U.S. patent application number 10/626761 was filed with the patent office on 2004-04-15 for method for repairing a damaged portion of a human organ.
Invention is credited to Elia, James P..
Application Number | 20040071637 10/626761 |
Document ID | / |
Family ID | 46299660 |
Filed Date | 2004-04-15 |
United States Patent
Application |
20040071637 |
Kind Code |
A1 |
Elia, James P. |
April 15, 2004 |
Method for repairing a damaged portion of a human organ
Abstract
An organ derived from genetic material is inserted in a
patient's body. Genetic material is inserted at a selected site in
the body to grow an organ.
Inventors: |
Elia, James P.; (Scottsdale,
AZ) |
Correspondence
Address: |
Gerald K. White, Esq.
GERALD K. WHITE & ASSOCIATES, P.C.
Suite 835
205 W. Randolph Street
Chicago
IL
60606
US
|
Family ID: |
46299660 |
Appl. No.: |
10/626761 |
Filed: |
July 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10626761 |
Jul 24, 2003 |
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09794456 |
Feb 27, 2001 |
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09794456 |
Feb 27, 2001 |
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09064000 |
Apr 21, 1998 |
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09064000 |
Apr 21, 1998 |
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08837608 |
Apr 21, 1997 |
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08837608 |
Apr 21, 1997 |
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08326857 |
Oct 21, 1994 |
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5759033 |
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08326857 |
Oct 21, 1994 |
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08087185 |
Jul 2, 1993 |
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5397235 |
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08087185 |
Jul 2, 1993 |
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08053886 |
Apr 27, 1993 |
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5372503 |
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Current U.S.
Class: |
424/50 ;
424/93.21 |
Current CPC
Class: |
C12N 5/0654 20130101;
A61C 8/00 20130101; A61K 35/44 20130101; C12N 2501/155 20130101;
A61C 8/0018 20130101; C12N 2501/48 20130101; C12N 2501/60 20130101;
A61K 48/0058 20130101; A61C 8/0001 20130101; A61C 8/0006 20130101;
A61K 48/005 20130101; C12N 5/069 20130101; A61K 48/0075 20130101;
A61K 35/32 20130101; A61C 8/0039 20130101 |
Class at
Publication: |
424/050 ;
424/093.21 |
International
Class: |
A61K 048/00; A61K
007/28 |
Claims
Having described my invention in such terms as to enable those
skilled in the art to understand and practice it, and having
described the presently preferred embodiments thereof, I claim:
1. In combination with an implant site in the alveolar bone of a
patient, the improvements which enable the growth of a tooth at
said site, said improvements comprising, in combination with said
site, implant means comprising genetic material assembled in vitro
to cause a tooth to grow at said site.
2. A method for preparing an implant for placement at a selected
implant site in the body of a patient to form an organ, comprising
the steps of (a) selecting said implant site; (b) preparing an
implant adapted for placement at said site and including genetic
material which causes the formation of an organ at said implant
site.
3. In combination with an implant site in a patient, the
improvements which enable the growth of an organ at said site, said
improvements comprising, in combination with said site, implant
means comprising genetic material assembled in vitro to cause an
organ of grow at said site.
4. A method for producing ex vivo an organ to implant in the body
of a patient, including the steps of (a) providing at least one
cell; (b) providing genetic material to activate the cell to grow
an organ; and, (c) combining said genetic material and said
cell.
5. Apparatus for growing an organ to implant in the body of a
patient, comprising in combination (a) at least one cell; (b)
genetic material; and, (c) means for combining said cell and said
genetic material to grow an organ.
Description
[0001] This invention relates to a method and apparatus for
installing a dental implant in the alveolar or basal bone of a
patient.
[0002] More particularly, the invention relates to a method and
apparatus for a dental implant which reduces the likelihood of the
implant becoming infected, which does not require an opening of
precise size to be drilled or formed in the alveolar bone to
receive the dental implant, which can mount an implant on existing
alveolar bone without requiring alteration of the structure of the
bone, which prevents the juncture of the dental implant and
artificial tooth attached to the implant from being exposed in the
event the patient's gums recede, which enables bone mass lost as
the patient ages to be replaced, and which enables an implant to be
used when drilling an opening in the alveolar bone is precluded due
to the existence of a nerve in the bone.
[0003] Dental implants are well known in the art. See, for example,
U.S. Pat. No. 5,006,070 to Komatsu, U.S. Pat. No. 4,693,686 to
Sendax, U.S. Pat. No. 4,812,120 to Flanagan et al., U.S. Pat. No.
4,818,559 to Hama et al., U.S. Pat. No. 4,671,768 to Ton, and U.S.
Pat. No. 4,175,565 to Chiarenza et al. Such prior art dental
implants and methods for installing the same have
disadvantages.
[0004] First, the implants normally must be press fit or wedged
into an opening formed in the alveolar bone. Force fitting an
implant into the alveolar bone is not desirable because it is
uncomfortable for the patient, runs the risk of cracking the jaw
bone, further damages the bone, and, most importantly, increases
the likelihood of infection because dental implants ordinarily are
provided with an assortment of ridges, points, or teeth which serve
as desirable sites for bacteria, both before and after the implant
is inserted in the bone. As a consequence, dental implants
typically appear medieval.
[0005] Second, force fitting an implant in the alveolar bone
requires that the opening formed in the bone have a specific size
which roughly conforms to the outer dimensions of the implant so
the implant can be force fit into the opening. If a dental surgeon
selects a drill of improper size, or waggles the drill while
forming the hole in the alveolar bone, the implant may not seat
properly in the bone and will work free from the jaw.
[0006] Third, the surface area of the portion of the implant
imbedded in the jaw is typically reduced because of the common
belief that fenestrations of various size must be formed in the
implant to permit bone to grow through and anchor the implant.
[0007] Fourth, conventional implant procedures often can not be
used because the drilling of a opening in the alveolar bone is
prohibited by a nerve which passes through the bone.
[0008] Fifth, conventional implant procedures also often can not be
successfully used when the jaw bone has significantly receded, as
can be the case with older patients.
[0009] Sixth, conventional implant procedures do not offer a way of
replacing alveolar bone which has been lost due to aging or to some
other cause resulting in injury to the bone.
[0010] Seventh, conventional implant procedures typically do not
permit the ready adjustment of the position of the implant after
the implant is inserted in the opening formed in the alveolar bone.
Correcting the position of an improperly installed implant is often
difficult, unless the implant is completely removed from the
alveolar bone, which is a time consuming process.
[0011] Accordingly, it would be highly desirable to provide an
improved dental implant method and apparatus which would not
require the force fitting of an implant in the alveolar bone, would
not require the formation of a specific size opening in the jaw
bone, would provide an implant less likely to loosen after being
inserted in the alveolar bone, would permit an implant to be used
on alveolar bone housing a nerve, would enable implants to be
successfully utilized on alveolar bone which has receded with age,
and would permit the position of the implant to be readily adjusted
after the implant is inserted in an opening in the alveolar
bone.
[0012] Therefore, it is a principal object of the invention to
provide an improved dental implant method and apparatus.
[0013] Another object of the invention is to provide an improved
dental implant which can be inserted in an opening in the alveolar
bone without requiring that the opening must, within close
tolerances, have a specific shape and dimension.
[0014] A further object of the invention is to provide an improved
dental implant which permits ready adjustment of the position of
the implant after the implant is placed in an opening formed in the
jawbone.
[0015] Still another object of the invention is to provide a dental
implant method which permits an implant to be attached to alveolar
bone housing a nerve.
[0016] Yet a further object of the invention is to provide a dental
implant method which allows an implant to be utilized on alveolar
bone which has experienced significant loss and recession of its
mass.
[0017] Another and further object of the instant invention is to
provide an improved dental implant which is less likely to loosen
after insertion in the alveolar bone.
[0018] These and other, further and more specific objects and
advantages of the invention will be apparent to those skilled in
the art from the following detailed description thereof, taken in
conjunction with the drawings, in which:
[0019] FIG. 1 is a front view of a dental implant apparatus
constructed in accordance with the principles of the invention;
[0020] FIG. 2 is a section view of the dental implant apparatus of
FIG. 1 illustrating internal construction details thereof;
[0021] FIG. 3 is a side view of a portion of the lower jaw bone
illustrating the implant of FIG. 1 installed in an opening formed
in alveolar bone;
[0022] FIG. 4 is a top view of a portion of the jaw bone of FIG. 3
further illustrating the installation of the implant of FIG. 1
therein;
[0023] FIG. 5 is a perspective view illustrating a sheet of
protective material used to shield hydroxyapatite composition used
to pack an implant into an opening in the alveolar bone;
[0024] FIG. 6 is a top view of a portion of the lower jaw bone
illustrating the insertion of an implant in an opening formed by
laterally drilling into the jaw bone;
[0025] FIG. 7 is a side view of the jaw bone of FIG. 7 further
illustrating the lateral opening formed in the jaw bone;
[0026] FIG. 8 is a side partial section view illustrating an
alternate embodiment of the implant of the invention inserted in an
opening formed in the alveolar bone;
[0027] FIG. 8A is a side view illustrating a portion of the implant
of FIG. 8 after the healing cap is removed;
[0028] FIG. 9 is a perspective view illustrating a healing cap used
in the implant of FIG. 8;
[0029] FIG. 10A is a side section view illustrating normal alveolar
bone structure around an incisor tooth;
[0030] FIG. 10B is a side section view illustrating the recession
of the alveolar bone structure from around the incisor tooth of
FIG. 10A;
[0031] FIG. 10C is a side view illustrating the insertion of an
implant in the bone structure of FIG. 10C after the incisor tooth
is removed or falls out;
[0032] FIG. 10D is a side view illustrating the alveolar bone
structure of FIG. 10B after the incisor tooth is removed and a
circular drill is used to cut away some of the alveolar bone to
form a cylindrical anchor peg;
[0033] FIG. 10E is a side partial section view illustrating a
dental implant slidably installed on the anchor peg of FIG. 10D and
packed with a malleable hydroxyapatite composition;
[0034] FIG. 10F is a side partial section view illustrating the
alveolar bone structure of 10B after the incisor tooth is removed
and an implant is slid onto the existing alveolar bone structure
without altering the structure;
[0035] FIG. 11 is a perspective view illustrating an implant of the
type which can be fit to an existing alveolar bone structure;
[0036] FIG. 12 is a side partial section view illustrating a
molding procedure utilized in another embodiment of the
invention;
[0037] FIG. 13 is a perspective view of a sacrificial coping
utilized in the embodiment of the invention illustrated in FIG.
12;
[0038] FIG. 14 is a perspective view illustrating another step in
the molding procedure of FIG. 12;
[0039] FIG. 15 is a perspective view illustrating a finished dental
bridge produced according to the method of FIGS. 12 and 14;
[0040] FIG. 16 is a side partial section view illustrating an
artificial tooth removably attached to an implant apparatus;
[0041] FIG. 17 is a side partial section view illustrating a hip
implant procedure;
[0042] FIG. 18 is a partial side section view illustrating an
interlocking opening formed in bone during an implant procedure
according to the invention; and, FIGS. 19 to 21 illustrate an
alternate implant procedure in accordance with my invention.
[0043] Briefly, in accordance with my invention, I provide an
improved dental implant. The implant comprises a body having a
closed top and a bottom and a longitudinal axis extending through
the top and bottom; and, a head supported on the top of the body
and adapted to support an artificial tooth. The body extends
downwardly from the top and terminates at a lower end remote from
the head. The body includes a smooth continuous surface extending
from the top to the bottom and defining the periphery of the top
and the bottom. The smooth surface circumscribes the longitudinal
axis. The body also includes a hollow centrally defined therein,
circumscribed by the continuous surface, and extending into the
body through the bottom a selected distance toward the top. The
hollow only opens at the lower end of the body. The head can have a
smaller width than the body. The hollow can be an involute. The
continuous surface can be shaped such that when any cross section
of the body is taken perpendicular to the longitudinal axis, each
point on the continuous surface is generally equidistant from the
longitudinal axis.
[0044] In another embodiment of the invention, I provide a method
of anchoring a dental implant in the alveolar bone of a patient.
The method comprises the steps of forming an opening in the
alveolar bone; inserting a dental implant in the opening, the
implant comprising a body and a head supported on the body and
adapted to support an artificial tooth, the dental implant only
partially filling the space in the opening; and, packing the space
in the opening which is unoccupied by the dental implant with a
hydroxyapatite composition. The opening can be large enough to
permit the implant to be readily tilted from side to side after
insertion in the opening. After the opening is packed with
hydroxyapatite composition, the implant can be adjusted or tilted
from side to side and the hydroxyapatite composition then
repacked.
[0045] In a further embodiment of the invention, I provide a dental
implant comprising a body; a head supported on the body and having
a longitudinal axis and including an upper portion adapted to
support an artificial tooth and having a distal tip and a
peripheral surface circumscribing the longitudinal axis and
extending downwardly from the distal tip toward the body, and, a
lower portion supported on the body; and, a healing cap. The
healing cap is adapted to be removably attached to the upper
portion of the head and includes a prophylactic portion which, when
the healing cap is attached to the upper portion, slidably extends
downwardly from the tip over and covers at least a portion of the
peripheral surface such that when the implant is inserted in an
opening in the alveolar bone, a solidified filler composition at
least partially fills the opening, extends downwardly from the
distal tip toward the body, and covers the prophylactic portion,
the lower portion, and the body, and the healing cap is removed
from the head, a space exists intermediate the portion of the
peripheral surface and the solidified filler composition such that
an artificial tooth can extend into the space and cover the distal
tip of the head. The filler composition can be a hydroxyapatite
composition.
[0046] In still another embodiment of the invention, I provide a
method of anchoring a dental implant to the alveolar bone of a
patient. The method comprises the steps of placing the dental
implant at a selected site on the alveolar bone, the dental implant
comprising a body and a head supported on the body and adapted to
support an artificial tooth; packing a malleable hydroxyapatite
composition around the dental implant and against alveolar bone of
the patient; and, covering the malleable hydroxyapatite composition
with a pliable sheet of material to at least partially prevent gum
tissue from growing into the hydroxyapatite composition while the
hydroxyapatite composition solidifies.
[0047] In yet another embodiment of the invention, I provide a
dental implant for a ridge of alveolar bone normally at least
partially covered by gum tissue. The implant comprises a body
having a top and a pair of opposed feet each extending downwardly
from the top to a tip at a lower end remote from the top, the feet
having an inner surface shaped, contoured, and dimensioned to
conform to the ridge of alveolar bone when the gum tissue is
removed from the ridge; and, a head supported on the body and
adapted to support an artificial tooth.
[0048] In yet still another embodiment of the invention, I provide
a method of anchoring a dental implant to the existing alveolar
bone of a patient, the bone having an existing outer surface. The
method comprises the steps of removing alveolar bone to form an
outwardly projecting anchor peg having a selected shape and
dimension; and, inserting a dental implant over the anchor peg. The
dental implant comprises a body and a head support on the body and
adapted to support an artificial tooth. The body extends downwardly
from the head to a lower end remote from the head and having an
aperture formed in the lower end. The aperture is shaped and
dimensioned to be slidably inserted on and conform to the outwardly
projecting anchor.
[0049] Turning now to the drawings, which depict the presently
preferred embodiments of the invention for the purpose of
illustrating the practice thereof and not by way of limitation of
the scope of the invention and in which like reference characters
refer to corresponding elements throughout the several views, FIG.
1 illustrates dental implant apparatus which is constructed in
accordance with the principles of the invention and includes a
dental implant which has the general shape of a wine bottle and
includes a cylindrical head 10 attached to a body 11. The closed
top 12 of body 11 has a smooth continuous conical outer surface
which tapers from the smooth continuous outer cylindrical surface
14 of the bottom 11 into the smooth cylindrical outer surface 13 of
head 10. The conical outer surface of top 12, as do smooth
cylindrical surfaces 14 and 13, completely circumscribes
longitudinal axis and centerline 18. Head 10 can, if desired, be
bent at some selected angle with respect to axis 18 and body 11 as
indicated by dashed lines 10B or can be tapered in the manner of
head 10A in FIG. 12. The bottom of body 11 extends downwardly from
the top 12 and terminates at lower end 17 remote from the head 10.
Involute or hollow 15 is formed centrally within body 11, is
circumscribed by continuous surface 14, and extends upwardly into
body 11 a selected distance toward top 12. Hollow 15 opens only at
the lower end 17. Head 13 has a smaller diameter than body 11. An
internally threaded aperture 19 is formed in head 13 to receive the
externally threaded end 20 of a healing cap. The frustroconical
head 21 of the healing cap has a cylindrical aperture 22 formed
therein. Cylindrical member 23 is attached to pliable fabric sheet
24 and is shaped to be removably snap fit into aperture 22. The
sheet 24 can be secured to the healing cap or head 10 using any
convenient means. For example, an aperture 25 can be formed through
a pliable sheet 24A and sized such that end 20 slides through
aperture 25 and permits sheet 24A to be compressed between head 21
and the circular distal end 26 of head 10. Rib 16 outwardly depends
from the smooth cylindrical wall circumscribing and defining hollow
15 and, when hollow 15 is filled with hydroxyapatite or bone in a
manner which will be described, prevents the dental implant from
rotating about axis 18. Most infection in a tooth begins at the gum
line and works its way downwardly toward the root of the tooth. The
smooth continuous outer surfaces 13, 14 of the implant of FIG. 1
facilitate determining how far, if at all, infection has penetrated
downwardly along the outer surfaces of the implant. The extension
of the outer surfaces of the implant from the distal end 26 of the
head to the lower end 17 make it difficult for infection to enter
hollow 15. In many conventional implants, once infection extends a
short distance into the bone, it is a simple matter for the
infection to spread laterally under portions of the implant.
Consequently, in the implant of FIG. 1 it is important that
perforations are not formed through the continuous outer surfaces
13, 14, or the conical surface of top 12. The large area of
surfaces 13 and 14 and of the outer conical surface of top 12 help
distribute the forces which are produced on an artificial tooth
mounted on the implant and decrease the likelihood that the implant
will come loose. The smooth curvature and lack of ridges or points
extending outwardly from implant surfaces 13 and 14 also decreases
the likelihood that stress fractures will be formed in the alveolar
bone during the use of an artificial tooth attached to the
implant.
[0050] The installation of the implant apparatus of FIGS. 1 and 2
in alveolar bone is illustrated in FIGS. 3 and 4. As shown in FIG.
4, an opening 27 is drilled or otherwise formed at a selected
location in the alveolar bone and the dental implant is inserted in
opening 27. FIG. 4 illustrates opening 27 immediately after the
dental implant has been inserted therein. Opening 27 is larger than
the dental implant so that the head 10 can be grasped manually or
with a dental instrument and tilted from side to side in opening
27. The space between the dental implant and the sides of opening
27 which circumscribe the implant is packed with a malleable
hydroxyapatite composition 28. Hollow 15 can also be packed with
the hydroxyapatite composition 28 before the implant is inserted in
opening 27. After the composition 28 is packed into opening 27
around the dental implant, the head 10 can, if desired, be
laterally moved in directions like those indicated by arrows A to
tilt and reposition the implant in opening 27. After the dental
implant is in the desired position in opening 27, the
hydroxyapatite composition is repacked, and member 23 is snapped
into aperture 22 in head 21 to position sheet 24 over opening 27 in
the manner illustrated in FIG. 3. Sheet 24 can be trimmed as
appropriate to cover opening 27. Although not shown in FIG. 4, gum
tissue ordinarily at least partially covers and helps maintain
sheet 24 in its desired position. Sheet 24 can comprise GORTEX or
any other suitable pliable material which helps prevent gum tissue
from growing into the hydroxyapatite composition while it
solidifies. If desired, sheet 24 can comprise a resorbable
material. The GORTEX is left in place for a period of two to twelve
months while the surrounding bone grows into and causes the
hydroxyapatite composition to solidify and anchor the dental
implant in place. After the hydroxyapatite composition has
solidified, the healing cap and the sheet 24 are removed such that
the gum tissue covers the solidified hydroxyapatite composition.
The internally threaded aperture 19 in the head 10 of the implant
is used to attach an artificial tooth to the implant.
[0051] GORTEX is produced by W. L Gore & Assoc., Inc.
Regenerative Technologies of 3773 Kaspar Avenue, Flagstaff, Ariz.
86003-2500, USA. If desired, a pliable sheet 24A can include a
layer of GORTEX or similar pliable material laminated with an
undercoating of collagen, polyglycolic acid, or another desired
material. The collagen imparts a stiffness to sheet 24A and over
time is gradually dissolved by the body. GORTEX is an expanded
polytetrafluroethylene (e-PTFE) material.
[0052] Hydroxyapatite is a crystalline substance containing calcium
and phosphorus and is found in certain rocks. It is the basic
constituent of bone. The hydroxyapatite composition used to pack
opening 27 can simply comprise a dry hydroxyapatite powder. The
hydroxyapatite is, however, normally mixed with a liquid substance
to form a slurry or more malleable composition which is more
readily packed and remains in fixed position than dry
hydroxyapatite powder. Hydroxyapatite powder can be mixed with
water, plaster, collagen, dextran, epinephrine, or some other
desirable material. The hydroxyapatite can be obtained from natural
mineral sources, from ground bone, etc. Materials other than
hydroxyapatite compositions can be used to fill and pack opening
27. Such other materials can include organic and inorganic matrices
and/or combinations thereof. These matrices can be porous,
non-porous, active and/or resorbable matrices, or totally inert.
For example, coral and coral analogs, polymethyl methacrylate,
polyethylene, PTFE (polytetrafluroethylene), polysufone, polymers,
polyethylene glycols, osteomin (bone ash), autogenous bone, freeze
dried demineralized bone, resorbable and non-resorbable
hydroxyapatite, xenographs (bovine), miniscrews, allografts,
composites, polyethylene glycol propionaldehyde, HAPSET, or the
patient's own bone can be utilized.
[0053] In some cases, it is preferable to produce an opening for a
dental implant by forming an aperture in the alveolar bone which
opens laterally or outwardly away from the inside of the patient's
mouth. Such an outwardly opening aperture 32 is illustrated in
FIGS. 6 and 7. In FIG. 7, the dental implant has not yet been
inserted on floor 33 of aperture 32. FIG. 6 illustrates the implant
in aperture 32. A malleable hydroxyapatite composition is utilized
to pack the dental implant in aperture 32. Once aperture 32 is
packed with hydroxyapatite composition and the implant is properly
positioned in the hydroxyapatite composition and aperture 32, a
healing cap is used to attach a pliable layer 24 of material to
head 10 to protect the hydroxyapatite composition from invasion by
epithelial or other living tissue while the composition hardens.
After an appropriate period of time has passed and the bone has
grown into and hardened the hydroxyapatite composition, the healing
cap and layer of material are removed and an artificial tooth is
attached to head 10 using internally threaded aperture 19.
[0054] An alternate embodiment of a healing cap 34 is illustrated
in FIGS. 8 and 9. Cap 34 includes internal cylindrical aperture 35
shaped to slidably fit over the circular distal end 26 of head 10
and to cover at least a portion of the cylindrical peripheral
surface 13 of head 10 of the wine bottle shaped implant of FIG. 1.
The pliable sheet 24 in FIG. 8 has a circular aperture 37 formed
therethrough which is large enough to slide a selected distance up
the conical tip of cap 34, in the manner shown in FIG. 8, but which
is too small to slide over the cylindrical upper end 39 of cap 34.
Consequently, the conical end 40 of cap 34 functions to hold the
sheet 24 in position against the hydroxyapatite composition 28 in
the manner illustrated in FIG. 8. Further, a portion of the conical
end 40 of cap 34 extends downwardly along surface 13 and past end
26 so that after the composition 28 has solidified and cap 34 is
removed from head 10, a conically shaped space 41 (FIG. 8A) exists
intermediate the solidified composition 28 and the upper portion of
surface 13. When an artificial tooth 50 is subsequently attached to
head 10 using the internally threaded aperture 19 formed therein,
the lower portion of tooth 50 can include a cylindrical aperture 51
which slides over the upper end of head 10 and covers distal end
26. As would be appreciated by those of skill in the art, either
sample implants or impression analogs of the head 10, 10A (FIG. 12)
of the support member 70 (FIG. 12) of each implant can be provided
to a dental laboratory so that the lower margins of an artificial
tooth 50 can be perfectly sized to extend into and completely fill
the conically shaped space 41. Distal end 26 ordinarily is
positioned at the gum line after the implant is inserted in an
opening 38 formed in the alveolar bone. Accordingly, the portions
of the artificial tooth 50 extending into space 41 extend below the
gum line of the patient.
[0055] FIG. 10A illustrates a normal, healthy alveolar bone 52
supporting an incisor tooth 53. In FIG. 10B, the bone 52 has
receded due to age or other factors. In FIG. 10C, tooth 53 has been
removed; a cylindrical aperture 54 has been drilled or otherwise
formed in the bone 52; an implant has been inserted in aperture 54;
a malleable hydroxyapatite composition 28 has been packed into
aperture 54, around the implant, and against the bone 52; a layer
of pliable material 24 has been attached to head 10 with the head
21 of a healing cap and extends over the hydroxyapatite composition
28; and, the gum tissue has been positioned over material 24. After
the bone 52 grows into the hydroxyapatite composition 28 and the
composition 28 solidifies, the healing cap and material 24 are
removed, and an artificial tooth is attached to head 10. The
hydroxyapatite composition applied to the implant and bone 52 in
FIG. 10C is used to augment or build the bone 52 back up to a shape
and dimension resembling or duplicating its original normal shape
and dimension illustrated in FIG. 10A. A particular advantage of
the dental implant methodology of the invention is that it permits
hydroxyapatite compositions to be used to augment and enlarge
existing alveolar bone structure while at the same time
facilitating the anchoring of an implant to alveolar bone. To
facilitate the anchoring of an implant in the existing alveolar or
basal bone, indents or grooves can be formed in the bone or in the
surface of the implant to receive hydroxyapatite or other material
used to fill or pack into or around the alveolar or basal bone and
the implant.
[0056] In FIG. 10D, the tooth 53 has been removed from the alveolar
bone 52 of FIG. 10B and a circular drill has been used to remove
some of the bone 52 to form a cylindrical anchor peg 56 which is
shaped and dimensioned to be slidably received by the involute 15
of the implant of FIG. 1 in the manner illustrated in FIG. 10E.
After involute or hollow 15 is slid onto peg 56, malleable
hydroxyapatite composition is packed around the body 11 and head 10
of the implant and the head 21 of the healing cap is used to attach
pliable material 24 to head 10. If desired, hydroxyapatite
composition 28 can also be inserted in hollow 15 before hollow 15
is slid onto peg 56. One the hydroxyapatite composition has
solidified, the healing cap and material 21 are removed, and an
artificial tooth is attached to head 10. The bone 52 illustrated in
FIGS. 10D and 10E includes a nerve 65.
[0057] In FIG. 10F, the tooth 53 has been removed from the alveolar
bone 52 of FIG. 10B and shape of the ridge 64 of bone 52 has not
been altered. An implant has been placed on ridge 64. The implant
includes head 61, body 62, and arch or U-shaped aperture 63.
Aperture 63 is shaped and dimensioned to conform to and slide on to
ridge 64 in the manner illustrated in FIG. 10F. The implant of FIG.
10F can be formed by making a mold of ridge 64 and using the mold
to eventually produce an implant with an aperture 63 which will
conform to ridge 64. Various techniques for making a mold of ridge
64 and using the mold to produce a duplicate of the ridge or to
produce a shape which will conform to the ridge 64 are well known
in the art and will not be discussed herein. After the implant of
FIGS. 10F and 11 is slidably inserted on ridge 64 in the manner
shown in FIG. 10F, malleable hydroxyapatite composition is pressed
against and molded around against the implant and bone 52 and
covered with a layer 24 which is secured to head 61 by head 21 of
the healing cap illustrated in FIG. 1. The externally threaded end
20 of the healing cap is rotated into internally threaded aperture
67 formed in the upper end of head 61. If desired, an aperture(s)
68 can be formed through body 62 to permit a screw(s) to pass
through the aperture 68 and into the bone 52 to secure the implant
to the bone 52. In addition, a slot, indicated by dashed lines 66
in FIG. 10F, can be cut through ridge 64 to receive a panel 69
which is attached to arch 63 in the position indicated by dashed
line 70.
[0058] FIGS. 12 to 15 depict apparatus using in a molding method
which is used in conjunction with the implant apparatus and
methodology of the invention. In FIG. 12, an implant having a head
10A and bottom 11A is held in position in opening 79 formed in
alveolar bone by a solidified hydroxyapatite composition 28.
Composition 28 solidified when the surrounding alveolar bone 80
grew into the composition 28 in opening 79. Head 10A has a conical
head which tapers upwardly from body 11A toward the gum tissue 81.
Head 10A has outer smooth continuous surface 13A. Body 11A includes
outer smooth continuous surface 14A. Frustoconical support member
70 is attached to head 10A. Sacrificial frustoconical coping 71 is
slid over member 70. Sacrificial frustoconical coping 74 is slid
over member 73. If desired, copings 71 and 74 can be metal and not
be sacrificial. Member 73 is attached to the head 10A (not shown)
of another implant (not shown) in the alveolar bone 80. Rubber,
silicone, or some other acceptable material is used to form a
negative mold 72 extending over and around copings 71 and 74 in the
manner shown in FIG. 12. The use of such molding materials in
dentistry is well known and will not be discussed herein. The
negative mold includes upstanding hollow conical member 85;
frustoconical hollows 83 and 84 which conform and adhere to copings
71 and 74, respectively; and, surfaces 86 and 87 which conform to
gum tissue 81. When the negative mold 72 is removed from members 70
and 73, copings 71 and 74 are removed with and are imbedded in the
mold 72.
[0059] After mold 72 has set and is removed from members 70 and 73
and from the patient's mouth, mold 72 is used to make a positive
stone mold 78. This is, as is well known, accomplished by inverting
mold 72, place mold 72 in a container which circumscribes mold 72,
and by pouring a stone mold slurry into sacrificial copings 71 and
74 and over surfaces 86 and 87. After the stone mold slurry hardens
to form mold 78, the mold 78 and mold 72 are heated until mold 72
melts and flows off of stone mold 78, or, mold 72 can simply be
peeled off of the hardened stone mold with or without copings 71
and 74. The positive stone mold 78 which remains replicates the gum
line 81, support members 72 and 73, and the upper portion of each
head 10A as shown in FIG. 12. The stone mold 78 also replicates 82A
the conical groove or detent 82 formed around the upper portion of
each implant head 10A. In FIG. 14, each conical groove 82 has a
shape and dimension equal to the shape and dimension of conical
groove 82 in FIG. 14. Also, in FIG. 14, the portions of the stone
mold which replicate frustoconical members 70 and 73 are not
visible because new sacrificial copings 71A and 74A have been
slipped over said portions of the stone mold (or the copings 71 and
74 which were originally used in the mouth to make mold 72 can
remain on said portions of the stone mold). While the shape and
dimension of each coping can vary, in FIGS. 12 to 14, each coping
71, 74, 71A, 74A is of equivalent shape and dimension. The shape
and dimension of each support member 70 and 73 can also vary as
desired. In FIG. 12, however, each frustoconical support member 70
and 73 is of equal shape and dimension.
[0060] In FIG. 14 a pontic comprised of frustoconical support
member 77 and ribs 75 and 76 has been constructed above the upper
surface 90 of stone mold 78. The pontic interconnects sacrificial
copings 71A and 74A and is positioned adjacent surface 90. The
pontic is typically constructed from wax, but any other desired
material can be utilized. Once the construction of the pontic is
completed, the sacrificial bridge support of FIG. 14 is removed
from mold 78 and mold 78 is discarded, or, mold 78 is retained for
use in subsequent porcelain work. After the sacrificial bridge
support is removed from mold 78, its shape and dimension and
appearance is identical to that of the finished metal bridge
support pictured in FIG. 15.
[0061] In the next step of the molding process, the sacrificial
bridge support is submersed or "invested" in a stone mold slurry
and, before or as the slurry hardens, a small escape channel is
formed which leads from the sacrificial bridge support through and
to the upper surface of the slurry. After the stone mold slurry
hardens, it is heated to melt the wax pontic and the sacrificial
copings 71A and 74A. The melted wax and melted materials from the
copings 71 A and 74A flows out of the stone mold through the escape
channel. After all of the melted material flows out of the stone
mold, a hollow exists in the stone mold which is a negative of the
sacrificial support bridge of Fig. 14 and of the bridge of FIG. 15.
The investment molding process is continued by pouring molten metal
S through the escape channel into this hollow and allowing the
metal to harden. After the metal hardens, the finished support
bridge of FIG. 15 has been formed in the stone mold. The stone mold
is broken away from the bridge to free the finished bridge from the
mold. Porcelain or another desired material is placed on the bridge
supports 74B, 77A, and 71B to build artificial teeth on the bridge.
Ordinarily, a single artificial tooth is built on each bridge
support. After artificial teeth are constructed on the bridge
supports, the bridge is inserted in the patient's mouth by placing
hollow support 71B over member 70 and by placing hollow support 74B
over member 73. Supports 74B and 71B can be glued or otherwise
affixed to members 73 and 70, respectively.
[0062] A method of removably attaching a bridge support 74B and
artificial tooth 91 to a member 73 is illustrated in FIG. 16. In
FIG. 16 a fastener 94 is inserted into aperture 92 and threaded
into internally threaded aperture 93 in member 73. Precise
alignment of apertures 92 and 93 is not required because the
diameter of aperture 92 is slightly larger than that of aperture
93. The undersurface 95 of fastener conforms to and bears against a
portion of conical surface 96 to prevent the tooth 91 from moving
in the directions of arrows B. When fastener 94 is removed from
apertures 92 and 93, coping 74B can be pulled upwardly off of and
free from support member 73.
[0063] In FIG. 16, the upper distal end 26A of head 10A contacts
the bottom of support member 73. The outer peripheral conical
surface of head 10A is contiguous with and lies in a common conical
plane with the outer conical surface 13A of head 10A. Coping 74B
conforms to surface 13A and to the outer conical surface of member
73 so that coping 74B slidably engages and fits said conical
surfaces in the manner illustrated in FIG. 16. The co-planar
relationship of the conical surface of member 73 and the conical
surface 13A of member 10A is important in the practice of the
invention because it enables coping 74B and tooth 91 to extend
sealingly downwardly below the gum line, i.e. to extend downwardly
below end 26A.
[0064] Members 70 and 73 can be fabricated from metal or from
plastic, rubber, copolymer, polymer, composites, or any other
desired material, as can the sacrificial copings 71, 74, 71A,
74A.
[0065] The implant method and apparatus of the invention have
several advantages. First, since the opening which is formed in the
bone to receive the implant does not have to conform to the shape
and dimension of the implant, special drills are not necessary when
the opening is formed in the alveolar or basal bone to receive the
implant. Second, drilling an opening in the bone which is larger
than and does not conform to the shape and contour of the implant
decreases the amount of heat generated during the drilling process.
This is important because bone is damaged when exposed to heat in
excess of 130 degrees centigrade for one minute or more.
Conventional implants require that a cylindrical opening be drilled
in the bone. Drilling such openings requires the use of internally
irrigated slowly rotating burrs and is more likely to generate heat
which damages the bone adjacent the cylindrical opening. When an
opening is drilled for the implant of the invention, a higher speed
externally irrigated burr can be utilized. Third, the implant of
the invention permits non-resorbable hydroxyapatite to be utilized
to fill in the opening around the implant. The non-resorbable
hydroxyapatite produces a strong, tough structure which is less
likely to have saucerization. Saucerization occurs when bone is
lost from around the implant due to stress or bacterial invasion.
This use of non-resorbable hydroxyapatite is particularly
advantageous when a bone ridge which has receded is being augmented
to duplicate the original shape and size of the ridge. Fourth, the
lateral insertion of an implant in the manner illustrated in FIGS.
6 and 7 is useful in the case where a tooth has been missing for
some time and adjacent teeth have migrated into and partially
filled the space of the missing tooth. When this occurs,
conventional implants either are forced to be so small that they
are weak or are prevented from being utilized due to the small size
of the space remaining between the adjacent teeth. The implant of
FIGS. 1 and 8 solves this problem because it has a large base with
a thin neck which can extend between the remaining adjacent teeth.
Fifth, the implant method of the invention covers the junction
between a support member 70 and the head 10A (FIG. 12) of the
implant. In conventional implants, this junction is exposed to oral
fluids and can corrode and fail. Further, dentists often do not
screw or otherwise install member 70 snugly against the top of head
10A, leaving a septic gap. Sixth, the implant of FIGS. 1, 8 and 12
can be long or short and still provide a large outer surface area
for anchoring the implant in the alveolar or basal bone.
[0066] As would be appreciated by those of skill in the art, the
implant methodology described above in connection with dental
implants can be utilized to carry out implants in bone throughout
the body. For example, in FIG. 17, the "ball" at the top of femur
100 has been removed and an oversized opening 101 has been formed
in the top of femur 100. Implant 103 is inserted in opening 101.
The lower portion of implant 103 is the body thereof and the upper
portion of implant 103 (the portion nearest artificial "ball" 105)
is the head of the implant 103. Each implant in the prior art and
illustrated herein includes a lower portion, or body, and an upper
portion, or head. A hydroxyapatite (HA), hydroxyapatite cement
(HAC) or other composition 102 is packed around implant 103 to
secure implant 103 in opening 101. An internally threaded
cylindrical aperture (not visible) is formed in implant 103 to
receive the externally threaded end 104 of an artificial "ball"
105. It is advantageous to form opening 101 by laterally cutting or
drilling into the top of femur 100 in the manner illustrated in
FIG. 6. This reduces the amount by which the femur has to be
laterally displaced away from the hip socket during formation of
opening 10, thus reducing trauma to surrounding nerves, muscles,
blood vessels and soft tissue.
[0067] In FIG. 18, the opening 108 in bone 107 and the implant 106
are shaped and dimensioned such that when implant 106 is laterally
slid into opening 108, a mechanical lock is formed and implant 106
cannot be removed from opening 108 in the direction of arrow C.
Similarly, opening 108 and implant 106 can be formed such that
implant 106 is inserted in opening 108 in the direction directly
opposite that of arrow C and is rotated 90 degrees about an axis
parallel to arrow C such that after implant 106 is so rotated, it
cannot be displaced out of opening 108 in the direction of arrow C
because the longer dimension of implant 106 has been turned to a
position similar to that shown in FIG. 18 under the inwardly
extending lips 109 and 110 of opening 108.
[0068] The opening 108 illustrated in FIG. 18 can be formed and an
implant inserted in opening 108 which flares outwardly like implant
106 but which can be readily withdrawn from opening 18 in the
direction of arrow C. The implant is anchored in opening 108 by
packing HA, HAC, or another composition in opening 108 and around
implant 106. The composition 102 used to pack around an implant 103
can include magnetic fibers and have a viscosity which permits the
fibers to align when a magnetic force is applied to the
composition. The composition 102 can also, in combination with the
magnetic fibers or in place of the magnetic fibers, include fibers
which do not respond to the magnetic force.
[0069] As noted earlier, active compositions can be utilized in
combination with or in place of hydroxyapatite compositions. Such
active compositions, or tissue growth factors, can be intermixed
with hydroxyapatite or other materials utilized as packing around
an implant, can be coated on an implant 103, or can be inserted in
situ intermediate the implant 103 and opening 101 to cause, for
example, the bone to grow back inwardly toward the implant. In the
event implant 103 is coated with a bone growth factor or a bone
growth factor is inserted in situ intermediate an implant 103 and
opening 101 in the bone, positioning means can be utilized to
maintain implant 103 in its desired position in opening 101 until
bone ingrowth contacts implant 103 and maintains it in position.
The positioning means can also be utilized to maintain an implant
in position until a filler material is packed in opening 101 around
the implant to anchor the implant in position. Such positioning
means can consist of a collar or template which fixedly and/or
resorbably contacts or supports implant 103 and is anchored to
surrounding bone or other tissue. The positioning means can also
consist of a putty or gel which is packed around the implant 103 to
maintain it in position while bone grows into the putty or gel and
to the implant or until the putty or gel sets up. Once bone
ingrowth secures implant 103 in its desired position, the collar or
template which is used to support the implant is removed or is
resorbed. Resorption of the collar or implant can occur according
to the natural physiological process of the body or can be
triggered and/or facilitated by external means such as heat,
electricity, enzymes injected into tissue, etc.
[0070] By way of further example of the template just referred to,
an implant to replace a missing first molar in the lower jaw of a
patient is carried out as follows. First, the space between the
second premolar and the second molar which bounded the missing
first molar may be laser scanned or an impression taken to define
the space so that the shape and dimension of the tooth which will
fill the space can be defined. An impression is taken of the lower
teeth and a plaster model of the lower teeth is made using well
known molding techniques. This plaster model, as does the patient's
mouth, includes on open spot which at one time was occupied by the
patient's missing first molar. A model is made of the artificial
tooth which will be mounted on the implant. The model is properly
positioned in the open spot in the plaster model and a impression
is made of the plaster model using plaster, plastic or any other
desired material. This plastic model will fit over and conform to
the lower teeth in the patient's mouth. An opening is formed
through the plastic model and an externally threaded screw or other
attachment means is attached through and extends downwardly from
the plastic model so that the implant which will be utilized in the
mouth of the patient can be detachably secured to the externally
threaded screw. The externally threaded screw positions the implant
in the exact desired orientation, both laterally and vertically,
with respect to the plastic model and with respect to the opening
formed in bone in the patient's mouth (or with respect to bone in
the patient's mouth on which the implant is set). An oversized
opening 27 (FIG. 3) is drilled in the alveolar bone. The bottom of
the opening is prepacked with a selected amount of hydroxyapatite
or other composition. The implant 11 is threaded onto the
externally threaded screw in the plastic model and the plastic
model is fit over the crowns of the patient's lower teeth to force
the implant 11 into the opening 27 and force the hydroxyapatite
composition up and around the implant 11. Openings can be formed in
and through the plastic model to permit hydroxyapatite composition
to be added to or removed from opening 27. Or, in the event implant
11 is simply coated with a bone or tissue growth factor, openings
need not be formed through the plastic model to permit access to
opening 27 because the plastic model positions the implant 11 in
the exact desired location in opening 27 and maintains the implant
11 in that position until the tissue growth factor causes an
outgrowth of new bone from opening 27 which contacts and anchors
implant 11 in position. The coating of bone or tissue growth factor
can occur just prior to insertion of the implant, after the implant
is inserted, or well prior to insertion of the implant. After the
implant 11 is anchored by the growth of new bone toward the
implant, the externally threaded screw is turned out of the
implant, the plastic model is removed and an artificial tooth can
be threaded into or otherwise attached to the anchored implant 11.
After (of before, if desired) the artificial tooth is attached to
implant 11, a tissue growth factor can be applied around the
implant to the surface of the implant, to the surface of bone
around implant II, or to gum tissue to promote the growth of gum
tissue over the surface of the bone and adjacent the artificial
tooth.
[0071] Growth factors can be utilized to induce the growth of "hard
tissue" or bone and "soft tissues" like ectodermal and mesodermal
tissues. As used herein, the term growth factor encompasses
compositions and living organisms which promote the growth of hard
tissue, such as bone, or soft tissue in the body of a patient. The
compositions include organic and inorganic matter. The compositions
can be genetically produced or manipulated. The living organisms
can be bacteria, viruses, or any other living organism which
promote tissue growth. By way of example and not limitation, growth
factors can include platelet-derived growth factor (PDGF),
epidermal growth factor (EGF), fibroblast growth factor
(acidic/basic)(FGF a,b), interleukins (IL's), tumor necrosis factor
(TNF), transforming growth factor (TGF-B), colony-stimulating
factor (CSF), osteopontin (Eta-1 (OPN), platelet-derived growth
factor (PDGP), interferon (INF), bone morphogenic protein 1
(BMP-1), and insulin growth factor (IGF). Recombinant and
non-recombinant growth factors can be utilized as desired. Bacteria
or viruses can, when appropriate, be utilized as growth factors.
For example, there is a bacterial hydrophilic polypeptide that
self-assembles into a nanometer internal diameter pore to build a
selective lipid body. Various enzymes can be utilized for the
synthesis of peptides which contain amino acids that control
three-dimensional protein structure and growth. Growth factors can
be applied in gels or other carriers which regulate the rate of
release of the growth factors and help maintain the growth factors,
and the carrier, at a desired location in the body. Time release
capsules, granules, or other carriers containing growth factor can
be activated by tissue pH, by enzymes, by ultrasound, by
electricity, by heat, by selected in vivo chemicals or by any other
selected means to release the growth factor. The carrier can be
resorbable or non-resorbable. Or, the growth factor itself can be
activated by similar means. Either the carrier or the growth factor
can mimic extracellular fluid to control cell growth, migration,
and function. The growth factor can be administered orally,
systemically, in a carrier, by hypodermic needle, through the
respiratory tract, or by any other desired method. The growth
factor can also be administered into a capsule or other man-made
composition or structure placed in the body. While administration
of the growth factor is presently usually localized in the
patient's body, circumstances may arise where it is advantageous to
distribute a growth factor throughout the patient's body in uniform
or non-uniform concentrations. An advantage to growth factors is
that they can often, especially when in capsule form or in some
other containment system, be inserted to a desired site in the body
by simply making a small incision and inserting the growth factor.
The making of such a small incision comprises minor surgery which
can often be accomplished on an out-patient basis. The growth
factors can be multifactorial and nonspecific.
[0072] A variety of collagen materials can be used alone and in
combination (Types 1 to 12) to form a containment sock, pocket or
other structure for a growth factor, which structure may have
useful features of controlled degradation and porosity for tissue
reconstruction. Other known naturally occurring materials such as
biopolymers, crosslinked protein scaffolds, and gels can be used
alone or in combination with each other or with any other material
to form a containment system for hydroxyapatite or other tissue
augmentation materials. A containment pocket or other structure can
be formed with synthetic organic materials such as polymers or
plastics, with natural inorganic materials (e.g., hydroxyapatite
and other ceramics), with organic materials (e.g., biopolymers), or
with synthetic inorganic materials.
[0073] Possible polymers usable in a pocket or other containment
structure constructed in accordance with the invention include,
without limitation, poly (Amides), poly(Esters), poly(Orthoesters),
poly(Anhydrides), poly (Ureas), poly(Orthoesters),
poly(Anhydrides), poly(Ureas), poly(Alkyl 2-Cyanoacrylates),
poly(Dihydropyrans), poly(Acetals), poly(Phosphazenes), and
poly(Dioxinones). Each of the foregoing polymers is biodegradable
in natural systems by undergoing a hydrolytic, enzymatic, or other
breakdown or degradation and, as such, is capable of providing
biodegradable matrices, scaffolds and other useful structures of a
containment structure. Examples of biodegradable polyamides include
glutamic acid, glutamic acid/leucine, biodegradable nylon, glutamic
acid/ethyl glutamate, hydroxyalkyl-L-glutamine, and collagen.
Examples of biodegradable polyesters include D, L lactic acid,
glycolic acid/lactic acid, L-lactic acid, caprolactone/D,L lactic
acid, diglycolic acid/transcyclonhexanedimethanol, and
polyesterhydrogels.
[0074] In one embodiment of the packing material 102 used in the
invention, hydroxyapatite is mixed with a biodegradable polymer,
with or without a growth factor impregnated therein, to provide a
composition which resists penetration by epithelial tissues but
which promotes growth of adjacent bone or soft tissue
structure.
[0075] In a further embodiment of the invention, a pocket or other
containment structure is fabricated from a microporous material
containing a drug or other agent in its pores which promotes the
growth of living tissue. The pore sizes can be in the range of 25
to 400 microns, or can have any desired size. The containment
structure can be positioned in an opening 101, adjacent selected
soft tissue or bone, or at any other location in the patient's
body.
[0076] In another embodiment of the invention, hydroxyapatite or
another tissue augmentation material is mixed with a material to
produce a mixture which is sensitive to ultraviolet light and which
hardens and sets after being dispensed at a desired location
intermediate the tissue and underlying bone. UV light is delivered
by fiber optic means to the location at which the augmentation
material is dispensed intermediate tissue and underlying bone. The
UV light promotes the hardening or setting up of the tissue
augmentation material.
[0077] In still another embodiment of the invention, a volume of
tissue augmentation material is provided with a coating which
resists migration from the tissue augmentation material of tissue
augmentation drugs or other growth factors or materials. The
coating can be biodegradable and break down over time.
[0078] The hydroxyapatite (HA) and hydroxyapatite cement (HAC)
compositions which can be utilized to pack around implants in
accordance with the invention are inorganic, crystalline materials.
The hexagonal rhombic prism structure and calcium and phosphate
composition of HA's and HAC's are very similar to the natural
ceramic hydroxyapatite mineral that makes up the inorganic portion
of bone and teeth. HA's and HAC's are bioactive and interact with
bone and teeth by forming a direct physicochemical bond with these
hard tissues. Consequently, HA's and HAC's are osteoconductive and
initiate bone ingrowth. HA's and HAC's can also harbor
osteoinductive material like osteocalcin which helps form new bone
cells. A distinct advantage of HAC's is that they can, while still
in a relatively low viscosity state, be interposed between an
implant and opening in the bone to readily conform to implant and
bone surfaces. Neither HAC's or HA's generate any appreciable heat
when used to pack around an implant. HAC's and HA's can be mixed
with bodily fluids.
[0079] HAC'S, HA's, growth factor compositions, and other packing
compositions used to pack around an implant can be formulated to
expand after being inserted intermediate an implant and surrounding
bone. Such expansion is advantageous because after an opening is
cut in bone, the bone adjacent the opening tends to shrink "away"
from the opening, enlarging the opening. By way of example, an HAC
packing composition can be formulated to expand by intermixing a
gas generating material or a material with a thermal coefficient of
expansion with the packing composition. The gas generating material
forms pores in the packing composition and causes it to expand. The
gas generated is preferably carbon dioxide, nitrogen, or another
inert gas is preferred. The gas generating or expandable material
can be resorbable. If desired, the packing composition can be
aerated with a gas before it is inserted in an opening to anchor an
implant in place. Polyethylene has a coefficient of thermal
expansion of about 0.00018 per degree Centigrade. Polyethylene or
another polymer material with a preferred coefficient of thermal
expansion can be utilized as a component in the packing
composition. Or, the packing composition can include a liquid
component which expands when the liquid component sets and
solidifies.
[0080] In one embodiment of the invention, a dental implant and
crown are designed to custom fit in the alveolar bone and
efficiently dissipate occlusal stress generated during use of the
crown to chew food. Implants other than dental implants can also be
designed using the following principles.
[0081] A ruler, X-ray, laser scanner, impressions of the teeth and
jaws, or other means are used to define the shape and dimension of
the space to be occupied by the artificial crown which is attached
to the implant and to define the shape and dimension of the
alveolar bone in or on which the implant is to be positioned. A
force diagram can be generated which defines how the roots of each
original tooth in the mouth of an individual dissipate the stresses
generated on the tooth during chewing and/or biting. Similarly, a
force diagram can be generated defining an optimal root design for
uniformly dissipating stress into alveolar bone, for dissipating
more stress into stronger areas of the alveolar bone, etc. Such an
optimal root design is ordinarily arrived at with the use of a
computer and is important because many dental problems derive from
the interaction of teeth with bone surrounding the teeth. The
quality of the bone adjacent teeth varies. Some bone can withstand
occlusal stress better than other bone. Some areas of the jaw have
more alveolar bone adjacent to and supporting a tooth than do other
areas of the jaw. Another factor which can be utilized to determine
the optimal shape and dimension of the implant (and crown) is the
material used to fabricate the implant.
[0082] An eight foot long two inch by four inch piece of lumber
better resists a force which is applied perpendicular to the length
of the lumber and to a two inch side of the lumber than it resists
the same force applied to a four inch side of the lumber and
perpendicular to the length of the lumber. Similarly, the
orientation of an implant root with respect to the surrounding bone
can have a bearing on the ability of the root and the implant to
resist a force vector which is applied to the implant at a
particular point and at a particular orientation. Therefore, the
orientation of the roots of the implant is another factor which can
be taken into consideration by a computer in designing the optimal
implant. Still another factor is the shape and position of the
tooth (or teeth) which opposes and will contact the crown on the
implant after the implant and crown are anchored in alveolar
bone.
[0083] In the dental implant art, the "Theory of Available Bone"
teaches that implants are customized to fit in existing bone. The
preferred method of the invention directly contradicts the Theory
of Available Bone because the method of the invention teaches
optimizing the effectiveness of an implant by first definig the
optimal shape and dimension and the density or other physical
properties of the bone which should be available to anchor the
implant. In the method of the invention, if a sufficient volume of
bone is not available, additional bone volume is generated by
packing HA, HAC or some other material on existing bone to generate
new bone, by using growth factors to generate new bone, or by using
any other desired procedure to generate new bone. If the density of
the existing bone is not sufficient, existing bone can be removed
and replaced with HA, HAC, or another desired composition which
will have the desired density or other physical properties or which
will cause new bone to grow which has the desired density or other
physical properties. HAC can form bone consisting of about 77% by
weight mineral composition. This is denser than natural bone and
can be particularly desirable in forming new bone in the posterior
bone areas of the mouth. The bone in the posterior areas of the
mouth supports the molars. Such bone typically is less dense than
the bone in the anterior areas of the mouth. Bone in the anterior
areas of the mouth supports incisors. In addition, if the existing
bone volume is too great, bone can be removed; for example, a bone
spur could be removed. Consequently, the method of the invention
propounds a "Theory of Optimal Bone--Optimal Implant" design and
implementation in which existing bone structure can be altered and
the design of each implant can, if appropriate, differ from the
design of the other implants in a patient's mouth in order to
insure that a implant is formed which effectively distributes the
occlusal forces generated on the implant and bone during use of the
teeth. Any desired set of criteria or parameters can be used in
defining the desired volume, density, and other physical properties
of the bone used to support an implant. For example, but not by way
of limitation, the volume of bone typically will approximate the
volume of the original bone structure which is (or was) present in
the mouth when the patient is a young adult. Such bone volume is
readily measured or, in the event portions of the original bone
structure have been lost, can be readily approximated. The desired
density of the bone typically presently will be at least equal to
the density of the original bone structure. Further, by way of
example, the largest possible bite force is not necessarily
produced in a direction which is perpendicular to the occlusal
plane. The posteriorly and medially directed forces generally reach
higher values than the anteriorly and laterally directed forces,
respectively.
[0084] A computer can also be utilized to determine the position of
the implant at which the implant optimally distributes stresses
into surrounding bone. The optimal position of the implant can be
determined based upon selected factors included, but not limited
to, the morphology of the surrounding alveolar bone, the size and
stability of adjacent teeth, etc. For example, once the shape and
dimension of an implant is determined, the implant may better
distribute stress if it is positioned in (or on) alveolar bone
closer to a first adjacent tooth than to a second adjacent tooth
because the quality of bone is better near the first adjacent
tooth.
[0085] The shape and dimension of the crown can depend on factors
including, but not limited to, the type of tooth (a molar has more
cusps than an incisor), the size of the space in the patient's
mouth in which the crown must fit, and the material used to
fabricate the crown (a stronger material might enable portions of
the crown to be smaller than if a weaker material is used).
[0086] After the shape and dimension of the implant and crown are
defined, the implant and crown can be manufactured using
computerized equipment. A computerized lathe system could, for
example, be used to cut the implant from a piece of metal and to
cut, mold, or otherwise form the crown which is secured to the
implant. Or, the implant and crown can be produced utilizing any
desired conventional production methods. After the implant and
crown are produced, the implant is anchored at the desired position
in the alveolar bone using any of the procedures earlier described.
For example, on opening can be formed in the alveolar bone, the
implant inserted in the opening, and HA or other material packed
around the implant to anchor the implant in the opening. The crown
can be attached to the implant before or after the implant is
secured in the alveolar bone.
[0087] Locating an implant in the upper molar area of the mouth can
be difficult because the alveolar crestal bone is thin and adjacent
the sinuses. Consequently, the mass or volume of available bone in
which to anchor an implant is marginal. In order to position an
implant in the alveolar crestal bone in the upper jaw, a first
prior art procedure was developed. In this first prior art
procedure, the alveolar bone is scored along a rectangular line.
The portion of the alveolar bone circumscribed by the score line,
referred to herein as the "pad", is then carefully pushed inwardly
to avoid tearing the Schneiderian membrane and to form a
rectangular opening through the alveolar bone. A block-shaped base
is inserted through the rectangular opening in the alveolar bone to
a position in which the base contacts or is adjacent the pad. The
area around the base is filled with loose hydroxyapatite material
and the opening in the alveolar bone is covered with the gum or
another material to permit the hydroxyapatite to harden. Six to
nine months later, the gum is reopened to anchor an implant and/or
artificial crown in the block-shaped base.
[0088] The foregoing first prior art procedure for positioning an
implant in the molar alveolar bone has several disadvantages.
First, avoiding rupture of the Schneiderian membrane is sometimes
difficult, which means there is an increased risk that infection in
the patient's sinus will spread into the hydroxyapatite or other
areas of the graft. Second, the block-shaped base must be covered,
or buried, while the hydroxyapatite hardens. This means a second
later operation is required to insert an artificial crown or
implant in the base once the hydroxyapatite hardens. Third, the
insertion of an implant is postponed for six to nine months while
the sinus graft heals. Fourth, the block-shaped base tends to shift
out of its desired position adjacent the pad, which makes it
difficult, if not impossible, to properly position the implant when
the gum is later reopened and the implant is inserted in the
block-shaped base.
[0089] A second prior art procedure, termed the lateral sinus lift
procedure, was developed to overcome shortcomings in the first
procedure discussed above. In this second prior art procedure, a
cut is made through the maxilla, exercising care not to rupture the
Schneiderian membrane. The cut forms a flap which is displaced, or
lifted, laterally and upwardly into the sinus cavity, again without
rupturing the Schneiderian membrane which lines the sinus cavity.
Avoidance of damage to the Schneiderian membrane during the lateral
sinus lift is important because rupture of the membrane permits the
rapid spread of infection in the sinus cavity. In the event the
Schneiderian membrane is ruptured, a resorbable collagen pad is
used to cover the rupture, or the rupture is otherwise repaired.
After the flap is lifted, the space intermediate the flap and the
alveolar crest is filled with porous hydroxyapatite. Six months
later, an opening, i.e., an osteotomy, is carefully drilled through
the alveolar crest and into the hardened hydroxyapatite. The
opening closely conforms to the shape and dimension of an implant
which is fitted into the opening.
[0090] The foregoing second prior art procedure for positioning an
implant in the molar alveolar bone has several disadvantages.
First, avoiding rupture of the Schneiderian membrane is sometimes
difficult, which means there is an increased risk that infection
from the sinus will spread into the graft. Second, the incision
through which the hydroxyapatite is inserted must be sealed. Third,
the insertion of an implant is postponed for six months while the
sinus graft heals. This means a second operation is required to
insert the implant. Fourth, the insertion of the implant requires
the formation of an opening which closely conforms to the shape and
dimension of the implant.
[0091] A third prior art procedure for positioning an implant
adjacent the sinuses is similar to the second prior art procedure
described above in that a lateral sinus lift is also performed.
However, in the third prior art procedure, after the lateral sinus
lift is performed an opening is carefully drilled through the
alveolar crest. This opening conforms to and receives the upper
portion of an implant. Since the alveolar crest is thin, the lower
portion of the implant extends from the alveolar crest into the
space intermediate the alveolar crest and the flap of bone bent
inwardly during the lateral sinus lift. Hydroxyapatite is then
packed between the alveolar crest and the flap of bone and is
packed around the implant.
[0092] The foregoing third prior art procedure for positioning an
implant in the molar alveolar bone has several disadvantages.
First, avoiding rupture of the Schneiderian membrane is sometimes
difficult, which means there is an increased risk that infection
will travel from the sinus into the graft. Second, gum tissue must
be used to cover, or bury, the implant while the hydroxyapatite
solidifies. This necessitates a later operation to expose the
implant to attach an artificial crown to the implant. Third, the
insertion of the artificial crown in the implant is postponed for
six months while the sinus graft heals. Fourth, the insertion of
the implant requires the formation of an opening which closely
conforms to the shape and dimension of the implant.
[0093] One method of the implant of the invention facilitates the
insertion of an implant in the alveolar crest adjacent the atrophic
posterior maxilla. This method of the invention is illustrated in
FIGS. 19 to 21. In FIG. 19, a retractor 114 is utilized to draw
soft tissue away from the posterior maxilla 111. A drill or other
tool is used to cut through the maxilla 111 to form a rectangular
groove 130 defining a flap 112. If necessary, the maxilla 111 can
be scored along line 131 to facilitate the inward and upward
bending of flap 112 into sinus cavity 121 to the position
illustrated FIG. 20. An opening 132 is formed through the alveolar
bone 117. An implant 119 is inserted through opening 132 into the
area intermediate flap 112 and the alveolar bone 117.
Hydroxyapatite cement (HAC) 120 is used to pack around implant 119
intermediate flap 112 and bone 117. The HAC is inserted through
opening 132 or through the opening formed in the maxilla when flap
112 is bent upwardly and inwardly into the sinus cavity 121. If
desired, the Schneiderian membrane can be scraped away from and off
of the bone to facilitate bonding of the HAC with the bone, The HAC
has a putty like consistency and rapidly sets up and hardens,
typically within 10 to 15 minutes. When the HAC hardens, it seals
the sinus cavity 121. Sealing the sinus cavity 121 is critical
because bacteria in the sinus cavity 121 which may invade the graft
through a breach in the Schneiderian membrane are sealed in the
sinus cavity. Consequently, the method of the invention permits the
Schneiderian membrane to be cut through, enables an implant to be
quickly placed adjacent the maxilla, and does not require the
formation through the alveolar bone (or hardened HAC) of an opening
which closely conforms to the implant being utilized. The
orientation of implant 119 can, until HAC 120 hardens, be adjusted
by canting or tilting implant 119 in opening 132 and in the area
intermediate flap 112 and bone 117. HAC is presently preferred in
the practice of this method of the invention because it includes
hydroxyapatite and because it rapidly sets up. Any other desirable
packing material can, however, be utilized in place of HAC. Various
other packing materials are discussed earlier herein.
[0094] The method of the invention may enable an implant and crown
to be completely installed in one operation. In contrast to the
prior art procedures described above, the method of the invention
does not require that an initial incision be made, be closed, and
then be reopened at a later date to complete the implant procedure.
In the method of the invention, the implant and/or artificial crown
attached to the implant can extend through the gum into the mouth
soon after an opening is formed through alveolar bone and after the
Schneiderian membrane is ruptured.
[0095] The method illustrated in FIGS. 19 to 21 can also be carried
out without forming flap 112. In this procedure, opening 132
through the alveolar bone 118 is formed and HAC putty is packed
between the maxilla 111 and other bone 133 bounding the sinus
cavity 121. The implant 119 is positioned in the HAC. If desired,
the entire sinus cavity 121 can be filled with HAC or another
packing material. Again, if desired, the implant and/or artificial
crown attached to the implant can extend through the gum into the
mouth.
[0096] In another embodiment of the invention, genetically produced
living material is used to form an implant in the bone of a
patient. The DNA structure of a patient is analyzed from a sample
of blood or other material extracted from a patient and a
biocompatible tooth bud 122 (FIG. 3) is produced. The bud 122 is
placed in an opening 123 in the alveolar bone and packing material
is placed around or on top of the bud 122. The size of opening 123
can vary as desired. The packing around bud 122 can comprise HAC
124, hydroxyapatite, blood, growth factors, or any other desirable
packing material. The bud 122 grows into a full grown tooth in the
same manner that tooth buds which are in the jaws of children
beneath baby teeth grow into full sized teeth. In a first variation
of this embodiment of the invention, analysis of the DNA of the
patient is used to identify and select in vitro the genetic
material which causes the creation and growth of a tooth bud. This
genetic material at least includes a gene or genes, and may include
other portions of the DNA. A transcriptional activator is utilized
to activate trascription of these tooth bud genes in vitro. An
enhancer is used to drive the specific expression of the
transcriptional activator. After the enhancer drives the expression
of the transcriptional activator, the trascriptional activator
transactivates the tooth bud genes. Nutrients and/or other growth
factors can be used to sustain and/or promote the creation and
growth of, or if appropriate, to cause the differentiation of, a
tooth bud after the tooth bud genes are activated. After the tooth
bud reaches a desired size, it is transplanted into the jaw bone of
a patient. As used herein, the term tooth bud designates a
partially grown tooth. Nutrients and/or other growth factors can be
used to sustain and promote the growth of, or if appropriate, to
cause the differentiation of, the tooth bud after it is
transplanted into the jaw of a patient. Instead of tooth bud genes,
genes which cause the morphogenesis and further growth of other
organs or hard or soft tissue in the body can be identified from
the patient's DNA and utilized to grow in vitro organs or tissue
for transplant into the body. The organs or tissue can be partially
or completely grown at the time of transplant. In a second
variation of the above embodiment of the invention, the structure
of the gene or genes which control the growth of a tooth bud in a
human being is known, and the genetic material comprises comparable
artificially produced genes, or genes harvested from other human
beings or animals are transactivated to create and grow a tooth
bud. Such artificially produced genes or genes from other animals
are transactivated to create and grow a tooth bud in vitro, after
which the bud (or other organ or tissue) is transplanted into the
body of the patient. The tooth bud grows in a tooth which is
comprised of dense, semirigid, porous, calcified skeletal
tissue.
[0097] In another embodiment of the invention, instead of
transplanting a bud 122 into the jaw of a patient, a quantity of
genetically produced living material which causes bud 122 to form
in the alveolar bone can be placed at a desired position in the
alveolar bone such that bud 122 is morphogenetically created in
vivo and grows into a full sized tooth. Instead of forming an
opening 123, a needle or other means can be used to simply inject
the genetically produced living material into a selected location
in the alveolar bone. As would be appreciated by those skilled in
the art, genetically produced materials can be inserted in the body
to cause the body to grow, reproduce, and replace leg bone, facial
bone, and any other desired soft and hard tissue in the body. In
one variation of this embodiment of the invention, the genetic
material is placed at a desired position in the alveolar bone (by,
for example but not by way of limitation, forming an opening 123 to
receive the genes or by utilizing a needle to insert the genes at a
desired site) to create and grow morphogenetically a tooth bud and,
subsequently, a tooth. The genetic material is presently preferably
accompanied by a transcriptional activator to turn on the genes'
expression, an enhancer to drive the specific expression of the
transcriptional activator, and by nutrients and/or other growth
factors which promote the in vivo creation and growth of a tooth
bud and tooth. The genes can be transcriptionally activated either
prior to being inserted or after insertion in the alveolar bone.
Instead of tooth bud genes, genes which cause the morphogenetic
creation and growth of other organs or other hard or soft tissue in
vivo can be identified from the patient's DNA or from another
source, and the genetic material can comprise comparable
artificially produced genes or genes removed from another animal or
otherwise generated. The genetic material is then inserted at
desired locations in a patient's body and utilized to create and
grow morphogenetically in vivo organs or other hard or soft tissue.
Such genes presently preferably are accompanied by a
transcriptional activator to turn on the gene's expression, an
enhancer to drive the specific expression of the transcriptional
activator, and by nutrients and/or other growth factors which
promote the creation and growth of a tooth bud and tooth. The genes
can be transcriptionally activated prior to or after they are
inserted in a patient's body. Any desired substance or means can,
as would be appreciated by those of skill in the art, be utilized
to cause the activation or initiation of a gene or genes to express
themselves by creating and growing morphogenetically an organ or
other hard or soft tissue at a desired location or location(s) in
the body of a patient.
[0098] The gene or genes used to create and grow morphogenetically
a particular organ or other tissue in vivo or in vitro can, if
desired and appropriate, be accompanied by or be connected to other
genes or DNA material which does not play a part in the growth of
the desired organ or other tissue.
[0099] In another embodiment of the invention, I provide a method
for curing dental disease. The method comprises the step of
introducing into the body a substance or form of energy which
replaces or alters a gene or genes in the patient's DNA to improve
the ability of the patient's to defend against, weaken, or destroy
bacteria or viruses which cause dental disease. The replaced or
altered genes express themselves in at least some of new cells
subsequently produced by the patient's body. For example, the
altered or new genes in the patient's DNA may make it more
difficult for bacteria, cytokines, or bacterial antigens to
penetrate the gum tissue in the mouth of a patient. The particular
embodiment of the invention which is preferred is using a chemical
substance, heat, electromagnetic energy, or any other means to
alter the structure of an existing gene or genes in the patient's
DNA or the bacteria's or virus' DNA in vivo, i.e. alters the DNA
while the DNA is in the patient's body. This embodiment can be used
to improve the body's capability to defend against any disease or
illness and is different from current prior art methods of
importing new genes which are intended to replace or supersede the
original genes existing in the patient's DNA. Morphogenesis or
morphogenetics is the origin and evolution of morphological
characters and is the growth and differentiation of cells and
tissues during development.
[0100] The HAC 120, 124 or other packing material used in the
implant methods of the invention can include BIODEL or other small
polymer beads or carriers of antibiotic materials.
[0101] As used herein, hydroxyapatite cement (HAC) is a cement
composed entirely or in substantial part of calcium phosphate
salts. HAC can be combined with water to form a dense paste which
is applied and shaped intraoperatively. HAC sets in vivo in
approximately 10 to 15 minutes to form a structurally stable
implant composed of microporous hydroxyapatite. The calcium
phosphate salts tetracalcium phosphate and anhydrous dicalcium
phosphate are the primary components of HAC. These salts react in
water to isothermically form hydroxyapatite. After the calcium
phosphate salts in powder form are mixed with water, the resulting
composition sets in about ten to fifteen minutes. The
microenvironment in the set cement is saturated with calcium
phosphate salts. Hydroxyapatite precipitates in situ from this
microenvironment during a reaction which typically takes from four
to six hours.
[0102] A further embodiment of the invention concerns the
integration of a dental implant into the lower jaw of a patient.
Portions of the bone comprising the lower jaw are hollow and lined
with marrow or other soft tissue. A first small opening 134 (FIG.
3) can be formed through the outside of the jaw and a second small
vent opening can be formed through the inside of the jaw or
elsewhere. A pressurized tube or other means is used to inject
hydroxyapatite cement slurry through opening 134 into the hollow
area in the lower jaw. The second opening serves as a vent which
permits air or other material to escape from within the lower jaw
when hydroxyapatite cement slurry is injected in the jaw. If
desired, the first opening can be made slightly larger than the
tube used to inject HAC slurry into the jaw such that the first
opening permits air or other material in side the jaw to vent
outwardly through the first opening while HAC slurry flows from the
tube into the jaw. In this case, the second vent opening may not be
required. An X-ray(s) can be taken of the jaw to insure that the
desired areas of the lower jaw are filled with HAC slurry.
[0103] After the HAC slurry is injected into the jaw, the first and
second openings are plugged with HAC putty, polyglycolic acid, bone
wax, or another desirable material. After the HAC slurry which was
injected into the jaw hardens sufficiently, on opening can be made
through the alveolar bone of the lower jaw and into the hardened
HAC to receive an implant.
[0104] A HAC slurry injection method similar to the slurry
injection method described above for the lower jaw can be used to
inject HAC slurry into a space between the sinuses and alveolar
bone of the upper jaw. A small access opening is drilled through
the maxilla. Or, the Caldwell-Luc approach can be utilized to gain
access to the sinus through the nose. Once access is gained to the
sinus, an instrument is used to score and rupture the sinus
membrane so that HAC injected into the sinus can contact and bond
to the underlying bone. HAC slurry or another desirable material is
then injected into the sinus through the opening with a tube or by
using other means. After the HAC slurry hardens, an opening can be
formed through the alveolar bone and into the hardened HAC to
receive an implant. HAC slurry, injectible hydroxyapatite, or other
desired materials-including but not limited to bioactive osteogenic
materials--which facilitate the formation of new bard bone by the
body, can similarly be injected into the "hollow" soft tissue inner
marrow areas of the femur or other bones of the body through small
holes formed in the bones.
[0105] Genes express themselves by creating and growing
morphogenetically any organ or other hard or soft tissue.
Transciptional activators turn on a gene's expression.
[0106] Transcription is the synthesis of messenger RNA (mRNA), the
first step in relaying the information contained in DNA.
Transcription begins as the interaction between a strand of DNA and
the enzyme RNA polymerase. Enzymes can be growth factors. Various
enzymes can be utilized in the synthesis of peptides which contain
amino acids that control three-dimensional protein structure and
growth.
[0107] In accordance with the invention, genetic material plus
growth factor(s) are implanted directly or indirectly to grow,
reproduce, and replace desired soft and hard tissue in the
body.
[0108] The first step in making an implant is to analyze the DNA.
DNA arrays (biochips) and other DNA sequencing methos are known in
the art. The genetic material can includes a gene or genes and/or
other portions of DNA. A transcriptional activator is utilized to
activate transcription. The genetic material can be from the
patient, can be artificially produced, or can come from other human
beings or animals.
[0109] Genetic material is well conserved in nature. The Drosophila
eyeless gene (ey), the mouse small ey gene (pax-6), and the
Aniridia gene in humans are all homologous.
[0110] Transgenic animals have attached a promoter (a growth
factor) to a specific gene. The resultant initiation of
transcription produces a desired protein. For example, human growth
hormone can be produced by a farm animal. Promoters are tissue
specific. To produce the protein albumin, the gene for albumin is
attached to a promoter that is found only in liver tissue. Once the
albumin producing promoter--gene pair is inserted into the genome,
albumin is produced by future generations.
[0111] The initiation of transcription in the fly Drosophila is
caused by a transcriptional activator which is obtained from yeast
and is called GAL 4. GAL 4 causes tissue specific expression in
flies. An upstream gene for eye formation in a fly is ey (eyeless).
A growth factor is attached to the ey gene to grow an eye. Two sets
of flies are mated to produce a generation of flies having
additional eyes.
[0112] The first set of flies is genetically engineered to randomly
insert GAL 4 into its genome at twenty different locations.
[0113] The second set of flies is also genetically manipulated by
placing in the eggs of the second set of flies the recombinant
eyeless gene and GAL 4 binding sites. The eggs mature to produce
flies each having the eyeless gene in every cell in the flies
body.
[0114] Genomic engineering of all kinds has created an infinite
range of genetic possibilities for implants and growth factors due
to DNA cloning and recombinant DNA. Cis position and trans position
genes are possible. In additional, annealing techniques allow DNA
with DNA, RNA with RNA, or DNA with RNA. Polymerases catalyze the
combining of nucleotides to form RNA or DNA. Transcription factors
are DNA-binding proteins that control gene activity. Translation is
the second step in the relay of genetic information. During
translation, the sequence of triplets in mRNA is tanslated into a
corresponding sequence of amino acids to form a polypeptide as the
gene product. Termination codons signal the end of translation.
[0115] Antisense RNA (or DNA), cDNA's, and expression vector can be
genetically manipulated or produced. The term DNA as used herein
also includes mitochondrial DNA.
[0116] Genomic manipulation can also be based on locating,
isolating, attaching, and manipulating single molecules. For
example, the process of transcription (as seen through atomic force
microscopes) has been halted by the removal of a single nucleoside
triphosphate (NTP) that the RNA molecule needed for transcription.
Thus, the atomic and subatomic levels are important in genetic
engineering.
[0117] Genetic engineering can create implants and growth factors
which behave in desired manners and produce selected desired
results and pathways. As used herein, genetic engineering can
create materials that are able to control the flow of matter and/or
energy in a deliberate way by spatial, temporal, physicochemical or
other physical means alone or in combination.
[0118] Desired tissues and organs can also be produced by the
process of nucleation.
[0119] Genes control structure and function. A gene or a bit of
genetic material may act as a master control gene which activates
thousands of other genes to construct a living organ. Each one of
two or more different genes can produce the same organ. For
example, in Drosophila, the ey gene and the toy gene both are
capable of eye formation.
[0120] Since genomic engineering can create a myriad of genetic
possibilities, a pathway description of cellular interactions,
intracellular and extracellular matrix combinations, and mitogenic
or morphogenic stages is impractical.
[0121] Complex tissues and organ systems are formed through
cellular proliferation and differentiation. This orderly process is
regulated by peptide growth factors which are secreted locally and
mediate cellular events by triggering cell surface receptors on
their target cell(s).
[0122] Cells stick together, viruses stick to cells, and white
blood cells stick to invading organisms. Optical tweezers developed
at Bell Labs in the 1980's can measure and evaluate the
"stickiness" of cells and viruses. Sticky cells can be used to
attach genetic implants to selected sites. This is, for example,
important when placing a soft tissue implant in or on a site of an
artery wall. In this manner, an additional heart could be grown
from a genetic implant. Once matured to a reasonable state, this
new heart can be the body's primary heart and the old heart can be
evacuated surgically. Any venous or arterial connections,
reconfigurations, or ligations can be surgically attended to. Any
other organ can be similarly produced at any desired site in soft
or hard tissue.
[0123] Genetic implant can form a single pre cursor area and later
split in two. For example, the ET gene causes two eyes to form from
a single region.
[0124] Multifactorial and nonspecific cells (such as stem cells and
germinal cells) can provide the necessary in vivo and in vitro
cascade of genetic material once an implanted master control gene's
transcription has been activated. Likewise, any host cell, cloned
cell, cultured cell, or cell would work. Genetic switches (such as
the insect hormone ecdysone) can be used to control genes inserted
into humans and animals. These gene switches can also be used in
cultured cells or other cells. Gene switches govern whether a gene
is on or off making possible precise time of gene activity.
[0125] Cellular products and their derivatives can be growth
factors. Viral vectors can carry and insert new genes into
chromosomes. Growth factors can positively or negatively control
genetic transcription. Snippets of DNA with characteristic DNA
fingerprints can be used as implant materials. Transcription factor
binding sites as well as receptor sites can be genetically
engineered and utilized as needed. Receptor sites can also be in
the nucleus of cells.
[0126] Genetic implant preferably integrate biologically into the
host environment.
[0127] Murine and human genomes (and perhaps the entire metazoa)
are considerably conserved at the nucleic acid and gene linkage
levels.
[0128] In early tooth germ, bone morphogenic proteins BMP-2 and
MPB-4 regulate expression of the homeobox containing genes MSX-1
and MSX-2. These genes, along with the eyeless gene in Drosophila
may be considered upstream genes.
[0129] The homeobox containing gene MHox regulates the
epithelial-mesenchymal interactions required for skeletal
organogenesis. The paired-like homeobox gene MHox is required for
early events of skeletogenesis in multiple lineages.
[0130] The homeobox gene controlling the growth of kidneys has been
identified.
[0131] Organs, a join capsule, a ligament, or a ligament with an
organ attached can be grown at any hard or soft tissue site.
[0132] Genes express themselves by creating and growing
morphogenetically any organ or other hard or soft tissue.
Transciptional activators turn on a gene's expression.
[0133] Genes may also play important roles in mechanisms that
control the differentiation of structures within and between organs
during organogenesis.
[0134] Gap junction proteins permit the exchange of regulatory
molecules between cells and play important roles during
organogenesis.
EXAMPLE 1
[0135] MSX-1 and MSX-2 are the homeobox genes that control the
generation and growth of a tooth. A sample of skin tissue is
removed from the patient and the MSX-1 and MXS-2 homeobox gene(s)
are removed from skin tissue cells. The genes are stored in an
appropriate culture medium.
[0136] Germinal cells in the process of transcription are obtained
from the patient by biopsy or surgical excision. The germinal cells
are in hard bone tissue adjacent the apex of the immature forming
root of a patient's tooth. These cells are selected because they
are actively transcribing root structure and contain active growth
and transcription factors which facilitate the formation of the
tooth germ. The germinal cells are placed in an appropriate
nutrient culture medium outside the patient's body. The homeobox
genes MSX-1 and MSX-2 are added to the nutrient culture with the
germinal cells. The nutrient culture is maintained at an optimum
temperature, which is presently preferably 98.6 degrees F., but can
be varied as desired. The homeobox genes MSX-1 and MSX-2 are
permitted to bind with transcription factors in germinal cells.
After the genes bind with transcription factors, the germinal cells
and bound genes are replanted in the patient's body at the tooth
site from which the germinal cells were harvested.
EXAMPLE 2
[0137] Example 1 is repeated, except that the homeobox genes are
provided with a genetically engineered binding site for attaching
to the receptor site on the transcription factor. Similar results
are obtained.
EXAMPLE 3
[0138] Example 1 is repeated, except that the germinal cells are
obtained from soft periodontal ligament tissue immediately adjacent
the apex of the immature forming root of a patient's tooth. These
cells are selected because they are actively transcribing root
structure and contain active growth and transcription factors which
facilitate the formation of the tooth germ.
EXAMPLE 4
[0139] Example 1 is repeated, except that the homeobox genes are
provided with a genetically engineered binding site for attaching
to the receptor site on the transcription factor. Similar results
are obtained.
EXAMPLE 5
[0140] MSX-1 and MSX-2 are the homeobox genes that control the
generation and growth of a tooth. A sample of skin tissue is
removed from the patient and the MSX-1 and MXS-2 homeobox gene(s)
are removed from skin tissue cells. A tooth is removed from the
mouth of a patient. The tooth that was removed had an immature root
structure. Transcription was occurring at the apex of the tooth
that was removed. The homeobox genes MSX-1 and MSX-2 are placed at
the apex of socket immediately following the extracting of the
tooth. The genes bind with the transcription factor(s) and express
themselves to begin the genetic cascade to form early tooth germ.
The patient's body completes the formation of the tooth.
EXAMPLE 6
[0141] Example 5 is repeated, except that the homeobox genes are
provided with a genetically engineered binding site for attaching
to the receptor site on the rsciption factor. Similar results are
obtained.
EXAMPLE 7
[0142] Example 5 is repeated, except that prior to insertion of the
homeobox genes in the tooth socket, tissue on the bottom of the
tooth socket is loosened to expose bone cells.
EXAMPLE 8
[0143] Example 5 is repeated, except that after the tooth is
pulled, add a transcription factor and energy to activate genes to
initiate the formation of tooth germ.
EXAMPLE 9
[0144] Example 8 is repeated, and the transcription factor and
energy activate the MSX-1 and MSX-2 genes.
EXAMPLE 10
[0145] Example 1 is repeated, except that BMP-2 and BMP-4 growth
factors are obtained by recombinant or natural extraction from
bone.
EXAMPLE 11
[0146] MSX-1 and MSX-2 are the homeobox genes that control the
generation and growth of a tooth. A sample of skin tissue is
removed from the patient and the MSX-1 and MXS-2 homeobox gene(s)
are removed from skin tissue cells. The genes are stored in an
appropriate nutrient culture medium.
[0147] BMP-2 and BMP-4 growth factors are obtained by recombinant
or natural extraction from bone.
[0148] Living stem cells are harvested from the bone marrow, the
blood of the patient, or from cell culture techniques. The stem
cells are placed in a nutrient culture medium at 98.6 degrees. The
temperature of the culture medium can be varied as desired but
ordinarily is between 40 to 102 degrees F.
[0149] MXS-1 and MXS-2 transcription factors are obtained which
will initiate the expression of the MXS-1 and MXS-2 homeobox
genes.
[0150] The MXS-1 and MXS-2 transcription factors, BMP-2 and BMP-4
bone morphogenic proteins, and MXS-1 and MXS-2 genes are added to
the nutrient culture medium along with the living stem cells.
EXAMPLE 12
[0151] Example 11 is repeated except that the transcription factors
bind to a receptor complex in the stem cell nucleus.
EXAMPLE 13
[0152] Example 11 is repeated except that the MXS-1 and MXS-2
transcription factors are not utilized. The transcription of the
MXS-1 and MXS-2 homeobox genes is activated by applying an electric
spark to the nutrient culture medium.
EXAMPLE 14
[0153] Example 13 is repeated except that the stem cells are
starved and the transcription of the MXS-1 and MXS-2 homeobox genes
is activated by applying an electric spark to the nutrient culture
medium.
EXAMPLE 15
[0154] WT-1 and PAX genes are obtained from a sample of skin tissue
is removed from the patient. The genes are stored in an appropriate
nutrient culture medium. PAX genes produce PAX-2 and other
transcription factors.
[0155] BMP-7 and other kidney related BMP growth factors are
obtained by recombinant or natural extraction from bone.
[0156] Living stem cells are harvested from the bone marrow, the
blood of the patient, or from cell culture techniques. The stem
cells are placed in a nutrient culture medium at 98.6 degrees. The
temperature of the culture medium can be varied as desired but
ordinarily is between 40 to 102 degrees F.
[0157] The WT-1 and PAX genes, and BMP-7 and other kidney BMPS are
added to the nutrient culture medium along with the living stem
cells.
[0158] A primitive kidney germ is produced. The kidney germ is
transplanted in the patient's body near a large artery. As the
kidney grows, its blood supply will be derived from the artery.
EXAMPLE 16
[0159] The Aniridia gene is obtained from a sample of skin tissue
is removed from the patient. The gene(s) is stored in an
appropriate nutrient culture medium.
[0160] Aniridia transcription factor (activates expression of the
Aniridia gene) and growth factors (function to help stem cells
differentiate during morphogenesis to form an eye) are
obtained.
[0161] Living stem cells are harvested from the bone marrow, the
blood of the patient, or from cell culture techniques. The stem
cells are placed in a nutrient culture medium at 98.6 degrees. The
temperature of the culture medium can be varied as desired but
ordinarily is between 40 to 102 degrees F.
[0162] The Aniridia transcription factor and growth factors and the
Aniridia gene are added to the nutrient culture medium along with
the living stem cells.
[0163] A primitive eye germ is produced. The kidney germ is
transplanted in the patient's body near the optic nerve. As the
kidney grows, its blood supply will be derived from nearby
arteries.
EXAMPLE 17
[0164] The Aniridia gene is obtained from a sample of skin tissue
is removed from the patient. The gene(s) is stored in an
appropriate nutrient culture medium.
[0165] Aniridia transcription factor (activates expression of the
Aniridia gene) and growth factors (function to help stem cells
differentiate during morphogenesis to form an eye) are obtained and
added to the nutrient culture medium.
[0166] An eye germ develops. A branch of the nearby maxillary
artery is translocated to a position adjacent the eye germ to
promote the development of the eye germ. The eye germ matures into
an eye which receives its blood supply from the maxillary
artery.
[0167] The term "cell nutrient culture" as used herein can include
any or any combination of the following: the extracellular matrix;
conventional cell culture nutrients; and/or, a cell nutrient such
as a vitamin. As such, the cell nutrient culture can be
two-dimensional, three dimensional, or simply a nutrient, and is
useful in promoting the processes of cellular dedifferentiation,
redifferentiation, differentiation, growth, and development.
[0168] As used herein, the term "physiological nutrient culture" is
a selected media(s) to control and direct an event(s) in living
host system(s) (e.g., cardiovascular, pulmonary, musculoskeletal,
etc.), organ(s), tissue(s), cell(s). A media is a fluid solution,
gel, or quasi-solid soultion (mechanical mixture) which supports
and directs normal developmental pathways for cell and cell
products. An event is one of the sequence of growth, division,
cellular aggregation, development of cellular form, development of
aggregate cellular form, secretions, etc. which lead to the
development of an organ. A physiological nutrient culture can
affect macromolecule(s), molecule(s), atom(s), and subatomic
particle(s) in said living things. A physiolocial nutrient culture
can include macromolecule(s), molecule(s), atom(s), and subastomic
particle(s). A cell nutrient culture is a physiological nutrient
culture. A physiological nutrient culture is not necessarily a cell
nutrient culture. A physiological nutrient culture promotes
cellular survival and cellular proliferation in a desired form(s)
or function(s), and promotes differentiation to a selected specific
function.
[0169] Growth factors control cell growth, division,
differentiation, migration, structure, function, and self-assembly.
Growth factors include chemical regulators and
structural/mechanical regulators. Growth factors, particularly when
mimicking the extracellular matrix, exert geometric and
nongeometric physical, mechanical, chemical, electrical, and/or
structural forces on a cell. They can change a cell's content,
shape, form, and/or function. In essence, they can have a
kaleidoscopic effect which is very useful in creating and promoting
the growth and morphogenesis of irregularly structured cells,
tissues, or complex tissues and organs such as neurons, nervous
tissue, or the brain. These growth factors can activate and
regulate genetic transcription.
[0170] The invention utilizes the body as an organ/tissue factory.
There may, however, be occasions where the organ/tissue is
completely grown ex-vivo before replant or transplant.
[0171] Physical examinations can be done on any patient to
ascertain applications of the inventions herein described.
[0172] Genetic manipulation to any portion of a gene, gene(s)
protein, growth factor, or cell(s) whether taken from the patient
or from any other source can be done to improve organ or tissue
longevity, function, or any other attribute. These materials may be
synthesized in any fashion.
[0173] The extracellular matrix (ECM) may constantly change as a
result of mechanical, endocrine, or genetic factors.
[0174] A nutrient package's wall thickness can be two or less
nanometers, or it can be any other thickness desired. Its wall can
be fabricated from protein or from any other biological or
synthetic material desired.
[0175] An organ, as used herein, consists of two or more kinds of
tissues joined into one structure that has a certain task. For
example, the heart is an organ who job is to circulate blood
throughout the body. The heart is made up of connective tissue,
muscle tissue, and nervous tissue. Organ systems comprise groups of
organs. A major activity in the body is performed by each organ
system. For example, the digestive system comprises organs that
enable the body to use food. Likewise, the nervous system includes
organs that carry signals from one area of the body to another.
[0176] Genetic material comprising a portion of a gene, a gene,
genes, a gene product (i.e., a composition a gene causes to be
produced like, for example, an organ-producing growth factor),
growth factor, or an ECM (extracellular matrix) can be used in or
on the body to grow an organ or tissue. For example, the vascular
epithelial growth factor gene (VEGF) or its growth factor
equivalent can be inserted into the body to cause an artery to
grow. When insertion of a gene, portion of a gene, gene product,
growth factor, or ECM in vivo or ex vivo is referred to herein in
connection with any of the implant techniques of the invention, it
is understood that a cell nutrient culture(s), physiological
nutrient culture(s), carrier(s), enhancer(s), promoter(s), or any
other desired auxiliary component(s) can be inserted with the gene
or at the same location as the gene, growth factor, ECM, etc.
[0177] An artery is an organ from the circulatory system. An artery
can be grown in the heart, legs, or other areas by injecting a gene
or other genetic material into muscle at a desired site. Size,
vascularity, simplicity of access, ease of exploitation and any
other desired factors can be utilized in selecting a desired site.
The gene is one of several known VEGF genes which cause the
production of vascular endothelial growth factors. Several VEGF
genes which produce vascular endothelial growth factors are
believed to exist because nature intends for there to be several
pathways (i.e., genes) which enable of the production of necessary
growth factors. The existence of several pathways is believed
important because if one of the genes is damaged or inoperative,
other similar genes can still orchestrate the production of
necessary growth factors. VEGF genes are used by the body to
promote blood-vessel growth. VEGF genes are assimilated (taken in)
by muscle cells. The genes cause the muscle cells to make a VEGF
protein which promotes the growth of new arteries. VEGF proteins
can be made in a lab and injected into a patient intravenously,
intraluminally, or intramuscularly to promote the growth of an
artery. Or, the genes (or other genetic material) can be applied
with an angioplasty balloon, with the assistance of a vector, or by
any other method.
[0178] It is not always desirable to grow a completely new organ.
Sometimes growing a portion of an organ is desirable. For example,
in some heart attacks or strokes, a portion of the heart or brain
remains viable and a portion dies. An injection of a gene to form
cardiac muscle and/or an injection of a gene to form an artery can
be utilized to revive or replace the dead portion of the heart. The
dead portion of the heart may (or may not) be used as a matrix
while the new muscles and vessels grow. Thus, in this example, a
partial new organ and is grown in a pre-existing organ. A pacemaker
may (or may not) be necessary. A second injection of a gene may (or
may not) be necessary to stop cardiac muscle growth once it is
completed. Portions of organs throughout the body can similarly be
repaired or replaced. It may be necessary to provide gene(s) or
growth factor(s) sequentially. For instance, one or more blood
vessels are grown by inserting an appropriate gene or other genetic
material into a selected area. Second, an appropriate gene or other
genetic material is inserted in the selected area to grow a bone or
other organ.
[0179] The size and shape limitation of the desired structure can
come from a containment and boundary contact inhibition phenomenon
or by a chemical inhibition.
[0180] A variation on the theme of growing a portion of an organ is
as follows: a portion of a heart dies. The pericardium is utilized
as a scaffold and seeded with cells and/or genes to grow new
muscle, and genes (or other genetic material) to grow new arteries.
Immediately adjacent the dead cardiac muscle, onto or into the
pericardium, the appropriate cells, genes, and/or growth factors
(or other genetic material) are placed. Once the new muscle and
blood vessels have grown, the function specific tissue can be
applied to the damaged portion of the heart and paced, if
necessary, to augment cardiac action. If the surgeon desires, the
dead muscle can be removed and the new muscle and blood vessels can
be surgically rotated into the excised region and secured. This
probably can be done endoscopically. In essence, the pericardium is
utilized to allow the new muscle wall to grow. The new muscle wall
is then transplanted into the damaged heart wall. This procedure
utilizes the body as a factory to grow an organ and/or tissue,
after which the organ and/or tissue is transplanted to a desired
region. On the other hand, the new muscle wall may integrate itself
into the old wall and not require transplantation.
[0181] It may be advantageous to grow an organ and adjacent tissue.
For example, a severe burn victim may lose organs and tissues
(skin, blood vessels, fat, muscles, etc.). The gene(s), gene
product(s), and/or ECM (or other genetic material) may be assembled
utilizing any appropriate delivery vehicle or system. By way of
example, and not limitation, four spray cans or other delivery
apparatus can be utilized. First, muscle gene in a spray can is
applied in a light mist or layer. Then fat, blood vessel, and
finally skin gene(s) are applied, each from a separate spray can.
Or, possibly, all four components can be admixed in and applied
from a single spray can. Carriers, matrixes, isolating layers,
and/or form or shape defining products may or may not be used by
the operator. All the genes can be in the same spray can or
combined with other substances. As can be appreciated by those
skilled in the art, any method of inserting the gene(s), grow
factors, or ECM into or onto the body can be utilized. Nutrients,
analgesics, antiseptics, moisture restoring compositions and
methods, and appropriate post-operative dressings can be utilized
pursuant to operator discretion on an as-need basis.
[0182] It may be desirable to restore a single function in a
multifunctional organ. For example, a pancreas produces digestive
enzymes and it produces insulin in the Islets of Langerhans. A
practitioner may choose to stimulate only a desired portion. For
example, inserting a gene for the creation of more Islets of
Langerhans can be utilized to selectively restore an appropriate
insulin production level without affecting the production of
pancreatic digestive enzymes.
[0183] There is a mechanotransduction interplay the occurs from the
extracellular matrix (ECM) to and across the cell membrane, through
the cell's cytoskeleton, and, to the cell's DNA. Cellular products
are produced during this process and the process of morphogenesis
is aided by this procedure. It may be possible to rejuvenate an
organ by inserting a growth factor (especially a growth factor that
can mimic extracellular fluid to control cell growth, division,
migration, structure, function, and self-assembly) into or around
an organ that no longer operates to optimal capacity or to a
desired capacity. For example, in the interplay from the ECM to the
DNA as described above, if for any reason the DNA falls into
disrepair, cellular fitness and function become altered and a
disease state may occur. The organ or tissue no longer functions as
well as desired. The insertion of the growth factor into or around
the organ may rejuvenate and restore the fitness and function to
this organ even though the cellular DNA remains is disrepair. This
procedure may, in some cases, allow the cell to repair, restore,
change and reverse its DNA damage so that it can replicate normally
henceforth. Booster shots of the growth factor may be
necessary.
[0184] Organs and/or tissues can be formed utilizing the patient's
own cells, For example, a skin cell(s) is removed from the
intraoral lining of a cheek. The cell is genetically screened to
identify DNA damage or other structural and/or functional problems.
Any existing prior art genetic screening technique can be utilized.
Such methods can utilize lasers, DNA probes, PCR, or any other
suitable device. If the cell is damaged, a healthy undamaged cell
is, if possible, identified and selected. If a healthy cell can not
be obtained, the damaged cell can be repaired by excision,
alkylation, transition or any other desired method. A growth
factor(s) is added to the cell to facilitate dedifferentiation and
then redifferentiation and morphogenesis into an organ or function
specific tissue. Any machine known in the art can be used to check
the genetic fitness of the organ and its stage of morphogenesis. A
cell nutrient culture may or may not be utilized depending on the
desired functional outcome (i.e., growth of an artery, of
pancreatic Islet cells, of a heart, etc.) or other circumstances.
Replantation can occur at any appropriate stage of morphogenesis.
The foregoing can be repeated without the patient's own cells if
universal donor cells such a germinal cells are utilized. Germinal
cells do not require a dedifferentiation. They simply differentiate
into desired tissues or organs when properly stimulated. Similarly,
the DNA utilized in the foregoing procedure can come from the
patient or from any desired source.
[0185] During reimplantation one of the patient's own cells is
returned to the patient. During implantation, a cell not originally
obtained from the patient is inserted on or in the patient.
[0186] In the example above, if germinal cells (and in some cases,
stem cells) are utilized a direct differentiation and morphogenesis
into an organ can occur in vivo, ex vivo, or in vitro.
[0187] A variant on the above two examples involves inserting a
selected gene(s) or portion of a gene into a cell. For example, a
cell is removed, analyzed, and repaired if desired or necessary to
assure quality (e.g., proper interaction to give structural
(protein) or chemical (enzyme) product) and functional outcome
(e.g., the production of an organ). A gene(s) or a portion of a
gene is secured from the patient cell by sampling or is secured
from any other source. The gene is inserted into the cell. A growth
factor(s) can be inserted in the cell simultaneously with the gene
or at the time preceding or following insertion of the gene. Organ
formation occurs and replantation is performed utilizing any
acceptable technique. Inserting an appropriate growth factor or
other gene product in a cell may, without requiring the insertion
of a gene in the cell, trigger the process which causes the cell to
grow an organ. Similarly, controlling the ECM contacting a cell can
cause mRNA to select and copy a segment of the cell's DNA. This
segment of the cell's DNA interacts with one or more components in
the cell to produce a growth factor or other gene product which
triggers the growth of an organ.
[0188] An organ or tissue can be made utilizing pellet, capsule, or
other carrier carrying a growth factor, a gene, a growth factor and
a gene, or any other desired genetic material. These pellets can
include ECM producing compositions or components and can be
inserted anywhere in the body. Once inserted in the body, the
carriers can be fixed or can be movable; and, they can contain
living material, nonliving material, or living and nonliving
material. As such, they can be prepackaged pharmaceutical carriers
inserted to grow selected tissues and organs. The materials inside
the carriers can be from the patient or from any other source. Each
carrier can be porous, resorbable, semisolid, gelatinous, or have
any other desired physical attribute.
[0189] An auxiliary organ or a portion of an auxiliary organ can be
grown. For example, a two chambered auxiliary pump for the heart
can be grown. Most heart problems occur on the left side.
Augmentation and enlargement of the existing heart can help restore
optimal function and help prevent pathological enlargement of a
poorly performing section of the heart.
[0190] An auxiliary organ can be grown in the body years before the
anticipated expiration of the original organ. Genetic or other
testing can predict organ failure years in advance allowing an
early diagnosis of the future failure of an organ.
[0191] Avascular necrosis can be corrected with the insertion of a
gene(s) and/or growth factor or other genetic material in the body.
For example, avascular necrosis is diagnosed near a joint space.
VEGF or BMP genes, or, VEGF or BMP growth factors produced by VEFG
or BMP genes, respectively, or any other desired genetic based
material can be inserted to regrow blood vessels and/or bone.
Auxiliary placement apparatus like fixation plates and/or screws,
fixing compositions, or any other desired system can be utilized to
strengthen or secure tissue. The genes and/or growth factors can be
placed adjacent the auxiliary placement apparatus, can be placed in
a composition adjacent the auxiliary placement apparatus, can be
placed remote from the auxiliary placement apparatus, or, can be
placed at any other desired location.
[0192] Cellular dedifferentiation, differentiation,
redifferentiation, and morphogenesis are directed and controlled by
growth factors (or their genetic counterparts) controlling cell
growth, migration, structure, function, and/or self-assembly. A
growth factor (or gene or other genetic material) can be inserted
into or onto the body to grow missing limbs or body parts. The
insertion of a multifactorial and nonspecific growth factor (or
gene) is required. Such a growth factor is pluripotent, senses what
body part or other component is missing, and directs adjacent cells
to reconstruct the body part along genetically predetermined
pathways. The process is not unlike the salamander regrowing a
severed tail or limb. Other growth factors may or may not be
required.
[0193] The insertion of a growth factor (or its gene counterpart)
in the body can be utilized to prevent and/or reduce inflammation.
Growth factors control cell migration. As such, they can be
powerful cell inhibitors to prevent inflammatory cells from
migrating into an area. Such an application has major usefulness in
the treatment of arthritis or other autoimmune or inflammatory
diseases. Thus a growth factor can be inserted in the body to
control cell migration or to perform other functions described
herein.
[0194] A rotator cuff deficiency often prevents normal sports
activities. Ligament dysfunction can prevent jogging. Venous
insufficiency can hinder prolonged standing or walking. Such
musculoskeletal injuries or deficiencies can be corrected by
inserting a gene(s) and/or growth factor(s) or other genetic
material into the body to create new tissue and/or organs which
replaces or augments existing tissue.
[0195] A hybrid organ or other structure can be fabricated
genetically to include specific tissues which function as needed.
For example, a kidney containing Islets of Langerhans cells can be
produced. Such a kidney is useful for a patient with diabetes
mellitus and renal failure. Other hybrid structures can be grown
according to need.
[0196] Gene Trace Systems, Inc. of Menlo Park, Calif. has developed
fully automated DNA sequencing technology that combines DNA
probing, sequencing, and sizing reactions with laser-based "time of
flight" mass spectrometry. This technology (1) identifies the
sequence of base chemicals in a DNA strand in five seconds, (2)
permits genetic screening tests that cost as little as a few
dollars, and (3) is used for gene discovery and expression,
genotyping, and disease diagnosis and identification.
[0197] The Biological Microcavity Laser (TBML) analyzes blood and
cell samples in minutes. TBML (1) is a kind of "lab-on-a-chip"
which utilizes tiny fingers of laser light to image cells which are
placed in a small chamber, (2) permits information concerning each
cell in a cell sample of millions to be extracted in a few minutes,
(3) is a tool for studying cell structure changes and sequencing
DNA, (4) can identify the stages of morphogenesis, and (5) is based
on a laser device called a VCSEL (vertically-cavity
surface-emitting laser). Cells being analyzed with TBML do not have
to be killed and stained, as cells normally do for typical
laboratory analysis.
[0198] Stem cells associated with the central nervous system
differentiate to multiple fates: neurons, astrocytes, and
oligodendrocytes. The differentiation of these stem cells is
influenced by extracellular signals. For example, platelet-derived
growth factor is known to support neuronal differentiation. In
contrast, ciliary neurotrophic factor and thyroid hormone T3 act on
stem cells to generate astrocytes and oligodendrocytes.
[0199] Pax genes are key regulators during organogenesis of kidney,
eye, ear, nose, limb muscle, vertebral column and brain.
[0200] The extracellular matrix (ECM) is a dense, fibrous network
of proteins and sugars forming a complex natural environment
surrounding individual cells or groups of cells. Components of the
matrix, including proteins such a laminin and fibronectin, bind to
specific molecules called integrins on the cell surface. Through
these integrins the matrix sends cells various signals that
regulate what genes are active. These signals ultimately influence
whether cells proliferate, specialize, migrate, or even eliminate
themselves. The ECM has the ability to command cells to use
particular, tissue-specific genes. This allows the microenvironment
outside of cells to confer tissue specificity. For example,
capillary epithelial cells roll up to form normal blood vessels
only if grown on the proper matrix molecules.
[0201] A gene corresponds to a segment of the DNA that codes for
the synthesis of a single polypeptide chain. The definition of a
gene product, as used herein, is the polypeptide or ribosomal RNA
coded for by a gene, i.e., which a gene causes to be produced. A
gene product can include proteins, transcription factor(s), and/or
RNA. For example, VEGF is a gene, while VEGF growth factor is a
gene product.
[0202] Genes, a gene, a portion of a gene, ECM, and/or a nutrient
media can be inserted into a cell or groups of cells by direct
insertion (for example, an apparatus like a micropipette), with a
cell fragment (for example, a plasmid from a bacterium), with a
virus vector, liposome, by phagocytosis, with the help of
pore-forming substance, electrically, chemically, or by any other
desired technique of crossing the cell membrane to reach the
nucleus or any other desired site in the cell. A gene(s) can be
transferred in the form of naked plasmid DNA. For example, an
intramuscular injection can be made of plasmid DNA encoding the
secreted angiogenic growth factor such as vascular endothelial
growth factor (VEGF).
[0203] In accordance with one embodiment of the invention, a gene,
growth factor, ECM (or other genetic material) and/or nutrient
media is inserted into or onto the body at a specific location to
induce and promote the morphogenesis and growth of an organ or
desired organ sub-structure at that location. A desired organ
sub-structure can comprise a cell, group of cells, neuron, dermis,
Islet cells, etc. Also in accordance with the invention, a gene or
other genetic material is inserted into or onto a cell or group of
cells outside the body to induce and promote morphogenesis and
growth of an organ or desired structure. Growth factors can also be
utilized in combination with or in place of a gene. The resulting
induced organ or other structure is transplanted to a desired
location in a patient's body.
[0204] Gene products can be inserted in a patient's body to produce
an organ or other structure. For example, VEGF growth factor
inserted in the body produces an organ, i.e., an artery.
[0205] Selected ECM compositions or other environmental factors can
induce the morphogenesis of organs or selected organ
sub-structures. As used herein, environmental factors include, but
are not limited to, compositions which exert physical, mechanical,
chemical, electrical, and/or structural forces on living cells.
[0206] Another variant of the invention inserts a gene and a growth
factor at a selected location or locations in the body of a patient
to grow a selected organ or structure. As exemplified by cloning
technology, an enucleated ovum is a viable growth factor. Other
subunits of a cell also qualify as growth factors. A gene and the
extracellular matrix may also be inserted at a selected location or
locations in a patient's body to grow an organ. Likewise, a growth
factor and the extracellular matrix can be inserted in a patient's
body to form an organ.
EXAMPLE 18
[0207] A 36 year old Caucasian male experiences pain in his left
leg. A medical examination reveals a damaged one inch long section
of a large artery in his left leg. The examination also reveals
that this damaged section of the artery is nearly completely
clogged with plaque and that the wall of the artery is weakened.
The weakening in the arterial wall makes attempting to clean out
the artery risky and also makes it risky to attempt to insert a
stent in the artery.
[0208] Recombinant cDNA encoded to combine with a cell ribosome to
produce the human growth factor VEGF is assembled into a eukaryotic
expression plasmid. The recombinant cDNA is from cDNA libraries
prepared from HL60 leukemia cells and is known to cause the growth
of arteries. The plasmid is maintained at a room temperature of 76
degrees F.
[0209] The clones are placed in 1.0 milliliters of a normal saline
carrier solution at a room temperature of 76 degrees F. to produce
an genetic carrier solution. The genetic carrier solution contains
about 250 ug of the cDNA clones. A nutrient culture can, if
desired, be utilized in conjunction with or in place of the saline
carrier. Each clone is identical. If desired, only a single clone
can be inserted in the normal saline carrier solution. The saline
carrier solution comprises 0.09% by weight sodium chloride in
water. A saline carrier solution is selected because it will not
harm the DNA clone.
[0210] Two sites are selected for injection of the genetic carrier
solution. While the selection of sites can vary as desired, the
sites are selected at the lower end (the end nearest the left foot
of the patient) of the damaged section of the artery so that the
new arterial section grown can, if necessary, be used to take the
place of the damaged section of the artery in the event the damaged
section is removed.
[0211] The first site is on the exterior wall of the artery on one
side of the lower end of the damaged section of the artery. A
containment system is placed at the first site.
[0212] The second site is inside the wall of the artery on the
other side of the lower end of the artery.
[0213] The genetic carrier solution is heated to a temperature of
98.6 degrees F. 0.25 milliliters of the genetic carrier solution is
injected into the containment system at the first site. 0.25
milliliters of the genetic carrier solution is injected at the
second site inside the wall of the artery. Care is taken to slowly
inject the genetic carrier solution to avoid entry of the solution
into the artery such that blood stream will carry away the cDNA in
the solution.
[0214] After two weeks, an MRI is taken which shows the patient's
leg artery. The MRI reveals new growth at the first and second
sites.
[0215] After four weeks, another MRI is taken which shows the
patient's leg artery. The MRI shows that (1) at the first site a
new artery is growing adjacent the patient's original leg artery,
and (2) at the second site a new section of artery is growing
integral with the original artery, i.e., at the second site the new
section of artery is lengthening the original artery, much like
inserting a new section of hose in a garden hose concentric with
the longitudinal axis of the garden hose lengthens the garden
hose.
[0216] After about eight to twelve weeks, another MRI is taken
which shows that the new artery growing adjacent the patient's
original artery has grown to a length of about one inch and has
integrated itself at each of its ends with the original artery such
that blood flows through the new section of artery. The MRI also
shows that the new artery at the second site has grown to a length
of one-half inch.
[0217] In any of the examples of the practice of the invention
included herein, cell nutrient culture can be included with the
gene, the growth factor, the extracellular matrix, or the
environmental factors.
[0218] In any of the examples of the practice of the invention
included herein, the concept of gene redundancy can be applied. For
example, the Examples 1 to 14 concerning a tooth list the genes
MSX-1 and MSX-2. These genes differ by only two base pairs. Either
gene alone may be sufficient. A further example of redundancy
occurs in growth factors. Looking at the Examples 10 to 14, BMP4 or
BMP2 alone may be sufficient. Redundancy can also be utilized in
connection with transcription factors, extracellular matrices,
environmental factors, cell nutrient cultures, physiological
nutrient cultures, vectors, promotors, etc.
[0219] One embodiment of the invention inserts genetic material
(gene, growth factor, ECM, etc.) into the body to induce the
formation of an organ. Similar inducing materials inserted ex vivo
into or onto a living cell in an appropriate physiological
nurturing environment will also induce the growth of an organ. The
VCSEL laser allows early detection in a living cell of a
morphogenic change indicating that organ formation has been
initiated. With properly timed transplantation, organ growth
completes itself.
[0220] During the ex vivo application of the invention, a gene
and/or growth factor is inserted into a cell or a group of cells;
an ECM or environmental factor(s) are placed around and in contact
with a cell or group of cells; or, genetic material is inserted
into a subunit of a cell to induce organ growth. An example of a
subunit of a cell is an enucleated cell or a comparable
artificially produced environment. In in vivo or ex vivo
embodiments of the invention to induce the growth of an organ, the
genes, growth factors, or other genetic material, as well as the
environmental factors or cells utilized, can come from any desired
source.
EXAMPLE 19
[0221] Genetically produced materials are inserted in the body to
cause the body to grow, reproduce, and replace in vivo a clogged
artery in the heart. This is an example of site-specific gene
expression. A plasmid expression vector containing an
enhancer/promoter is utilized to aid in the transfer of the gene
into muscle cells. The enhancer is utilized to drive the specific
expression of the transciptional activator. After the enhancer
drives the expression of the transcriptional activator, the
transcriptional activator transactivates the muscle/artery genes.
Saline is used as a carrier. Cardiac muscle can take up naked DNA
injected intramuscularly. Injecting plasmid DNA into cardiac (or
skeletal) muscle results in expression of the transgene in cardiac
myocytes for several weeks or longer.
[0222] Readily available off-the-shelf (RAOTS) cDNA clones for
recombinant human VEGF165, isolated from cDNA libraries prepared
from HL60 leukemia cells, are assembled in a RAOTS expression
plasmid utilizing 736 bp CMV promoter/enhancer to drive VEGF
expression. Other RAOTS promoters can be utilized to drive VEGF
expression for longer periods of time. Other RAOTS recombinant
clones of angiogenic growth factors other than VEGF can be
utilized, for example, fibroblast growth factor family, endothelial
cell growth factor, etc. Downstream from the VEGF cDNA is an SV40
polyadenylation sequence. These fragments occur in the RAOTS pUC118
vector, which includes an Escherichia coli origin of replication
and the Beta lactamase gene for ampicillin resistance.
[0223] The RAOTS construct is placed into a RAOTS 3 ml syringe with
neutral pH physiologic saline at room temperature (or body
temperature of about 37 degrees C.). The syringe has a RAOTS 27
gauge needle.
[0224] Access to the cardiac muscle is gained by open heart
surgery, endoscopic surgery, direct injection of the needle without
incision, or by any other desired means. The cardiac muscle
immediately adjacent a clogged artery is slowly injected with the
RAOTS construct during a five second time period. Injection is slow
to avoid leakage through the external covering of muscle cells.
About 0.5 ml to 1.0 ml (milliliter) of fluid is injected containing
approximately 500 ug phVEGF165 in saline (N=18). The readily
available off-the-shelf cDNA clones cause vascular growth which
automatically integrates itself with the cardiac muscle. Anatomic
evidence of collateral artery formation is observed by the 30th day
following injection to the RAOTS construct. One end of the artery
integrates itself in the heart wall to receive blood from the
heart. The other end of the artery branches into increasing smaller
blood vessels to distribute blood into the heart muscle. Once the
growth of the new artery is completed, the new artery is left in
place in the heart wall. Transplantation of the new artery is not
required.
[0225] Blood flow through the new artery is calculated in a number
of ways. For example, Doppler-derived flow can be determined by
electromagnetic flowmeters (using, for example, a Doppler Flowmeter
sold by Parks Medical Electronic of Aloha, Oreg.) both in vitro and
in vivo. RAOTS external ultrasound gives a semiquantitative
analysis of arterial flow. Also, RAOTS angiograms or any other
readily available commercial devices can be utilized.
[0226] VEGF gene expression can be evaluated by readily available
off-the-shelf polymerase chain reaction (PCR) techniques.
[0227] If controls are desired, the plasmid pGSVLacZ containing a
nuclear targeted Beta-galactosidase sequence coupled to the simian
virus 40 early promoter can be used. To evaluate efficiency, a
promoter-matched reporter plasmid, pCMV Beta (available from
Clontech of Palo Alto, Calif.), which encodes Beta-galactosidase
under control of CMV promoter/enhancer can be utilized. Other RAOTS
products can be utilized if desired.
EXAMPLE 20
[0228] A patient, a forty year old African-American female in good
health, has been missing tooth number 24 for ten years. The space
in her mouth in which her number 24 tooth originally resided is
empty. All other teeth except tooth number 24 are present in the
patient's mouth. The patient desires a new tooth in the empty
"number 24" space in her mouth.
[0229] A full thickness mucoperiosteal flap surgery is utilized to
expose the bone in the number 24 space. A slight tissue reflection
into the number 23 tooth and number 25 tooth areas is carried out
to insure adequate working conditions.
[0230] A Midwest Quietair handpiece (or other off-the-shelf
handpiece) utilizing a #701 XXL bur (Dentsply Midwest of Des
Plaines, Ill.)(a #700, #557, #558, etc. bur can be utilized if
desired) is used to excavate an implant opening or site in the
bone. The implant opening is placed midway between the roots of the
number 23 and number 25 teeth. The opening ends at a depth which is
about fifteen millimeters and which approximates the depth of the
apices of the roots of the number 23 and number 25 teeth. Care is
taken not to perforate either the buccal or lingual wall of the
bone. In addition, care is taken not to perforate or invade the
periodontal ligament space of teeth numbers 23 and 25.
[0231] An interrupted drilling technique is utilized to avoid
overheating the bone when the #701XXL bur is utilized to form the
implant opening. During a drilling sequence, the drill is operated
in five second increments and the handpiece is permitted to stall.
Light pressure and a gentle downward stroke are utilized. The bur
is removed from the opening after the handpiece is permitted to
stall. This sequence is repeated until an implant opening having
the desired depth is created. In the event a standard off-the-shelf
implant drill is utilized, the foregoing technique is not utilized
and, instead, the manufacturer's recommended drilling technique is
followed.
[0232] Once the implant opening is created, 0.5 ml of EDTA
(ethylene diamine tetra acetic acid) is lavaged to the bottom of
the implant opening or site and allowed to set for two minutes. The
EDTA solution is then washed off with sterile water. This removes
the smear layer which forms when the #701XXL bur is used to form
the implant opening. 0.5 cc of propylene glycol alginate solution
is mixed with freeze dried MSX-1 matrix proteins. The resultant gel
is backloaded into a Luhrlock syringe through an 18 gauge needle.
Once loaded, a smaller 27 gauge needle is be placed on the syringe
to allow the need to be bent when it is inserted in the implant
site in the mouth. The gel loses handling qualities after about two
hours and is therefore preferably utilized within ten or fifteen
minutes after being admixed.
[0233] The tip of the 27 gauge needle is placed at the bottom of
the implant opening and 0.25 ml of gel is ejected into the bottom
of the implant opening. The needle is slowly removed from the
implant opening while, at the same time, the syringe is operated to
express additional gel to fill the implant opening from the bottom
of the opening to the coronal aspect of the bone surrounding the
implant opening. Gum tissue is drawn over the implant opening to
close the opening and is sutured in place with Ethicon suture.
[0234] Alginate gel begins to be absorbed by the patient's body
within 48 hours and binds MSX-1 proteins to bone in or adjacent the
implant opening. Within about six (6) months, the formation of a
tooth is radiographically confirmed.
EXAMPLE 21
[0235] Example 20 is repeated, except that the MSX-1 alginate
matrix proteins are omitted, and in their place at least one MSX-1
gene, a plasmid, and a promoter/enhancer are mixed with and
included in the gel that is loaded into the syringe and injected
into the implant opening. Similar results are obtained.
EXAMPLE 22
[0236] Example 21 is repeated, except a 0.09% saline solution is
utilized as a carrier instead of the alginate gel. Similar results
are obtained.
EXAMPLE 23
[0237] Example 21 is repeated, except a MSX-2 gene is utilized in
place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 24
[0238] Example 22 is repeated, except a MSX-2 gene is utilized in
place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 25
[0239] Example 21 is repeated, except a PAX-9 gene is utilized in
place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 26
[0240] Example 22 is repeated, except a PAX-9 gene is utilized in
place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 27
[0241] Example 21 is repeated, except a PAX-9 protein is utilized
in place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 28
[0242] Example 22 is repeated, except a PAX-9 protein is utilized
in place of the MSX-1 gene. Similar results are obtained.
EXAMPLE 29
[0243] Example 21 is repeated, except at least one MSX-2 gene is
included in combination with the MSX-1 gene. Similar results are
obtained.
EXAMPLE 30
[0244] Example 22 is repeated, except at least one MSX-2 gene is
included in combination with the MSX-1 gene. Similar results are
obtained.
EXAMPLE 31
[0245] Example 21 is repeated, except at least one MSX-2 gene is
included in combination with the MSX-1 gene along with BMP2, BMP4,
and BMP7 growth factors. Similar results are obtained.
EXAMPLE 32
[0246] Example 22 is repeated, except at least one MSX-2 gene is
included in combination with the MSX-1 gene along with BMP2, BMP4,
and BMP7 growth factors. Similar results are obtained.
[0247] For the development of a tooth in accordance with the
invention, an upstream initiator gene(s) and/or growth factor(s)
inserted directly in vivo or transplanted into the body at a very
early stage of morphogenesis is sufficient for tooth formation. The
general approach delineated above for a tooth and an artery is
appropriate for any organ or organ system. When an organ is grown
ex vivo other regulator and/or signaling compositions can be
utilized in addition to initiator genes (like MSX-1) and/or growth
factors. During growth of a tooth, the genetically produced
materials noted below can be utilized:
1 Initiation Proliferation Morphogenesis Bmp2, 4 Bmp2, 4 Bmp4 EGF
Dlx1-3 Collagens FGF8 EGR1 Dlx1-3 Lef1 FGFs Lef1 Msxl Lef1 Msx1
Msx2 Msx1 Msx2 Shh Msx2 Notch1-3 Notch1-3 Pax9 Pax9 RAR RAR (alpha,
beta RXR omega) RXR (alpha, beta Tuftelin omega) Syndecan Tenascin
TGF-beta s
[0248] In the Islets of Langerhans, the initiators are: Pax-6,
Pax-4, ISL-1, NKX6A. Other factors are the TGF family, Gastrin,
IDX-1, PDX-1, INGAP, NeuroD, HNF3beta, IPF-1, helix-loop-helix
protein Beta-2, etc.
[0249] In accordance with the invention, site preparation prior to
the insertion of a gene and/or growth factor into the body can
occur at any selected site. For example, examples of site
preparation include debridement of a burn wound, the application of
EDTA or citric acid to a bone site, or any other desired site
preparation.
[0250] As used herein, genetic material includes a gene(s), a
portion of a gene, a growth factor(s), a gene product(s), and/or
ECM which individually or collectively function to cause the
genesis and growth of an organ.
EXAMPLE 33
[0251] Example 18 is repeated except that the patient is a 24 year
old Caucasian male and the genetic carrier solution is injected
into two sites in the right leg of the patient. The first site is
on the exterior wall on one side of the right leg artery. The
second site is inside the wall of the right leg artery on the other
side of the artery. The right leg artery is not blocked and is a
normal healthy artery. Similar results are obtained, i.e., a new
section of artery grows integral with the original right leg
artery, and a new section of artery grows adjacent the original
right leg artery.
EXAMPLE 34
[0252] Example 18 is repeated except that VEGF growth factor is
utilized in the genetic carrier solution in place of the cDNA.
Similar results are obtained.
EXAMPLE 35
[0253] Example 18 is repeated except that the patient is a 32 year
old Caucasian female, the cDNA produces a VEGF growth factor which
promotes the growth of veins, and the genetic carrier solution is
injected into two sites in the right leg of the patient. The first
site is on the exterior wall on one side of a large right leg vein.
The second site is inside the wall of the right leg vein on the
other side of the vein. The right leg vein is not blocked and is a
normal healthy artery. Similar results are obtained, i.e., a new
section of vein grows integral with the original right leg vein,
and a new section of vein grows adjacent the original right leg
vein.
EXAMPLE 36
[0254] Example 18 is repeated except that the patient is a 55 year
old Caucasian male, and the genetic carrier solution is injected
into two sites in the coronary artery of the patient. The first
site is on the exterior wall on one side of the artery. The second
site is inside the wall of the artery on the other side of the
artery. A section of the artery is damaged, is partially blocked,
and has a weakened wall. The first and second sites are each below
the damaged section of the artery. Similar results are obtained,
i.e., a new section of artery grows integral with the original
artery, and a new section of artery grows adjacent the original
artery. The new section of artery has integrated itself at either
end with the original artery so that blood flows through the new
section of artery.
* * * * *