761, 1995). The formation of CaO
and TCP results in a weakening in mechanical properties and
chemical stability. It has been reported that hydroxyapatite with
lower Ca/P ratio begins to turn into .beta.-TCP by loss of water at
800.degree. C. (T. Kanazawa, T. Umegaki, and H. Monma, Apatites,
New Inorganic Materials, Bull, Ceramic Soc. Jpn., 10, 461-468
(1975)). The temperature of decomposition is known to be dependent
on the purity and Ca/P ratio of the powder. The decomposition of
hydroxyapatite with a high Ca/P ratio is inhibited even at higher
temperatures.
Thus, a superior hydroxyapatite would require excellent
compositional homogeneity and could be subjected to a high
temperature without decomposition, facilitating densification and
maintaining mechanical integrity, and this is provided in
accordance with the invention. FIGS. 3 and 4 illustrate the effect
of sintering temperature on the XRD patterns of nano-hydroxyapatite
powder and a comparative example of conventional hydroxyapatite
powder (Aldrich), respectively.
Trial 2 nanocrystalline compact showed only hydroxyapatite peaks
with no secondary .beta.-TCP and CaO phases up to 1300.degree. C.
On the other hand, the XRD results showed that the conventional
(Aldrich) compact sintered at 1000.degree. C. has decomposed
significantly to .beta.-TCP with some CaO. By 1300.degree. C., the
main component was .beta.-TCP with some CaO contained in the
.beta.-TCP matrix. Whereas the comparative compact began to
transform to .beta.-TCP by 1000.degree. C., the nanocrystalline
compact was found to be resistant to decomposition even at
1300.degree. C.
EXAMPLE 4
Determination of Optimal Conditions-Grinding Method
The size of particle agglomerates can be reduced by techniques such
as wet grinding. Smaller agglomerates allow for ceramic
densification at lower sintering temperatures. By using a wet
grinding technique, that is grinding the as-synthesized wet gel in
a heated mortar until a fine powder is obtained, the size of the
agglomerates can be reduced. If the gel is left to dry, capillary
pressure begins to build up between the particles as the solvent
between the particles is evaporated, squeezing the particles
together to form large agglomerates. By wet grinding, the
agglomerates are continually broken apart as more surface area is
exposed. It is expected that wet ground powder has a higher surface
area, and higher green and sintered densities than a dried gel. The
green crystallite sizes would be expected to be similar given that
the precipitation conditions are identical. The synthesis
conditions of the calcined hydroxyapatite powders used to determine
the effect of wet grinding are presented in Table 3. XRD
crystallite size, BET surface area, green density and bulk density
after sintering at 1100.degree. C. are presented in Table 4.
TABLE-US-00003 TABLE 3 Effect of Grinding Method: Synthesis
Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time Rxn/Aging Addition
Rate Grinding Concentration Amount Concentration Amount NH.sub.4OH
Trial (hr) Temp (.degree. C.) (ml/min) Method (M) (ml) (M) (ml)
Amount (ml) 1 12 25 15 Dry 0.500 300 0.300 300 30 2 12 25 15 Wet
0.500 300 0.300 300 30
TABLE-US-00004 TABLE 4 Effect of Grinding Method: Results XRD BET
Green % Theoretical Crystallite Surface Density Sintered Bulk Trial
Size (nm) Area (m.sup.2/g) (g/cc) Density 1 42 85.6 1.31 83.0 2 40
107.5 1.68 94.7
Results in Table 4 clearly confirm that wet grinding strongly
affect the agglomerate size. The wet ground hydroxyapatite powders
possess higher surface area, green density and sintered bulk
densities than the dry ground powders. These results suggest that
by grinding the gel while it is still wet, agglomerates size can be
reduced thereby enhancing densification. Furthermore, wet grinding
the gel does not affect the crystallinity of the material as shown
by the XRD patterns of Trials 1 and 2. The wet and dry ground
materials had a similar hydroxyapatite crystallite size. The
PA-FTIR spectra showed the presence of OH.sup.-, H.sub.2O, and
PO.sub.4.sup.3- as well as HPO.sub.4.sup.2- and a minor
CO.sub.3.sup.2- peak. Since wet grinding did not affect the
crystallinity of the material but did significantly reduce
agglomeration, it should be utilized in the processing of the
hydroxyapatite precursor gel.
EXAMPLE 5
Determination of Optimal Conditions--Reaction and Aging
Temperature
By altering the temperature of the precipitation reaction and the
aging process, the crystal nucleation and growth can be controlled.
By precipitating at low temperatures, crystal growth can be
minimized resulting in finer crystals. The effect of processing
temperature on XRD crystallite size, BET surface area, green
density, and bulk density after sintering at 1100.degree. C. were
investigated in our study (see Tables 5 and 6).
TABLE-US-00005 TABLE 5 Effect of Reaction and Aging Temperatures:
Synthesis Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time
Rxn/Aging Addition Rate Grinding Concentration Amount Concentration
Amount NH.sub.4OH Trial (hr) Temp (.degree. C.) (ml/min) Method (M)
(ml) (M) (ml) Amount (ml) 3 12 0 15 Wet 0.500 300 0.300 300 30 2 12
25 15 Wet 0.500 300 0.300 300 30 4 12 70 15 Wet 0.500 300 0.300 300
30
TABLE-US-00006 TABLE 6 Effect of Reaction and Aging Temperatures:
Results XRD BET Green % Theoretical Crystallite Surface Density
Sintered Bulk Trial Size (nm) Area (m.sup.2/g) (g/cc) Density 3 47
63.0 1.50 92.2 2 40 107.5 1.68 94.7 4 >100 61.09 1.50 83.8
As shown in Table 6, the calcined powders reacted and aged at
70.degree. C. had larger crystallites than the powders reacted and
aged at room temperature and 0.degree. C. Since room temperature
processing readily yields high green and sintered densities,
25.degree. C. is the preferred reaction and aging temperature for
the chemical precipitation of hydroxyapatite.
EXAMPLE 6
Effect of Aging Time
The crystallinity and structural development of hydroxyapatite can
be affected by varying the aging time. By increasing the aging
time, the hydroxyapatite precipitate undergoes recrystallization.
As a result, occluded impurities are removed and crystal strain is
reduced as free energy of the crystal decreases, while the crystal
structure becomes perfected and the exposed area is decreased.
Needle-like and rod-like structures redissolve and are
recrystallized in more orderly morphologies such as spheres with
the shapes of the primary particles approaching a homogeneous
distribution. This phenomena can be also accompanied with a
decrease in surface area. Furthermore, longer aging times ensure
that the reagents are fully reacted and precipitate out of the
solution. The synthesis conditions of the hydroxyapatite gels used
to determine the effect of aging time are presented in Table 7.
TABLE-US-00007 TABLE 7 Effect of Aging Time: Synthesis Conditions
Aging Ca(NO.sub.3).sub.2 CaN NHP Time Rxn/Aging Addition Rate
Grinding Concentration Amount Concentration Amount NH.sub.4OH Trial
(hr) Temp (.degree. C.) (ml/min) Method (m) (ml) (M) (ml) Amount
(ml) 5 12 25 2 Wet 0.500 300 0.300 300 30 6 100 25 2 Wet 0.500 300
0.300 300 30 7 12 25 3 Wet 0.167 900 0.100 900 90 8 100 25 3 Wet
0.167 900 0.100 900 90
TABLE-US-00008 TABLE 8 Effect of Aging Time: Results XRD BET Green
% Theoretical Crystallite Surface Density Sintered Bulk Trial Size
(nm) Area (m.sup.2/g) (g/cc) Density 5 44 58.52 1.31 82.6 6 41
65.68 1.70 80.4 7 45 63.57 1.43 87.7 8 33 89.71 1.88 95.3
The XRD patterns of Trials 5, 6, 7, and 8 agree with the JCPDS
hydroxyapatite file (9-0432), and no other phases were observed.
Trial 8 possessed a smaller XRD crystallite size than Trials 7
while similar grain sizes were noted for Trials 5 and 6. These
results indicate that hydroxyapatite aged for 100 hours had a
noticeably smaller average crystallite size than hydroxyapatite
aged for 12 hours in hydroxyapatite prepared with the lower
precursor concentration. Although FTIR spectra of Trials 5, 6, 7,
and 8 possessed peaks characteristic of hydroxyapatite, the
HPO.sub.4.sup.2- peak at 875 cm.sup.-1 and the peaks of
PO.sub.4.sup.3- at 1030-1090 cm.sup.-1 and 560-600 cm.sup.-1 were
reduced in intensity and were broadened for the sample aged for 100
hours. The XRD patterns and the FTIR spectra indicated that the
hydroxyapatite aged for 100 hours underwent significant dissolution
and reprecipitation so that the crystallite size of the
reprecipitated hydroxyapatite was smaller than that of the
originally precipitated hydroxyapatite. Alternatively, amorphous
calcium phosphate may have nucleated into small crystallites during
long aging times reducing the average crystallite size.
Significant differences in the effect of aging time are observed
for the hydroxyapatite synthesized using high and low precursor
concentrations. In both cases, an increase in surface area is
observed as aging time is increased, though a decrease in surface
area is expected with longer aging times as predicted by Ostwald
ripening. Instead of an Ostwald ripening phenomenon, there is a
conversion from a low surface area amorphous calcium phosphate to a
higher surface area crystalline hydroxyapatite; this interpretation
is consistent with the decrease in XRD crystallite size as aging
time is increased. The hydroxyapatite synthesized using 0.500 M
Ca(NO.sub.3).sub.2 and 0.300 M (NH.sub.4).sub.2HPO.sub.4 precursor
concentrations aged for 12 hours (Trial 5) resulted in a higher
sintered density than that aged for 100 hours (Trial 6). However,
for hydroxyapatite synthesized using 0.167 M Ca(NO.sub.3).sub.2 and
0.100 M (NH.sub.4).sub.2HPO.sub.4 precursor concentrations, aging
for 100 hours (Trial 8) resulted in a higher sintered density than
aging for 12 hours (Trial 7). These results suggest that particle
morphology of the originally precipitated hydroxyapatite
synthesized at high precursor concentrations (Trial 5) favors
densification, while the particle morphology of the reprecipitated
hydroxyapatite synthesized at low precursor concentrations (Trial
8) favors densification.
EXAMPLE 7
Effect of NH.sub.4OH Concentration
pH can affect chemical precipitation by altering the solubility of
the precipitate; the solubility of hydroxyapatite decreases as pH
increases. As a result, nucleation would be favored decreasing
crystallite size. Furthermore, different pH's affect agglomeration
by inducing a surface charge on the particles in solution. Similar
surface charges in the solution of the particles repel each other
reducing agglomeration in the solution. However, the same polar
solvents that prevented agglomeration during precipitation
introduce surface hydroxyl groups onto ceramic particles during the
drying process. As the ceramic gel dries, the surface hydroxyl
groups promote agglomeration of particles. It is therefore
desirable to use a nonpolar solvent, to wash the gel in order to
remove the surface hydroxyl groups. Finally, the different pHs
during the chemical precipitation are expected to affect crystal
morphology, and the morphology becomes increasingly rod-like.Iadd.,
or spherical to needle-like, .Iaddend.with increasing pH.Iadd., for
example to aspect ratios ranging from about 2.3:1 to
5.9:1.Iaddend..Tanahashi et al. reported that the solution pH
greatly influenced the growth rate and morphology of hydroxyapatite
and that fibrous hydroxyapatite could be prepared at high pH.
Hydroxyapatite synthesized through hydrothermal treatment at a pH
of 11 to 12 also resulted in nanometer-sized rod-like crystals.
However, the addition of glycerin during the synthesis confounded
the relationship between high pH and the synthesis of rod-like
hydroxyapatite, with the effect of additives on the synthesis of
rod-like hydroxyapatite. The synthesis conditions of the calcined
hydroxyapatite powders used to determine the effect of NH.sub.4OH
are presented in Table 9.
TABLE-US-00009 TABLE 9 Effect of NH.sub.4OH Concentration:
Synthesis Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time
Rxn/Aging Addition Rate Grinding Concentration Amount Concentration
Amount NH.sub.4OH Trial (hr) Temp (.degree. C.) (ml/min) Method (M)
(ml) (M) (ml) Amount (ml) 9 12 25 2 Wet 0.500 300 0.300 300 10 5 12
25 2 Wet 0.500 300 0.300 300 30 10 12 25 2 Wet 0.500 300 0.300 300
100 11 100 25 3 Wet 0.167 900 0.100 900 30 12 100 25 3 Wet 0.167
900 0.100 900 90 13 100 25 3 Wet 0.167 900 0.100 900 300
TABLE-US-00010 TABLE 10 Effect of NH.sub.4OH Concentration: Results
XRD BET Green % Theoretical Crystallite Surface Density Sintered
Bulk Trial Size (nm) Area (m.sup.2/g) (g/cc) Density 9 50 72.58
1.59 94.3 5 44 58.52 1.31 82.6 10 52 59.30 1.68 81.0 11 40 72.16
1.58 87.3 12 33 89.71 1.88 95.3 13 Not HAP Not HAP Not HAP Not
HAP
The XRD patterns show that all of the calcined hydroxyapatite
samples, except for Trial 13, have good crystallinity and a pure
hydroxyapatite phase. The peaks of the FTIR spectra were also
consistent with hydroxyapatite. Trials 9, 5, and 10 correspond to
10 ml, 30 ml, and 100 ml of NH.sub.4OH at high precursor
concentrations. The XRD results of Trials 9 and 5 suggest that the
addition of more NH.sub.4OH gives rise to smaller XRD crystallites,
which is consistent with the effect of increased pH which decreases
solubility, favoring nucleation. However, the XRD crystallite size
of Trial 10 is larger than Trial 5. This phenomenon can be
explained by examining Trials 11,12, and 13 which correspond to 30
ml, 90 ml, and 300 ml of NH.sub.4OH at low precursor
concentrations. The XRD crystallite sizes of Trials 11 and 12
decrease as pH is increased. Similar to Trial 10, Trial 13 deviates
from the trend established by Trials 11 and 12. Instead of the
anticipated further decrease in XRD crystallite size,
as-synthesized Trial 13 is not hydroxyapatite but a combination of
monetite (CaHPO.sub.4) and brushite (CaHPO.sub.4.2H.sub.2O) Trial
10 may occur in a similar metastable state as Trial 13, though not
as pronounced because of its shorter aging time and higher
precursor concentrations. Thus, the possible presence of monetite
and brushite during the synthesis of Trial 10 may give rise to the
deviation in the crystallite size. Furthermore, samples prepared
under similar conditions as Trial 13 have resulted in
hydroxyapatite, confirming the metastability of this region.
Trial 9, the hydroxyapatite derived with 10 ml of NH.sub.4OH,
resulted in the highest surface area and the highest % theoretical
sintered bulk density under a high precursor concentration
synthesis. A low pH at high precursor concentrations produces a
particle morphology and distribution favorable towards
densification since the addition of NH.sub.4OH is known to affect
particle morphology. Conversely, at low precursor concentrations,
the highest surface area and highest % theoretical sintered bulk
density occurred at an intermediate pH, indicating that this amount
of NH.sub.4OH resulted in a particle morphology and distribution
favorable toward densification.
EXAMPLE 8
Effect of Addition Rate
By varying the precursor addition rate, nucleation and crystal
growth rates can be controlled. Rapid addition of precursors
results in localized high concentrations of precursors, exceeding
the solubility of hydroxyapatite in those regions, which favors
nucleation and formation of small particles. However, rapid
addition is also expected to result in a nonuniform particle
morphology and distribution. Conversely, slow addition of
precursors results in a more homogenous mixture of reactants
favoring crystal growth and formation of larger particles.
Furthermore, slow addition of precursors is anticipated to result
in a uniform particle morphology and distribution. Thus, relatively
few nuclei will be formed by adding Ca(NO.sub.3).sub.2 slowly;
crystal growth removes the precursors as fast as it is added.
Adding Ca(NO.sub.3).sub.2 quickly yields more and smaller
particles. The synthesis conditions of the experiment investigating
the effect of addition rate are presented in Table 11.
TABLE-US-00011 TABLE 11 Effect of Addition Rate: Synthesis
Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time Rzn/Aging Addition
Rate Grinding Concentration Amount Concentration Amount NH.sub.4OH
Trial (hr) Temp (.degree. C.) (ml/min) Method (M) (ml) (M) (ml)
Amount (ml) 5 12 25 2 Wet 0.500 300 0.300 300 10 6 12 25 15 Wet
0.500 300 0.300 300 10 7 100 25 3 Wet 0.167 900 0.100 900 90 8 100
25 48 Wet 0.167 900 0.100 900 90
TABLE-US-00012 TABLE 12 Effect of Addition Rate: Results XRD BET
Green % Theoretical Crystallite Surface Density Sintered Bulk Trial
Size (nm) Area (m.sup.2/g) (g/cc) Density 5 67 73.58 1.59 94.3 6 54
65.20 1.52 91.8 7 33 89.71 1.74 95.6 8 31 65.35 1.91 95.3
The XRD patterns of Trials 9, 14, 15, and 12 corresponded to the
JCPDS hydroxyapatite file (9-0432) and no other phases were found.
All FTIR spectra possess peaks characteristic of nanocrystalline
hydroxyapatite. Trials 9 and 15 possessed a larger XRD crystallite
size and a higher BET surface area than Trials 14 and 12,
respectively, and gave rise to higher sintered densities. The
larger XRD crystallite sizes of Trials 9 and 12 compared to 14 and
12 suggest that a slower addition rate favors crystal growth, as
anticipated. In addition, by using a slow addition to obtain a more
uniform particle morphology and distribution, the final sintered
bulk densities were enhanced. These effects were significant for
Trials 9 and 14, but addition rate did not play a dominant role in
Trials 15 and 12. The lesser role of addition rate at low precursor
concentrations can be attributed to the difference in molar flow
rates. The difference in molar rates between Trials 15 and 12 is
7.5.times.10.sup.-3 moles/min whereas the difference in molar flow
rates between Trials 9 and 14 is 7.4.times.10.sup.-2 moles/min.
These results confirm that crystallite size depends on the rate of
addition with slower rates of addition resulting in larger
crystallites, but to observe this effect at low precursor
concentrations, a much higher flow rate should be used. To obtain a
densified nanocrystalline hydroxyapatite ceramic,
Ca(NO.sub.3).sub.2 should be added slowly to the basic
(NH.sub.4).sub.2HPO.sub.4 solution.
EXAMPLE 9
Effect of Precursor Concentration
By varying the precursor concentration, the synthesis of
nanocrystalline hydroxyapatite can be further controlled by
affecting the kinetics of hydroxyapatite synthesis. By reducing the
precursor concentration, the kinetics of the reaction are slowed.
The synthesis conditions of the hydroxyapatite gels used to
determine the effect of precursor concentration are presented in
Table 13.
TABLE-US-00013 TABLE 13 Effect of Precursor Concentration:
Synthesis Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time
Rxn/Aging Addition Rate Grinding Concentration Amount Concentration
Amount NH.sub.4OH Trial (hr) Temp (.degree. C.) (ml/min) Method (M)
(ml) (M) (ml) Amount (ml) 9 12 25 2 Wet 0.500 300 0.300 300 10 16
12 25 3 Wet 0.167 900 0.100 900 30 17 100 25 2 Wet 0.500 300 0.300
300 30 15 100 25 3 Wet 0.167 900 0.100 900 90
TABLE-US-00014 TABLE 14 Effect of Precursor Concentration: Results
XRD BET Green % Theoretical Crystallite Surface Density Sintered
Bulk Trial Size (nm) Area (m.sup.2/g) (g/cc) Density 9 67 73.58
1.59 94.3 16 46 1.82 85.1 17 41 65.68 1.70 80.1 15 33 89.71 1.74
95.6
The XRD patterns of Trials 9, 17, and 15 correspond to
hydroxyapatite while the XRD pattern of Trial 16 corresponds to
monetite (CaPO.sub.3OH). The FTIR spectra of Trials 9, 17, and 15
also showed the characteristic hydroxyapatite nanocrystalline
peaks. By reducing the precursor concentration in Trial 9 to the
precursor concentration of Trial 16, hydroxyapatite synthesis
enters an intermediate state where monetite is the product. In
Table 8, "Effect of Aging Time," Trials 7 and 8 were both found to
be hydroxyapatite regardless of aging time, but unlike Trial 16,
Trials 7 and 8 were synthesized under a higher pH. Tables 15 and 16
present the synthesis conditions and results proving that Trial 16
is an intermediate state, observable because of the shorter aging
time, low precursor concentration and low pH; under the same
conditions as Trial 16, except with longer aging times, Trial 11
was determined to be hydroxyapatite. Thus, the effect of lowering
precursor concentration at the synthesis conditions of Trials 9 and
16 is to slow the kinetics of the reaction.
TABLE-US-00015 TABLE 15 Effect of Aging Time on Trial 16: Synthesis
Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time Rxn/Aging Addition
Rate Grinding Concentration Amount Concentration Amount NH.sub.4OH
Trial (hr) Temp (.degree. C.) (ml/min) Method (m) (ml) (m) (m1)
Amount (ml) 16 12 25 3 Wet 0.167 900 0.100 900 30 11 100 25 3 Wet
0.167 900 0.100 900 30
TABLE-US-00016 TABLE 16 Effect of Aging Time on Trial 16: Results
XRD BET Green % Theoretical Crystallite Surface Density Sintered
Bulk Trial Size (nm) Area (m.sup.2/g) (g/cc) Density 16 Not HAP Not
HAP Not HAP Not HAP 11 40 72.16 1.58 87.3
At longer aging times and higher pH (Trials 17 and 15), a kinetic
effect is also observed. Because of the low precursor
concentration, the rate of reaction is expected to be slower for
Trial 15 than Trial 17 as confirmed by the smaller XRD crystallite
size of Trial 15. Furthermore, the slower kinetics of Trial 15
compared to Trial 17 resulted in a higher surface area, and a
particle morphology and size distribution favoring
densification.
Two synthesis conditions, Trial 9 and 15, were determined to give
rise to the optimal hydroxyapatite powders as assessed by %
theoretical sintered bulk density. Trial 15 possessed the highest
pressurelessly sintered bulk density of all trials investigated.
The 95.6% theoretical sintered bulk density was obtained using a
low precursor concentration, 100 hour aging time, an aging
temperature of 25.degree. C., 3 ml/min Ca(NO.sub.3).sub.2 addition
rate, 90 ml of NH.sub.4OH, and wet grinding. A high theoretical
density of 94.3% was obtained using the synthesis conditions of
Trial 9: high precursor concentration, 12 hour aging time, an aging
temperature of 25.degree. C., 2 ml/min addition rate, 10 ml of
NH.sub.4OH, and wet grinding. Thus, optimal conditions were
determined for the precursor concentrations investigated.
SUMMARY OF EXAMPLES 1-9
Nanocrystalline hydroxyapatite was synthesized successfully by
chemical precipitation. The effects of NH.sub.4OH amount, aging
time, aging temperature, grinding method, precursor concentration,
and Ca(NO.sub.3).sub.2 addition rate on the crystallite size,
agglomeration, morphology, crystallinity and the molecular
structure were examined. By identifying the important processing
parameters and the method by which they can be controlled, the
crystallite size can be reduced to enhance the mechanical
properties of bulk hydroxyapatite. Furthermore, using the
parameters to reduce agglomeration, to control the particle
morphology and size distribution, and to control the chemical
reactivity of the particles, full densification can be achieved at
lower sintering temperatures. The XRD patterns of the
nano-hydroxyapatite precursor gel were in good agreement with the
JCPDS hydroxyapatite file (9-432); the peaks were substantially
broadened due to the nanocrystalline nature of hydroxyapatite. The
grinding method affected the surface area and the state of
agglomeration with wet grinding being favored. Reaction and aging
temperatures during precipitation affected the crystal growth rate
with room temperature favored. Aging time affected the conversion
of the precipitate into a crystalline hydroxyapatite, the
crystallite size, and the particle morphology and size
distribution. Short aging times were preferred by high precursor
concentrations and long aging times were preferred by low precursor
concentrations. Amount of NH.sub.4OH affected the solubility of
hydroxyapatite and the particle morphology and size distribution.
Low NH.sub.4OH amounts were preferred at high precursor
concentrations favored low NH.sub.4OH amounts while intermediate
NH.sub.4OH amounts were preferred at low precursor concentrations.
Precursor addition rate affected the nucleation and crystal growth
rates and particle morphology. Slow addition rates were preferred
at both high and low precursor concentrations. Precursor
concentration affected the rate of reaction of hydroxyapatite.
Optimal conditions were determined for both precursor
concentrations. The nano-hydroxyapatite precursor gel heat treated
at 550.degree. C. gave an ultrafine grain size of 40 nm by TEM
observation. This high-purity nano-hydroxyapatite also had higher
B.E.T. surface areas than samples heat treated to 700.degree. C. or
900.degree. C. and was used to prepare compacts for pressureless
sintering. The nano-hydroxyapatite compact had superior
sinterability when compared to conventional hydroxyapatite. The
highly densified hydroxyapatite was obtained by pressureless
sintering at 1100.degree. C. Also, the dense compacts derived from
nanocrystalline hydroxyapatite demonstrated excellent resistance to
high-temperature decomposition, compared to the conventional
hydroxyapatite. This should give rise to superior properties in
bioceramic applications. The nano-hydroxyapatite synthesized in
this study was resistant to thermal decomposition into .beta.-TCP
and CaO up to 1300.degree. C.
EXAMPLE 10
Colloidal and Hot Pressing of Nanocrystalline Hydroxyapatite
By only controlling the synthesis parameters without any subsequent
powder processing, 96% theoretical bulk density was obtained,
indicating the superiority of this nanocrystalline hydroxyapatite
powder. To further illustrate the improvements of the
nanocrystalline hydroxyapatite and its processing over the
conventional hydroxyapatite and conventional processing and to
exceed the 96% theoretical bulk density obtained from pressureless
sintering, the nanocrystalline powders were densified by colloidal
and hot pressing.
Table 17 presents the synthesis conditions of the hot pressed
powders, and Table 18 illustrates the effect of hot pressing on the
sintered densities and compares the densities obtained from hot
pressing to those obtained from pressureless sintering at
1100.degree. C. All powders were hot pressed at a pressure of 54
MPa and at a ramp rate of 10.degree. C./min and with a dwell time
of 30 minutes at 1100.degree. C. After hot pressing, the pellets
were polished with 600 grit and 800 grit SiC. Densities were
measured by Archimedes' method in water.
TABLE-US-00017 TABLE 17 Effect of Hot Pressing: Synthesis
Conditions Aging Ca(NO.sub.3).sub.2 CaN NHP Time Rxn/Aging Addition
Rate Grinding Concentration Amount Concentration Amount NH.sub.4OH
Trial (hr) Temp (.degree. C.) (ml/min) Method (M) (ml) (M) (ml)
Amount (ml) 18 12 0 2 Wet 0.500 300 0.300 300 30 9 12 25 2 Wet
0.500 300 0.300 300 10 19 12 25 13 Wet 0.167 900 0.100 900 90
TABLE-US-00018 TABLE 18 Effect of Hot Pressing: Results %
Theoretical % Theoretical BET Bulk Density Bulk Density XRD Surface
Green by Pressureless by Hot Crystallite Area Density Sintering
Pressing Trial Size (nm) (m.sup.2/g) (g/cc) at 1100.degree. C. at
1000.degree. C. 18 36 53.70 1.56 67.7 3.05 g/cc 9 67 72.58 1.59
94.3 98.5 19 38 70.77 1.49 91.1 99.0
From the results presented in Table 18, hot pressing is observed to
have a dramatic impact on the sintering of the hydroxyapatite
powder. Hot pressing increased the % theoretical bulk density of
the powder from Trial 9, one of the optimal conditions determined
in the previous section, to 98.5% and enabled Trial 19 to achieve
99% theoretical density. The pellets of Trial 9 and 19 possessed a
glassy finish and were slightly translucent. The .beta.-TCP
decomposition products, barely detectable by XRD, were found in the
XRD patterns of the hot pressed powders from Trials 9 and 19.
Furthermore, the grain sizes of the sintered pellets were found to
be less than 225 nm by SEM, indicating that an ultrafine
microstructure was present after the sintering process. Remarkably,
even with a powder with poor pressureless sintering characteristics
such as that of Trial 18, the bulk density can be increased from
2.14 g/cc to 3.05 g/cc through hot pressing. Though this sample
decomposed significantly into .beta.-TCP, this pellet was pore-free
as indicated by the transparency of the pellet. The operating
conditions presented for hot pressing provide an upper limit for
sintering temperature and a lower limit for the applied pressure
because of the slight decomposition detected in the XRD patterns.
Observations indicate that densification stops before 1000.degree.
C., and that 900.degree. C. or 800.degree. C. may be the preferred
sintering temperature. By hot pressing, the sintering temperature
can be reduced by 200.degree. C. or 300.degree. C. Increasing the
applied pressure is also anticipated to facilitates the sintering
process. The most dramatic results from hot pressing are associated
with a less crystalline and a more amorphous hydroxyapatite
starting powder. Hot pressing seems to favor powders synthesized
under either low temperature or low precursor concentration
conditions. The results from hot pressing are a further
demonstration of the superiority of the nanocrystalline
hydroxyapatite powder; without any special powder processing, full
densification of hydroxyapatite can be achieved. Colloidal
Pressing
The sample (Trial 20) prepared by colloidal pressing was
synthesized under the similar conditions as Trial 15. The
as-synthesized hydroxyapatite gel, instead of rinsing and
centrifuging with ethanol in the last two washing steps, was washed
with water. A slurry was prepared, and this slurry was colloidally
pressed. After careful drying, the pellet was CIPed to 300 MPa and
sintered to 1100.degree. C. for 2 hours at 5.degree. C./min. A
highly translucent pellet was obtained with a 95.8% theoretical
density. However, slight decomposition was detected in the XRD
patterns. These data do strongly suggest that the hydroxyapatite
prepared by the method described in previous section is well suited
to colloidal pressing as indicated by the translucent pellet. A
mild hydrothermal treatment of the precipitate prior to colloidal
pressing may improve sintering by increasing the crystallinity of
the material and by reducing the reactivity of the as-synthesized
gel; the hydroxyapatite phase will be more stable and decomposition
will be reduced. Furthermore, by controlling the pH and ionic
strength of the slurry (e.g. by the addition of NH.sub.4NO.sub.3),
the state of agglomeration and particle morphology can be
controlled to enhance densification.
EXAMPLE 11
Synthesis and Characterization of Hydroxyapatite-Zirconia
Composites
A composite including an apatite and a structural additive was
prepared, with the additive selected to enhance the mechanical
properties. To further strengthen hydroxyapatite and to maintain
the nanocrystallinity after sintering, the addition of a secondary
component is proposed. Many types of hydroxyapatite composites have
been developed to take advantage of both the properties of
hydroxyapatite and of the secondary phases. Hydroxyapatite-polymer
composites have been developed to improve upon the mechanical
reliability of conventional hydroxyapatite. Hydroxyapatite has also
been used as the reinforcing phase in glass-hydroxyapatite
composites. Hydroxyapatite composites formed with another secondary
ceramic phase such as alumina or zirconia have been shown to
significantly improve the mechanical properties of hydroxyapatite.
The hydroxyapatite-alumina composites required complex processing
such as glass encapsulated hot isostatic pressing. Significant
improvements in mechanical properties were observed when vol %
alumina in the composite increased above 50%. However, as the
volume % of alumina is increased, the bioactivity of the composite
decreases. The mechanical properties of the hydroxyapatite-zirconia
composites are expected to match or exceed the
hydroxyapatite-alumina composites while using a smaller volume % of
zirconia. This is because zirconia has more mechanisms by which it
can provide mechanical reinforcement than alumina. Zirconia
dispersiods can toughen the hydroxyapatite matrix by a
transformation toughening mechanism as well as crack deflection. By
using nanocrystalline materials processing, the mechanical
properties can be further enhanced. The zirconia dispersion can
then be used to "pin" the hydroxyapatite grains suppressing grain
growth during calcination and sintering to preserve nanometer-sized
crystallites.
In trying to develop a composite with the optimal mechanical
properties, the effects of the grain sizes of the hydroxyapatite
and zirconia, dopant concentration, milling time, and milling
intensity were investigated. Nanocrystalline hydroxyapatite and
zirconia were synthesized by chemical precipitation. Through the
previous studies on the synthesis and characterization of
hydroxyapatite, the processing parameters can be controlled to
obtain a specified grain size and particle morphology and sintered
density.
Synthesis of Nanocrystalline Hydroxyapatite
Aqueous solutions of 0.300 M (NH.sub.4).sub.2HPO.sub.4 and 0.500 M
Ca(NO.sub.3).sub.2 were prepared so that the Ca:P ratio was 10:6
and were mixed with a magnetic stirrer. The pH of the
(NH.sub.4).sub.2HPO.sub.4 aqueous solution was varied by adding 30
ml of concentrated NH.sub.4OH. 300 ml of a 0.500 M solution of
Ca(NO.sub.3).sub.2 was added to 300 ml of 0.300 M aqueous
(NH.sub.4).sub.2HPO.sub.4 at 10 ml/min. The combined solutions were
magnetically stirred for 12 hours and aged at room temperature. The
white precipitate was collected by filtration with a Buchner funnel
and washed at least three times with distilled water with a
decreasing concentration of NH.sub.2OH each time and finally with
ethanol. The gel was air dried at room temperature for 24 hours and
then dried in a 150.degree. C. oven for 12 hours. The gel was then
finely ground with an alumina mortar and pestle. The ground powders
were then heat treated in air at 550.degree. C. with a heating rate
of 10.degree. C./min, and a dwell time of 2 hours.
Synthesis of Nanocrystalline Zirconia
A 2.00 M ZrOCl.sub.2.8 H.sub.2O (3 mol % Y.sub.2O.sub.3) stock
solution is prepared from reagent grade ZrOCl.sub.2.8 H.sub.2O and
Y.sub.2O.sub.3 and deionized water. The stock solution is allowed
to stir for 24 hours prior to use. 25 ml of the 2.00 M
ZrOCl.sub.2.8 H.sub.2O (3 mol % Y.sub.2O.sub.3) is pipetted 225 ml
of ethanol under constant stirring. This working solution is
allowed to stir for 30 minutes. Next, a base solution is prepared
by pipetting 100 ml of ammonium hydroxide into 250 ml of ethanol
under constant stirring and by allowing the solution to stir for at
least 15 minutes. The precipitation reaction occurs when the 0.200
M working solution is added to a base solution at 15 ml/min under
constant stirring. The solution is allowed to stir and age for 24
hours. Next, the solution is centrifuged at 1500 rpm for 20 minutes
and decanted. The resulting gel is redispersed in ethanol and
centrifuged 4 more times under the same conditions to quench the
reaction and to remove all the chloride ions. The gel is then
ground with a pestle in a preheated mortar until a fine powder is
obtained. This powder is allowed to dry in a 110.degree. C. oven
overnight. Finally, the powder is calcined at 550.degree. C. for 2
hours with a ramp rate of 10.degree. C./min.
Proof of Concept and Initial Studies
In these series of experiments, composites formed from conventional
hydroxyapatite (Aldrich), conventional zirconia (Toso),
nanocrystalline hydroxyapatite, and nanocrystalline zirconia heat
treated at 550.degree. C. were investigated. The composite was
formed by dry milling the hydroxyapatite with 10 vol % of zirconia
for 24 hours, CIPing at 300 MPa for 3 minutes, pressureless
sintering for 2 hours in air at sintering temperatures of
1100.degree. C., 1200.degree. C., and 1300.degree. C. This dry ball
milling ensured good mixing and contact between the two components
without the transformations that might occur by high-energy ball
milling. The XRD patterns of the nanocrystalline
Y.sub.2O.sub.3-doped ZrO.sub.2 indicated the presence of zirconia
as 12 nm crystallites. A PA-FTIR spectrum indicated the presence of
Zr-O-Zr, H.sub.2O and ZrOH peaks. The calcined nanocrystalline
Y.sub.2O.sub.3-doped ZrO.sub.2 possessed a BET surface area of 140
m.sup.2/g and an average pore size of 9 nm. After calcination at
550.degree. C., the nanocrystalline hydroxyapatite had a XRD
crystallite size of 32 nm and a BET surface area of 66.8
m.sup.2/g.
The XRD patterns of the sintered nano-hydroxyapatite/nano-zirconia
composite indicated that the composite was thermally stable up to
1200.degree. C., and that significant phase transformation of
hydroxyapatite and zirconia into tricalcium phosphate and
monoclinic zirconia, respectively, occurred at 1300.degree. C. When
comparing the sinterability of nano-hydroxyapatite and zirconia
reinforced hydroxyapatite, the composite required a higher
sintering temperature of 1200.degree. C. to achieve full
densification while the pure nano-hydroxyapatite required
1100.degree. C. to achieve full densification. The nanocrystalline
composite possessed better sinterability than any composite
containing a conventional hydroxyapatite and/or ZrO.sub.2 powder.
By 1200.degree. C., the nano-hydroxyapatite/nano-zirconia composite
attained 98% theoretical density of hydroxyapatite while
nano-hydroxyapatite/zirconia (Toso) achieved less than 70%
theoretical density by 1300.degree. C.
TEM micrographs indicated that there were no glassy phases at the
grain boundaries showing that the nanocomposite achieved good
densification without the precipitation of undesirable secondary
phases. Zirconia grains were intragranularly dispersed within the
hydroxyapatite matrix. With smaller grain sizes, a more
mechanically robust material is obtained. The pure nanocrystalline
hydroxyapatite possessed a compressive strength of 745 MPa while
the conventional micron-sized hydroxyapatite possessed a
compressive strength of 150 MPa. Further reinforcement of the
nanocrystalline hydroxyapatite with a secondary dispersoid of
nanocrystalline zirconia resulted in an even higher compressive
strength of 1020 MPa. This improvement in compressive strength is
believed to be due to the intragranular toughening of the
nanocrystalline hydroxyapatite matrix by the nano-ZrO.sub.2
dispersoids.
Another method for the synthesis of nanocrystalline hydroxyapatite
yields an improved nanocomposite with an even higher compressive
strength, a lower sintering temperature and greater thermal
stability. The method of producing the composite uses ajar mill to
disperse the zirconia into the hydroxyapatite. Recent experiments
suggests that better mixing and contacting between the zirconia and
hydroxyapatite can be achieved by co-precipitation, or by
dispersing zirconia particles during either the chemical
precipitation or the aging of the nanocrystalline
hydroxyapatite.
The proof of concept and initial studies of the synthesis of
hydroxyapatite/zirconia nanocomposite used an earlier method for
the synthesis of nanocrystalline hydroxyapatite. By using the
recently optimized method for the synthesis of nanocrystalline
hydroxyapatite (Trial 9 or 15), an improved nanocomposite with an
even higher compressive strength, a lower sintering temperature and
greater thermal stability may be produced. The method of producing
the composite reported above used a jar mill to disperse the
zirconia into the hydroxyapatite. Recent experiments suggest that
better mixing and contacting between the zirconia and
hydroxyapatite can be achieved by dispersing zirconia particles
during either the chemical precipitation or the aging of the
nanocrystalline hydroxyapatite.
EXAMPLE 12
Synthesis and Characterization of Nanocrystalline Carbonate
Hydroxyapatite
Since the mineral phase of human bone has recently been identified
as carbonate apatite, not hydroxyapatite.sup.7, a nanocrystalline
carbonate apatite can be used as a reactive layer on a bioceramic
to enhance bioactivity for bone growth on the surfaces of the
implant. Because the poor mechanical properties of carbonate
apatite prevent it from being used as a structural material, the
focus of this work will be the synthesis and the characterization
of nanocrystalline carbonate apatite powder. With the ability to
synthesize a high surface area carbonate apatite powder, the
bioactivity of artificial bone crystals can be controlled.
To further illustrate the versatility of the preparative technique
developed for synthesis of hydroxyapatite, the chemical
precipitation process in which nanocrystalline hydroxyapatite is
synthesized was modified to derive nanocrystalline carbonate
apatite, Ca.sub.10(PO.sub.4).sub.6CO.sub.3 (Type A where the
CO.sub.3.sup.2- occupies the monovalent anionic (OH.sup.-) sites)
or Ca.sub.10-x(PO.sub.4).sub.6-2x(CO.sub.3).sub.2x(OH).sub.2(1-x)
(Type B where the CO.sub.3.sup.2- occupies the trivalent anionic
(PO.sub.4.sup.3-) sites). Type A carbonate apatite is a
well-defined class of compounds normally synthesized at elevated
temperatures. In contrast, Type B carbonate apatite is a poorly
defined class of compounds typically synthesized at low
temperatures under aqueous conditions. Carbonate apatite can be
generated by either saturating the reaction solution with carbon
dioxide or by adding another carbonate source such as sodium
bicarbonate or ammonium bicarbonate, followed by a hydrothermal
treatment, in an attempt to stabilize the carbonate ion in the
precipitate.
Synthesis of Nanocrystalline Carbonate Apatite
Aqueous solutions of 0.075 M to 0.300 M (NH.sub.4).sub.2HPO.sub.4
and 0.500 M Ca(NO.sub.3).sub.2 were prepared so that the Ca:P ratio
varied from 6.67 to 1.67 and were mixed with a magnetic stirrer.
The pH of the (NH.sub.4).sub.2HPO.sub.4 aqueous solution was
adjusted by adding 10 ml of concentrated NH.sub.4OH. 300 ml of a
0.500 M solution of Ca(NO.sub.3).sub.2 was added to 300 ml of 0.300
M aqueous (NH.sub.4).sub.2HPO.sub.4 at 3 ml/min. A gas stream
composed of 5% CO, and 95% N.sub.2 was bubbled through the
precipitate immediately after addition or 6 hours after addition
for 18 hours. Some trials were magnetically stirred for 100 hours
and aged at room temperature, while others were aqueously aged for
50 hours followed by 50 hours of hydrothermal treatment at
180.degree. C. The white precipitate was collected by
centrifugation at 1500 rpm for 15 minutes. After decanting, the
precipitate was redispersed in a solution of distilled water and
NH.sub.4OH by magnetically stirring for 20 minutes; this procedure
was repeated two more times with decreasing amounts of NH.sub.4OH,
and two times with ethanol. The gel was air dried at room
temperature for 24 hours, and then dried in a 150.degree. C. oven
for an additional 24 hours. The gel was then finely ground with an
alumina mortar and pestle. The ground powders were then heat
treated in air at 550.degree. C., 700.degree. C. and 900.degree. C.
with a heating rate of 10.degree. C./min, and a dwell time of 2
hours.
Proof of Concept and Initial Studies
The synthesis of hydroxyapatite is known to undergo an induction
period. Prior to hydroxyapatite formation, the precipitate is
thought to convert from an amorphous calcium phosphate to an
octacalcium phosphate and then to hydroxyapatite. Furthermore, the
induction period increases with increasing pH. By synthesizing the
hydroxyapatite at a low pH, higher solubility of hydroxyapatite is
anticipated to aid the incorporation of the carbonate ion. In this
initial study, the effect of carbonate substitution during pre- and
post-HAP formation, the effect of varying the Ca/P ratio, and the
effect of aqueous aging versus hydrothermal treatment were
examined. In all samples, a mixed phase of hydroxyapatite, Type A
and Type B carbonate apatite was detected. Introducing CO.sub.2
immediately after the addition of Ca(NO.sub.3).sub.2 was found to
minimize the formation of CaCO.sub.3, as determined by the XRD
patterns and FTIR spectra. If CO.sub.2 was added 6 hours after
Ca(NO.sub.3).sub.2 addition was completed, significant CaCO.sub.3
formed because more calcium cations were in solution as a result of
the reprecipitation process, while calcium was bound in the
precipitate immediately after Ca(NO.sub.3).sub.2 addition. In both
aqueous aging and hydrothermal treatment, CaCO.sub.3 was detected
in the XRD patterns when [(NH.sub.4).sub.2HPO.sub.4]<0.224 M.
For aqueously aged samples, both Type A and Type B carbonate
apatites were detected in FTIR spectra. 879 cm.sup.-1 is assigned
to Type A carbonate apatite, and 873 cm.sup.-1 is assigned to Type
B carbonate apatite. Type A is favored over Type B for aqueously
aged samples when [(NH.sub.4).sub.2HPO.sub.4]=0.3 M. For this
sample, the XRD crystallite size was determined to be 25 nm. This
is considerably smaller than the XRD crystallite size determined
from hydroxyapatite synthesis which strongly suggests that the
presence of the carbonate ions restricts crystal growth. CaCO.sub.3
became the dominant phase for aqueously aged samples when
[(NH.sub.4).sub.2HPO.sub.4]<0.224 M. For hydrothermally aged
samples, both Type A and Type B carbonate apatites were detected in
the FTIR spectra but the relative intensity of the Type A and Type
B peaks suggests that hydrothermal treatment is more selective
towards Type A carbonate apatite formation. Hydrothermal treatment
stabilized the apatite phase with CaCO.sub.3 becoming the dominant
phase when [(NH.sub.4).sub.2HPO.sub.4]<0.075 M. In a subsequent
experiment, carbonate apatite was synthesized under the following
conditions: (1) 300 ml 0.5 M Ca(NO.sub.3).sub.2, (2) 300 ml 0.3 M
(NH.sub.4).sub.2HPO.sub.4, (3) 10 ml NH.sub.4OH, (4) 80.degree. C.
reaction and aging temperature, (5) 3 ml/min Ca(NO.sub.3).sub.2,
and (6) immediate introduction of CO.sub.2 after Ca(NO.sub.3).sub.2
was added at 3 ml/min. The XRD pattern was identified as an
apatite, with the FTIR spectra detecting Type A and Type B with
Type A slightly favored. The XRD crystallite size for this sample
was 65 nm, also considerably smaller than sizes measured for
hydroxyapatite synthesized at similar conditions. These results
suggest that Type B will be favored when synthesized at
temperatures below 25.degree. C. Furthermore, the introduction of
carbonate into the apatite structure may be more carefully
controlled by using NH.sub.4HCO.sub.3 instead of CO.sub.2(g). The
surface areas for nanocrystalline carbonate apatite is expected to
be similar to or greater than the surface areas of nanocrystalline
hydroxyapatite synthesized under similar conditions.
This example illustrates the versatility of the process developed
for synthesizing nanocrystalline hydroxyapatite and the benefits of
carefully controlling the process parameters. By introducing a
carbonate source and controlling the processing parameters, a
nanocrystalline carbonate apatite, both Type A and Type B, was
synthesized. Through further refinement, Type A and Type B
carbonate apatite can be selectively synthesized, and the degree of
substitution of carbonate ions for the phosphate ions in Type B
carbonate apatite can be controlled. Important parameters will be
reaction and aging temperatures, carbonate source, method of
carbonate introduction, precursor concentrations, aging time, and
pH.
SUMMARY OF EXAMPLES
The above examples demonstrate superior processes and products
resulting from densifications of nanocrystalline hydroxyapatite.
The grain sizes of calcined samples varied from 30 nm to 100 nm
depending how pH, aging time, reaction and aging temperature,
Ca(NO.sub.3).sub.2 addition rate, precursor concentration, and
grinding method were controlled, while the grain sizes of
conventional hydroxyapatite were on a micron scale. For example,
the surface area of one sample of the invention after calcination
at 550.degree. C. is 159.5 m.sup.2/g while the conventional sample
after calcination at 550.degree. C. has a very small surface area
of 5.4 m.sup.2/g. The sample of the invention retained phase
uniformity after calcination at 550.degree. C., but the
conventional sample began to transform into tricalcium phosphate at
550.degree. C. with substantial conversion to tricalcium phosphate
and calcia by 700.degree. C. In a sample of the invention 96% of
the theoretical density was obtained at a low sintering temperature
of 1100.degree. C. by pressureless sintering for nanocrystalline
hydroxyapatite which was stable up to 1300.degree. C. However, the
conventional sample achieved only 70% of the theoretical density at
1200.degree. C. with decomposition into tri-calcium phosphate.
Furthermore, the densified conventional sample contained large
pores and microcracks. Our nanocrystalline hydroxyapatite has high
purity and phase homogeneity as well as superior sinterability
compared to the conventionally prepared hydroxyapatite. When our
nanocrystalline hydroxyapatite was sintered using either colloidal
or hot pressing, 99% theoretical bulk density with a grain size of
less than 250 nm can be obtained. Dense nanocrystalline
hydroxyapatite compacts further possessed a compressive strength as
high as 745 MPa, while the conventional micronsized hydroxyapatite
compacts from a similar pressureless sintering treatment possessed
a compressive strength of 150 MPa. Additionally, further
reinforcement of the hydroxyapatite can be accomplished by
introducing a secondary dispersoid such as zirconia which would
greatly improve the toughness and chemical stability of
hydroxyapatite by pinning the mobility of any intergranular and
intragranular defects. A dense composite of nanocrystalline
hydroxyapatite and 10 wt % nanocrystalline 3 mol %
Y.sub.2O.sub.3-doped ZrO.sub.2 possessed an even higher compressive
strength of 1020 MPa. With more complete characterization, the
densified nanocrystalline hydroxyapatite and
hydroxyapatite-zirconia composites can easily be developed into
dental and orthopedic weight-bearing implants. Furthermore, the
processing of nanocrystalline hydroxyapatite can be adapted to
synthesize a nanocrystalline carbonate apatite illustrating the
versatility of our process. This process can also be used to
selectively synthesize Type A and Type B carbonate apatite as well
as to control the degree of substitution of the carbonate ion into
the apatite structure.
Those skilled in the art would readily appreciate that all
parameters listed herein are meant to be exemplary and that actual
parameters will depend upon the specific application for which the
methods and apparatus of the present invention are used. It is,
therefore, to be understood that the foregoing embodiments are
presented by way of example only and that, within the scope of the
appended claims and equivalents thereto, the invention may be
practiced otherwise than as specifically described.
* * * * *