U.S. patent application number 15/294954 was filed with the patent office on 2017-02-02 for methods of treating degenerative bone conditions.
This patent application is currently assigned to Agnovos Healthcare, LLC. The applicant listed for this patent is Agnovos Healthcare, LLC. Invention is credited to Joel Batts, Ryan Belaney, David Harness, James G. Howe, Bryan Huber, Olaf Schulz, Rick Swaim.
Application Number | 20170027591 15/294954 |
Document ID | / |
Family ID | 46755961 |
Filed Date | 2017-02-02 |
United States Patent
Application |
20170027591 |
Kind Code |
A1 |
Schulz; Olaf ; et
al. |
February 2, 2017 |
METHODS OF TREATING DEGENERATIVE BONE CONDITIONS
Abstract
A combination suction and irrigation device for a medical
procedure. The device includes an elongated body having a proximal
end and a distal end and defines an open channel that extends from
the proximal end to the distal end. The open channel is open at
both the proximal end and the distal end. A suction port is in
communication with the open channel and is connectable to a source
of suction. An irrigation port is in communication with the open
channel and is connectable to a source of irrigation fluid. A valve
selectively opens and closes the open channel to flow relative to
the suction port and to the open proximal end, and to flow relative
to the irrigation port.
Inventors: |
Schulz; Olaf; (Lakeland,
TN) ; Howe; James G.; (Shelbourne, VT) ;
Swaim; Rick; (Lakeland, TN) ; Huber; Bryan;
(Stowe, VT) ; Batts; Joel; (Lakeland, TN) ;
Harness; David; (Eads, TN) ; Belaney; Ryan;
(Oakland, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Agnovos Healthcare, LLC |
Rockville |
MD |
US |
|
|
Assignee: |
Agnovos Healthcare, LLC
Rockville
MD
|
Family ID: |
46755961 |
Appl. No.: |
15/294954 |
Filed: |
October 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13173701 |
Jun 30, 2011 |
|
|
|
15294954 |
|
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|
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61361177 |
Jul 2, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2217/005 20130101;
A61M 1/0058 20130101; A61L 2430/02 20130101; A61L 15/28 20130101;
A61L 27/12 20130101; A61L 24/0042 20130101; A61B 17/17 20130101;
A61L 24/02 20130101; A61B 17/1668 20130101; A61L 27/58 20130101;
A61B 17/16 20130101; A61B 17/1659 20130101; A61B 2217/007 20130101;
A61L 2400/06 20130101; A61M 1/0035 20140204 |
International
Class: |
A61B 17/16 20060101
A61B017/16; A61B 17/17 20060101 A61B017/17; A61M 1/00 20060101
A61M001/00 |
Claims
1. A combination suction and irrigation device for a medical
procedure, comprising: an elongated body having a proximal end and
a distal end and defining an open channel that extends from the
proximal end to the distal end, the open channel being open at both
the proximal end and the distal end; a suction port in
communication with the open channel, the suction port being
connectable to a source of suction; an irrigation port in
communication with the open channel, the irrigation port being
connectable to a source of irrigation fluid; a valve for
selectively opening and closing the open channel to flow relative
to the suction port and to the open proximal end, and to flow
relative to the irrigation port.
2. The combination suction and irrigation device recited in claim
1, wherein the suction port is located proximal of the irrigation
port.
3. The combination suction and irrigation device recited in claim
1, further including a syringe body in communication with the
irrigation port.
4. The combination suction and irrigation device recited in claim
1, further including a connector extending from the elongated body,
the connector configured to mount a syringe body to the elongated
body.
5. The combination suction and irrigation device recited in claim
4, wherein the connector is located proximal of the suction
port.
6. The combination suction and irrigation device recited in claim
4, wherein the connector is located proximal of the valve.
7. The combination suction and irrigation device recited in claim
4, wherein the valve, the suction port, the irrigation port, and
the connector, are all located along a proximal portion of the
elongated body, the proximal portion having a wider dimension than
a distal portion of the elongated body that extends distally of the
proximal portion.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.120 of U.S. application Ser. No. 13/173,701, entitled
"METHODS OF TREATING DEGENERATIVE BONE CONDITIONS" filed on Jun.
30, 2011, which is herein incorporated by reference in its
entirety. Application Ser. No. 13/173,701 claims priority under 35
U.S.C. .sctn.119(e) to U.S. Provisional Application Ser. No.
61/361,177, entitled "METHODS OF REPLACING DEGENERATIVE BONE" filed
on Jul. 2, 2010, which is herein incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods of treating
patients suffering from bone degeneration, such as osteopenia and
osteoporosis. More particularly, the invention provides methods of
treating patients suffering from bone degeneration by replacing at
least a portion of the degenerated bone material.
BACKGROUND
[0003] Bone mineral density (BMD) is a term that is commonly
recognized as relating to the amount of calcified matter present
per square centimeter of bone. It is understood that the term does
not refer to a true density (as in mass per volume of material) but
rather is used to communicate information about the strength of the
bone and the susceptibility 20 of the bone to fracture. Typically,
BMD is evaluated using methods, such as Dual Energy X-ray
Absorptiometry (or DEXA scan), ultrasound, and Quantitative
Computed Tomography (QCT). Of the foregoing, DEXA scan often is
considered to be the most reliable evaluation of BMD. For example,
ultrasound is generally limited to evaluation of the calcaneus bone
and is not useful for directly measuring sites common to
osteoporotic fracture, such as the hip and spine. QCT typically is
used with the spine and must be done following strict protocols in
laboratories to provide acceptable reproducibility. Further test
methods for evaluating BMD include single photon absorptiometry
(SPA), dual photon absorptiometry (DPA), digital X-ray
radiogammetry (DXR), and single energy X-ray absorptiometry
(SEXA).
[0004] BMD is a highly important physical characteristic since it
can be a direct indicator of susceptibility to fracture. In most
adult populations, BMD peaks around the age of 30-35 and tends to
slowly decline thereafter. The reduction in BMD arises from a
decline in new bone cell production such that the resorption of
existing bone cells by the body exceeds the rate of new bone cell
production. FIG. 1 (which is available online at
http://courses.washington.edu/bonephys/opbmd.html) illustrates the
typical decline in BMD (shown in mg/cm.sup.2) for adults and shows
how the decline can vary based upon both race and gender. Menopause
in women is a highly significant event in relation to BMD as the
decrease in BMD sharply accelerates for a period of time after
menopause. Thus, post-menopausal women typically are encouraged to
have BMD testing regularly to assess if treatment is required and
what type of treatment should be pursued. The National Osteoporosis
Foundation recommends BMD testing for the following individuals:
all women aged 65 and older regardless of risk factors; younger
postmenopausal women with one or more risk factors; postmenopausal
women who present with fractures (to confirm the diagnosis and
determine disease severity); estrogen deficient women at clinical
risk for osteoporosis; individuals with vertebral abnormalities;
individuals receiving, or planning to receive, long-term
glucocorticoid (steroid) therapy; individuals with primary
hyperparathyroidism; individuals being monitored to assess the
response or efficacy of an approved osteoporosis drug therapy; and
individuals with a history of eating disorders.
[0005] Reduced BMD commonly is recognized in relation to the
conditions of osteopenia and osteoporosis, and the existence of
these conditions is defined upon a patient's score from a BMD test,
particularly the T-score from a DEXA scan. The T-score from a DEXA
scan is a normalized value that indicates how a patient's BMD
compares to the average of a young adult at peak BMD. The
normalized value is expressed in standard deviations from the
average. Thus, a T-score of 0 indicates no difference in BMD
compared to the average young adult, a negative T-score indicates
BMD below the average, and a positive T-score indicates BMD above
the average. T-score is a normalized value because the average
value varies depending upon race and gender. T-score also can vary
from one bone to another in the same individual. Generally, a bone
with a T-score of greater than -1 is considered to be within the
normal range (although the negative score still indicates BMD below
the normalized average). The condition of osteopenia typically is
considered to exist for bone with a T-score of -1 to -2.5. The
condition of osteoporosis typically is considered to exist for bone
with a T-score of less than -2.5.
[0006] BMD can be correlated to bone strength and thus can be a
predictor of risk for bone fracture. In general, the risk for bone
fracture is expected to increase with every standard deviation
below normal. In the elderly, bone fracture (particularly hip or
vertebral fractures) can be correlated to increased mortality.
Thus, improving BMD can be a goal of medical intervention in
osteopenic and/or osteoporotic patients since BMD can be correlated
to increased risk for fracture. While several interventions have
been tried, there still remains a need in the art for treatments
that can effectively increase BMD.
[0007] Treatment and prophylaxis of bone degeneration (i.e., loss
of BMD) can take on many faces. Prevention typically starts in
childhood with exercise and proper nutrition that includes
sufficient calcium and vitamin D as both exercise and nutrition
have been shown to be necessary for maximum BMD development. This
is important because decrease in BMD with age has been shown to be
slower when actual BMD at the peak age is greater.
[0008] When conditions of osteopenia and osteoporosis are present,
many different therapies are available. Estrogen treatment of
postmenopausal women may slow onset and/or progression of bone
degeneration. Similarly, Selective Estrogen Receptor Modulators
(SERM's), such as raloxefine, may be used to simulate increased
estrogen in the body and thus slow bone loss. Calcitonin may be
prescribed and is a material that is naturally produced by cells in
the thyroid gland. Calcitonin acts directly on osteoclasts (via
receptors on the cell surface for calcitonin) to modify the
osteoclasts and thus stop bone resorption. Bisphosphonates, such as
etidronate (DIDRONEL.RTM.), pamidronate (AREDIA.RTM.), alendronate
(FOSAMAX.RTM.), risedronate (ACTONEL.RTM.), zoledronate
(ZOMETA.RTM. or RECLAST.RTM.), and ibandronate (BONIVA.RTM.), can
increase bone strength through increased mineralization density and
decrease bone resorption. The bisphosphonates are all related to
pyrophosphate, which is a byproduct of cellular metabolism and is a
natural circulating inhibitor of mineralization in the blood and
urine. Although pyrophosphates cannot enter bones (i.e., because
the cell lining destroys pyrophosphate with alkaline phosphatase),
bisphosphonates can enter the bone (and attach very strongly) due
to chemical substitution in the compounds. Although such drugs may
provide some level of usefulness, recent studies have suggested
that long-term use of bisphosphonates can increase the risk of
spontaneous subtrochanteric and femoral shaft fractures (i.e.,
atypical fractures). Denosumab (PROLIA.RTM.) is another
pharmaceutical that was recently approved by the U.S. Food and Drug
Administration for twice-a-year injections in osteoporotic patients
with high fracture risk or patients that cannot tolerate other
treatments. Denosumab is a fully human, monoclonal antibody that
binds the RANK ligand and alters the body's natural bone remodeling
process. Although long-term effects of the use of this antibody are
not yet known, doctors have been warned to monitor patients for
adverse reactions, such as osteonecrosis of the jaw, atypical
fractures, and delayed fracture healing. Further, since the
antibody alters the body's immune system, there has been evidence
that use of the antibody can increase risk of serious infection in
the patient. Yet another treatment, teriparatide (FORTEO.RTM.), is
a recombinant parathyroid hormone (rPTH) that has the paradoxical
effect of increasing bone mass by altering the pattern of exposure
to the body's natural parathyroid hormone (PTH) and thus altering
the skeletal effect of chronic PTH elevation, which can result in
increased bone breakdown, a loss of calcium, and osteoporosis.
Through activation of various bone metabolic pathways, the rPTH
increases the number of active osteoblasts, decreases the naturally
programmed death of osteoblast cells, and recruits bone-lining
cells as osteoblasts. The drug appears to act largely upon the
bone-building osteoblast cells and stimulating them to over
activity. Safety studies in rats indicated a possibly increased
risk of osteosarcoma associated with use of rPTH. Thus, there
remains a need in the art for treatments that do not require
long-term medication use with possible effects that, although
unintended, may still be harmful.
[0009] Non-pharmaceutical treatments typically are used only after
a fracture occurs. For example, fractures (particularly vertebral)
may be treated by instant fixation wherein poly (methyl
methacrylate) cement (typically referred to as "bone cement") or a
similar non-resorbable material, is inserted into the fracture to
permanently harden and "fix" the bone in place. Although such
treatments can attend to the presenting fracture, the unnatural
physical properties (i.e., hardness, modulus, etc.) of the bone
after the treatment are believed to increase the possibility of
fracture of adjacent bone, particularly where the adjacent bone is
in an advanced state of osteoporosis. Moreover, such treatments do
not result in formation of natural bone in the fracture but rather
function as non-resorbable bone replacements.
[0010] Despite the presence of pharmaceutical and surgical
treatments for bone degeneration and fracture, there remains a need
in the art for further treatments that can increase BMD in key
areas to reduce risk of fractures and concomitant health risks,
including death. Particularly, it would be useful to have means for
treatments that target specific areas of the skeleton at high
fracture risk by actually forming new, healthy (i.e., normal) bone
material. Such treatments would not be subject to the current
limitations of the art.
SUMMARY OF THE INVENTION
[0011] The present invention provides for improvement of bone
structure in patients suffering from a degenerative bone condition,
such as osteopenia or osteoporosis. Specifically, the invention
allows for selective replacement of degenerated bone material in
localized areas of bones with a bone regenerative material that is
resorbed by the body over time and replaced by newly generated bone
material. Beneficially, the newly formed bone material is bone
material that is natural to the patient in that it is not a bone
transplant (e.g., cadaver bone) or a non-resorbable bone
replacement (e.g., bone cement). Moreover, the newly formed bone
material is not degenerative in nature but is healthy bone material
in the sense that the bone material (which can include the
immediately surrounding portions of the bone) exhibits
characteristics, such as BMD and compressive strength, that make
the newly formed bone material, in certain embodiments,
substantially similar to bone material in an average, healthy, 30
year old individual (i.e., at the age where BMD is typically at its
peak). In other embodiments, the newly generated bone can be
characterized as being improved in relation to osteopenic bone or
osteoporotic bone. The improvement further may be characterized in
relation to a specific scale, such at in relation to T-score from
DEXA scans.
[0012] In certain embodiments, the invention thus can be directed
to a method of treating a patient suffering from a degenerative
bone condition. Specifically, the method can comprise forming a
void in a localized area of a bone, such as by mechanical
debridement of the degenerated bone material or otherwise breaking
apart the degenerated bone material to form the void. Optionally, a
portion of the degenerated bone material can be removed from the
formed void. In some embodiments, the degenerated bone material may
remain in the void but, because of the degenerated state of the
bone material, the material does not take up a significant volume
of the formed void. The method further can comprise at least
partially filling the formed void with a bone regenerative
material.
[0013] In certain embodiments, the degenerative bone condition
specifically can be selected from the group consisting of
osteopenia and osteoporosis. While the patient to be treated can be
suffering from any condition that causes bone degeneration, the
terms osteopenia and osteoporosis may be considered to generally
encompass patients suffering from any condition that causes a
reduction in BMD to the extent that a T-score calculated by DEXA
scan is below a certain threshold. For example, since osteopenia
technically is defined as being present when a T-score for the area
of bone scanned is less than -1.0, and since osteoporosis
technically is defined as being present when a T-score for the area
of bone scanned is less than -2.5, these clinical terms (and the
present methods of treatment thereof) can be considered applicable
to treating bone degeneration regardless of the underlying
condition from which the bone loss arises (whether it be from
natural bone loss with aging or as a side effect of a specific
underlying disease or medical treatment (e.g., steroid
treatments).
[0014] In specific embodiments, the bone regenerative material used
according to the invention can comprise an osteoinductive material,
osteoconductive material, osteogenic material, osteopromotive
material, or osteophilic material. Preferably, the bone
regenerative material comprises calcium sulfate. In further
embodiments, the bone regenerative material may comprise calcium
phosphate. In other embodiments, the bone regenerative material may
comprise tricalcium phosphate granules. In specific embodiments,
the bone regenerative material may comprise a combination of all
three types of materials. In some embodiments, the bone
regenerative material can comprise a material exhibiting a
tri-phasic resorption profile in vivo.
[0015] The bone regenerative material may be characterized as being
a material that causes formation of new, non-degenerated bone
material in the formed void. Specifically, the non-degenerated bone
material may have a density that is substantially identical to
normal bone (i.e., bone from a typical, healthy 30 year old
individual), particularly bone from the same generalized area.
Specifically, this may be characterized in relation to a T-score
measured by Dual Energy X-ray Absorptiometry (DEXA). Preferably,
the portion of the bone including the newly formed bone material
has a T-score that is greater than -1.0, greater than -0.5, or is
at least 0.
[0016] In certain embodiments, the bone regenerative material may
be characterized as promoting remodeling of the localized area of
the bone over time to be substantially identical to normal bone.
Specifically, the remodeling may be indicated by the localized 10
area of the bone (after implantation of the bone regenerative
material into the void) initially having a T-score that is greater
than 2.0, the T-score gradually reducing over time to have a
T-score that is about 0 to about 2. Preferably, the remodeled,
localized area of the bone maintains a T-score of greater than
about 0 for a time of at least 1 year measured from the time of new
bone material formation.
[0017] In further embodiments, the bone regenerative material may
be characterized as promoting formation of new bone material of
substantially normal BMD in the area of the bone adjacent the
formed void. This can be described as a gradient effect, which is
discussed further herein.
[0018] The bone for void formation can be any bone that is
degenerative in nature and would be a desirable area for treatment
according to the invention (e.g., to prevent future fractures). In
some embodiments, the bone can be selected from the group
consisting of hip, femur, vertebrae, radius, ulna, humerus, tibia,
and fibula.
[0019] In further embodiments, the invention specifically can be
characterized as providing a method of increasing BMD in a
localized area of a bone. The method can comprise forming a void in
the localized area of the bone and optionally removing a content of
the cleared bone material. The method further can comprise at least
partially filling the formed void with a bone regenerative material
such that new bone material is generated within the void, the
density of the generated bone material being greater than the
density of the bone material that was originally present in the
void space. Preferably, the increase in BMD is indicated by the
generated bone material having a T-score that is at least 0.5 units
greater than the T-score of the native bone material prior to being
removed to form the void. Even greater improvements in T-score can
be seen, as described further herein. In specific embodiments, the
T-score of the native bone material prior to being removed to form
the void can be less than about -1.0 and the generated bone
material can have a T-score that is greater than -1.0 or that is at
least about -0.5. The invention further is beneficial in that the
increase in BMD may be maintained for a time of at least about 1
year measured from the time of new bone material generation.
[0020] In still further embodiments, the invention may be
characterized as providing a method of creating a defined BMD
profile in a localized area of a bone. As further described herein,
the methods of the invention surprisingly not only improve bone
quality in the localized area of the bone treated, but also can
provide a specific BMD profile wherein BMD in the localized area is
dramatically improved and is followed by a gradual return to a
substantially normal density. The inventive method can comprise
forming a void in the localized area of the bone and at least
partially filling the formed void with a bone regenerative material
such that new bone material is generated within the void over time
and at least a portion of the bone regenerative material is
resorbed. Preferably, a majority of the bone regenerative material
is resorbed. The BMD profile in the localized area of the bone can
be such that T-score increases from an initial score of less than
-1, as measured prior to forming the void, to a maximum score of at
least about within a defined time from the time of filling the void
with the bone regenerative material. Thereafter, the T-score in the
localized area of the bone can decrease over time to a score of
about -0.5 to about 2.0 (i.e., a substantially normal range).
[0021] In yet further embodiments, the present invention can be
characterized as providing methods of remodeling a localized area
of degenerative bone to be substantially identical to normal bone.
Similar to the above, the inventive methods surprisingly can
function to essentially reset the bone quality in the localized
area of the bone treated. In other words, the bone that is in a
degenerative state is replaced with a bone regenerative material,
and the in-growth of new, natural bone material is not degenerated
bone material but is substantially normal bone material. Thus, the
bone in the localized area can be characterized as being remodeled
from degenerated bone material to normal bone material. As more
fully described below, the remodeling does not refer to a natural
process spontaneously occurring in the body but refers to a
manipulated restoration of bone quality through carrying out of the
inventive methods. Specifically, the method can comprise forming a
void in the localized area of the bone and at least partially
filling the formed void with a bone regenerative material thereby
generating in-growth of new bone material in the formed void.
Preferably, the bone material in the localized area before forming
the void has a T-score of less than -1 indicating bone
degeneration, and wherein new bone material present after
remodeling has a T-score of greater than -1.0 (more preferably
greater than about 0) indicating the bone in the localized area has
been remodeled to be substantially identical to normal bone.
[0022] In still further embodiments, the invention can be
characterized as providing methods of restoring vertebral body
height or correcting angular deformity in a fractured vertebra
(particularly an osteopenic or osteoporotic vertebra) by causing
in-growth of new bone material that is substantially identical to
normal bone. The method can comprise forming a void in the area of
the fracture, which can include mechanically increasing the space
in the fracture and optionally removing a content of the bone
material in the area of the fracture. The method further can
comprise at least partially filling the formed void with a bone
regenerative material such that new bone material is generated
within the void over time. Preferably, the new bone material has a
T-score indicating the new bone material is substantially identical
to normal bone (e.g., a T-score of at least -0.5 or at least
0).
[0023] In even further embodiments, the present invention can be
characterized as providing methods of improving bone quality at a
localized area of a bone. As described herein, bone quality can be
described in relation to measurable characteristics, such as BMD,
compressive strength, and resistance to fracture. Thus, the methods
of improving bone quality can be evidenced by an increase in one or
both of these characteristics (as well as other measurable
characteristics that may be useful for defining bone quality). In
some embodiments, the method can comprise replacing a volume of
degenerated bone material from a localized area of bone having a
T-score of less than -1.0 with newly formed, natural bone material
such that the same localized area of the bone has a T-score of
greater than -1.0 (preferably at least -0.5 or at least 0). In
further preferred embodiments, the T-score of the localized area of
bone after the inventive procedure can exceed the T-score of the
degenerated bone by at least 1.0 unit. In specific embodiments, the
replacing of the degenerated bone material can comprise forming a
void in the localized area of the bone and at least partially
filling the formed void with a bone regenerative material thereby
generating in-growth of new, natural bone material in the formed
void.
[0024] In other aspects, the invention can provide various
materials for use in methods of treating degenerated bone material.
Such materials specifically may be provided in a combination, such
as a kit, to facilitating ease of carrying out the various
inventive methods. Thus, the invention may be characterized as
providing a kit for use in replacing degenerated bone material in a
localized area of a bone with a bone regenerative material that
promotes generation of new bone material that is substantially
identical to normal bone.
[0025] In some embodiments, a kit according to the invention can
comprise one or more of a cannulated drill bit, a guide wire, a
working cannula, a debridement probe, an amount of the bone
regenerative material suitable for filling a void in the localized
area of the bone, and an injection device for delivering the bone
regenerative material. In further embodiments, a kit according to
the invention may comprise an instrument bender suitable for
adjusting the geometry of a probe (i.e., any device that may
function to break away bone material or otherwise debride or to
tamp or pack a material into a void) to accommodate the anatomy of
the void in the localized area of the bone. Specifically, the probe
device may comprise a head that is shaped to accommodate the
anatomy of the void in the localized area of the bone. In other
words, the probe may be pre-bent to a defined angle (or multiple
angles formed by multiple bends). In further embodiments, a kit
according to the invention may comprise one or more of a tissue
protector, cannulated obdurator, guidewire, drill, flexible working
cannula, working cannula obdurator, debridement probe, and
suction/irrigation device. A kit further may include an instruction
set in any form suitable to teach, illustrate, describe, or
otherwise show how to use the various components of the kit to
treat a patient suffering from a degenerative bone condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Having thus generally described the invention, reference is
made herein to the various drawings presented herewith,
wherein:
[0027] FIG. 1 is a graph showing the typical decline in BMD
(mg/cm.sup.2) of the total hip in relation to age, gender, and
ethnicity;
[0028] FIG. 2a is a scanning electron micrograph of normal
bone;
[0029] FIG. 2b is a scanning electron micrograph of osteoporotic
bone;
[0030] FIGS. 3a-3i are radiographic images showing the injection of
a bone regenerative material into a void created in the proximal
femur of a patient in a medial to lateral fashion according to one
embodiment of the invention;
[0031] FIG. 4 is an enhanced radiograph of a proximal femur
illustrating embodiments of the invention wherein filled voids of
varying shapes and dimensions may be made for filling with a bone
regenerative material;
[0032] FIGS. 5a-5c are illustrations showing defined steps of a
surgical technique for replacing degenerated bone material in the
distal radius of a patient according to one embodiment of the
invention;
[0033] FIGS. 6a-6c illustrate defined steps of a surgical technique
for replacing degenerated bone material in the vertebra of a
patient according to one embodiment of the invention;
[0034] FIGS. 7a-7e are scanning electron microscopy images showing
changes over time in a bone regenerative material used as an
implant according to one embodiment of the invention, such changes
facilitating controlled in-growth of new bone material;
[0035] FIG. 8 shows a 13-week gross specimen in the canine proximal
humerus after insertion of a graft formed of a bone regenerative
material according to the present invention and shows formation of
dense, cancellous bone, even beyond the margins of the original
defect;
[0036] FIG. 9 is a graphical representation of an exemplary BMD
profile that can be elicited in a localized area of a bone
according to one embodiment of the invention;
[0037] FIG. 10 is a graph showing bone remodeling in a localized
area of a bone showing altering of the BMD from an osteoporotic
model to a model substantially identical to normal bone;
[0038] FIG. 11 is an illustration of a tissue protector instrument
that may be used in carrying out a method according to an
embodiment of the invention;
[0039] FIG. 12 is an illustration of a cannulated obdurator that
may be used in carrying out a method according to an embodiment of
the invention;
[0040] FIG. 13 is an illustration of a guidewire that may be used
in carrying out a method according to an embodiment of the
invention;
[0041] FIG. 14 is an enlarged illustration of the tip of a drill
that may be used in carrying out a method according to an
embodiment of the invention;
[0042] FIG. 15 is an illustration of a flexible working cannula
that may be used in carrying out a method according to an
embodiment of the invention;
[0043] FIG. 16 is an illustration of a working cannula obdurator
that may be used in carrying out a method according to an
embodiment of the invention;
[0044] FIG. 17 is an illustration of a debridement probe that may
be used in carrying out a method according to an embodiment of the
invention;
[0045] FIG. 18 is an illustration of a suction/irrigation
instrument that may be used in carrying out a method according to
an embodiment of the invention;
[0046] FIG. 19 is an illustration of a 180.degree. working cannula
that may be used in carrying out a method according to an
embodiment of the invention;
[0047] FIG. 20 is a radiograph showing insertion of a debridement
probe used in creation of a void in a proximal femur according to
one embodiment of the invention;
[0048] FIG. 21 is a radiograph showing a graft material in situ
filling a formed void according to one embodiment of the
invention;
[0049] FIG. 22 is a graph showing the mean peak load observed
across pairs of matched cadaver femurs tested for fracture
resistance after void formation and filling with a bone
regenerative material according to one embodiment of the
invention;
[0050] FIG. 23 provides a radiograph of a proximal femur prior to
injection of a bone regenerative material in a method according to
one embodiment of the invention;
[0051] FIG. 24 provides a CT image of the same area of the proximal
femur shown in FIG. 23 prior to injection of the bone regenerative
material;
[0052] FIG. 25 provides a radiograph of the proximal femur from
FIG. 23 intra-operative during injection of a bone regenerative
material according to the invention;
[0053] FIG. 26 provides a radiograph of the left femur from FIG. 23
at 6 weeks post treatment in a method according to one embodiment
of the invention;
[0054] FIG. 27 provides a CT image of the left femur from FIG. 23
at 12 weeks post treatment in a method according to one embodiment
of the invention;
[0055] FIG. 28 provides a CT image of the treated, left femur from
FIG. 23 at 24 weeks post treatment;
[0056] FIG. 29 is a graph providing data over the course of up to
two years showing average T-scores at the femoral neck in the
treated hip of patients that were treated according to certain
embodiments of the invention;
[0057] FIG. 30 is a graph providing data over the course of up to
two years showing average T-scores of the total hip in the treated
hip of patients that were treated according to certain embodiments
of the invention;
[0058] FIG. 31 is a graph providing data over the course of up to
two years showing average T-scores of the Ward's triangle area in
the treated hip of patients that were treated according to certain
embodiments of the invention;
[0059] FIG. 32 is a graph providing data over the course of up to
two years showing the average percent improvement in bone mineral
density (BMD) of the femoral neck in the treated hip of patients
that were treated according to certain embodiments of the present
invention in reference to the BMD of the femoral neck of the
untreated, contralateral hip in the same patients;
[0060] FIG. 33 is a graph providing data over the course of up to
two years showing the average percent improvement in bone mineral
density (BMD) of the total hip in the treated hip of patients that
were treated according to certain embodiments of the present
invention in reference to the BMD of the total hip of the
untreated, contralateral hip in the same patients; and
[0061] FIG. 34 is a graph providing data over the course of up to
two years showing the average percent improvement in bone mineral
density (BMD) of the Ward's triangle area in the treated hip of
patients that were treated according to certain embodiments of the
present invention in reference to the BMD of the total hip of the
untreated, contralateral hip in the same patients.
DETAILED DESCRIPTION OF THE INVENTION
[0062] The invention now will be described more fully hereinafter
through reference to various embodiments. These embodiments are
provided so that this disclosure will be thorough and complete, and
will fully convey the scope of the invention to those skilled in
the art. Indeed, the invention may be embodied in many different
forms and should not be construed as limited to the embodiments set
forth herein; rather, these embodiments are provided so that this
disclosure will satisfy applicable legal requirements. As used in
the specification, and in the appended claims, the singular forms
"a", "an", "the", include plural referents unless the context
clearly dictates otherwise.
[0063] The present invention arises from the recognition of the
ability to use various bone regenerative materials in replacement
therapy for degenerative bone material. Particularly, it has been
found that when degenerated bone material in a localized area of a
bone is replaced by certain bone regenerative materials, new bone
material is generated in the localized area of the bone as the bone
regenerative materials are resorbed by the body. Surprisingly, it
has been found that even when existing bone is in an advanced state
of degeneration (e.g., osteoporosis), the body's ability to form
new, healthy bone material that is substantially identical to
normal bone is retained.
[0064] As used herein, the term "normal bone" or "normal bone
material" is intended to refer to bone or bone material exhibiting
the characteristics of healthy bone for a person (preferably of the
same gender and race as the patient being treated) at the age when
BMD typically is at its peak (i.e., around 30-35 years of age). In
other words, according to one embodiment, it has been found that
when an osteoporotic, elderly, Caucasian woman is treated according
to the present invention, it is possible to grow new bone that is
not osteoporotic but is substantially identical (i.e., in relation
to BMD and/or compressive strength) to bone in the average
Caucasian woman of age 30-35. Of course, such effects can be seen
in both genders and across all races. Thus, the present invention
provides the ability to locally change bone quality. More
specifically, it is possible according to the invention to upgrade
bone quality in a localized area from a degenerative state to a
less degenerative state, preferably from a degenerative state to a
substantially normal state. In other words, it is possible to
upgrade bone quality in a localized area such that the bone
material has a density that is substantially identical to the BMD
of a person of the same race and gender at the average age of peak
BMD (i.e., about 30-35 years old). Such localized area can include
the newly formed bone as well as surrounding portions of the bone
that were not replaced according to the invention.
[0065] As described above, there are multiple methods in the art
for evaluating BMD, and any suitable method capable of quantifying
BMD in a meaningful manner to identify states of normalcy and
degeneration could be used in relation to the present invention.
For ease of understanding, the effectiveness of the inventive
methods is described throughout the present disclosure in relation
to T-score as evaluated by Dual Energy X-ray Absorptiometry (DEXA)
scanning. This is a well-recognized method of evaluating BMD.
Moreover, since common conditions of bone degeneration can actually
be defined by a patient's T-score, DEXA scan results provide a
meaningful way for quantifying the results of the present invention
in relation to improvements in BMD. DEXA scanning machines
typically report BMD in units of g/cm.sup.2. Because of differences
in machine manufacturers, however, reports of BMD in units of
g/cm.sup.2 are not standardized. To assist in standardization,
T-score can be equated to BMD in mg/cm.sup.2 according to the
following equation:
T-score=(BMD-reference BMD)/SD
wherein reference BMD and standard deviation (SD) are referenced to
an average patient of age 30-35 where BMD is expected to be at its
peak, and wherein BMD and SD both are provided in units of
mg/cm.sup.2. The resulting T-score provides a consistent,
reproducible evaluation of BMD that can be used to provide evidence
of changes in BMD. In the U.S., T-score typically is calculated
using a reference of the same race and gender. According to World
Health Organization (WHO) standards, T-score is evaluated based on
reference values for Caucasian females. For ease of reference,
T-scores discussed herein were obtained by DEXA scans using a
Hologic Delphi.TM. Bone Densitometer (available from Hologic, Inc.,
Danbury Conn.). Another means for characterizing scan data is
Z-score, which is the number of standard deviations away from the
mean for persons of the same age, gender, and ethnicity as the
tested patient. The invention also encompasses, however, further
methods for evaluating increases in bone quality--e.g., BMD,
compressive strength, or resistance to fracture--such as could be
achieved using one or more alternative testing methods--e.g.,
ultrasound, QCT, SPA, DP A, DXR, or SEXA.
[0066] In specific embodiments, the benefits of the invention can
be characterized based on the relative improvement in BMD after
employing one or more of the inventive methods. By "relative
improvement" is meant the improvement in the bone quality factor
(e.g., BMD, compressive strength, or resistance to fracture) in
relation to the condition of the localized area of the bone prior
to onset of treatment according to the invention. This manner of
characterizing the invention can be independent of achieving a
standard intended to define normal bone conditions in young,
healthy adults. For example, relative improvement specifically may
take into consideration the improvement in bone quality for the
individual patient and the effect on quality of life. For example,
a patient with an extremely poor BMD in the proximal femur (e.g.,
-3 T-score) could have a significantly improved quality of life
through improvement in the T-score of perhaps 1.5 units. The ending
T-score of -1.5 would still indicate an osteopenic state, but the
relative improvement in the bone quality in the area of the
proximal femur could be sufficiently significant to be indicative
of an effective treatment regardless of whether the defined, normal
BMD is achieved. In some embodiments, however, effective treatment
can be expressly related to the ability to achieve a normal BMD for
the localized area of the bone treated.
[0067] In some embodiments, the methods of the present invention
can be described in relation to increases in BMD as evidenced by
increases in T-score (either of the specific bone material that is
replaced and new bone material that is generated or of the
localized area of the bone generally), which can be reproduced by
one of skill in the art using the methods already described herein.
Thus, the benefits of the invention can be described in relation to
an improved T-score, which can be correlated to a lessened state of
degeneration (i.e., a relative improvement in BMD) or to a change
in BMD such that the bone is categorized as normal (i.e.,
non-degenerative) or greater. In some embodiments, T-score may be
improved by at least 0.25 units, at least 0.5 units, at least 0.75
units, at least 1.0 unit, at least 1.25 units, at least 1.5 units,
at least 1.75 units, at least 2.0 units, at least 2.25 units, at
least 2.5 units, at least 2.75 units, or at least 3.0 units. In
other embodiments, BMD may be increased such that the T-score is at
least at a minimum level. For example, BMD maybe increased such
that T-score is at least-I, at least -0.75, at least -0.5, at least
-0.25, at least 0, at least 0.25, at least 0.5, at least 0.75, at
least 1.0, at least 1.25, at least 1.5, at least 1.75, at least
2.0, at least 2.5, at least 3.0, at least 4.0, or at least 5.0. In
other embodiments, T-score may be defined as being greater than -1,
which can be indicative of BMD falling within an accepted normal
range. In other embodiment, T-score may be about -1.0 to about 2.0,
about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to
about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about
-0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0,
about 0 to about 1.5, or about 0 to about 1.0. Moreover,
degenerated bone material according to the invention may be
described as bone having a T-score of less than -1.0, less than
about -1.5, less than -2.0, less than -2.5, or less than -3.0. The
importance of the above values are more readily evident from the
further description of the invention provided below.
[0068] The invention as described herein could find use with
virtually any bone in a patient's body where improved BMD is
desired. In specific embodiments, the replacement methods are
expected to be used only in localized areas of bone. In other
words, entire lengths of bone are not replaced or regenerated, but
only discrete or localized sections or areas of a particular bone
are replaced. The methods preferably are used in localized areas of
a bone because the methods make use of the body's natural ability
to resorb the bone regenerative materials that are used and replace
the materials with newly generated bone. In specific embodiments,
it has been found that such bone regeneration can take place by
in-growth of bone material from the surrounding bone material. For
clarity, it is understood that, in certain embodiments, the words
"bone" and "bone material" can take on independent meanings.
Specifically, "bone" may refer to the general, overall anatomical
structure (e.g., the femur or a vertebra) while "bone material" may
refer to a plurality of bone cells and calcified extracellular
matrices that are present (or generated) in and around a discrete,
localized area of a greater bone structure. Thus, where bone
material is removed, the overall bone remains. Moreover, where a
void is formed in a bone, new bone material can be generated
therein.
[0069] In some embodiments, the methods of the invention
particularly may be carried out in bones that are particularly
subject to possible fracture in a patient suffering from a bone
degenerative condition. Such bone degenerative condition can refer
to any condition that is characterized by a loss of BMD. In
specific embodiments, the bone degenerative condition can refer to
osteopenia or osteoporosis. Since these conditions can be defined
in relation to a T-score within a defined range, the terms can be
used herein to refer to bone degeneration generally regardless of
whether the degeneration arises from natural bone cell resportion
that is not sufficiently countered by new bone cell production or
whether the degeneration arises from a separate condition that
causes bone degeneration as a symptom or side effect.
[0070] In specific embodiments, the inventive methods may be
carried out on bone associated with the hip joint. This
particularly may encompass the bone structures recognized generally
as the hip bone, innominate bone, or coxal bone (i.e., the ischium,
ilium, and pubis), as well as the proximal portion of the femur and
the subtrochanteric portion of the femur (although the femur in
general is encompassed by the invention). Portions of the femur
particularly of interest according to the invention are the head,
the neck, the greater trochanter, and the lesser trochanter, as
well as the area recognized as "Ward's area" (or "Ward's
triangle"). Such areas of the bone particularly are subject to
fracture associated with falls in the elderly or atypical
fractures.
[0071] Other bones that may be treated according to the present
invention include the vertebrae and other major bones associated
with the legs and arms, such as the radius, ulna, humerus, tibia,
and fibula. Of particular interest, in addition to the bones of the
hip area, are the vertebrae, the distal radius, and specific bone
segments that may be subject to atypical fracture.
[0072] The invention makes use of specific bone regenerative
materials. This term can include various materials that can be
useful in regenerating bone or bone material, particularly
materials that also may be filled into a void and promote in-growth
of new bone material into the filled void. Thus, in some
embodiments, the bone regenerative material may be characterized as
a bone filler material. Preferably, the bone regenerative material
includes a substantial proportion of material that is resorbable by
the mammalian body. For example, the bone regenerative material may
comprise at least 40%, at least 50% by weight, at least 60% by
weight, at least 70% by weight, at least 80% by weight, or at least
90% by weight of materials that are resorbable by the mammalian
body. Further, it is preferable for the material to resorb at a
rate substantially similar to the rate of in-growth of new bone
material. In some embodiments, the bone regenerative material may
include a content of material that is not readily resorbable but
that is otherwise compatible with formation of new bone material
(e.g., that may be taken up into the structure of the bone
including the newly generated bone material).
[0073] In certain embodiments, the bone regenerative material may
be a material that is recognized as an osteoconductive or
osteoinductive material. By "osteoinductive" is meant materials
that lead to a mi to genesis of undifferentiated perivascular
mesenchymal cells leading to the formation of osteoprogenitor cells
(i.e., cells with the capacity to form new bone or bone material).
By "osteoconductive" is meant materials that facilitate blood
vessel incursion and new bone or bone material formation into a
defined passive trellis structure. Various compounds, minerals,
proteins, and the like are known to exhibit osteoinductive,
osteoconductive, osteogenic, osteopromotive, or osteophilic
activity. Accordingly, such materials can be useful according to
the present invention.
[0074] In particular, the following are non-limiting examples of
materials that may be used for their osteoinductive or
osteoconductive ability according to the present invention:
demineralized bone matrix (DBM), bone morphogenetic proteins
(BMPs), transforming growth factors (TGFs), fibroblast growth
factors (FGFs), insulin-like growth factors (IGFs),
platelet-derived growth factors (PDGB), epidermal growth factors
(EGFs), vascular endothelial growth factors (VEGFs), peptides,
anorganic bone mineral (ABM), vascular permeability factors (VPFs),
cell adhesion molecules (CAMs), calcium aluminate, hydroxyapatite,
coralline hydroxyapatite, alumina, zirconia, aluminum silicates,
calcium phosphate, tricalcium phosphate, brushite (dicalcium
phosphate dihydrate), tetracalcium phosphate, octacalciumphosphate,
calcium sulfate, polypropylene fumarate, pyrolytic carbon,
bioactive glass, porous titanium, porous nickel-titanium alloy,
porous tantalum, sintered cobalt-chrome beads, ceramics, collagen,
autologous bone, allogenic bone, xenogenic bone, coralline, and
derivates or combinations thereof, or other biologically produced
composite materials containing calcium or hydroxyapatite structural
elements. The foregoing may be used as the bone regenerative
material or as an additive in a specific bone regenerative material
composition.
[0075] In specific embodiments, the bone regenerative material used
in the present invention particularly can be a material comprising
calcium sulfate and may comprise additional ingredients as desired.
The calcium sulfate specifically can be a-calcium sulfate
hemihydrate, .beta.-calcium sulfate hemihydrate, calcium sulfate
dihydrate, or mixtures thereof. In some embodiments, particularly
where calcium sulfate is combined with further materials, the
calcium sulfate composition may be provided as an aqueous solution
or slurry, which can include water and, optionally, one or more
additives selected from the group consisting of inorganic salts and
surface active agents such as sodium chloride, potassium chloride,
sodium sulfate, potassium sulfate, EDT A, ammonium sulfate,
ammonium acetate, and sodium acetate. The calcium sulfate further
may include additional ingredients, including any of the
osteoinductive and osteoconductive materials described herein, as
well as accelerants useful to accelerate the reaction of calcium
sulfate hemihydrate to calcium sulfate dihydrate, plasticizers, or
biologically active agents.
[0076] In some embodiments, the bone regenerative material
specifically may include calcium phosphate. Particularly, the
material may comprise calcium sulfate and calcium phosphate. The
calcium phosphate may be in the form of a bioceramic material
described has having a specific geometry or shape, such as pellets,
granules, wedges, blocks, or disks of various sizes. Non-limiting
examples of calcium phosphate that may be used according to the
invention include hydroxyapatite, tricalcium phosphate (e.g.,
.alpha.-tricalcium phosphate, .beta.-tricalcium phosphate),
tetracalcium phosphate, anhydrous dicalcium phosphate, monocalcium
phosphate monohydrate, dicalcium phosphate dihydrate, heptacalcium
phosphate, octocalcium phosphate, calcium pyrophosphate,
oxyapatite, calcium metaphosphate, carbonatoapatite, dahlite, and
combinations or mixtures thereof. In specific embodiments, the
calcium phosphate is .alpha.-tricalcium phosphate,
.beta.-tricalcium phosphate, or a mixture thereof. In some
embodiments, it can be useful for the calcium phosphate to be
present in two or more forms that can lead to formation of
brushite, such as tricalcium phosphate and calcium phosphate mono
hydrate.
[0077] In certain preferred embodiments, the bone regenerative
material used in the present invention may comprise calcium
sulfate, calcium phosphate, and a particulate material, such as
tricalcium phosphate granules or a further particularized
osteoinductive or osteoconductive material, such as demineralized
bone matrix (DBM). Specific examples of materials that can be
particularly useful according to the invention are the materials
commercially available under the trade names PRO-DENSE.RTM. and
PRO-STIM.RTM. (Wright Medical Technology, Inc., Arlington, Tenn.).
Although such materials are particularly useful for carrying out
the invention, other materials that are useful in bone applications
may be useful in certain embodiments of the invention. Although not
wishing to be bound by theory, it is believed that materials
exhibiting bone regenerative properties can provide more
advantageous results in various embodiments, particularly materials
exhibiting a multi-phasic profile, as otherwise described herein.
Examples of further materials that may be useful in certain
embodiments of the invention include those known under the names
OSTEOSET.RTM., MIIG.RTM.X3, CELLPLEX.RTM., ALLOMATRIX.RTM.,
ALLOMATRIX.RTM. RCS, IGNITE.RTM., ACTIFUSE.RTM., CEM-OSTETIC.RTM.,
GENEX.RTM., PROOSTEON.RTM. 500R, BONEPLAST.RTM., CERAMENT.RTM.,
a-BSM.RTM., CONDUIT.RTM. TCP, y-BSM.RTM., .about.-BSM.RTM.,
EQUIVABONE.RTM., CARRIGEN.RTM., MASTERGRAFT.RTM., NOVABONE.RTM.,
PERIOGLAS.RTM., Chondromimetic, VITOSS.RTM., PLEXUR.RTM. Bone Void
Filler, BONESOURCE.RTM. BVF, HYDROSET.RTM., NORIAN.RTM. SRS.RTM.
Fast Set Putty, NORIAN.RTM. CRS.RTM. Fast Set Putty, ALLOFUSE.RTM.,
INTERGRO.RTM. DBM Putty, OPTEFORM.RTM. OPTEFIL.RTM. OPTECURE.RTM.
ACCELL.RTM. 100 ACCELL.RTM. CONNEXUS.RTM. ACCELL.RTM. EV03.RTM.,
OPTIUM DBM.RTM., PROGENIX.RTM. DBM Putty, OSTEOFIL.RTM. DBM,
DBX.RTM., GRAFTON.RTM., GRAFTON PLUS.RTM., PUROS.RTM. Demineralized
Bone Matrix, INFUSE.RTM. Bone Graft, OP-I.RTM., OSTEOCEL.RTM.,
TRINITY.TM. Matrix, and TRINITY REVOLUTION.TM.. Various embodiments
of bone regenerative materials that may be useful according to the
invention are those described in U.S. Pat. No. 6,652,887; U.S. Pat.
No. 7,211,266; U.S. Pat. No. 7,250,550; U.S. Pat. No. 7,371,408;
U.S. Pat. No. 7,371,409; U.S. Pat. No. 7,371,410; U.S. Pat. No.
7,507,257; U.S. Pat. No. 7,658,768; and U.S. Pat. App. Pub. No.
2007/0059281, the disclosures of which are incorporated by
reference herein in their entireties.
[0078] In some embodiments, the bone regenerative material may be
in the form of a particulate composition that hardens or sets upon
mixing with an aqueous solution. Such compositions may include one
or more forms of calcium sulfate and one or more forms of calcium
phosphate. Preferably, the composition may include at least one
form of calcium sulfate and at least two forms of calcium
phosphate. Specifically, the composition may include a calcium
sulfate hemihydrate (hereinafter "CSH") powder and a
brushite-forming calcium phosphate mixture comprising monocalcium
phosphate monohydrate (hereinafter "MCPM") powder and a
.beta.-tricalcium phosphate (hereinafter ".beta.-TCP") powder.
[0079] Such particulate composition can be useful for forming a
bone regenerative material comprising calcium sulfate dihydrate
(hereinafter "CSD"), which is the product of the reaction between
CSH and water. The CSD component can confer good mechanical
strength to the bone regenerative material, stimulate bone growth,
and provides a relatively fast resorption rate in vivo, such that a
porous structure in the bone regenerative material is quickly
created upon implantation. Thus, the CSD component can be rapidly
replaced with bone tissue in-growth into the implant site.
[0080] The two calcium phosphate components can react to form
brushite upon mixing with an aqueous solution. The presence of the
brushite in the bone regenerative material can slow the resorption
rate of the bone regenerative material as compared to a composition
comprising CSD only. Thus, the use of such a biphasic bone
regenerative material can provide a dual resorption rate defined by
the CSD component and the brushite component.
[0081] In addition to a slower resorption rate, the use of such a
particulate composition as a bone regenerative material in the
present invention can provide high mechanical strength, good
handling characteristics, and a reasonable setting time.
Additionally, such bone regenerative material is particularly
useful for producing high quality bone when used according to the
invention.
[0082] In some embodiments, the CSH powder can have a bimodal
particle distribution--i.e., a particle distribution characterized
by two peaks in a plot of particle size vs. the volume percentage
of particles of each size, although other particle distributions
are contemplated by the invention. For example, the bimodal
particle distribution of the CSH powder can be characterized by
about 30 to about 60 volume percent of particles having a mode of
about 1.0 to about 3.0 microns and about 40 to about 70 volume
percent of particles having a mode of about 20 to about 30 microns,
based on the total volume of the CSH powder. In yet another
embodiment, the bimodal particle distribution comprises about 40 to
about 60 volume percent of particles having a mode of about 1.0 to
about 2.0 microns and about 40 to about 60 volume percent of
particles having a mode of about 20 to about 25 microns. The median
particle size of the CSH powder is preferably about 5 to about 20
microns, more preferably about 8 to about 15 microns, and most
preferably about 10 to about 15 microns.
[0083] A particulate composition useful in a bone regenerative
material useful according to the invention preferably comprises a
CSH powder in an amount of at least 50 weight percent based on the
total weight of the particulate composition. In further
embodiments, a bone regenerative material useful according to the
invention may comprises a CSH powder in an amount of at least 60
weight percent, at least 65 weight percent, at least 70 weight
percent, at least 75 weight percent, at least 80 weight percent, at
least 85 weight percent, or at least 90 weight percent. In other
embodiments, the CSH powder can be present in an amount of about 50
weight percent to about 99 weight percent, about 60 weight percent
to about 98 weight percent, about 65 weight percent to about 95
weight percent, about 70 weight percent to about 95 weight percent,
or about 70 weight percent to about 90 weight percent.
[0084] The CSH is preferably a-calcium sulfate hemihydrate, which
exhibits higher mechanical strength as compared to the beta form
upon setting to form CSD. The presence of CSD in the bone
regenerative material used in the invention can contribute to rapid
generation of bone material. The CSH powder can be made by the
process disclosed in U.S. Pat. No. 2,616,789, which is incorporated
entirely herein by reference in its entirety. The CSH powder may
include further components, such as an accelerant capable of
accelerating the conversion of CSH to the dihydrate form, thereby
causing the bone regenerative material made therefrom to set more
quickly. Exemplary accelerants include calcium sulfate dihydrate
crystals (available from U.S. Gypsum), particularly CSD coated with
sucrose (available from VWR Scientific Products). A process of
stabilizing the dihydrate crystals by coating with sucrose is
described in U.S. Pat. No. 3,573,947, which is hereby incorporated
by reference in its entirety. Other non-limiting examples of
accelerants that could be used include alkali metal sulfates and
sulfides (e.g., potassium sulfate, sodium sulfate, and calcium
sulfide--including hydrates thereof). The accelerant may be present
in an amount of up to 1.0 weight percent, based on the total weight
of the particulate composition. In some embodiments, the
particulate composition includes about 0.001 to about 0.5 weight
percent of the accelerant, more typically about 0.01 to about 0.3
weight percent. Mixtures of two or more accelerants can be
used.
[0085] The calcium phosphate portion of the particulate composition
useful in a bone regenerative material according to the invention
can comprise a MCPM powder (Ca(H.sub.2PO.sub.4).sub.2H.sub.2O) and
a .beta.-TCP powder (Ca.sub.3(PO.sub.4).sub.2). As understood in
the art, the main reaction product of MCPM, .beta.-TCP, and water
is brushite, otherwise known as dicalcium phosphate dihydrate
(CaHPO.sub.4.2H.sub.2O) (DCPD). The brushite-forming powders may
also participate in other reactions that would result in the
formation of certain calcium phosphates with a greater
thermodynamic stability than DCPD, such as hydroxyapatite,
octacalcium phosphate, and the like. A certain amount of the
.beta.-TCP powder may also remain unreacted. The .beta.-TCP powder
can have a median particle size of less than about 20 microns.
Typically the .beta.-TCP powder will have a median particle size of
about 10 microns to about 20 microns. The .beta.-TCP powder portion
of the particulate composition can have a bimodal particle size
distribution characterized by about 30 to about 70 volume percent
of particles having a mode of about 2.0 to about 6.0 microns and
about 30 to about 70 volume percent of particles having a mode of
about 40 to about 70 microns based on the total volume of the
.beta.-tricalcium phosphate powder. In one embodiment, the
.beta.-TCP powder has a bimodal particle size distribution
characterized by about 50 to about 65 volume percent of particles
having a mode of about 4.0 to about 5.5 microns and about 35 to
about 50 volume percent of particles having a mode of about 60 to
about 70 microns based on the total volume of the .beta.-tricalcium
phosphate powder.
[0086] Reference to MCPM is intended to encompass monocalcium
phosphate (MCP), which is simply the anhydrous form of MCPM that
releases the same number of calcium and phosphoric acid ions in
solution. However, if MCP is used in place of MCPM, the amount of
water used to form the bone regenerative material may need to be
increased to account for the water molecule missing from MCP (if it
is desired to produce precisely the same dissolution product as
formed when using MCPM).
[0087] The presence of the brushite component can slow the in vivo
resorption of the bone regenerative material as compared to a
calcium sulfate. In turn, the slower resorption rate may enable the
bone regenerative material to provide structural support for longer
periods of time.
[0088] A bone regenerative material as described above can be
particularly useful according to the invention as it can become a
highly porous matrix of calcium phosphate material after being
administered in vivo due to the relatively quick resorption of the
calcium sulfate component of the mixture. The remaining porous
matrix of calcium phosphate provides excellent scaffolding for bone
in-growth during the natural healing process.
[0089] The amount of MCPM powder and .beta.-TCP powder present in
the particulate composition can vary and depends primarily on the
amount of brushite desired in the bone graft substitute cement. The
brushite-forming calcium phosphate composition (i.e., the combined
amount of MCPM and .beta.-TCP powders) can be present at a
concentration of about 3 to about 30 weight percent based on the
total weight of the particulate composition. In further
embodiments, the brushite-forming calcium phosphate composition can
be present at a concentration of about 5 to about 25 weight
percent, about 10 to about 20 weight percent, about 12 to about 18
weight percent, or about 20 weight percent. The relative amounts of
MCPM and .beta.-TCP can be selected based on their equimolar,
stoichiometric relationship in the brushite-forming reaction. In
one embodiment, the MCPM powder can be present at a concentration
of about 3 to about 7 weight percent, based on the total weight of
the particulate composition, and the .beta.-TCP can be present in
an amount of about 3.72 to about 8.67 weight percent.
[0090] The particulate composition also may include a granule,
particle, or powder content as otherwise described herein. In
specific embodiments, the composition may include a plurality of
.beta.-TCP granules having a median particle size greater than the
median particle size of the .beta.-TCP powder. The .beta.-TCP
granules typically have a median particle size of about 75 to about
1,000 microns, about 100 to about 400 microns, or about 180 to
about 240 microns. The granules serve to further reduce the
resorption rate of the bone graft substitute cement and contribute
to scaffold formation. The .beta.-TCP granules can be present at a
concentration of up to 20 weight percent, based on the total weight
of the particulate composition. In other embodiments, the
.beta.-TCP granules can be present at a concentration of up to 15
weight percent or up to 12 weight percent based on the total weight
of the composition. The granules particularly are useful to provide
a third phase (as more fully described herein in relation to
tri-phasic materials) that exhibits slower resorption than the
remaining materials used in the bone regenerative composition
(e.g., in comparison to the calcium sulfate phase and the brushite
phase describe above).
[0091] The aqueous component that is mixed with the particulate
composition to form a bone regenerative material useful according
to the invention can be selected in order to provide the
composition with a desired consistency and hardening or setting
time. Typically, the aqueous solution is provided in an amount
necessary to achieve a liquid to powder mass ratio (LIP) of at
least 0.2, at least 0.21, or at least 0.23. A preferred LIP ratio
range is about 0.2 to about 0.3 or about 0.2 to about 0.25.
Examples of suitable aqueous components include water (e.g.,
sterile water) and solutions thereof. Optionally, a bone
regenerative material according to the invention may include one or
more additives selected from the group consisting of sodium
chloride, potassium chloride, sodium sulfate, potassium sulfate,
EDT A, ammonium sulfate, ammonium acetate, and sodium acetate. In
one preferred embodiment, the aqueous mixing solution used is a
saline solution or a phosphate buffered saline solution. An
exemplary aqueous solution is 0.9% NaCl saline solution available
from Baxter International (Deerfield, Ill.) and others. The aqueous
solution may include one or more organic or inorganic carboxylic
acid-containing compounds (hereinafter carboxylic acids or
carboxylic acid compounds) which may or may not contain a hydroxyl
group on the alpha carbon, optionally titrated to a neutral pH
using a suitable base (e.g., neutralized to a pH of about 6.5 to
about 7.5 using an alkali metal base such as sodium hydroxide or
potassium hydroxide), which can alter water demand, flowability,
and/or viscosity of the bone regenerative material upon mixing.
Exemplary carboxylic acids include glycolic acid and lactic acid.
Preferred carboxylic acids have a single carboxylic acid group, 1
to 10 total carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
carbon atoms including the carbonyl carbon), and 0-5 hydroxyl
groups (e.g., 0, 1, 2, 3, 4, or 5) attached to the carbon chain. In
one embodiment, the mixing solution is a 0.6M solution of glycolic
acid neutralized to a pH of 7.0 using NaOH. Reference to the
carboxylic acid compound herein encompasses both the free acid and
salt forms. The carboxylic acid may be neutralized to a pH of about
6.5 to about 7.5 in solution using, for example, an alkali metal
base, and then isolated as a crystalline powder by evaporation of
the solvent (e.g., water). The crystalline powder is typically
isolated in a salt form, such as an alkali metal salt form (e.g.,
lithium, sodium, or potassium salts). Exemplary dry crystalline
powders of a carboxylic acid, in salt form, include sodium
glycolate, potassium glycolate, sodium lactate, and potassium
lactate. The powdered carboxylic acid salt can be added to any of
the other powder ingredients that together form the particulate
portion of the bone regenerative material, such as the CSH
component or either of the calcium phosphate components. However,
in certain embodiments, the powdered carboxylic acid is stored in a
separate container so that it can be reconstituted with the aqueous
solution prior to mixing the solution with the remaining
particulate components of the composition.
[0092] A bone regenerative material useful according to the
invention may include one or more additives that may be selected
from any of the individual materials described herein. The
additives can be in a powder, liquid, or solid form and can be
mixed or encapsulated by the bone regenerative material. Exemplary
additives suitable for use in the invention include accelerants
(such as sucrose-coated calcium sulfate dehydrate particles),
cancellous bone chips, salts (e.g., chloride, potassium chloride,
sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium
acetate, and sodium acetate), plasticizers that may alter the
consistency and setting time of the composition (e.g., glycerol and
other polyols, vinyl alcohol, stearic acid, hyaluronic acid,
cellulose derivatives and mixtures thereof, including alkyl
celluloses, such as methylhydroxypropylcellulose, methylcellulose,
ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate butyrate, and mixtures or salts thereof), and any
"biologically active agent" (i.e., any agent, drug, compound,
composition of matter or mixture that provides some pharmacologic
affect that can be demonstrated in vivo or in vitro), particularly
any agent recognized as being an anti-osteopenic or
anti-osteoporotic agent. Specific pharmacologic agents can include
medicaments to treat osteoporosis, such as bisphosphonates, RANKL
inhibitors, proton pump inhibitors, hormone therapies, and SERMs,
teriparatide, and rPTH. Further examples of biologically active
agents include, but are not limited to, peptides, proteins,
enzymes, small molecule drugs, dyes, lipids, nucleosides,
oligonucleotides, polynucleotides, nucleic acids, cells, viruses,
liposomes, microparticles, and micelles. It includes agents that
produce a localized or systemic effect in a patient. Further
examples of biologically active agents include antibiotics,
chemotherapeutic agents, pesticides (e.g., antifungal agents and
antiparasitic agents), antivirals, anti-inflammatory agents, and
analgesics. Exemplary antibiotics include ciprofloxacin,
tetracycline, oxytetracycline, chlorotetracycline, cephalosporins,
aminoglycocides (e.g., tobramycin, kanamycin, neomycin,
erithromycin, vancomycin, gentamycin, and streptomycin),
bacitracin, rifampicin, N-dimethylrifampicin, chloromycetin, and
derivatives thereof. Exemplary chemotherapeutic agents include
cisplatinum, 5-fluorouracil (5-FU), taxol and/or taxotere,
ifosfamide, methotrexate, and doxorubicin hydrochloride. Exemplary
analgesics include lidocaine hydrochloride, bipivacaine and
non-steroidal anti-inflammatory drugs such as ketorolac
tromethamine. Exemplary antivirals include gangcyclovir,
zidovudine, amantidine, vidarabine, ribaravin, trifluridine,
acyclovir, dideoxyuridine, antibodies to viral components or gene
products, cytokines, and interleukins. An exemplary antiparasitic
agent is pentamidine. Exemplary anti-inflammatory agents include
.alpha.-1-anti-trypsin and .alpha.-1 antichymotrypsin. Useful
antifungal agents include diflucan, ketaconizole, nystatin,
griseofulvin, mycostatin, miconazole and its derivatives as
described in U.S. Pat. No. 3,717,655, the entire teachings of which
are incorporated herein by reference; bisdiguanides such as
chlorhexidine; and more particularly quaternary ammonium compounds
such as domiphen bromide, domiphen chloride, domiphen fluoride,
benzalkonium chloride, cetyl pyridinium chloride, dequalinium
chloride, the cis isomer of 1-(3-chlorallyl)-3,5,7-triaza-1
azoniaadamantane chloride (available commercially from the Dow
Chemical Company under the trademark Dowicil 200) and its analogues
as described in U.S. Pat. No. 3,228,828, the entire teachings of
which are incorporated herein by reference, cetyl trimethyl
ammonium bromide as well as benzethonium chloride and
methylbenzethonium chloride such as described in U.S. Pat. Nos.
2,170,111; 2,115,250; and 2,229,024, the entire teachings of which
are incorporated herein by reference; the carbanilides and
salicylanilides such 3,4,4' trichlorocarbanilide, and
3,4,5-tribromosalicylanilide; the hydroxydiphenyls such as
dichlorophene, tetrachlorophene, hexachlorophene, and
2,4,4'-trichloro-2'-hydroxydiphenylether; and organometallic and
halogen antiseptics such as sine pyrithione, silver sulfadiazone,
silver uracil, iodine, and the iodophores derived from non-ionic
surface active agents such as described in U.S. Pat. Nos. 2,710,277
and 2,977,315, the entire teachings of which are incorporated
herein by reference, and from polyvinylpyrrolidone such as
described in U.S. Pat. Nos. 2,706,701, 2,826,532 and 2,900,305, the
entire teachings of which are incorporated herein by reference.
Useful growth factors include any cellular product that modulates
the growth or differentiation of other cells, particularly
connective tissue progenitor cells. The growth factors that may be
used in accordance with the present invention include, but are not
limited to, fibroblast growth factors (e.g., FGF-1, FGF-2, FGF-4);
platelet derived growth factor (PDGF) including PDGF-AB, PDGF-BB
and PDGF-AA; bone morphogenic proteins (BMPs) such as any of BMP-1
to BMP-18; osteogenic proteins (e.g., OP-1, OP-2, or OP-3);
transforming growth factor-.alpha., transforming growth
factor-.beta. (e.g., .beta.1, .beta.2, or .beta.3); LIM
mineralization proteins (LMPs); osteoid-inducing factor (OIF);
angiogenin(s); endothelins; growth differentiation factors (GDF's);
ADMP-1; endothelins; hepatocyte growth factor and keratinocyte
growth factor; osteogenin (bone morphogenetic protein-3);
heparin-binding growth factors (HBGFs) such as HBGF-1 and HBGF-2;
the hedgehog family of proteins including indian, sonic, and desert
hedgehog; interleukins (IL) including IL-1 thru -6;
colony-stimulating factors (CSF) including CSF-1, G-CSF, and
GM-CSF; epithelial growth factors (EGFs); and insulin-like growth
factors (e.g., IGF-I and -II); demineralized bone matrix (DBM);
cytokines; osteopontin; and osteonectin, including any isoforms of
the above proteins. The biologically active agent may also be an
antibody. Suitable antibodies, include by way of example, STR0-1,
SH-2, SH-3, SH-4, SB-10, SB-20, and antibodies to alkaline
phosphatase. Such antibodies are described in Haynesworth et al.,
Bone (1992), 13:69-80; Bruder, S. et al., Trans Ortho Res Soc
(1996), 21:574; Haynesworth, S. E., et al., Bone (1992), 13:69-80;
Stewart, K., et al, J Bone Miner Res (1996), 11(Suppl.):S142;
Flemming J E, et al., in "Embryonic Human Skin. Developmental
Dynamics," 212: 119-132, (1998); and Bruder S P, et al., Bone
(1997), 21(3): 225-235, the entire teachings of which are
incorporated herein by reference. Other examples of biologically
active agents include bone marrow aspirate, platelet concentrate,
blood, allograft bone, cancellous bone chips, synthetically derived
or naturally derived chips of minerals such as calcium phosphate or
calcium carbonate, mesenchymal stem cells, and chunks, shards,
and/or pellets of calcium sulfate. Additives, particularly
pharmacological additives, more particularly anti-osteoporotic
additives, can be present in a solid form that is mixed into the
bone regenerative material or placed into the bone void and
encapsulated by the bone regenerative material. The pharmacologic
therapies can be eluting, dissolving, disintegrating, or
evaporating from the bone regenerative material.
[0093] A bone regenerative material useful in the methods of the
present invention can be formed by a variety of methods depending
upon the exact nature of the composition. In some embodiments, the
bone regenerative material may be in a particulate form that could
be packed into a formed void in a bone. In other embodiments, the
bone regenerative material can be an injectable, flowable form that
may be prepared by mixing a particulate composition, such as
described above, with an aqueous solution as described herein using
manual or mechanical mixing techniques and apparatus known in the
art. Specifically, the components can be mixed at atmospheric
pressure or below (e.g., under vacuum) and at a temperature that
will not result in freezing of the aqueous component of the mixture
or significant evaporation. Following mixing, the homogenous
composition typically has an injectable, paste-like consistency,
although the viscosity and flowability of the mixture can vary
depending on the additives therein. The bone regenerative material
can be transferred to a delivery device, such as a syringe, and
injected into the created void. In some embodiments, the material
can be injected through an 11 to 16-gauge needle up to, for
example, 10 cm long.
[0094] In certain embodiments, the nature of the bone regenerative
material may be characterized in relation to injection force ranges
in which the material can be injected. In various embodiments, the
material may have an injection force of up to 1,200 N, up to 1,000
N, up to 800 N, up to 600 N, up to 500 N, or up to 400 N. In other
embodiments, injection force ranges may be about 1 N to about 1,200
N, about 2 N to about 1,000 N, about 3 N to about 800 N, about 4 N
to about 700 N, about 5 N to about 660 N, about 10 N to about 660
N, or about 10 N to about 330 N.
[0095] In specific embodiments, a bone regenerative material useful
according to the invention can be one that will generally set, as
defined by the Vicat needle drop test set forth below, in about 3
to about 25 minutes, more preferably about 10 to about 20 minutes.
The bone regenerative material preferably will reach a hardness
comparable to or greater than bone within about 30 to about 60
minutes. Setting of the material can occur in a variety of
environments, including air, water, in vivo, and under any number
of in vitro conditions.
[0096] A hardened bone regenerative material useful according to
the invention preferably exhibits complex dissolution with a
self-forming porous scaffold and certain mechanical strength
properties, particularly as characterized by diametral tensile
strength and compressive strength. For example, the material may
exhibit a diametral tensile strength of at least 4 MPa after curing
for one hour in ambient air following preparation of the material
to be a state for delivery, more preferably a diametral tensile
strength of at least 5 MPa, most preferably at least 6 MPa.
Further, the bone regenerative material may exhibit a diametral
tensile strength of at least 8 MPa after curing for 24 hours in
ambient air following preparation of the material for delivery,
more preferably a diametral tensile strength of at least 9 MPa
after curing for 24 hours, and most preferably at least 10 MPa.
[0097] A bone regenerative material useful in the present invention
also exhibits a high level of compressive strength, such as a
compressive strength of at least 15 MPa after curing for one hour
in ambient air following preparation of the material for delivery,
more preferably a compressive strength of at least 40 MPa. Further,
preferred embodiments of the bone regenerative material may exhibit
a compressive strength of at least 50 MPa after curing for 24 hours
in ambient air following preparation of the material for delivery,
more preferably a compressive strength of at least 80 MPa.
[0098] In certain embodiments, the strength of the hardened bone
regenerative material may be increased though addition of various
materials. Although the invention encompasses any material
recognized in the art for increasing one or both of tensile
strength and compressive strength, particular useful can be
embodiments that incorporate one or more fibrous materials. Thus,
the invention specifically encompasses fiber composites of the bone
regenerative material.
[0099] The fiber composites useful in the invention particularly
can include biodegradable polymer fibers. Such fibers not only can
provide for increased strength properties for the bone regenerative
material but also can provide for sustained delivery of one or more
of the biologically active agents disclosed above (e.g., growth
factors, antibiotics, etc.) since the active agent may be mixed
with the polymer prior to fiber formation, and the active agent
will be slowly released in vivo as the fibers biodegrade. In
further embodiments, non-biodegradable fibers also may be used,
although it is preferable for any non-biodegradable fibers to be
inert in nature. Non-limiting examples of materials that have been
shown to be useful as fibers for increasing the strength of a bone
regenerative material include poly(L-lactic acid) (PLLA),
polyethylene terephthalate (PET) (e.g., MERSILENE.RTM. sutures),
polyethylene, polyester (e.g., FIBERWIRE.RTM.), poliglecaprone
(e.g., MONOCRYL.RTM.), polyglycolic acid, and polypropylene. Of
course, one of skill in the art with the benefit of the present
disclosure would be able to recognize even further material that
could be provided in fiber form or otherwise to increase the
strength of the bone regenerative material used according to the
present invention.
[0100] Fibers used for increasing the strength of the bone
regenerative material may have various sizes. Preferably, fibers
used in various embodiments can have an average diameter of about 1
.mu.m to about 100 .mu.m, about 2 .mu.m to about 75 .mu.m, about 3
.mu.m to about 50 .mu.m, about 4 .mu.m to about 40 .mu.m, or about
5 .mu.m to about 25 .mu.m. Such fibers further preferably have an
average length of about 100 .mu.m to about 1,000 .mu.m, about 150
.mu.m to about 900 .mu.m, about 200 .mu.m to about 800 .mu.m, or
about 250 .mu.m to about 750 .mu.m.
[0101] Fibers used for increasing the strength of the bone
regenerative material also may be included in varying
concentrations. Specifically, the fibers may comprise about 0.1% to
about 10%, about 0.25% to about 9%, about 0.5% to about 8%, about
0.75% to about 7%, about 1% to about 6%, or about 1.5% to about 5%
by weight of the bone regenerative material.
[0102] Preferably, the fibers are added in a concentration so as to
appreciably increase the strength of the bone regenerative material
as compared to the material without any fiber additive.
Specifically, the fibers may be added in an amount to increase the
tensile strength of the bone regenerative material by at least 5%,
at least 10%, at least 15%, at least 20%, or at least 25%.
Similarly, addition of the fiber component may increase compressive
strength by at least 10%, at least 15%, at least 20%, at least 25%,
or at least 30%.
[0103] In some embodiments, addition of the fiber component may
cause the bone regenerative material to increase in viscosity,
which may reduce injectability of the material. To overcome this
increase in viscosity, it may be useful to inject the material
using a syringe with a tapered nozzle. Such nozzle configuration
can lower the force needed to inject the more viscous paste through
a needle.
[0104] In preparation, the fibers may be added to a dry mixture of
the materials used in the bone regenerative material. The combined
materials may be wetted to form a paste. It further can be useful
to include additional processing steps to improve mixing of the
fibers into the bone regenerative material and to reduce the
presence of fused fiber groups. For example, the cut fibers may
undergo ultrasonic agitation for a defined time (e.g., 30-60
minutes), and such agitation may be carried out with the fibers in
a liquid medium in which the fiber polymer is insoluble (e.g.,
isopropyl alcohol). The sonicated fibers can then be added to the
dry ingredients used for the bone regenerative material and blended
(e.g., by stirring). The combination is then filtered and dried
under vacuum. The combined materials may then be wetted for forming
the paste material for use.
[0105] The methods of the present invention generally comprise
replacing a defined volume of degenerated bone material (optionally
in an area having a defined shape) with a bone regenerative
material that causes generation of new bone material of greater
density (or other bone quality measure as described herein) than
the replaced, degenerated bone material. The term "degenerative
bone material" or "degenerated bone material" can mean bone
material that is clinically categorized as osteopenic or
osteoporotic. The terms more specifically can mean bone having a
T-score of less than -1, less than -1.5, less than -2, less than
-2.5, or less than -3. Such degenerated bone material typically
will exist within a bone that generally also is categorized as
osteopenic or osteoporotic.
[0106] The inventive methods generally can be described as methods
for improving bone quality of a localized area of a bone.
Specifically, bone quality can correspond directly to BMD but also
may refer to the general strength of the bone (including
compressive strength) and the ability of the bone to resist
fracture in and around the localized area of the bone. This ability
to improve bone quality in part arises from the recognition that
the localized areas of the bone can in effect be reset to a
healthier bone quality--that of normal bone or the bone quality of
a similar patient under conditions where BMD is recognized to be at
its peak. Surprisingly, it has been found that degenerative bone
material in a localized area of a bone, such as from a patient
suffering from osteoporosis, can be replaced by using a bone
regenerative material that causes generation of new bone material
in the localized area. What is particularly surprising is that the
newly generated bone material is not of osteoporotic quality. This
is unexpected because one would expect that when a patient suffers
systemically from osteoporosis, any new bone material formed in
such patient would be of reduced quality (i.e., would be
osteoporotic and exhibit low density). The present invention,
however, has shown that after implantation of the bone regenerative
material into the osteopenic or osteoporotic bone, the material is
resorbing at a predicable rate and is not negatively affected by
the systemic disease. Subsequent generation of dense, new bone
material at the localized area of the bone improves bone quality
and BMD as measured by T-score on DEXA. Specifically, the Tscores
indicate the newly generated bone material is substantially similar
to normal bone in that it exhibits a density that is at least at a
level that would be expected to be seen in patients at their peak
BMD (e.g., a T-score in the range of about -1 to about 1) and not
in an osteopenic or osteoporotic state. In further embodiments, the
newly generated bone material can exhibit a compressive strength
that is substantially similar to (or exceeds) the compressive
strength of normal bone. Such characteristics may be related to the
newly formed bone material, specifically to the localized area of
the bone in general (i.e., the newly formed bone material and the
existing bone material in the immediately surrounding area).
[0107] In certain embodiments, the methods of the invention can
comprise active steps for forming a void within a bone in a
patient. Specifically, the methods can comprise forming a void in a
localized area of a bone. Any methods useful for forming such void
can be used according to the invention. In some embodiments, the
methods can comprise chemically dissolving or otherwise eliminating
bone material within a defined area of the bone to form a void. In
other embodiments, liquid lavage may be used create a void within a
bone, such as the methods described in U.S. Pat. Pub. No.
2008/0300603, which is incorporated herein by reference. In further
embodiments, sonication could be used to clear bone material in a
localized area. In other embodiments, a void may be created through
use of an inflatable or expandable device (e.g., a balloon or an in
situ expandable reamer). Expandable meshes also could be used. In
specific embodiments, the methods can comprise any mechanical means
for creating a void within a localized area of a bone.
[0108] In some embodiments, the methods can comprise drilling or
otherwise channeling (e.g., by stabbing with a cannulated or solid
needle, probe, or the like) into the interior of the localized area
of the bone. In some embodiments, the channel formed in this manner
may provide the void desired for a specific method of treatment. In
other, preferred embodiments, the drilling or channeling can be
characterized as means for forming access to the interior of the
localized area of the bone to be treated so that a void of
dimensions greater than the channel can be formed. Using the
channel to access the area of the bone to be treated, a void of a
predetermined shape and size can be formed by any means useful for
creating a void, including any of the methods described above.
Depending upon the degenerative state of the bone (i.e., the
progression of the osteopenia or osteoporosis), formation of a void
may include removal of at least a portion of the degenerated bone
material.
[0109] FIG. 2a and FIG. 2b show scanning electron micrographs of
normal bone and osteoporotic bone, respectively. As seen therein,
the normal bone shows a pattern of strong interconnected plates of
bone material. Much of this material is lost in osteoporosis, and
the remaining bone has a weaker, rod-like structure, some of the
rods being completely disconnected. Such disconnected bone may be
measured as bone mass but contribute nothing to bone strength. In
some embodiments, the void may be formed simply by breaking apart
the degenerated bone material, such as by scraping, drilling, or
the use of specialized materials for reaming out the bone to form
the void. Such clearing may be otherwise described as breaking,
crumbling, crushing, pulverizing, reaming, expanding, or otherwise
dismantling or pushing or moving aside the bone material within the
area for void formation. In some embodiments, this may be referred
to as debridement of the bone in the localized area, insufflation,
or snaking. Preferably, the area of debridement conforms to the
predetermined shape and size of the desired void.
[0110] Because of the loss of BMD, the degenerated bone material
that is broken apart to form the void may simply be left as remnant
material in the formed void. In other embodiments, it may be
desirable to remove some or all of the degenerated bone material
that is cleared to form the void. Thus, void formation according to
the invention may be characterized as breaking apart the
degenerated bone material in the localized area and removing at
least a portion of the material, or void formation may be
characterized simply as the breaking apart step. In some
embodiments, the active steps for forming a void in a bone may be
referred to as clearing damaged and/or degenerated bone material
from the localized area of the bone. Clearing thus can encompass
the complete or partial destruction of the degenerated bone
material and/or removal of all or part of the degenerated bone
material from the void. In specific embodiments, the invention can
be characterized as removing damaged and/or degenerated bone
material from a localized area of a bone to form a void of
predetermined shape and size. In other embodiments, the method can
be characterized as forming an amorphous void of defined
volume.
[0111] The methods further can comprise at least partially filling
the formed void with a bone regenerative material, such as
described herein. The amount of bone regenerative material used can
depend upon the volume of the void formed in the preceding step. In
various embodiments, the volume of bone regenerative material used
can range from about 1 cm.sup.3 to about 200 cm.sup.3, about 2
cm.sup.3 to about 150 cm.sup.3, about 2 cm.sup.3 to about 100
cm.sup.3, about 2 cm.sup.3 to about 75 cm.sup.3, about 5 cm.sup.3
to about 50 cm.sup.3, about 10 cm.sup.3 to about 40 cm.sup.3, or
about 15 cm.sup.3 to about 35 cm.sup.3. The foregoing volumes thus
can be representative of the actual volume of the void formed in
the bone, as described above. In specific embodiments, volumes can
be specifically related to the bone and the area being treated. For
example, in relation to the distal radius, volume may be about 1
cm.sup.3 to about 10 cm.sup.3, about 1 cm.sup.3 to about 8
cm.sup.3, or about 1 cm.sup.3 to about 5 cm.sup.3. In relation to a
vertebral body, volume may be about 1 cm.sup.3 to about 30
cm.sup.3, about 2 cm.sup.3 to about 25 cm.sup.3, or about 2
cm.sup.3 to about 20 cm.sup.3. In relation to the proximal femur,
volume may be about 5 cm.sup.3 to about 100 cm.sup.3, about 5
cm.sup.3 to about 80 cm.sup.3, or about 10 cm.sup.3 to about 50
cm.sup.3. In relation to the proximal humerus, volume may be about
5 cm.sup.3 to about 200 cm.sup.3, about 5 cm.sup.3 to about 150
cm.sup.3, about 5 cm.sup.3 to about 100 cm.sup.3, or about 10
cm.sup.3 to about 80 cm.sup.3.
[0112] The shape of the void formed in the bone can vary depending
upon the bone being treated. In some embodiments, the shape of the
formed void may substantially correspond to the shape of the area
in the proximal femur known as Ward's area. In some embodiments,
the shape of the void may substantially conform to the shape of the
localized area of the bone being treated. For example, in relation
to treatment of the distal radius, the void may substantially
conform to the shape of the distal 1-5 cm of the bone. In specific
embodiments, the shape of the formed void may not be critical to
the success of the method; however, the invention is intended to
encompass formation of voids of defined shape and size that may be
desirable in the specific bone being treated.
[0113] In certain embodiments, specifically in treating patients
exhibiting particularly advanced stages of bone degeneration, at
least some degree of treatment may be achieved without creating a
void prior to injection of the bone regenerative material. As
discussed previously, the effect of bone loss related to
osteoporosis is a reduction in the density of the bone material, or
formation of larger, more pronounced spaces within the bone. In
advanced osteoporosis, cavitation of the bone make allow for
injecting a bone regenerative material directly into a localized
area of a bone exhibiting such increased porosity. In specific
embodiments, the force of injecting the bone regenerative material
itself may artificially enlarge the space within the bone and thus
may in effect form a void that is immediately filled. In other
embodiments, the injected bone regenerative material may simple
permeate the degenerated bone of increased porosity and thus
substantially fill pore volume in the localized area of the bone
being treated. Accordingly, in certain embodiments, the invention
encompasses simultaneously creating and filling a void in a
localized area of a bone. Although such embodiments may occur, it
is expected that most effective results are achieved by at least
forming a channel into the area of the degenerated bone to be
filled with the bone regenerative material. More preferably, a void
will be formed as otherwise described above.
[0114] Any means useful for inserting the bone regenerative
material into the formed void may be used. For example, when the
bone regenerative material is in a flowable form, the material may
be injected into the formed void, such as by using a syringe. Thus,
in particular embodiments, it can be useful for the bone
regenerative material to be introduced into the void in a
substantially flowable state and then harden in vivo. In other
embodiments, it may be useful to substantially harden the bone
regenerative material outside the body and then pack the hardened
material into the void. Still further, the bone regenerative
material may take on further physical conditions, such as a
putty-like consistency. In some embodiments, the bone regenerative
material may be in a particulate form of varying sizes that can be
packed into the void. Moreover, the bone regenerative material may
be filled into the void in addition to one or more additional
materials that can assist in filling the void and may provide one
or more further beneficial functions, such as providing temporary
or permanent support to the localized area. In specific
embodiments, an eluting substrate, such as BMP or a peptide soaked
expanding sponge, could be inserted into the void prior to
insertion of the bone regenerative material.
[0115] In some embodiments, the bone regenerative material may be
inserted into the created void in connection with an additional
reinforcing agent (e.g., a screw or other cylindrical body or a
hollow-core material--e.g., coating the reinforcing agent or
included within a hollow core of the reinforcing agent).
Beneficially, however, the methods of the present invention allow
for filling of the formed void without the need for any further
reinforcing agent (whether the reinforcing agent is resorbable or
non-resorbable). In specific embodiments, the bone regenerative
material used in the invention can be a material that hardens to
immediately provide the localized area of the treated bone with
sufficient strength such that the treated area of the bone has a
fracture resistance that is at least equivalent to the fracture
resistance of the bone prior to treatment. Such advantage is more
particularly described in the Examples below. As also described
herein, the need for reinforcing agents is further negated by the
substantial increase in bone strength established by the in-growth
of new bone material that is substantially identical in
characteristics to natural, healthy bone. Such increases in bone
qualities begin to be seen relatively soon (e.g., within a time of
less than one week up to a time of about 16 weeks).
[0116] In some embodiments, the invention particularly can provide
a method of treating a patient suffering from a degenerative bone
condition. Particularly, the patient may be suffering from and/or
diagnosed as having a condition of osteopenia or a condition of
osteoporosis. Alternately, the patient may be suffering from any
other condition having the effect of causing bone degeneration,
particularly a loss of BMD and/or bone strength.
[0117] The invention particularly is useful in that the formation
of the void clears the localized area of the degenerated bone
material so that the bone regenerative material can be provided
therein. Preferably, the bone regenerative material promotes
formation of new, non-degenerated bone material in the void.
Advantageously, the newly formed bone material is natural to the
patient. Preferably, the newly formed bone material has a density
that is substantially identical to or exceeds that of normal bone.
In other words, the newly formed bone material has a density that
is substantially identical to the density of bone in a person
(preferably of the same race and gender) at an age of about 30-35
years. In particular embodiments, this can mean that the newly
formed bone material has a T-score when measured by DEXA that is
greater than -1, preferably is at least -0.5 or at least 0. In
other embodiments, T-score for the newly formed bone material may
be In other embodiment, T-score may be about -1.0 to about 2.0,
about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to
about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about
-0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0,
about 0 to about 1.5, or about 0 to about 1.0. In other embodiment,
the newly formed bone material may have a BMD that sufficiently
exceeds the BMD prior to treatment (as indicated by improved
T-score) such that the patient is viewed as having a significant
relative improvement in BMD. The newly formed bone also can have a
compressive strength that is substantially identical to or exceeds
that of normal bone.
[0118] The inventive methods are particularly beneficial in that
the treated, localized area of the bone can effectively be
remodeled over time to be substantially identical to normal bone
(i.e., exhibiting normal BMD, and/or normal compressive strength,
and/or normal resistance to fracture). Moreover, in some
embodiments, the effects of the bone regenerative material for
generating new, natural bone growth can actually extend outside the
bounds of the formed void. Particularly, it has been found
according to the invention that a gradient effect may be provided
in that new, natural bone material of improved density may be
formed within the originally formed void, but new bone material
also can be generated in the area of the bone adjacent the formed
void. This is particularly beneficial in that the areas of the bone
adjacent the formed void also are strengthened such that the
incidence of adjacent fractures is reduced.
[0119] As previously noted, the methods of the invention can be
practiced in a variety of bones in the mammalian body. In a
particularly useful embodiment, the inventive methods may used in a
bone in the hip area of a patient. For example, following is an
exemplary method for treating a patient suffering from a
degenerative bone condition by replacing bone material in a
localized area of the patient's femur, specifically the proximal
femur. The surgical technique uses a lateral approach similar to a
standard core decompression or hip screw. One distinction in the
technique is the creation of the geometry of the defect or void to
receive the graft (i.e., the bone regenerative material), which
will subsequently regenerate dense, new, natural bone to augment
the bone quality in the localized area of the bone, strengthen the
femoral neck and Ward's Triangle, and decrease risk of
insufficiency fracture. The following procedure (varying in
geometry) may be utilized in other areas of metaphyseal bone, such
as the vertebral body, distal radius, proximal humerus, and
tibia.
[0120] To carry out the technique, the patient may be positioned on
a radiolucent table in the supine position. Radiology support can
be provided by C-arm equipment and an xray technician to provide
x-ray navigation during the procedure. As noted above, the lateral
approach to the proximal femur can be used. In other embodiments, a
greater trochanter approach also could be used. A small incision
can be made just distal to the greater trochanter, and a guidewire
can be introduced into the proximal femur under fluoroscopic
guidance in anterioposterior (AP) and lateral views. A cannulated
5.3 mm drill can be introduced over the guidewire up to the femoral
head, and a channel can be formed up to (and alternately through)
the site for void formation. This channel can be referred to as a
core. In alternate embodiments, any means for breaking away the
weak, osteoporotic bone material may be employed, such as using a
countersink drill, or a cortical punch and blunt obdurator to
create the space. The drill and guidewire can be removed, and a
working cannula can be introduced into the core to form the
surgically-created defect, or void. A debridement probe can be used
to create space within the localized area of the femur for
implantation of the bone regenerative material. Specifically, the
probe may have a precisely angled head for accommodating the
endosteal anatomy of the femoral neck and Ward's Triangle. Creating
this geometry to allow a complete fill of the neck and Ward's
Triangle offers the greatest potential for complete regeneration
and higher ultimate bone strength. The surgically-created defect
(or void) preferably is washed and aspirated before proceeding. The
bone regenerative material is prepared if necessary and injected
through a long cannula into the surgically-created defect.
Injection through the cannula eliminates pressurization as well as
a selfventing potential down the medullary canal. After injection
of the bone regenerative material, the incision is closed in
standard fashion. Beneficially, such procedure can be performed
with minimal down-time for the patient and preferably requires no
over-night hospitalization (e.g., requiring only up to about 6-8
hours total time in a clinic, hospital, or other medical facility).
FIGS. 3a-3i provide radiographic images of injection of the bone
regenerative material, PRO-DENSE.RTM. (available from Wright
Medical, Arlington, Tenn.), into a void that was created in the
proximal femur of a patient just prior to injection of the bone
regenerative material. As seen in the images, the bone regenerative
material is filled into the void through a long cannula, which is
initially inserted up to the femoral head (FIG. 3a), maneuvered to
completely fill the void (FIG. 3b-FIG. 3h), and removed once
back-filling is complete (FIG. 3i).
[0121] Multiple variations of the above procedure could be
practiced within the scope of the invention. For example, FIG. 4
provides an enhanced radiograph of a proximal femur illustrating
the target fill area, any portion of which could be filled, with or
without initial debridement of the area. The figure also
illustrates the approximate area and size of the initial channel
that could be formed from a lateral approach. Specifically, FIG. 4
illustrates the channel extending laterally through the proximal
femur to the femoral head, and hatching is provided to illustrate
an exemplary area in the proximal femur, any portion of which may
be targeted as a candidate for removal of bone material and filling
with a bone regenerative material. As further, non-limiting
examples, one or more "struts" can be formed in the proximal femur
as branches from the initial channel and then filled with a bone
regenerative material. Still further, one or more struts could have
one or more portions that are significantly enlarged to increase
the amount of bone regenerative material that is placed into a
defined area of the bone. Yet further, a generalized, larger area
of the proximal femur could be debrided and filled. Further,
similar embodiments also could be envisioned in light of the
present disclosure.
[0122] A further surgical technique that may be used according to
the present invention is described below in relation to an
impending atypical femoral fracture. Such fractures most commonly
occur in the proximal one-third of the femoral shaft, but they may
occur anywhere along the femoral diaphysis from just distal to the
lesser trochanter to proximal to the supracondylar flare to the
distal femoral metaphysis. The fracture is atypical in that it
usually occurs as a result of no trauma or minimal trauma,
equivalent to a fall from a standing height or less. The fracture
may be complete, extending across the entire femoral shaft, often
with the formation of a medial spike, or incomplete, manifested by
a transverse radiolucent line in the lateral cortex.
[0123] The following specifically describes a technique for
introducing a bone regenerative material into the femoral body of a
patient, particularly a patient subject to an impending atypical
fracture, e.g., osteopenic or osteoporotic patients, by creating a
void in an intact femoral body prior to occurrence of an atypical
femoral fracture. The initial step--guide pin placement--includes
formation of a skin incision (e.g., 1 cm) proximal to the tip of
the greater trochanter. A serrated tissue protector sleeve with
cannulated centering guide and guide pin is inserted to the cortex
of the greater trochanter. The guide pin is advanced through the
cortex of the greater trochanter and is continued to the region of
impending fracture in the femoral shaft. The depth and position of
the guide pin can be confirmed by fluoroscopy in both planes.
[0124] Next, a defect is created and prepared for injection of the
bone regenerative material. Specifically, while maintaining the
serrated tissue protector in place, the cannulated centering guide
is removed, and a 5.3 mm cannulated drill is inserted and advanced
through the trochanter. The drill is then removed, leaving the
guide pin in place, and a flexible reamer is introduced. The reamer
is advanced over the guide wire and through the trochanter, and the
guide pin is then removed. The reamer is then advanced to the
region of impending fracture and removed. The working cannula with
insertion trocar is inserted through the serrated tissue protector
and seated inside the cortex (i.e., provided with a "snug" fit).
The serrated tissue protector and insertion trocar are then
removed. The injection cannula can be placed through the working
cannula and advanced to the region of the femoral fracture, and the
cannula can be used with suction to remove any created particulates
in the femur. The bone regenerative material is then injected,
preferably while monitoring (e.g., by fluoroscopy). The working
time for injection typically is approximately 2-4 minutes for
optimal fill results. The injection cannula and the working cannula
can then be removed. The soft tissue then can be irrigated, and the
skin is closed with appropriate means (e.g., sutures).
[0125] Another description of a surgical technique that may be used
according to the present invention is described below in relation
to the distal radius. The following specifically describes a
technique for introducing a bone regenerative material into the
distal radius of osteopenic or osteoporotic patients by creating a
void in an intact distal radius prior to any fragility fracture. To
carry out the technique, the patient may be positioned with the arm
on a radio lucent table with the palm of the hand facing upward.
Radiology support can be provided by C-arm equipment and an x-ray
technician to provide x-ray navigation during the procedure. To
form an injection portal, a 1 cm incision is made centered over the
radial styloid, and the subcutaneous tissue is bluntly dissected
down to the periosteum between the first and second dorsal extensor
compartments. A k-wire is inserted under fluoroscopic guidance 3-4
mm proximal to the radioscaphoid joint line and centered (dorsal to
volar) in the radial styloid. A cannulated drill is used to drill
into the metaphysis of the distal radius. A debridement probe can
be used to create space within the localized area of the distal
radius for implantation of the bone regenerative material.
Specifically, the probe may have a precisely angled head for
accommodating the endosteal anatomy of the distal radius. The
surgically-created defect preferably is washed and aspirated before
proceeding. The bone regenerative material is prepared if necessary
and injected through a cannula into the surgically-created defect.
After injection of the bone regenerative material, the incision is
closed in standard fashion. Such surgical technique would not be
expected to require hospitalization of the patient, which allows
for a beneficial treatment for bone degeneration with minimal
down-time for the patient. FIGS. 5a-5c provide illustrations of
specific steps in the above-described surgical technique. FIG. 5a
shows formation of access to the distal radius metaphysis. FIG. 5b
shows the mechanically formed void in the distal radius. FIG. 5c
shows the localized area of the radius after filling of the void
with a bone regenerative material.
[0126] Another description of a surgical technique that may be used
according to the present invention is described below in relation
to the vertebrae. The following technique utilizes an inflatable
tamp (or balloon tamp) such as those available from Kyphon, Inc.
(now a subsidiary of Medtronic, Inc.). Thus, as further described
herein, some methods according to the present invention may be
improvements on a kyphoplasty technique. In other embodiments,
however, techniques for replacing degenerative bone in vertebrae
may be substantially similar in nature to the techniques described
above in relation to the proximal femur and the distal radius. A
substantial distinction over known techniques for treating
vertebral fractures is that the methods of the present invention
would be carried out on a vertebra before the vertebra was affected
by an osteoporotic compression fracture (or any other type of
fracture).
[0127] In the exemplary surgical technique for replacing
degenerative bone in a vertebra, the patient may be positioned on a
radiolucent table in the prone position. Radiology support can be
provided by C-arm equipment and an x-ray technician to provide
x-ray navigation during the procedure. After confining the vertebra
and its corresponding pedicles to be treated with the radiological
tube in an antero-posterior projection, a small cutaneous incision
(approximately 1 cm) can be made in the dorsal or lumbar area into
which a bone biopsy need of 11/13 gauge is introduced through the
posterior portion of the pedicles, sloping anteriorly, medially,
and caudally. The approach in this exemplary method is bilateral.
Once the exact position of the needle is verified, a Kirshner wire
is introduced. A drill tip is advanced into the wall a few
millimeters from the anterior cortex margin to form an
intravertebral bone channel for successive passage of the balloon
tamp.
[0128] Successively, under fluoroscopic guidance in a lateral
projection, the probe is carefully pushed forward and placed in the
anterior two-thirds of the vertebra. It can have a range of length
comprised between 15 and 20 mm, with a maximum volume respectively
of 4 and 6 mL. Once the exact position of the balloons in the two
hemivertebrae is verified with the aid of two radiopaque markers
located at the extremities (proximal and distal), the balloons are
distended with a liquid containing 60% contrast medium, achieving a
lifting of the superior vertebral end-plates and creating a cavity
internally through compression of the surrounding cancellous bone.
The inflation stops when the space is created, there is contact
with the cortical somatic surface, or when the maximum pressure
(220 PSI) or dilation of the balloon is achieved. The 5 surgically
created void can then be washed and aspirated.
[0129] The bone regenerative material can be prepared as necessary.
The bone regenerative material then is loaded into dedicated
cannulas and moved forward through the working cannula until
correspondence with the anterior third of the void. Immediately
after, the bone regenerative material is pushed with slight
pressure using a plunger stylet under continuous fluoroscopic
guidance. The filling volume is usually 1-2 mL greater than that
which is obtained with the balloon, which allows the bone
regenerative material to distribute itself effectively. To complete
the procedure, all cannulas are extracted, the cutaneous incisions
are sutured, and the patient may be instructed to remain in bed for
the next few hours. The length of the procedure for each vertebra
treated typically is around 35-45 minutes. A traditional
radiographic inspection can be performed after the procedure to
evaluate the results obtained. FIGS. 6a-6c illustrate specific
steps from the exemplary procedure for replacing bone in a
vertebra. FIG. 6a shows insertion of a balloon tamp bilaterally in
the vertebra being treated. FIG. 6b shows inflation of the balloon
to mechanically form a void in the vertebra. FIG. 6c shows removal
of the balloons while backfilling the formed void in the vertebra
with a bone regenerative material.
[0130] Although the inventive methods may be characterized in terms
of treating a patient suffering from a degenerative bone condition
(such as osteopenia or osteoporosis), the invention further may be
characterized in relation to the ability to specifically alter
localized areas of bone, such as by improving BMD, improving bone
quality, improving bone strength, improving natural bone structure,
and the like. The invention also can be characterized in relation
to the ability to remodel localized areas of bone, including
providing the localized area of the bone with an exceedingly
increased density that gradually reduces to normal BMD. In certain
embodiments, the invention can be characterized as providing
various methods of improving bone quality at a localized area of a
bone. Bone quality can be characterized specifically in relation to
BMD, which can be evaluated in relation the Tscore from a DEXA
scan. Bone quality also may relate more generally to the overall
structure of the bone material in relation to the bone scaffolding.
Further, bone quality may specifically relate to bone
strength--i.e., compressive strength.
[0131] The specific mechanical strength of bone, whether it be in
relation to natural bone material or bone material regenerated in
surgically created defects (including those of osteopenic or
osteoporotic patients), presently cannot be directly measured in
living subjects because such testing currently requires removal of
significant segments of bone. Thus, direct measurement of bone
mechanical strength can only be measured through post-mortem
clinical retrieval studies. Nevertheless, research indicates that a
substantial increase in strength would be expected in association
with concurrent increases in BMD, as discussed herein. It further
would be expected to achieve further increased bone properties,
such as bone volume, trabecular thickness, trabecular number,
separation of trabeculae, measurements of interconnectivity, and
cortical wall thickness. Supportive evidence of such increases in
mechanical strength is provided in the appended Examples in
relation to a canine study in which both compressive strength and
the amount of calcified bone were directly measured on explanted
specimens of regenerated bone at both 13 and 26 weeks after
undergoing a cavitation and filling procedure according to the
present invention. At 13 weeks, the bone segments including the
regenerated bone material exhibited a substantial 172% increase in
calcified bone compared to normal bone taken from the same anatomic
location, as measured by quantitative histology. The corresponding
increase in compressive strength for the bone with the regenerated
bone material over the compressive strength of natural bone was
283%. At 26 weeks post-op, the newly regenerated bone material had
undergone remodeling, resulting in a gradual return towards normal
bone architecture and properties. The 24% increase in calcified
bone from histological analysis (again, compared to natural bone)
corresponded to a compressive strength that was 59% higher than
normal controls. It also is notable that increases in radiographic
density were seen, which correlated to the quantitative results
from histology.
[0132] Clinical evidence of BMD increases in human subjects is
provided in the appended Examples and is believed to support the
conclusion that increases in BMD can reasonably correlate to
increases in bone mechanical strength, particularly compressive
strength. Briefly, a study was performed using 12 human patients,
all of whom were deemed to be osteoporotic according to the World
Health Organization (WHO) definition. Each patient underwent
treatment according to the present invention in one hip with the
contralateral side remaining untreated for the purpose of
comparison. BMD was measured in both hips via DEXA prior to
treatment (baseline), and at pre-determined intervals including 6,
12, and 24 weeks. Mean femoral neck BMD increased 120%, 96% and
74%, respectively, at each interval compared to baseline. Mean
Ward's area BMD increased 350%, 286% and 189%, respectively, at
each interval compared to baseline. Two patients were further
evaluated at a 24 month study endpoint. These two patients
demonstrated mean BMD increases of 35% (femoral neck region) and
133% (Ward's area) at endpoint. Percent values at this level
suggest the graft material was resorbed and replaced by new bone
material as was observed in the canine study. There were no
appreciable changes in BMD measurements from baseline in the
untreated sides.
[0133] There are no known studies to date indicating that increased
BMD and increased strength in a human osteoporotic bone can be
precisely correlated to such values measured in healthy canine
subjects. Nevertheless, the large increase in both properties in
the canine study, together with the increase in BMD measured in the
clinical trial, are strong evidence of a corresponding increase in
bone strength for human osteoporotic bone that is treated according
to the presently described methods.
[0134] Bone quality may also relate to the ability of the bone to
resist fracture. Thus, embodiments of the invention that can be
characterized as relating to increasing bone quality may
specifically encompass improving the bone structure in a manner
such that the treated area of the bone has a reduced risk of
fracture in comparison to the risk of fracture prior to treatment
(e.g., when the patient is in an osteopenic or osteoporotic
condition).
[0135] Low BMD is among the strongest risk factors for fragility
fracture. In addition, the deterioration of cancellous bone
architecture is a contributory factor to bone fragility. So, while
osteoporosis has traditionally been defined as a disease
characterized by a lack of bone strength, it should be further
defined as a disease of low bone density and the deterioration of
bone quality. Although measurement of BMD is a powerful clinical
tool and the "gold standard" for identifying bone mass, bone
quality also is largely defined by bone turnover and
microarchitecture. When these aspects of bone deteriorate (e.g.,
thinning trabeculae and loss of connectivity), there is a
corresponding increase in bone fragility and fracture risk.
[0136] Various non-invasive methods can be employed to measure
microarchitecture including, but not limited to, high-resolution
peripheral quantitative computed tomography (pQCT), micro computed
tomography (uCT), and functional magnetic resonance imaging (fMRI).
Images obtained with such methods can be used to distinguish
between cortical and cancellous bone and visualize fine details of
trabecular microarchitecture previously only measured with an
invasive biopsy. Scans from CT (and likely MRI) can be modeled
computationally by microstructure finite element analysis (FEA) to
assess bone stiffness. Each of these methods can be used to assess
the architecture of bone. These architecture measurements include
bone volume, trabecular thickness, trabecular number, separation of
trabeculae, measurements of interconnectivity, and cortical wall
thickness.
[0137] As technology has improved, so too has the outcome
measurements of the computerized software. In combination, pQCT and
FEA can be used to predict fracture initiation point and fracture
potential under a specific load. This analysis is also known as
biomechanical computation tomography (BCT). Used in conjunction
with traditional studies, such as a comprehensive healthy animal
study, an osteoporotic animal study, or a cadaveric biomechanical
study, BCT can be used to predict the fracture potential of a
patient--including the risk of a fracture during a fall--and
provide information to assess bone quality improvement for a living
patient without the need for an invasive biopsy. Because of its
quantitative assessment, BCT can limit the inclusion/exclusion
criteria for any study as the spectrum of patient bone quality is
focused. Additionally, the duration of any study could potentially
be reduced since only specific subsets of "at risk" as opposed to
"estimated at risk" patients would be needed. Additionally, BCT can
reduce the need for a finite endpoint, such as an actual hip
fracture, which has a high association with mortality, to determine
the benefit of a provided treatment.
[0138] Therefore, in certain embodiments, evidence of bone quality
improvement according to the invention can be achieved by applying
BCT analysis to an implanted bone matrix, as described above, in
conjunction with other established scientific bone quality
assessments. The combined results can be useful to analyze the
change in bone density and bone quality over time and therefore
demonstrate the overall fracture risk reduction after treatment
according to the invention as compared to the condition of the
natural bone prior to treatment (i.e., while the bone was in an
osteopenic or osteoporotic condition). Using such methods, it thus
can be possible to quantify fracture risk before treatment and
after treatment according to the invention and, based upon the
quantified data, illustrate the ability of the invention to reduce
fracture susceptibility, or increase resistance to fracture. For
example, fracture potential may be scaled similarly to T-score in
BMD analysis such that a score of about 0 indicates the fracture
potential is similar to the potential for an average, healthy adult
of about age 30 (perhaps even including gender, race, and/or
nationality data if evidence suggests such factors should be
considered). A negative score could indicate a fracture potential
that is greater than in the average, healthy adult with the
potential increasing with more negative values (e.g., as score of
-2 indicating a greater fracture potential than a score of -1). A
positive score could indicate that fracture potential is less than
in the average, healthy adult with the potential decreasing with
more positive numbers (e.g., a score of 2 indicating a lesser
fracture potential than a score of 1).
[0139] In specific embodiments, a method of improving bone quality
at a localized area of a bone can comprise replacing a volume of
degenerated bone having a T-score of less than -1.0 with newly
formed, natural bone material having a T-score of greater than
-1.0. Preferably, the T-score of the bone with the newly formed,
natural bone material is at least -0.5, at least 0, at least 0.5,
or at least 1.0. In certain embodiments, the T-score of the treated
bone can exceed the T-score of the degenerated bone by at least 0.5
units, at least 1.0 unit, at least 1.5 units, at least 2.0 units,
at least 2.5 units, or at least 3.0 units. In embodiments where the
T-score of the treated bone exceeds the T-score of the degenerated
bone by at least a certain amount, it may not be necessary for the
T-score to also be greater than a defined minimum so long as the
increase in BMD evidenced by the increase in T-score represents a
sufficiently significant improvement in bone quality to be of use
for the patient (e.g., transforming the bone in the localized area
from a severely osteoporotic condition to a mildly osteoporotic
condition or from an osteoporotic condition to an osteopenic
condition).
[0140] In the method of improving bone quality, the replacing step
can comprise forming a void in the localized area of the bone by
clearing degenerative bone material in the area and optionally
removing a content of the degenerative bone material. The method
further can comprise at least partially filling the formed void
with a bone regenerative material, thereby generating in-growth of
new, natural bone material in the formed void.
[0141] In some embodiments, the ability to replace degenerative
bone material with bone material of improved quality particularly
can arise from the beneficial qualities of the bone regenerative
material that is used to fill the formed void in the bone.
Preferably, the bone regenerative material is a material as
described herein that provides for reliable, consistent resorption
by the body at a rate significantly consistent with the rate of new
bone material generation by the body. For example, it can be
particularly useful to utilize a material as described herein that
provides multi-phasic resorption profile in vivo that can optimize
the in-growth of new bone. Such materials can be bi-phasic (i.e.,
including at least two different materials that resorb at a
different rate in vivo), tri-phasic (i.e., including at least three
different materials that resorb at a different rate in vivo), or
can include an even greater number of different materials that
resorb at different rates in vivo.
[0142] In specific embodiments, the bone regenerative material may
comprise calcium sulfate as a first phase component that is
resorbed quickly, typically through simple dissolution, a brushite
(CaPO.sub.4) second phase component that undergoes osteoclastic
resorption (as well as simple dissolution), and a tricalcium
phosphate third phase that undergoes primarily osteoclastic
resorption. Any material that exhibits such tri-phasic resorption
profile could be used according to the invention. The changes over
time in a bone regenerative material having this kind of structure
that can facilitate controlled ingrowth of new bone material are
illustrated in FIGS. 7a-7e. Said figures illustrate graft
dissolution in an accelerated in vitro model that is approximately
six times faster than the resorption seen in vivo in a canine
model. A more detailed discussion of the resorption profile of the
bone regenerative material in relation to FIGS. 7a-7e is provided
in the Examples below.
[0143] While all phases in a multi-phasic material may begin some
degree of resorption shortly after graft placement, a multi-phasic
resorbing material can be described as one wherein the first phase
is dominated by resorption of the first material (e.g., a calcium
sulfate material) until most of the first phase is gone, the second
phase is dominated by resorption of the second material (e.g.,
brushite), and any further phases can be described as the time when
the remaining graft material(s) (e.g., granular TCP) are resorbed.
Specific times for complete resorption of each phase can depend
upon the specific materials used and the defect size.
[0144] Angiogenesis is a key early event during first phase
resorption because, as the calcium sulfate material resorbs, the
porous second phase is revealed and is conducive to vascular
infiltration. The porous second phase also can bind free proteins,
such as VEGF and BMP-2, at the implant/defect interface. Resorption
of the second phase then can release bound proteins, which can
recruit cells to the implant surface. The growth factors in the
interface region can stimulate proliferation and differentiation of
mesenchymal stem cells. Thereafter, differentiated osteoblasts lay
down osteoid, which then mineralizes to become newly woven bone.
The principles of Wolff s Law then can drive remodeling of the
newly formed bone material. This is further beneficial to the
patient in that strengthening of areas, such as the hip, that are
prone to debilitating fracture can promote confidence in the
patient that leads to greater movement and exercise, which in turn
can have a positive effect on total bone quality and overall
health.
[0145] In further embodiments, the invention provides methods for
increasing BMD in a localized area of a bone. The method can
comprise forming a void in the localized area of the bone, such as
by clearing native, degenerated bone material in the localized area
according to a suitable method, such as those described herein. The
cleared, native bone material optionally can be removed from the
formed void. The formed void then is at least partially filled with
a bone regenerative material as described herein. The bone
regenerative material filling the void can cause generation of new
bone material within the void, the density of the newly generated
bone material being greater than the density of the degenerated,
native bone material that was cleared to form the void in the
bone.
[0146] The increase in BMD can be indicated through comparison of
BMD scans of the localized area of the bone prior to removal of the
degenerated, native bone material and after generation of the new
bone material within the formed void. For example, when using a
DEXA scan, it is preferable for the density of the generated bone
material within the void to have a T-score that is at least 0.5
units greater than the T-score of the degenerated, native bone
material prior to being cleared to form the void. In further
embodiments, the T-score may be increased by at least 0.75 units,
at least 1.0 unit, at least 1.25 units, at least 1.5 units, at
least 1.75 units, at least 2.0 units, at least 2.25 units, at least
2.5 units, at least 2.75 units, or at least 3.0 units. In other
embodiments, T-score of the degenerated, native bone prior to
formation of the void in the localized area of the bone
specifically may be in a range indicating the presence of
osteopenia or osteoporosis, and the increase in BMD may be
sufficient so that the localized area of the bone no longer would
be characterized as being osteopenic or osteoporotic. For example,
prior to formation of the void, BMD in the localized area of the
bone may be less than -1.0, less than -1.5, less than -2.0, less
than -2.5, less than -3.0, less than -3.5, or less than -4.0. In
such embodiments, BMD may be increased such that the T-score is at
least at a minimum level. For example, BMD may be increased such
that T-score is greater than -1.0 or is at least -0.75, at least
-0.5, at least -0.25, at least 0, at least 0.25, at least 0.5, at
least 0.75, or at least 1.0. In further embodiments, BMD in the
localized area of the bone may be increased such that the T-score
at the localized area of the bone can be in a range that is
indicative of BMD falling within an accepted normal range. For
example, T-score may be within the range of greater than -1 to
about 2.0, about -0.5 to about 2.0, about 0 to about 2.0, about
-1.0 to about 1.0, about -0.5 to about 1.0, about -0.5 to about
0.5, or about 0 to about 1.0. In specific embodiments, the T-score
of the native bone material prior to being cleared for void
formation can be less than -1.0, and the generated bone material in
the formed void can have a T-score of at least -0.5 or at least 0.
Such would indicate that the localized area of the bone prior to
treatment would be considered to be at least osteopenic and that
the localized area of the bone after generation of the new bone in
the void would be considered to have a BMD that is substantially
identical to normal BMD for a person of the same gender and race at
the age of peak BMD. As previously described, the increase in BMD
can be simply sufficient to evidence a relative improvement in BMD
at the localized area.
[0147] In addition to the ability to cause formation of new,
natural bone that is of a normal density, the invention
beneficially allows for maintenance of the improved BMD for an
extended period of time. As described above, it was surprising to
find according to the present invention that newly formed bone
material in an osteoporotic patient was not of osteoporotic quality
but was substantially of the quality expected to be seen in a
patient of the same gender and race at the age of peak BMD. Thus,
the inventive methods have been found to be useful for essentially
re-setting the bone quality in the localized area that is treated
to the peak state (or to the normal state). Moreover, this
resetting of the localized area of the bone does not appear to be
affected by the patient's overall osteoporotic status. In other
words, the improved BMD is not a temporary phenomenon such that the
newly formed bone material quickly degenerates to an osteoporotic
state commensurate with the patient's overall status. On the
contrary, the newly formed bone material appears to take on the
full characteristics of the re-set status in that the newly formed
bone material progresses along the natural decline in BMD, such as
illustrated in FIG. 1. For example, as seen in FIG. 1, a 70 year
old Caucasian female under a typical decline in BMD could have a
localized hip BMD of about 775 mg/cm.sup.2. After treatment
according to the present invention, a localized area of hip bone
could be re-set to a normal BMD--e.g., about 950 mg/cm.sup.2 (or
the typical BMD at 30 years of age). After 10 years of additional,
typical decline in BMD, the same patient would be expected to have
an average BMD of around 700 mg/cm.sup.2 (i.e., the decline in
typical BMD between 70 and 80 years of age). The bone material in
the localized area of the hip treated according to the invention,
however, would be expected to be about 930 mg/cm.sup.2 (i.e., the
decline in typical BMD between 30 and 40 years of age). Of course,
it is understood that the foregoing is only an exemplary
characterization based on average values, and it is expected that
actual values could vary between patients. Thus, it is evident that
the inventive methods are not temporary solutions but can provide
long-term increases in BMD since the bone material generated by the
inventive methods is in effect re-set to a peak state and then
continues through the typical, natural decline in density that
accompanies aging (i.e., does not decline at an accelerated rate to
"catch-up" to the systemic osteoporotic state of the patient).
[0148] In light of this characteristic of the invention, certain
embodiments may encompass maintenance of the increased BMD for a
defined period of time. For example, the increase in BMD in the
localized area of the bone may be maintained for a time of at least
6 months, at least 1 year, at least 18 months, at least 2 years, at
least 3 years, at least 4 years, at least 5 years, or even longer.
Measurement of the time may be calculated from the time new bone
material is generated in the formed void. Preferably, maintenance
of the increased BMD includes maintaining a T-score that is greater
than -1.0, greater than -0.5, greater 0, or greater than 0.5. In
other embodiments, maintenance of the increased BMD includes
maintaining a T-score that is in the range of greater than -1.0 to
1.0, -0.5 to 1.0, or -0.5 to about 0.5. Similarly, the increase may
be characterized as a percentage increase in relation to untreated
bone. Thus, the treated bone may exhibit an increase in BMD for any
of the time periods noted above, such increase in BMD being at
least 10% greater, at least 15% greater, at least 20% greater, at
least 25% greater, at least 30% greater, at least 35% greater, at
least 40% greater, at least 45% greater, at least 50 greater, at
least 60% greater, at least 70% greater, at least 80% greater, or
at least 90% greater than the reference, untreated bone in the same
subject.
[0149] The methods of increasing BMD further are beneficial in that
the increase in BMD in the localized area of the bone may extend
beyond the borders of the void created in the bone. As seen in FIG.
2a and FIG. 2b, bone material is porous in nature being essentially
of a series of interpenetrating networks of scaffolding material
formed of bone cells. In healthy bone, the network is tightly
formed for dense, strong scaffolding material. In osteoporotic
bone, the network begins to degrade, the scaffolding thins,
weakens, and even falls apart, and the porosity of the bone
increases. Although not wishing to be bound by theory, it is
believed that because of this nature in osteoporotic bone, the
filling of the void formed in a bone according to the present
invention can cause the bone regenerative material to fill portions
of the bone in the areas adjacent the formed void. Thus, while new,
normal bone material is generated within the formed void as the
bone regenerative material is resorbed by the body, such new,
normal bone material also is generated in the areas of the bone
adjacent the formed void as a result of the bone regenerative
material extending beyond the borders of the filled void. Moreover,
such formation of new, healthy bone material exterior to the formed
void can arise from increased biological activity, such as
involving growth factors and cytokines at the interface that boost
the biological activity outside of the void margins. In some
embodiments, this can even lead to a gradient effect wherein the
density of the bone material in the localized area of the bone that
is treated according to the invention is at its lowest outside of
the void and away from any location where the bone regenerative
material may have entered, and the density of the bone material
gradually increases moving toward the area of the formed void. A
gradient effect thus may be elicited as per the following example
for an osteoporotic bone: the bone material immediately in the area
where the void was formed may have a normal or greater density
(e.g., T-score of around 0 to 1); the bone material immediately
adjacent the area of the formed void may also have a substantially
normal density, albeit less than inside the area where the void was
formed (e.g., a T-score of around -0.5 to 0.5); the bone material
somewhat further away from the formed void may also exhibit an
increased density, albeit less than bone material immediately
adjacent the formed void (e.g., a T-score of around -2 to -1); and
the bone material further away from the formed void may retain its
original, osteoporotic density (e.g., a T-score of less than -2.5).
Of course, the foregoing is merely exemplary of the gradient
effect, and actual T-scores and the extent of the effect in
relation to effective distance away from the formed void may vary
depending upon the actual density of the bone at the time of the
procedure, the type of bone regenerative material used, and the
force with which the bone regenerative material is placed into the
formed void and thus may extend beyond the borders thereof. This is
further illustrated in FIG. 8, which shows a 13-week gross specimen
in the canine proximal humerus after insertion of a graft formed of
a bone regenerative material according to the present invention.
The figure illustrates formation of dense, cancellous bone at the
graft site and new bone material extending even beyond the margins
of the original defect indicated by the dashed line.
[0150] In further embodiments, the methods of the invention can be
characterized in relation to a specific BMD profile elicited in a
localized area of a bone. As noted above, the inventive methods
have been found to not only re-set the newly formed bone material
to a normal density, but the methods also can cause the density in
the localized area of the bone to dramatically increase prior to
attaining a substantially normal density. This can be characterized
as a remodeling of the bone in the localized area according to a
specific density profile.
[0151] In some embodiments, the methods of creating a defined BMD
profile in a localized area of a bone can comprise forming a void
in the localized area of the bone by clearing degenerated bone
material in the area, and optionally removing a content of the
cleared, degenerated bone material. Although is not required for
the bone material to be removed from the void during or after void
formation, it may be desirable in some embodiments to partially or
completely remove the degenerated bone material from the void to
maximize the amount of the bone regenerative material that may be
placed within the void. Accordingly, after void formation, the
methods may further comprise at least partially filling the formed
void with a bone regenerative material such that new bone material
is generated within the void over time.
[0152] As the new bone material is generated within the void, part
or all of the bone regenerative material may be resorbed by the
body. Specifically, new bone in-growth may proceed, particularly in
an outside to inside manner in reference to the formed void, at a
rate substantially similar to the rate of resorption of the bone
regenerative material by the body.
[0153] Importantly, the newly generated bone material in the formed
void can be accurately characterized as being natural bone material
(in reference to the patient) in that the formed bone material
arises from influx of osteocytes from the treated patient and is
not allogenic bone or xenogenic bone. Thus, there is no little or
no opportunity for the bone regenerative material to elicit an
immune response that could limit the effectiveness of the bone
replacement treatment.
[0154] Regarding the defined BMD profile, successive BMD
evaluations over time, such as successive DEXA scans, can provide a
time-lapse profile of BMD in the localized area of the bone arising
from the implantation of the bone regenerative material. The BMD
profile provided according to the present invention is particularly
unexpected because the use of the bone regenerative material in a
surgically created void elicits a change in the localized area of
the bone such that BMD initially spikes to be significantly denser
than normal bone and then remodels over time with in-growth of new
bone material such that the density of the localized area of bone
treated according to the present invention approaches a
substantially normal value. The nature of a BMD profile achieved
according to certain embodiments of the present invention is shown
in FIG. 9, wherein BMD reported as a DEXA scan T-score is charted
as a function of time, where time 0 is the time of void formation
and implantation of the bone regenerative material. FIG. 9
illustrates a profile wherein the localized BMD of the bone to be
treated according to the invention is such that the bone would be
considered to be osteopenic or osteoporotic (i.e., a T-score of
less than -1 or less than -2.5). The broken line shown before time
0 indicates that the actual BMD, as characterized by T-score, can
be any value below the defined threshold (e.g., less than -1, less
than about -2.5, etc.). Upon replacement (at time zero) of the
degenerated bone in the localized area with the bone regenerative
material, the BMD in the localized area begins to sharply increase
to reach a maximum density. As illustrated in the representative
graph of FIG. 9, a maximum density corresponding to a T-score of
greater than about 5 is achieved within a time of about 1 week to
about 13 weeks. The solid line in FIG. 9 illustrates this sharp
increase in BMD, and the dashed line above a T-score of 5 indicates
that the maximum T-score achieved can be some value in excess of 5
and can typically occur at some time in the range covered by the
dashed line. In specific embodiments, the maximum T-score achieved
according to the defined BMD profile is at least 2.0, at least 3.0,
at least 4.0, at least 5.0, at least 6.0, at least 7.0, at least
8.0, at least 9.0, or at least 10.0. The time after implantation to
achieving maximum density (i.e., maximum T-score) can be in the
range of about 1 week to about 6 weeks, about 1 week to about 10
weeks, about 1 week to about 13 weeks, about 1 week to about 18
weeks, about 2 weeks to about 10 weeks, about 2 weeks to about 13
weeks, about 2 weeks to about 18 weeks, about 3 weeks to about 10
weeks, about 3 weeks to about 13 weeks, about 3 weeks to about 18
weeks, about 4 weeks to about 10 weeks, about 4 weeks to about 13
weeks, about 4 weeks to about 18 weeks, about 6 weeks to about 10
weeks, about 6 weeks to about 13 weeks, or about 6 weeks to about
18 weeks. After reaching a maximum density, the density of the
localized area of the bone begins to decrease for a time of up to
about 6 months, up to about 9 months, up to about 12 months, up to
about 18 months, up to about 24 months, from about 6 weeks to about
24 months, from about 13 weeks to about 18 months, or from about 18
weeks to about 12 months. Thereafter, the BMD of the localized area
of the bone stabilizes in a substantially normal range about -1.0
to about 2.0, about -1.0 to about 1.0, about -1.0 to about 0.5,
about -1.0 to about 0, about -0.5 to about 2.0, about -0.5 to about
1.5, about -0.5 to about 1.0, about -0.5 to about 0.5, about 0 to
about 2.0, about 0 to about 1.5, or about 0 to about 1.0. With the
foregoing values in mind, further graphs similar to that shown in
FIG. 9 could be prepared providing representative BMD profiles
encompassed by the invention that differ only in the maximum BMD
achieved and/or the time to achieving maximum BMD, and/or the time
after achieving maximum BMD until BMD decreases to the
substantially normal range. Actual embodiments of BMD profiles
achieved in test subjects are described in the Examples shown
below.
[0155] In further embodiments, the BMD may be substantially
maintained such that the defined BMD profile may be extended for a
prolonged period. In other words, BMD corresponding to a T-score of
about -1.0 to about 2.0, about -1.0 to about 1.0, about -1.0 to
about 0.5, about -1.0 to about 0, about -0.5 to about 2.0, about
-0.5 to about 1.5, about -0.5 to about 1.0, about -0.5 to about
0.5, about 0 to about 2.0, about 0 to about 1.5, or about 0 to
about 1.0 may be maintained for an additional year or more (i.e.,
the BMD profile in the localized area of the bone may be such that
BMD as reported by a T-score within the noted ranges may be
established and maintained for a time of at least 1 year, at least
2 years, at least 3 years, at least 4 years, at least 5 years, or
even more).
[0156] In further methods, the present invention may be
characterized in relation to the effect previously described above
in relation to remodeling of a localized area of degenerative bone
to be substantially identical to normal bone. In certain
embodiments, the invention particularly may be directed to methods
of remodeling a localized area of degenerative bone comprising the
following steps: forming a void in the localized area of the bone
by clearing degenerative bone material in the area and optionally
removing a content of the degenerative bone material; and at least
partially filling the formed void with a bone regenerative material
thereby generating in growth of new bone material in the formed
void. Specifically, the remodeling of the localized area of the
bone can be evidenced by the ability to cause the growth of new,
natural bone material in an area of the bone that was previously
osteopenic or osteoporotic (i.e., was bone that was considered to
be degenerated or otherwise viewed as being diseased and/or of low
quality, strength, and/or density).
[0157] In certain embodiments, the bone material in the localized
area treated according to the invention (i.e., before forming the
void) has a T-score of less than -1.0, which indicates bone
degeneration beyond what typically is considered a normal level,
and the new bone material present after remodeling has a T-score of
greater than -1.0, which indicates that the bone in the localized
area has been remodeled to be substantially identical to normal
bone. In such embodiments, the bone may be considered to have been
remodeled in the localized area because that area of the bone has
effectively been changed so that is no longer is considered to be
degenerated bone, osteopenic bone, osteoporotic bone, or the like,
but is rather considered to be in a state that is significantly
similar to bone of normal density for a person of the same gender
and race at peak BMD (i.e., normal bone). In other words, the bone
is remodeled from natural bone of low density to natural bone of
normal density.
[0158] This is not an effect that would have been expected prior to
the present invention. Osteoporosis (i.e., significant loss of BMD)
is typically seen as a systemic condition. Although actual T-score
may vary from site to site in the same patient, generally when
osteoporosis is present, the condition persists throughout the body
(e.g., a T-score of -2.8 in the distal radius versus a T-score of
-3 in the hip). As described above, it has been found according to
the present invention that although osteoporosis progresses
systemically, it is possible to locally re-set the body's bone
quality. In other words, a localized area of bone can be remodeled
away from an osteoporotic state to a normal state. This is
unexpected because osteoporosis is understood to arise from the
body's decreased ability to form new bone cells such that the rate
of bone cell resorption exceeds new cell formation. One would
assume that newly formed bone growing into an injury site would
simply be an extension of the surrounding bone--i.e., bone of low
quality would beget bone of low quality. The present invention
shows the opposite is true. By systematically removing defined
volumes of bone material in localized areas of bone and replacing
the material with a bone regenerative material as described herein,
the overall process sets in motion a regenerative process wherein
the influx of new bone cells causes formation of new, natural bone
material that is not merely an extension of the degenerative bone
in the surrounding area but is bone material substantially
identical to normal bone of normal density.
[0159] This remodeling is graphically illustrated in FIG. 10,
wherein the decline in BMD in a localized area of a bone in a
Caucasian female is estimated. As seen therein, BMD in the
localized area declines from a normal range around the age of 30,
and the rate of decline increases around the time of menopause and
then levels off to a less sharp decline. The point at age 70 on the
graph represents the time of undergoing a procedure according to
the present invention. The BMD at the localized area increase
dramatically and re-sets to a normal range (i.e., around the same
density at age 30). From that time forward, the new bone material
in the localized area continues a natural decline in BMD associated
with aging. Thus, the localized area of the bone has effectively
been remodeled from an osteoporotic state to a normal state.
[0160] The exact values shown in FIG. 10 are only representative
since the actual T-score values may vary from patient to patient.
The overall remodeling effect, however, would be expected to be
consistent from patient to patient. In other words, although the
exact BMD values may be somewhat greater or lesser than
illustrated, the remodeling would be consistent in the following:
the bone would exhibit a declining density to the point of reaching
an osteopenic or osteoporotic state; after implantation of a bone
regenerative material according to the methods of the invention,
there would be a rapid increase in BMD above a substantially normal
range; the BMD would decline to a substantially normal range; and
BMD would take up a rate of decline typically exhibited by healthy
bone material. Importantly, when the rate of normal decline is
again achieved after implantation, the decline begins from a point
of BMD typically exhibited in a normal, healthy individual at peak
BMD age. Thus, although BMD does continue to decline, the basis has
been changed to a normal density range and not an osteopenic or
osteoporotic density range. This is particularly important when the
procedures of the invention are carried out on women that have
already undergone menopause in that the rapid decline in BMD
associated with menopause will not be able to affect the newly
grown, dense bone. Depending upon the age of the female patient at
the time of treatment and the life span of the individual,
re-setting the nature of the bone in the localized area can
effectively alter the structure in the localized area such that the
localized area of the bone never achieves an osteopenic or
osteoporotic state again during the lifetime of the patient after
treatment. This ability to remodel osteopenic and osteoporotic bone
material to be substantially similar in structure to normal bone
material is further illustrated in the Examples provided below.
[0161] In addition to causing remodeling of the area of the
degenerative bone defined by the formed void, the invention also
can cause remodeling of the degenerative bone material in
substantially close proximity to the formed void. As described
above in relation to FIG. 8, the provision of the bone regenerative
material in the formed void can lead to a gradient effect wherein
not only is new bone material generated in the void that was filled
with the bone regenerative material, but new bone material also can
be formed in the area of the bone adjacent the formed, filled void.
Similarly, the invention can provide for remodeling of the
degenerative bone material in a localized area of a bone to the
extent that bone material having a T-score within the described
range can be formed in the area of the bone adjacent the formed
void. Thus, degenerative bone material in a localized area of a
bone that was not cleared and/or removed to form the void also can
undergo remodeling to be substantially normal. Specifically, newly
grown bone material may be graded in structure such that the
T-score of the bone material may increase from the area around the
void to the area within the void.
[0162] Also as already discussed above, a localized area of a
degenerative bone that is remodeled to be substantially identical
to normal bone preferably maintains the characteristics of the
remodeled state for an extended period of time. For example, the
remodeled, localized area of the bone can remain substantially
identical to normal bone for a time of at least about 1 year, at
least about 2 years, at least about 3 years, at least about 4
years, at least about 5 years, or even longer.
[0163] The invention can be utilized in relation to existing
surgical procedures, such as kyphoplasty or vertebroplasty. Unlike
these existing procedures, the methods used according to the
invention would be carried out on patients that are not currently
suffering from a vertebral fracture or otherwise weakened vertebra.
Rather, the present methods can be characterized as being carried
out prophylactically (i.e., to prevent a later fracture in a
degenerated bone). Specifically, in relation to the vertebrae, the
surgical method may be carried out on an osteoporotic vertebra that
is not fractured, but the surgical method used may be similar to a
surgical method employed in a traditional kyphoplasty. In such
embodiments, the methods of the invention may be as otherwise
described herein and be specifically carried out on one or more
vertebrae in a patient.
[0164] In other embodiments, the invention may be carried out on a
vertebra that is already fractured. Rather than carrying out a
traditional kyphoplasty, which would typically involve filling the
fractured area with a cement material, such as poly(methyl
methacrylate) (PMMA), the present invention can provide for
expanding or increasing the fracture as necessary to form a void
within the vertebra and filling the void with a bone regenerative
material. In specific embodiments, the vertebra treated according
to the invention is osteopenic or osteoporotic.
[0165] Thus, in certain embodiments, the invention can be described
as providing a method of restoring vertebral body height or
correcting angular deformity in a fractured vertebra (specifically
a fractured, osteopenic or osteoporotic vertebra) by causing
ingrowth of new bone material that is substantially identical to
normal bone. Specifically, the method may comprise forming a void
in the area of the fracture by mechanically clearing damaged or
degenerated bone material in and around the fracture and optionally
removing a content of the cleared bone material. The method further
can comprise at least partially filling the formed void with a bone
regenerative material such that new bone material is generated
within the void over time. Preferably, the new bone material that
is formed has a T-score indicating that the new bone material is
substantially identical to normal bone. In specific embodiments,
the T-score of the new bone material can be greater than -1, at
least -0.5, at least 0, at least 0.5, or at least 1.0 (or otherwise
within a normal range as described herein). Moreover, the invention
is advantageous in that the new bone material can remain
substantially identical to normal bone for a time of at least about
1 year (or more, as otherwise disclosed herein). Such time can be
measured from the time of new bone material generation in the area
of the bone where the void was formed and filled with the bone
regenerative material.
[0166] Although it is believed that the present invention provides
distinct advantages over other, known methods and materials for
treating osteoporosis and/or osteopenia, the present invention need
not necessarily be utilized to the exclusion of other treatments.
Specifically, the present methods of replacing degenerative bone
material with newly grown bone material that is native to the
patient and is substantially normal in bone quality may be used in
conjunction with pharmaceutical interventions recognized in the art
as beneficial for treating osteoporosis and/or osteopenia. For
example, treatment of patients according to the invention may be
carried out while the patient simultaneously is partaking of
pharmaceutical treatments, including hormone therapies (e.g.,
estrogen, SERM's, calcitonin, and recombinants, such as rPTH),
bisphosphonates, and antibodies (e.g., denosumab). Such
pharmaceutical treatments may be carried out prior to, concurrently
with, or after treatment according to the present invention.
Specifically, such treatments could be stopped for a specific
length of time prior to carrying out the inventive method.
Likewise, such treatments could be started a specific length of
time after carrying out the inventive method.
[0167] In another aspect, the present invention also provides
materials that can be used in methods for replacing degenerated
bone as described herein. Specifically, the various materials can
be pre-packaged in kit form. Thus, the inventive methods, or
specific steps in the methods, can be carried out using instruments
from a kit comprising various components. Exemplary materials that
may be provided in a kit according to the invention are described
below.
[0168] A kit according to the invention preferably would include a
drilling instrument, which could comprise a drill and/or a drill
bit, such as a cannulated drill bit. For example, a 5.3 mm OD
cannulated drill could be included. A kit also may include one or
more of a guide wire, a syringe, means for delivering a bone
regenerative material to a void, such as a large gauge injection
needle, a working cannula, a suction device, an aspiration device,
a tamp device, a curette, a reaming device, and means for bending
an instrument (such as a needle or a tamp) to a defined angle. In
some embodiment, the kit may include one or more tamp devices
(e.g., a debridement probe) having a head with a defined geometry.
In further embodiments, the kit may include a reaming device such
as the X-REAM.TM. Percutaneous Expandable Reamer (available from
Wright Medical Technology, Inc., Arlington, Tenn.) or a similar
instrument of suitable dimensions for use according to the methods
described herein. For example, any in situ expandable device
suitable for debriding bone or surgically creating a defect could
be used. In specific embodiments, the kit may include an amount of
a bone regenerative material suitable for filling a void in a
localized area of a bone.
[0169] Any materials useful for debridement of a bone can be
included in the inventive kit. For example, in addition to
curettes, rasps, trephines, and the like, one could use an
expanding device to create a space (expansion through balloon,
beaded bag, meshed bag, flexible wire, flexible and/or perforated
tubes, expanding whisk, rotating wire, expanding blade,
non-expanding flexible blade, or other similar devices). All of the
foregoing could be manually powered, or mechanized. They could be
constrained (e.g., a preformed blade stuck through an opening in a
tube), or unconstrained (e.g., a blade that is deformed through an
opening in the tube).
[0170] Specific examples of instruments that may be useful in
carrying out embodiments of the present invention, and thus may be
included in a kit according to the invention, are illustrated in
FIG. 11 through FIG. 19. FIG. 11 illustrates a tissue protector
that functions to provide a safe passage for other instruments
(e.g., a drilling instrument) from outside the body into the body
by protecting surrounding soft tissues from damage. The tissue
protector 110 includes a handle 111 and an elongated body 112 with
an open channel 113 therein. FIG. 12 illustrates a cannulated
obdurator, which can be used to centralize placement of a guidewire
(and may be passed through the interior of the tissue protector).
The obdurator 120 includes a flared head 121, an elongated body
122, and an open channel 123 therein. FIG. 13 illustrates the
cutting head section of a guidewire, which facilitates cutting into
the bone while maintaining the placement location in vivo. The
guidewire 130 includes a body 131 (shown in part) and the cutting
head 132, which is sufficient to cut into a bone without forming a
substantial drilled passage. FIG. 14 illustrates a drill, which is
used to create a passage or tunnel of defined dimension (e.g., 5.3
mm diameter) into the bone. The drill 140 includes a body 141 and a
cutting head 142. FIG. 15 illustrates a flexible working cannula.
Working cannulas function to provide safe passage of further
working instruments (e.g., debridement tools and syringe needles)
into the interior of the bone while protecting the surrounding
tissues. The illustrated cannula 150 includes a head 151, which is
shaped for attachment to further devices, a body 152, a cutting
head 153, and an open channel 154 therein. FIG. 16 illustrates a
further obdurator that may be used with a cannula, the obdurator
160 including a flared head 161 and an elongated body 16, and may
include a central channel (not shown). FIG. 17 illustrates a
debridement probe that is inserted into the bone to. 1 clear
degenerated bone material and form a void within the bone. The
probe 170 includes a handle 171, an elongated body 172, a head 173
(which may take on a particular dimension or shape for clearing of
bone material), and a curved portion 174. The presence of the
curved portion can be particularly advantageous to position the
head 173 for void formation of desired shape and volume. The curved
portion 174 may define an angle relative the body 172 of about
5.degree. to about 90.degree., about 10.degree. to about 75, about
10.degree. to about 60, about 15.degree. to about 50.degree., or
about 15.degree. about 45.degree.. FIG. 18 illustrates a
suction/irrigation device 180, which includes an elongate body 181
with an open channel 182 therethrough. The device also includes a
base 183 that accommodates an irrigation component (a syringe body
184, as illustrated) and a suction component (a port 185 as
illustrated) that may be connected to a vacuum source (not
illustrated). The device further includes a control valve 186 to
control application of suction and/or irrigation through the
channel 182. FIG. 19 illustrates another working cannula (a trough
working cannula 190) that includes a body 191 with a channel 192
therethrough.
[0171] A kit according to the invention may include one or more or
any combination of the illustrated instruments, or further
instruments that may be useful in carrying out a method according
to the invention. In certain embodiments, a kit would include all
instruments and bone regeneration material necessary to perform an
osteosupplementation procedure. This may include instruments
necessary to provide for skin incision, bone void creation,
debridement, mixing of the bone regeneration material, and delivery
of the bone regeneration material. Various combinations of the
following components particularly could be included into an
osteosupplementation kit according to the invention: scalpel,
tissue protector, cannulated obdurator, guidewire, drill, working
cannula, debridement probe, suction/irrigation device, bone
regenerative materials (including solid and liquid components for
forming a flowable material prior to implantation into the formed
void, preferably by injection), mixing apparatus (e.g., a mixing
chamber), syringe, and delivery needle (or other instruments useful
for delivering the bone regenerative material into the created
void.
[0172] In some embodiments, a kit may include only a minimal
content of components necessary to carry out the invention. For
example, minimally, a kit could include a debridement probe (e.g.,
a probe of specific bent geometry--such as an angle within any of
the ranges described herein) and/or a drill for forming a specific
sized entry channel and/or the bone regenerative materials. In
other embodiments, a cannulated obdurator also may be included. In
yet further embodiments, a working cannula could be included. In
still other embodiments, a suction/irrigation device could be
included. In still other embodiments, a tissue protector could be
provided. In yet another embodiment, a guidewire also could be
included. In still other embodiments, a mixing apparatus may be
included. In another embodiment, a syringe and delivery needle may
be included. Even further instruments, as may be evident to the
skilled person with the benefit of the present disclosure, could be
included in a kit according to the present invention.
[0173] In addition to any of the above described components, a kit
according to the invention can include an instruction set that
instructs how to use the kit components to treat a patient
suffering from a degenerative bone condition. For example, the
instruction set may provide instructions for using a scalpel to
make an access to the bone to be treated, using a tissue protector
within the incision to protect surrounding tissue, using a
guidewire or guide pin to form an initial entry path into the bone,
using a drill to form a channel into the interior of the bone,
using a debridement tool to clear degenerated bone material, using
a suction tool to remove cleared bone material, mixing of the bone
regenerative material (if necessary), using a syringe to inject the
bone regenerative material into the formed void, using an
irrigation device to clean the tissue area, and using closures to
close the tissue access incision. Similar instructions could be
included in relation to any combination of instruments included in
a specific kit. Further, the instructions may be in any suitable
form (e.g., written (such as a manual, pamphlet, one or more
written sheets, etc.) or digital media (such as CD, DVD, flash
drive, memory card, etc.).
EXPERIMENTAL
[0174] The present invention is more fully illustrated by the
following examples, which are set forth to illustrate the present
invention and provide full disclosure, and are not to be construed
as limiting thereof.
Example 1
Resorption Characteristics of Tri-Phasic Bone Regenerative
Material
[0175] An accelerated model illustrating the resorption
characteristics of a tri-phasic bone regenerative material was
carried out using pre-cast and weighed 4.8 mm.times.3.2 mm pellets
of the bone regenerative material that is commercially available
under the name PRO-DENSE.RTM.. The test was designed to illustrate
the changes over time in the bone regenerative material for
facilitating controlled in-growth of new bone material. The
accelerated in vitro model is approximately six times faster than
the resorption seen in vivo in a canine model, and the resorption
rate of the in vitro model is even faster in relation to human
models.
[0176] To begin the evaluation, the pellets were immersed in
distilled water. For daily testing, the pellets were removed from
the water, dried, and weighed to determine percent mass remaining.
The pellets were placed in fresh aliquots of distilled water after
measurements were taken. To analyze microscopically, the pellets
were embedded, cross sectioned and analyzed using scanning electron
microscopy (SEM) at 35.times. magnification.
[0177] The initial state of the bone regenerative material is shown
in FIG. 7a. The pellet is shown at 4 days in vitro in FIG. 7b
(which would be expected to correspond to the state at about 24
days in vivo). There is an initial burst of calcium sulfate
dissolution from the surface of the pellet, which exposes an outer
layer of fine brushite crystals and larger TCP granules (bright
white in the SEM images). The brushite forms a diffusion barrier
that slows the rate of CaS04 dissolution. At 8 days in vitro
(approximately 48 days in vivo) the procession of dissolution is
seen in FIG. 7c, and it is observed that the brushite crystals on
the exterior of the pellet (those that were first exposed) become
less dense, indicating that the brushite is also dissolving. FIG.
7d shows the pellet at 12 days in vitro (approximately 72 days in
vivo), and it can be seen that the relatively dense region of
brushite that surrounds the intact portion of the pellet moves
inward as dissolution continues. Finally, complete calcium sulfate
dissolution is seen in FIG. 7e as the TCP granules form an evenly
distributed scaffold after the majority of the CaS04 and brushite
have dissolved. It is likely that some of the brushite remains
attached to the TCP and acts to hold the granules together.
Example 2
Comparative Fracture Resistance in Osteoporotic Bone Before and
after Void Formation and Filling with Bone Regenerative
Material
[0178] To evaluate the effect on fracture susceptibility
immediately after performing a procedure according to the
invention, cadaver studies were carried out using ten matched pairs
of osteopenic or osteoporotic proximal femora. Initial DEXA scans
were carried out at the femoral neck and Ward's area, and the
T-scores for all tested bones were less than or equal to -2.0,
which was indicative of the bone material being in an osteopenic or
osteoporotic condition at the time of the testing. The matched
pairs were the right and left femur from the same cadaver. In each
test, a defect was created in one femur and filled with
PRO-DENSE.RTM. graft material. The radiographs in FIG. 20 and FIG.
21 show, respectively, insertion of a debridement probe used in
creation of the void in the proximal femur and the graft material
in place (dark area) filling the formed void. The contralateral
femur was left intact as a control. After allowing time for the
graft material to set, each proximal femur in the matched set was
loaded in compression at 20 mm/sec until failure was reached.
[0179] Test results showed no significant difference in peak load
between the proximal femur treated according to the invention and
the control (intact) femur. The mean peak load observed across the
ten pairs of matched cadaver femurs tested is shown in graph
provided in FIG. 22. As seen therein, all proximal femurs fractured
at a peak load of about 8,000 N. Thus, the tests indicated there
was no clinical risk related to decreased strength in a proximal
femur having undergone a procedure according to the invention
wherein a void was formed and filled with a bone regenerative
material. Specifically, this indicated that there was no increased
risk of fracture associated with the inventive methods immediately
after carrying out the procedure, even in the absence of any
extraneous support materials, such as pin, inserts, or the
like.
Example 3
In Vivo Canine Study Using Bone Regeneration Material in a Large,
Critically Sized, Longitudinal Proximal Humerus Model
[0180] A study was carried out to evaluate the I 3 and 26 week in
vivo performance of bone regeneration materials in a critically
sized canine longitudinal proximal humerus defect model. The
biologic response, namely new bone formation, implant degradation,
and biocompatibility, were evaluated qualitatively through radio
graphs and histology slides.
[0181] In this study, 16 skeletally mature canine subjects each
received bilateral longitudinal cylindrical defects (13 mm
OD.times.50 mm) in their proximal humeri. All subjects received
OSTEOSET.RTM. calcium sulfate bone graft substitute pellets (Wright
Medical Technology, Inc., Arlington Tenn.) in one of the two
defects. The contralateral defects were treated with either an
injected bolus of flowable PRO-DENSE.RTM. graft material or
preformed pellets of the PRO-DENSE.RTM. material, both of which are
commercially available. Half of each experimental group underwent
evaluation after 13 weeks and the other half after 26 weeks. An
additional 10 humeri from five unoperated dogs were obtained for
the purpose of generating comparative data on normal bone taken
from the same location. All samples were tested for compressive
strength and histomorphology.
[0182] A limited cranial approach to the greater tubercle of the
left and right humerus was performed on each subject through
incision and retraction of the cliedobrachialis muscle. Drilling
and reaming were used to create the defect of the size noted above
in each test site. The formed defects were then backfilled with one
of the test materials, alternating materials between the left and
right sides to randomize the defect site to the material used.
Pellets were tightly packed into each defect with forceps. The
bolus injectable was prepared by combining liquid and powder
components in a vacuum bone cement mixing apparatus (Summit
Medical; Gloucestershire, UK). After mixing for 30 seconds under a
20-23'' Hg vacuum, the material was transferred to a 20 cm.sup.3
syringe and the bolus (approximately 6 cm.sup.3) was delivered to
the defect through an 11-gauge, 6 cm.sup.3, ported, jamshidi-type
needle using a backfilling technique. The wounds were then
closed.
[0183] Biomechanical testing was conducted to determine the
ultimate compression strength and modulus of the newly formed bone
using the mechanical test specimen obtained from test sites in the
subjects. Testing was performed on an Instron Model 8874
servo-hydraulic mechanical testing system, equipped with a 1 kN
Dynacell Dynamic Load Cell and Bluehill Materials Testing Software
(system, load cell, and software: Instron Corp., Canton, Mass.). A
compression subpress (Wyoming Test Fixtures, Inc., Laramie, Wyo.,
serial no. WTF-SP-9), ASTM D695 conformant, was modified such that
the spherical cap was removed, and the loading rod was machined to
screw into the actuator of the test frame. Testing also was carried
out to evaluate the amount of new bone material formed in each test
specimen. Immediately prior to testing, the specimen length and the
diameter of each specimen at half the specimen length were
determined (+/-0.01 mm).
[0184] Specimens were subjected to unconfined, uniaxial compression
tests at a rate of 0.5 mm/min until obvious specimen failure was
observed, a significant drop in the load curve, or 30% strain of
the specimen was achieved. Specimen ultimate compressive strength
and modulus were calculated from the resulting stress-strain curves
by the software. Nine mechanical specimens from five additional
dogs were cored and tested in the same manner for use as
comparative "normal bone" specimens.
[0185] Stress vs. strain diagrams were produced for each specimen
using the Bluehill Materials Testing Software, and the ultimate
compressive strengths were determined as the stress at which the
stress-strain diagram resulted in a slope of zero. Ultimate
compressive strength (MPa) and modulus of elasticity, E (MPa) for
the specimens are shown below in Table 1. Specimens where the
OSTEOSET.RTM. material was used in two separate tests, and the
average values obtained in each test (I and II) are included.
Values for normal bone are included as a comparative. Table 2
similarly shows new bone and residual material area fraction at 13
and 26 weeks. These average values were determined through the
standard point counting technique.
TABLE-US-00001 TABLE 1 Ultimate Compressive Modulus of Elasticity,
E Test Group Strength (MPa) (SD) [n] (MPa) (SD) [n] Normal Canine
1.38 (0.66) [8] 117.04 (71.51) [8] Bone PRO-DENSE .RTM. 5.29 (2.61)
[5] 283 (217) [5] Flowable (13 wks) PRO-DENSE .RTM. 2.19 (0.41) [5]
150 (73.5) [5] Flowable (26 wks) PRO-DENSE .RTM. 1.49 (0.85) [3]
67.2 (50.5) [3] Pellets (13 wks) PRO-DENSE .RTM. 1.73 (0.96) [3]
118.4 (107.7) [3] Pellets (26 wks) OSTEOSET .RTM. 0.90 (0.44) [5]
40.8 (35.6) [5] Pellets I (13 wks) OSTEOSET .RTM. 0.47 (0.46) [4]
15.8 (23.6) [5] Pellets I (26 wks) OSTEOSET .RTM. 1.49 (na)
[1].sup. 24.1 (30.9) [3] Pellets II (13 wks) OSTEOSET .RTM. 0.73
(0.42) [3] 44.1 (59.9) [3] Pellets II (26 wks)
TABLE-US-00002 TABLE 2 Area Fraction of New Area Fraction of
Residual Test Group Bone (SD) [n] Material (SD) [n] Normal Canine
0.145 (0.024) [5] NA Bone PRO-DENSE .RTM. 0.394 (0.047) [5] 0.065
(0.033) [5] Flowable (13 wks) PRO-DENSE .RTM. 0.180 (0.034) [5]
0.015 (0.020) [5] Flowable (26 wks) PRO-DENSE .RTM. 0.200 (0.052)
[3] 0.025 (0.011) [3] Pellets (13 wks) PRO-DENSE .RTM. 0.178
(0.049) [3] 0.009 (0.000) [3] Pellets (26 wks) OSTEOSET .RTM. 0.186
(0.066) [3] 0.008 (0.007) [3] Pellets I (13 wks) OSTEOSET .RTM.
0.158 (0.055) [3] 0.002 (0.003) [3] Pellets I (26 wks) OSTEOSET
.RTM. 0.173 (0.043) [5] 0.000 (0.000) [5] Pellets II (13 wks)
OSTEOSET .RTM. 0.112 (0.026) [5] 0.000 (0.000) [5] Pellets II (26
wks)
[0186] As seen from the above data, the flowable PRO-DENSE.RTM.
material evidenced an effect on bone formation and mineralization
at 13 weeks exceeding that seen for normal bone (5.29 MPa vs. 1.38
MPa). This phenomenon decreased by the 26 weeks point where the
average values for compressive strength and modulus of elasticity
more closely matched that of normal bone. This phenomenon of
remodeling back to normal bone density is consistent with the bone
density values in Table 2, wherein bone area fraction in the 13
weeks tests for the flowable PRO-DENSE.RTM. material was
significantly higher than normal bone density, but the values in
relation to the flowable PRO-DENSE.RTM. material were much closer
to normal bone density at 26 weeks. These findings were consistent
with high levels of radiodensity seen in the 13 weeks radio graphs
of the specimens treated using the flowable PRO-DENSE.RTM.
material. The specimens treated with the pelletized PRO-DENSE.RTM.
material did not demonstrate the same degree of bone formation seen
in the defects treated with the flowable material. It is important
to note, however, that the pelletized material still resulted in
formation of bone with properties substantially similar to and even
greater than the properties seen with the normal bone specimens at
both the 13 week and 26 weeks time points.
[0187] The average values of the mechanical properties for the
OSTEOSET.RTM. pellet treated defects were lower than those of
normal bone; however, the differences were not determined to be
statistically significant. It also should be noted that the
relatively large standard deviations, as provided above, are very
common with this type of mechanical testing.
Example 4
Generation of New, Dense Bone Material in a Created Void that is
Filled with Bone Regeneration Material
[0188] To evaluate formation of new bone growth in an osteoporotic
patient, the left femur of an 80 year old human female was treated
according to the present invention. Specifically, a void was formed
in the proximal femur and filled with PRO-DENSE.RTM. graft
material. FIG. 23 provides a radio graph of the proximal femur
prior to injection of the graft, and FIG. 24 provides a CT image of
the same area of the proximal femur prior to injection. FIG. 25
provides a radiograph of the proximal femur intra-operative showing
the graft material in place in the proximal femur.
[0189] The table below provides T-score and Z-score values for the
left femur prior to undergoing the procedure. The table further
provides the same values for the right femur (untreated) to be used
as a comparative.
TABLE-US-00003 TABLE 3 (Time Zero) Left Femur (pre-treatment) Right
Femur (control) Region T-Score Z-Score T-Score Z-Score Neck -2.7
-0.4 -2.8 -0.5 Trochanter -2.7 -0.9 -2.9 -1.1 Intertrochanter -3.4
-1.5 -3.5 -1..7 Total Hip -3.3 -1.3 -3.5 -1.4 Ward's Area -3.1 -0.1
-2.7 0.3
[0190] Post surgery, the patient was evaluated at multiple
intervals to determine changes in density in the localized area of
the bone treated according to the invention and changes with time
in the control. Table 4 below shows test values at one week post
treatment. As seen therein, the treated femur already exhibits
dramatic improvements in density while the control femur exhibits
osteoporotic values similar to the pre-treatment values.
TABLE-US-00004 TABLE 4 (One Week Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score Z-Score T-Score Z-Score
Neck -1.1 1.2 -3.0 -0.6 Trochanter 0.1 1.9 -2.9 -1.1
Intertrochanter -0.8 0.7 -3.6 -1.7 Total Hip -0.8 1.3 -3.6 -1.5
Ward's Area 7.0 10 -3.0 0.0
[0191] FIG. 26 provides a radiograph of the treated, left femur at
6 weeks post treatment. As seen therein, the graft is beginning to
be resorbed by the body as the bone in the localized area remodels.
Table 5 provides the test values from the DEXA scans at 6 weeks
post treatment.
TABLE-US-00005 TABLE 5 (Six Week Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score Z-Score T-Score Z-Score
Neck 0.2 2.5 -2.8 -0.4 Trochanter -0.3 1.5 -2.8 -1.0
Intertrochanter -1.5 0.3 -3.5 -1.7 Total Hip -1.1 1 -3.5 -1.4
Ward's Area 5.9 8.9 -2.8 0.2
[0192] FIG. 27 provides a CT image of the treated, left femur at 12
weeks post treatment. The presence of the graft material (light
colored mass) is evident and shows further resorption. Table 6
provides the DEXA scan values at 12 weeks post treatment, and Table
7 provides the DEXA scan values at 18 weeks post treatment.
TABLE-US-00006 TABLE 6 (12 Week Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score Z-Score T-Score Z-Score
Neck -0.2 2.2 -3.2 -0.9 Trochanter -0.4 1.4 -3.1 -1.3
Intertrochanter -2.0 -0.2 -3.8 -2.0 Total Hip -1.6 0.5 -3.8 -1.7
Ward's Area 4.3 7.3 -3.2 -0.2
TABLE-US-00007 TABLE 7 (18 Week Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score Z-Score T-Score Z-Score
Neck -0.7 1.6 -2.8 -0.4 Trochanter 0.9 0.9 -3.0 -1.2
Intertrochanter -2.0. -0.2 -3.7 -1.9 Total Hip -1.7 0.4 -3.7 -1.6
Ward's Area 2.9 5.9 -2.9 0.1
[0193] FIG. 28 provides a CT image of the treated, left femur at 24
weeks post treatment. The presence of the graft material (light
colored mass) is significantly reduced as the graft material
continues to be resorbed and replaced by dense bone material. Table
8 provides the DEXA scan values at 24 weeks post treatment, and
Table 9 provides the DEXA scan values at 12 months post
treatment.
TABLE-US-00008 TABLE 8 (24 Week Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score Z-Score T-Score Z-Score
Neck -0.9 1.5 -2.9 -0.6 Trochanter -0.7 1.1 -3.1 -1.3
Intertrochanter -2.2 -0.3 -3.8 -2.0 Total Hip -1.8 0.3 -3.8 -1.7
Ward's Area 1.8 4.8 -3.2 -0.2
TABLE-US-00009 TABLE 9 (12 Month Post Treatment DEXA Scores) Left
Femur Right Femur (control) Region T-Score T-Score Neck -1.0 -3.0
Trochanter -1.2 -3.1 Intertrochanter -2.7 -4.0 Ward's Area 1.3
-3.2
Example 5
Increases in BMD in Localized Areas of Osteoporotic Bone Following
Void Formation and Filling with Bone Regenerative Material
[0194] Testing was carried out on 12 human patients, all of whom
were deemed to be osteoporotic according to the World Health
Organization (WHO) definition. In each patient, one femur was
treated according to the present invention, and the contralateral
side remained untreated for the purpose of comparison.
[0195] First, to obtain a baseline, BMD was measured in both hips
via DEXA. Thereafter, in the test site in the single hip of each
patient, a void was formed in the proximal femur by removing a
section of the osteoporotic bone, and the void was filled with
PRO-DENSE.RTM. graft material similar to the manner illustrated in
Example 4. The patients carried out normal daily activities with
follow-up scans taken at 1, 6, 12, 18, 24, 52, 78, and 104 weeks.
Note that all 12 patients were evaluated up to 24 weeks, eight
patients were tested up to 52 weeks, three patients were tested up
to 78 weeks, and two patients were tested for the full 104
weeks.
[0196] In each follow-up examination (as well as in the baseline
measurement), DEXA scan T-scores for each patient were recorded for
the femoral neck and for the total hip. As can be seen in reference
to FIG. 29, T-Scores at the femoral neck for all patients were less
than -2 at baseline; however, each patient exhibited a significant
increase in T-score at the one-week mark (ranging from about 1 to
almost 6). After this initial rapid increase, T-scores for each
patient gradually returned to a normal range for healthy bone
(using the average 30 year old as a reference). Within as little as
12 weeks, a few patients had Tscores drop to near or slightly below
zero. Even for patients tested out to 104 weeks, Tscores continued
to be near normal (although below zero). Similar trends were seen
in relation to T-scores in the total hip, as shown in FIG. 30.
Although the rapid increase in T-score was not as great as in the
femoral neck, initial increases were roughly proportional (i.e.,
each patient exhibiting an increase of about three points or
greater one week after undergoing the procedure). Again, T-scores
in the total hip decreased with progression of the test period;
however, the final score taken for each patient shows a remodeling
to a condition that is significantly improved from the baseline
score. Even greater improvements were seen in the Ward's area of
the treated hips. As seen in FIG. 31, within one week, T-scores for
most patients rose to the range of 5 to as much as 17. Again, the
practice of the invention in this area of the hip of the treated
patients again resulted in remodeling of the bone to be of a normal
quality (i.e., T-score of great than zero in this patients).
[0197] The effective, significant increase in bone quality at the
treated site after undergoing a replacement procedure according to
the invention is further illustrated in FIG. 32, which shows
average improvement in BMD at the femoral neck across the patient
population at the various intervals. In addition to the T-scores
(which illustrate the absolute change in bone quality from
osteoporotic bone to normal bone), the comparative mean changes
shown in FIG. 32 confirm that the inventive procedures can remodel
the basic bone structure of the treated area by removing bone of
low BMD and facilitating growth of new bone that has a
significantly greater BMD. As seen in FIG. 32, within one week
after undergoing the inventive procedure, BMD relative to the
control (which is the average BMD from the contralateral, untreated
hip in each patient) had increased by approximately 150%.
Thereafter, up to about 24 weeks, the relative increase in BMD at
the femoral neck shows a relatively rapid remodeling toward the BMD
of normal bone (BMD 120% greater than control at 6 weeks, 96%
greater than control at 12 weeks, and 74% greater than control at
24 weeks). From this point forward, the BMD began to slowly
decrease in a more normalized manner. At the two-year evaluation,
the two patients remaining in the study still exhibited a mean BMD
increase in the femoral neck of 35% relative to the control.
[0198] Similar results are seen in FIG. 33, which shows average
improvement in BMD in the total across the patient population at
the various intervals. As seen therein, within one week after
undergoing the inventive procedure, BMD relative to the control
(which is the average BMD from the contralateral, untreated hip in
each patient) had increased by approximately 68%. Thereafter, up to
about 24 weeks, the relative increase in BMD across the total hip
shows a relatively rapid remodeling toward the BMD of normal bone
(BMD 54% greater than control at 6 weeks, 45% greater than control
at 12 weeks, and 36% greater than control at 24 weeks). From this
point forward, the BMD began to slowly decrease in a more
normalized manner. At the two-year evaluation, the two patients
remaining in the study still exhibited a mean BMD increase across
the total hip of 18% relative to the control. Because of this
increase in BMD throughout the testing period, it would be expected
that the treated area of the bone would exhibit increased
compressive strength (as evidenced in the canine study described
above) and would have an increased resistance to fracture because
of the increased BMD and increased compressive strength. There were
no appreciable changes in BMD measurements from baseline in the
untreated sides (although FIG. 33 suggests a gradual decrease in
BMD across the total hip in the untreated sides from 20 weeks
forward).
[0199] Again, even greater results were seen in relation to BMD
increases in the Ward's area, as illustrated in FIG. 34. Within one
week after treatment according to the invention, average BMD had
risen by 400%. A gradual reduction is seen over time -355% greater
BMD at 6 weeks, 295% greater BMD ad 12 weeks, and 220% greater BMD
at 24 weeks. From the period cover 52 weeks after treatment to 104
weeks after treatment, BMD for the treated hips in the Ward's area
ranged from about 140% to about 200% greater than in the control
hip.
Many modifications and other embodiments of the invention will come
to mind to one skilled in the art to which this invention pertains
having the benefit of the teachings presented in the foregoing
descriptions and associated drawings. Therefore, it is to be
understood that the invention is not to be limited to the specific
embodiments disclosed and that modifications and other embodiments
are intended to be included within the scope of the appended
claims. Although specific terms are employed herein, they are used
in a generic and descriptive sense only and not for purposes of
limitation.
* * * * *
References