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Long-term mechanical properties of a novel low-modulus bone cement for the treatment of osteoporotic vertebral compression fractures

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In spite of the success of vertebroplasty (VP) and balloon kyphoplasty (BKP), which are widely used for stabilizing painful vertebral compression fractures, concerns have been raised about use of poly(methyl methacrylate) (PMMA) bone cements for these procedures since the high compressive modulus of elasticity (E) of the cement is thought to be one of the causes of the higher number of adjacent-level vertebral fractures. Therefore, bone cements with E comparable to that of cancellous bone have been proposed. While the quasi-static compressive properties of these so-called “low-modulus” cements have been widely studied, their fatigue performance remains underassessed. The purpose of the present study was to critically a commercial bone cement (control cement) and its low-modulus counterpart on the basis of quasi-static compressive strength (CS), E, fatigue limit under compression-compression loading, and release of methyl methacrylate (MMA). At 24 h, mean CS and E of the low-modulus material were 72% and 77% lower than those of the control cement, whereas, at 4 weeks, mean CS and E were 60% and 54% lower, respectively. The fatigue limit of the control cement was estimated to be 43–45 MPa compared to 3–5 MPa for the low-modulus cement. The low-modulus cement showed an initial burst release of MMA after 24 h followed by a plateau, similar to many other commercially available cements, whereas the control cement showed a much lower, stable release from day 1 and up to 1 week. The low-modulus cement may be a promising alternative to currently available PMMA bone cements, with the potential for reducing the incidence of adjacent fractures following VP/BKP.
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Long-term mechanical properties of a novel low-modulus bone cement for the
treatment of osteoporotic vertebral compression fractures
C. Robo, C. Öhman-Mägi, C. Persson
PII: S1751-6161(21)00124-7
DOI: https://doi.org/10.1016/j.jmbbm.2021.104437
Reference: JMBBM 104437
To appear in: Journal of the Mechanical Behavior of Biomedical Materials
Received Date: 8 November 2020
Revised Date: 20 February 2021
Accepted Date: 26 February 2021
Please cite this article as: Robo, C., Öhman-Mägi, C., Persson, C., Long-term mechanical properties
of a novel low-modulus bone cement for the treatment of osteoporotic vertebral compression fractures,
Journal of the Mechanical Behavior of Biomedical Materials (2021), doi: https://doi.org/10.1016/
j.jmbbm.2021.104437.
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© 2021 Published by Elsevier Ltd.
Long-term mechanical properties of a novel low-modulus bone cement for the
treatment of osteoporotic vertebral compression fractures
C. Robo, C. Öhman-Mägi, C. Persson
*
Division of Applied Materials Science, Department of Materials Science and
Engineering, Uppsala University, Uppsala, Sweden
*Corresponding author: Cecilia Persson, Division of Applied Materials Science,
Department of Materials Science and Engineering, Uppsala University, Uppsala,
Sweden. Email: Cecilia.Persson@angstrom.uu.se
Abstract
In spite of the success of vertebroplasty (VP) and balloon kyphoplasty (BKP), which
are widely used for stabilizing painful vertebral compression fractures, concerns have
been raised about use of poly(methyl methacrylate) (PMMA) bone cements for these
procedures since the high compressive modulus of elasticity (E) of the cement is
thought to be one of the causes of the higher number of adjacent-level vertebral
fractures. Therefore, bone cements with E comparable to that of cancellous bone have
been proposed. While the quasi-static compressive properties of these so-called “low-
modulus” cements have been widely studied, their fatigue performance remains
underassessed. The purpose of the present study was to critically a commercial bone
cement (control cement) and its low-modulus counterpart on the basis of quasi-static
compressive strength (CS), E, fatigue limit under compression-compression loading,
and release of methyl methacrylate (MMA). At 24 h, mean CS and E of the low-
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modulus material were 72% and 77% lower than those of the control cement,
whereas, at 4 weeks, mean CS and E were 60% and 54% lower, respectively. The
fatigue limit of the control cement was estimated to be 43-45 MPa compared to 3-5
MPa for the low-modulus cement. The low-modulus cement showed an initial burst
release of MMA after 24 h followed by a plateau, similar to many other commercially
available cements, whereas the control cement showed a much lower, stable release
from day 1 and up to 1 week. The low-modulus cement may be a promising
alternative to currently available PMMA bone cements, with the potential for
reducing the incidence of adjacent fractures following VP/BKP.
Keywords: PMMA bone cement, low-modulus, elastic modulus, fatigue,
vertebroplasty and kyphoplasty, adjacent fractures.
1. Introduction
Vertebroplasty (VP) and balloon kyphoplasty (BKP) are widely used treatments for
patients who suffer persistent pain due to osteoporotic vertebral compression fractures
[1, 2]. These techniques involve the injection of a bone cement, usually based on
poly(methyl methacrylate) (PMMA), into the fractured vertebra which relieves the
pain, and in some cases may restore its height. However, it is believed that the change
in load distribution in the spinal segment, attributed to the high stiffness of the cement
compared to that of the osteoporotic vertebral bone, results in new fractures in the
vicinity of the treated vertebrae [3-5]. The risk of these fractures has been reported to
be significant (12-20 %) [5-8], with a large number of them occurring at a level
adjacent to the treated vertebra (36-67 %) [3-6, 9-11]. It might be possible to reduce
the occurrence of adjacent-level fractures by using cements that a have a lower
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compressive modulus of elasticity (E) [12-17], in the range of that of the cancellous
bone in the vertebral body (10-900 MPa) [18-21]. Schulte et al. [22] comparatively
assessed the performance of a low-modulus silicon-based bone cement (VK100) and
standard PMMA bone cement in a human ex vivo vertebral augmentation model, and
concluded that the stiffness of the augmentation material had a significant effect on
the stiffness of the augmented vertebrae. Similar results have been attained for
PMMA bone cements modified with linoleic acid (LA), which are another promising
low-modulus alternative whose functional properties have been thoroughly
investigated [12-14, 23].
After injection into a fractured vertebral body, the bone cement will experience
dynamic cyclical loading, mainly in compression [24-26] and therefore, such loading
condition is most relevant to replicate in an in vitro setting. Fatigue properties of
standard bone cements alone have already been reported [27-32], as well as studies
that evaluated cements in an in vitro or ex vivo augmented models [33-36]. Moreover,
unreacted monomer release is a recognised unavoidable effect after implantation of
PMMA-based bone cements, which is rarely reported but is believed to have an effect
on the initial mechanical properties of the material [13, 37].
To the authors’ knowledge, there are only five literature reports available on the
fatigue performance of low-modulus bone cements [27, 38-41]. Kolb et al. [41]
investigated the fatigue fracture force (FFF) (defined as the force, during cyclical
loading, at which the deformation experienced a sudden increase) of a commercial VP
cement, Vertecem™ V+ (E= 1937 MPa) and its low-modulus counterpart,
Vertecem™ V+, which contained 8 mL of fetal bovine serum (E= 955 MPa). The
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standard and low-modulus cements were injected into multi-segmental cadaveric
fractured osteoporotic lumbar vertebrae and subjected to cyclic loading (4 Hz),
inducing coupled flexion-compression forces. Both groups of cements stabilized and
restored the fractured vertebrae to a level at least as high as that of the intact spine,
with comparable FFF ((FFF
unmodified cement
= 1760 ± 251 N; FFF
modified
= 1583 ± 407 N);
FFF of native vertebrae (FFF
native
= 1440 ± 590 N)). Harper et al. [39] investigated the
fatigue properties of bone cement based on n-butyl methacrylate monomer (PEMA-
nBMA) whose E was 700 MPa. Fatigue tests were performed by subjecting the
specimens to uniaxial cyclic tension-tension loads (2 Hz), where the upper stress level
corresponded to 30-70% of the tensile strength of each bone cement composition. The
fatigue limit of this cement was determined to be 12 MPa at 10
5
-10
6
cycles to failure.
Boger et al. [38, 40] carried out dynamic compression tests (4.5 MPa, 14 400 cycles at
4 Hz) in demineralized water at room temperature on augmented biopsy specimens of
an experimental VP cement, porous hyaluronic acid-modified Vertecem (E= 480
MPa). None of the specimens failed. Robo et al. [27] determined the fatigue limit of
the commercial low-modulus cement Resilience
®
, under compressive-compressive
loading. Resilience
®
did not exhibit lower E until 2 weeks after immersion in an
aqueous solution and had a fatigue strength in air of 31 MPa at 5 million cycles (2 Hz,
tests started after at least 2 weeks of storage in PBS at 37°C).
There are three shortcomings of the literature on the characterization of low-modulus
cements are: First, in most studies, the quasi-static compressive properties were not
determined after ageing in a biosimulating medium even though it has been reported
that test conditions (in particular, temperature) have a significant influence on the
mechanical properties of PMMA bone cements [42, 43]; Second, there are no studies
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in which the fatigue properties were determined, in such medium, under relevant
loading scenarios (namely, compression-compression (2 MPa to 5 MPa, at a
frequency of 2 Hz); Third, there are no studies in which the aforementioned
conditions have been applied to low-modulus cement compared to its higher modulus
counterpart.
The purpose of the present study was to compare a novel experimental low-modulus
PMMA bone cement (whose properties are attained by modification with small
amounts of linoleic acid) intended for use in VP/BKP with its higher modulus
counterpart, through (i) determination of its CS after ageing in PBS at 37°C for times
between 1 day and 4 weeks; (ii) estimation of its fatigue limit from compression-
compression tests performed in PBS at 37°C; and (iii) determination of the monomer
released up to 7 days from both formulations in comparison with a commercial low-
modulus cement.
2. Materials & Methods
2.1. Materials
A commercial VP bone cement, V-Steady
TM
(G21 S.r.l., San Possidonio, Italy) hereby
referred to as VS, was used as control to be modified with the additive, linoleic acid
(LA). The modified (low-modulus) cement is referred to as VS-LA. For both cements,
the powder is comprised of pre-polymerized PMMA beads, benzoyl peroxide, and
zirconium dioxide (ZrO
2
) and the liquid is comprised of methyl methacrylate
monomer, N,N-di-methyl-p-toluidine, and hydroquinone. The only difference in
composition between the two cements is that, for the low-modulus cement, 12 vol%
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of LA was pre-blended with the liquid. The concentration of LA was based on
preliminary studies in which it was found that that concentration gave a cement with
an E that was in the range of that of vertebral cancellous bone (10-900MPa)[18-21]. A
summary of the materials and tests is presented in Table 1.
Table 1. Summary of the experimental design and number of specimens tested.
Material
Number of specimens tested (n), pre-conditioning, and test conditions
Pre-conditioned in
PBS, at 37 °C, for 24
h, 2 weeks, or 4
weeks
Pre-conditioned in
PBS at 37 °C for a
minimum of 14 days
prior to testing Monomer release in
water at 37°C
Quasi-static
compression testing
in air at RT
a
Fatigue testing in PBS
at 37 °C
VS
Commercial, higher-modulus
bone cement (V-Steady)
6
b
23 12
VS-LA
Experimental low-modulus
bone cement
6 25 12
Resilience
low-modulus bone cement
previously available in the
market
n/a
c
n/a
c
12
a
One supplementary test was carried out after specimens had been pre-conditioned in PBS, at 37 °C for
2 weeks.
b
Number of specimens tested
c
Material was discontinued at the time of preparation of this manuscript, which resulted in these
experiments not being possible to complete.
2.2. Cement specimen preparation
The VS was prepared according to the manufacturer’s instructions for use by mixing
the powder and the liquid manually in a glass mortar with a spatula for 30 to 45 s at
room temperature. The VS-LA was prepared by adding 12 vol% linoleic acid in the
liquid and mixing it until dissolved in a centrifuge tube and then mixing the powder
and the modified liquid manually in glass mortar with a spatula for 30 to 45 s at room
temperature. The cement dough was transferred into metal moulds (6 mm and 12 mm
in diameter and height, respectively) in agreement with ISO 5833 [44]. The
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specimens were allowed to set in air at 37 °C for 1 h before being stored in PBS at
37°C.
2.3. Quasi-static compression testing
Quasi-static compressive properties of the cements were determined in air at room
temperature, after storage in PBS at 37 °C, for 24 h, 2 weeks, and 4 weeks. One
supplementary test was carried out in a biobath with PBS at 37 °C on specimens
stored in PBS at 37 °C for 2 weeks. All tests were performed using a universal testing
machines (AGS-X; Shimadzu, Kyoto, Japan or MTS Mini Bionix; MTS Systems
Corp., Eden Prairie, MN, USA) at a crosshead speed of 20 mm/min, as stipulated in
ISO 5833 [44]. E and compressive strength (CS) of the cements were determined
from the load versus-displacement curves, following the protocol detailed in ISO
5833 [44].
2.4. Fatigue testing
Specimens having surface flaws (>0.25 mm in diameter) and/or internal defects
(>1 mm in diameter) were rejected [45]. Accepted specimens were stored in PBS at
37 °C for a minimum of 14 days, as stipulated in ASTM F 2118 [45]. Tests were
performed in a universal testing machine (MTS Mini Bionix), using the up-and-down
method [46, 47], as previously described [26], due to this being an efficient method;
however, with the exception that the present tests were carried out on specimens
immersed in a circulating biobath containing PBS at 37 °C. A compressive preload of
20 N was applied to a specimen, followed by a constant-amplitude cyclical
compression-compression load at a frequency of 2 Hz. A test was stopped when either
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the specimen failed (loss of 15% of its original height [46]) or upon completion of 2
million cycles, herein defined as run-out. The applied loads corresponded to
maximum stress of between 40 and 80 MPa for the unmodified cement specimens and
between 2 and 25 MPa for the modified cement specimens. The first specimen was
tested at a stress level of two-thirds of the quasi-static compression strength after 2
weeks, and, thereafter, steps (up or down) depending on whether the specimen
survived to run-out or not of 2.5 MPa were used. A minimum of three specimens had
to survive at a particular stress level for it to be defined as the fatigue limit. Additional
testing was performed at additional stress levels (40 MPa for VS and 3.75MPa for
VS-LA) to determine the fatigue limit from an Olgive-type fit[48]. A Wölher
diagram, or S-N
f
curve (S= stress amplitude in MPa; N
f
= number of cycles to failure)
was plotted, as suggested in previous studies [48, 49] and the Olgive equation was
fitted to the results (Equation 1) in order to confirm the up-and-down test:
Equation 1
=  +
1 + log
where A, B, C, and D are cement constants, S is the applied stress amplitude (MPa),
and N
f
being the number of cycles to failure. The lower and upper asymptotes of the
S-N
f
curve correspond to A and B, respectively. C is the number of cycles at the
inflection point of the curve while D is correlated to the slope at the inflection
point[48]. The Levenberg-Marquardt non-linear regression method [50, 51] (Curve
Fitting Toolbox™ in MATLAB
®
versionR2012a; The MathWorks
®
Inc., Natick, MA,
USA) was used to obtain estimates of the cement constants.
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2.5. Determination of monomer release
Extracts were prepared as recommended by ASTM F451 [52], for monomer analysis
of cured bone cement. Commercial low-modulus cement Resilience
®
was also tested,
in addition to VS and VS-LA, for comparison. Rectangular specimens (thickness= 3 ±
0.1 mm, width= 5 ± 0.1 mm, length= 15 ± 0.1 mm) of standard and low-modulus
cements were prepared as described in subsection 2.2 and were allowed to cure at 30
± 1 min in air at room temperature. After that, the specimens were placed in 5 mL of
Type II reagent water at 37 °C for 1 h, 24 h and 7 days. Afterwards, 2 mL aliquots
from each solution were introduced in a headspace vial and closed hermetically. The
vials were incubated at 80 °C for 30 min. Monomer analysis was performed by
headspace gas chromatography-mass spectrometry (HS-GC/MS), by injecting 0.1 mL
of the vapor phase through a special syringe kept at 85 °C. A Trace GC gas
chromatograph with Triplus headspace autosampler coupled to a DSQII mass
spectrometer (ThermoFisher Scientific, Waltham, MA) was used. A TRB-624 column
(60m × 0.32 mm × 1.8 µm) with a helium flow of 1.8 mL/min was used for
separation. The oven temperature program consisted of a 2 min hold at 60°C,
followed by an 8 °C/min ramp to 220°C and a 5 °C/min hold at 220°C. The
temperatures of the injector, interface, and ionization source were set at 220, 260, and
200 °C, respectively. The concentration of monomer released in the extracts was
determined from integration of the corresponding peak area in the headspace
chromatogram.
2.6. Statistical analysis
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IBM SPSS Statistics v.22 (IBM Corp., Armonk, NY, USA) was used to perform
statistical analyses. The Shapiro-Wilk test was used in combination with normality
plots to assess normality of the data. Thereafter, the Levene test was used to test for
homogeneity of variances. Since the latter was significant in some cases, Welch’s
robust ANOVA was thereafter applied, in conjunction with the post hoc Tamhane test
to evaluate statistical differences between groups for E, CS and released monomer. A
difference was considered significant if p < 0.05.
3. Results and Discussion
The compressive properties of the cements are presented in Table 2. VS showed a
non-statistically significant decrease in E (p > 0.999) and CS (p > 0.96) when stored
over time at physiological conditions up to 4 weeks. On the other hand, VS-LA
showed a statistically significant increase in E (p < 0.001) and CS (p < 0.003) when
stored over time at physiological conditions up to 4 weeks. At 24 h, the E and CS of
VS-LA were 77% and 72% lower than those of VS and these differences were
statistically significant (p < 0.001). Whereas, at 4 weeks, the E and CS of VS-LA
were 54% and 60% lower than those of VS and these differences were statistically
significant (p 0.01). The compressive properties of VS-LA, at 4 weeks, were in the
upper range of healthy vertebral cancellous bone [21, 53]. Furthermore, the
complementary test, which consisted in testing the 2-weeks group in PBS at 37 °C
indicated that CS was 12% lower (p < 0.04) and E was 89% higher (p < 0.001) for
VS, and that CS was 32% lower (p < 0.001) and E was 19% higher (p < 0.001) for
VS-LA, with respect to the same cements when tested in air at room temperature.
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These differences, depending on the testing conditions, have previously been reported
[42, 43, 54] and were expected.
Table 2. Quasi-static compressive properties of V-steady
TM
(VS) and V-steady
TM
modified with
linoleic acid (VS-LA) after 24 h, 2 weeks and 4 weeks. All specimens were conditioned in PBS at
37°C up until they were tested. All compressive tests were carried out in air at room temperature except
for one supplementary test which was done in PBS at 37 °C of the 2 weeks groups. Six specimens per
group and time point were tested in compression.
VS cement VS-LA cement
Time Point CS
(±SD) E
(±SD) CS
(±SD) E
(±SD)
24 h
(tested in air) 100.7
(± 3.1) 2140.4
(± 128.8) 28.3
(± 5.1) 494.7
(± 51.8)
2 weeks
(tested in air) 96.3
(± 5.2) 2075.2
(± 114.3) 30.5
(± 0.8) 803.3
(± 65.8)
2 weeks
(tested in PBS at 37 °C) 84.4
(± 3.5) 3918.6
(± 215.5) 20.9
(± 0.5) 951.8
(± 39.4)
4 weeks
(tested in air) 91.5
(± 16.5) 2070.0
(± 103.1) 36.5
(± 0.6) 947.8
(± 64.4)
A different development of CS and E over time between VS and VS-LA can be
pointed out; the compressive properties of VS remained stable with a slight non
statistically significant tendency to decrease, whereas those of VS-LA tended to
increase. As briefly described by Nottrott et al.[54], two mechanisms controlling the
compressive properties of a bone cement may take place, competing with one another,
from the start of the conditioning of the bone cement in physiological-like conditions:
i) continuous polymerization and ii) plasticizing effects. Since monomer conversion
in acrylic bone cements is limited by vitrification [37], residual monomer will
continue to slowly diffuse, and to react with remaining free radicals, which in turn
increases the overall molecular weight contributing towards higher CS and E. On the
other hand, PBS at 37 °C, residual monomer, and residual linoleic acid may all act as
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plasticizers and contribute to lower CS and E. Nottrott et al. [42] reported an increase
in CS and E after 1 week followed by a decrease of both properties onwards over a
period of 1 year, for Palacos
®
R cement, which contains 67% less ZrO
2
radio-
opacifier than VS. This was attributed to water uptake [42]. In the case of VS, since
no 1-week time point was available, only a slight decrease in CS and E was observed
over the entire period, which can be attributed to the plasticizing effect of the PBS, at
37 °C, absorbed by the material during conditioning [42, 54, 55]. In contrast, VS-LA
exhibited an increase in CS and E over time which can be explained by the continuing
delayed polymerization, which due to presence of the linoleic acid that reduces glass
transition temperature, results in an earlier vitrification and hence a larger amount of
residual monomer than in VS [13, 37]. This residual monomer will continue to
polymerize and leach out and contributes to the higher CS and E after 4 weeks. The
effect and mechanism of action of linoleic acid which explains the low-modulus of
VS-LA with respect to VS has already been addressed elsewhere [13, 56-58].
Three VS cement samples (out of 3) survived a dynamic compressive stress amplitude
of 42.5 MPa until runout and 2 specimens (out of 4) survived a compressive stress
amplitude of 45.0 MPa (Figure 1); hence the fatigue limit was estimated to be
between 42.5 and 45.0 MPa. The VS-LA cement specimens survived compressive
stress amplitudes between 2.5 and 5 MPa until runout (Figure 1), particularly 1
specimen (out of 4) survived a stress amplitude of 5.0 MPa and 3 specimens (out of 3)
a stress amplitude of 2.5 MPa. An additional three samples were tested at 3.75 MPa,
which all survived to run-out. Hence, the fatigue limit of VS-LA was estimated to be
between 3.75 and 5.0 MPa.
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Figure 1. Data from the “up-and-down method” for VS and VS-LA where [×
××
×] represents failed
specimens and [ο
οο
ο] represents surviving specimens at 2 million cycles.
The S-N
f
results obtained and fit of the Olgive equation to them are presented in
Figure 2, with the estimated values of the Olgive equation parameters being given in
Table 3.
Table 3. Estimated Olgive equation parameters for VS and VS-LA cements. The 95% confidence
intervals are indicated in parentheses.
A [MPa] B [MPa] C D
VS 45.0 76.1 3.5 5.2
95% confidence
interval (35.6 ; 54.4) (71.1 ; 81.1) (2.7 ; 4.3) (-2.3 ; 12.8)
VS-LA 4.7 22.8 2.7 16.5
95% confidence
interval (3.8 ; 5.7) (20.3 ; 25.4) (2.6 ; 2.8) (5.2 ; 27.7)
The parameter B is an estimate of CS of the cement, with the results being within the
range obtained in the quasi-static tests. The parameter A is an estimate of the fatigue
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limit of the cement, with the result for VS-LA cement being within the range obtained
using the up-and-down fatigue test method. The fit of the Olgive equation to the
results obtained using VS specimens (Figure 2) was poorer (R
2
= 0.92; SSE= 358.33;
RMSE= 3.95) than that obtained using VS-LA (R
2
= 0.94; SSE= 78.29; RMSE= 1.74).
This and the more unusual shape of the best-fit curve to the VS data may be explained
in terms of the free volume which is less in VS compared to other standard cements,
and especially compared to VS-LA due to e.g. the presence of the relatively large
linoleic acid molecules. Considering that free volume can help dissipate internal
heating, less free volume will result in lower fatigue strength at high stress amplitudes
rather than showing a plateau. Nonetheless, the estimated fatigue limit of VS cement
is on the order of 40-50 MPa, which is consistent with the estimate obtained using the
up-and-down fatigue test method.
Figure 2. Fatigue test results (VS and VS-LA) and the Olgive equation fit to these results for VS and
VS-LA. N
f
is the number of cycles to failure; the dashed curves correspond to the 95% confidence
limits.
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As expected, VS-LA cement exhibited a significantly lower fatigue limit (4.7 MPa)
in PBS at 37 °C than its higher modulus counterpart, VS under compression-
compression; however, this is still three times higher than the intradiscal pressures
during normal daily activities [24, 59]. It is worth pointing out that at the time of the
submission of the present work, there is no commercially available low-modulus
PMMA-based bone cement. Resilience
®
, which is referred to in this and previous
work as a predicate device, has been removed from the market due to a need for re-
certification following the transition to a new regulatory framework for medical
devices used in the European Union (https://eumdr.com/). The fatigue limit of
Resilience
®
,
in air and at room temperature has been measured to be 31.0 MPa under
compression-compression [27]. However, the properties of this cement were are not
attained immediately but within 30 days as a result of a leaching process of one of its
components, poly(amino acid), which would result in this cement exhibiting higher
properties in the initial time points. Since the majority of adjacent vertebral fractures
occur within 1 to 4 months after vertebral augmentation [5, 60-62], a cement
displaying a lower modulus immediately could be beneficial. However, this remains
to be demonstrated in the clinical application.
The monomer release results are shown in Figure 3. The amounts of unreacted MMA
released from the VS and VS-LA cements were compared to that released from low-
modulus commercial bone cement, Resilience
®
. The monomer release from VS was
the lowest and remained almost constant throughout the 7-day test period, releasing
up to 116 mg/L of MMA, with no statistically significant difference between time
points (p > 0.98). A reason for this could be the lower free volume in this cement
compared to other standard cements, as mentioned earlier. VS-LA released higher
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amounts of monomer than VS, in agreement with previous studies [13, 27, 56]; the
monomer release from VS-LA consisted of an initial burst release (870 mg/L) that
was approximately 780% higher than that of VS (99 mg/L) after 1 day, followed by a
more stable but sustained release between day 1 and day 7 for a total release of 1125
mg/L compared to 118 mg/L for VS. There was a statistically significant difference
between the amount of monomer released from VS respect to VS-LA at each time
point (p < 0.001). Resilience
®
released the highest amount of monomer, behaving
similarly to VS-LA; however, the burst release occurred much earlier (5 h) with 778
mg/L followed by a more stable release of up to 1219 mg/L at 7 days. When
compared to other cements, VS-LA released less monomer [13, 27, 56]. López et al.
[13] reported concentrations of released monomer of approximately 120 mg/L and
750 mg/L at 24 h for regular Osteopal
®
V cement and its low-modulus counterpart
containing 1.5 wt%, (~6 vol%) of LA. Robo et al. [23] reported concentrations of
released monomer of 1627.8 mg/L and 2418.6 mg/L at 24 h for regular F20
®
and its
low-modulus counterpart containing 2vol% of LA. It is pointed out that in the present
work, extractions were done in water according to specification by ASTM F451-8
[52]. Even though the ions present in PBS might have an influence on the release
profile of MMA, the relative results presented are valid for the purpose of comparing
between VS, VS-LA and Resilience.
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Figure 3. Concentration of released MMA monomer from VS, VS-LA and Resilience
®
; n=12 per time
point.
Two limitations of this work are recognized. The first has to do with the number of
specimens used in the fatigue test and the monomer release test. In fatigue testing of
PMMA bone cement, it is recommended that at least 15 specimens be tested at a
given stress amplitude [45]. This was not feasible in the present study because of
limited supply of both cements. Monomer released was determined after only three
time points (1 h, 24 h, and 7 d). However, for both cements, the trends of the results
are clear. The second study limitation is that the mechanical test specimens did not
include supporting bony tissue. This is a limitation because once implanted, bone
cement will interdigitate with the surrounding tissue (bone and bone marrow),
forming a cement/bone construct, which has been shown to be able to support higher
loads than bone cement alone even when low-modulus cement is used [12, 13]. This
suggests that cement-only testing models may underestimate the performance of the
more relevant cement-bone composite. Therefore, an ex vivo fatigue study in an
osteoporotic cadaveric spine model, in physiologically relevant conditions, under
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compression-compression, would be a next appropriate step forward for long-term
biomechanical evaluation of VS-LA.
4. Conclusions
In this study, the quasi-static (CS and E) and dynamic (fatigue limit) compressive
properties and the monomer release profile of a novel low-modulus PMMA bone
cement proposed for use in VP/BKP (LA-modified PMMA bone cement) were
determined. After 24 h, the E and CS of the low-modulus material were 77% and 72%
lower than those of the control cement (VS), whereas after 4 weeks, the E and CS
were 54% and 60% lower, respectively. These quasi-static compressive properties of
the low-modulus cement are in the upper range of that of cancellous bone, which
could prevent the incidence of subsequent adjacent vertebral fractures. On the other
hand, the fatigue limit of the low-modulus cement was 91% lower than that of the
control, although still above the stresses experimented in the spine in vivo.
Furthermore, a more relevant in vitro model that utilizes bone/cement constructs in
order to consider the effect of cement-bone interdigitation would be recommended for
future mechanical testing, to give a better representation of cement performance in a
clinical setting. The low-modulus cement exhibited an initial burst release of MMA
monomer, which was 780% higher than that of the control after 24 hours, yet is
comparable to that of another low-modulus cement, and lower than that of many
standard cements on the market. The experimental low-modulus cement may be a
promising substitute to currently available vertebral augmentation PMMA bone
cements with potential for reducing the incidence of adjacent fractures following
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VP/BKP. While the present in vitro results are promising, the long-term performance
of the low-modulus cement remains to be evaluated in clinical trials.
Acknowledgements
This research study is part of the SOFTBONE project and has received funding from
EIT Health (Project nr 20519). EIT Health is supported by the European Institute of
Innovation and Technology (EIT), a body of the European Union that receives
support from the European Union´s Horizon 2020 Research and Innovation
Programme. Funding from the Royal Swedish Academy of Sciences (Kungliga
Vetenskapsakademien) is also gratefully acknowledged. The authors extend their
gratitude to Dr. Susan Peacock and Dr. Alejandro López for proof-reading the
manuscript and to Dr. Anders Persson and Mr. Yijun Zhou for their assistance with
MATLAB.
Competing interests
C.P. is co-owner of Inossia AB, which owns a patent on a low-modulus cement. Co-
authors C.R. and C.Ö-M. have no conflicts of interest.
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1(1)
CONFLICT OF INTERESTS
Uppsala, 04 March 2021
Conflict of Interests
Cecilia Persson is co-owner of Inossia AB, which owns a patent
of low-modulus cement. Co-authors Céline Robo and Caroline
Öhman have no conflict of interest.
Cecilia
Persson
Professor
Department of Materials
Science and Engineering
The Ångström Laboratory
Box 35
751 03 Uppsala
SWEDEN
Phone:
+46 18 471 79 11
Cecilia.Persson@
angstrom.uu.se
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... These so called low-modulus PMMA cements have been developed for osteoporotic patients in particular [20]. One such material is a linoleic acid modified PMMA (LA-PMMA), where the additive of linoleic acid essentially works as a plasticizer [21][22][23][24]. For the low modulus PMMA developed for vertebroplasty, 12 vol% LA has mostly been used [23,24]. ...
... One such material is a linoleic acid modified PMMA (LA-PMMA), where the additive of linoleic acid essentially works as a plasticizer [21][22][23][24]. For the low modulus PMMA developed for vertebroplasty, 12 vol% LA has mostly been used [23,24]. The LA-PMMA could have a potential also in discoplasty, for overcoming the mismatch in endplate-PMMA modulus and for reducing the risk for endplate fracture and subsidence. ...
... In the present study, a CS of 93 ± 7 MPa and 39 ± 1 MPa was obtained after 4 weeks, for V-steady and LA12, respectively. The same materials (LA12 and V-steady) and test conditions, previously gave a CS of 92 ± 17 MPa and 37 ± 1 MPa [23,24]. In contrast, there was a substantial difference between the E-modulus obtained in the current study as compared to previous ...
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Cement discoplasty has been developed to treat patients with advanced intervertebral disc degeneration. In discoplasty, poly(methylmethacrylate) (PMMA) bone cement is injected into the disc, leading to reduced pain and certain spinal alignment correction. Standard PMMA-cements have much higher elastic modulus than the surrounding vertebral bone, which may lead to a propensity for adjacent fractures. A PMMA-cement with lower modulus might be biomechanically beneficial. In this study, PMMA-cements with lower modulus were obtained using previously established methods. A commercial PMMA-cement (V-steady®, G21 srl) was used as control, and as base cement. The low-modulus PMMA-cements were modified by 12 vol% (LA12), 16 vol% (LA16) and 20 vol% (LA20) linoleic acid (LA). After storage in 37 °C PBS from 24 h up to 8 weeks, specimens were tested in compression to obtain the material properties. A lower E-modulus was obtained with increasing amount of LA. However, with storage time, the E-modulus increased. Standard and low-modulus PMMA discoplasty were compared in a previously developed and validated computational lumbar spine model. All discoplasty models showed the same trend, namely a substantial reduction in range of motion (ROM), compared to the healthy model. The V-steady model had the largest ROM-reduction (77%), and the LA20 model had the smallest (45%). The average stress at the endplate was higher for all discoplasty models than for the healthy model, but the stresses were reduced for cements with higher amounts of LA. The study indicates that low-modulus PMMA is promising for discoplasty from a mechanical viewpoint. However, validation experiments are needed, and the clinical setting needs to be further considered.
... However, the study found that the amount of methyl methacrylate (MMA) released reached a peak after 24 h, which was significantly higher than that of traditional PMMA bone cement (Robo et al., 2018a). In addition, in another study of low-modulus bone cement (VS-LA) obtained by adding 12 wt% LA to commercial bone cement (V-Steady), the early release of MMA monomers from VS-LA was also observed, the peak of which was much higher than the monomer level released by VS over the same period (Robo et al., 2021). In other work, PMMA was mixed with sodium hyaluronate solutions of different volume fractions to prepare porous low-modulus bone cement (Boger et al., 2008). ...
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The incidence of osteoporotic vertebral compression fractures (OVCFs) increases gradually with age, resulting in different degrees of pain for patients, even possible neurological damage and deformity, which can seriously affect their quality of life. Vertebral augmentation plays an important role in the surgical treatment of OVCFs. As the most widely used bone cement material, polymethyl methacrylate (PMMA) offers inherent advantages, such as injectability, ease of handling, and cost-effectiveness. However, with its application in the clinic, some disadvantages have been found, including cytotoxicity, high polymerization temperature, high elastic modulus, and high compressive strength. To improve the mechanical properties and the biological performance of conventional PMMA bone cement, several studies have modified it by adding bioceramics, bioglass, polymer materials, nanomaterials, and other materials, which have exhibited some advantages. In addition, other alternative materials, such as calcium phosphate, calcium sulfate, and calcium silicate cements—including their modifications—have also been explored. In this review, we examined the existing research on the side-effects of conventional PMMA bone cement, modified PMMA bone cement, and other alternative materials designed to improve properties in OVCFs. An overview of various modified bone cements can help further scientific research and clinical applications.
... Vertebral compression fractures often occur at the midthoracic (T7-T8) spine and the thoracolumbar junction (T12-L1) [13,14]. The clinical treatment of vertebral compression fractures includes conservative treatment (such as physical therapy and spinal orthosis), vertebroplasty (such as minimally invasive percutaneous vertebroplasty and kyphoplasty) and vertebral implantation (such as SpineJack ® and Vertebral Body Stent ® ) [15]. In clinical treatment of vertebroplasty, bone cement is commonly used. ...
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Fatigue life of Simplex P bone cement was tested at three different stress amplitudes by using specimens produced by two different mixers. Fatigue life data showed high variability in all instances. Statistical analysis showed that fatigue life was not affected by the type of mixer. Analysis of fracture surfaces showed that fatigue life variability could be attributed to the presence of defects, such as bubbles and mixing defects. Both Weibull and Tiryakioğlu distributions provided excellent fits to the fatigue life data. Moreover, the Gumbel parameters for fatigue initiator size data estimated in the Tiryakioğlu distribution agreed closely with fractographic measurements.
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Purpose The aim was to determine effects of diluent monomer and monocalcium phosphate monohydrate (MCPM) on polymerization kinetics and volumetric stability, apatite precipitation, strontium release and fatigue of novel dual-paste composites for vertebroplasty. Materials and methods Polypropylene (PPGDMA) or triethylene (TEGDMA) glycol dimethacrylates (25 wt%) diluents were combined with urethane dimethacrylate (70 wt%) and hydroxyethyl methacrylate (5 wt%). 70 wt% filler containing glass particles, glass fibers (20 wt%) and polylysine (5 wt%) was added. Benzoyl peroxide and MCPM (10 or 20 wt%) or N-tolyglycine glycidyl methacrylate and tristrontium phosphate (15 wt%) were included to give initiator or activator pastes. Commercial PMMA (Simplex) and bone composite (Cortoss) were used for comparison. ATR-FTIR was used to determine thermal activated polymerization kinetics of initiator pastes at 50–80°C. Paste stability, following storage at 4–37°C, was assessed visually or through mixed paste polymerization kinetics at 25°C. Polymerization shrinkage and heat generation were calculated from final monomer conversions. Subsequent expansion and surface apatite precipitation in simulated body fluid (SBF) were assessed gravimetrically and via SEM. Strontium release into water was assessed using ICP-MS. Biaxial flexural strength (BFS) and fatigue properties were determined at 37°C after 4 weeks in SBF. Results Polymerization profiles all exhibited an inhibition time before polymerization as predicted by free radical polymerization mechanisms. Initiator paste inhibition times and maximum reaction rates were described well by Arrhenius plots. Plot extrapolation, however, underestimated lower temperature paste stability. Replacement of TEGDMA by PPGDMA, enhanced paste stability, final monomer conversion, water-sorption induced expansion and strontium release but reduced polymerization shrinkage and heat generation. Increasing MCPM level enhanced volume expansion, surface apatite precipitation and strontium release. Although the experimental composite flexural strengths were lower compared to those of commercially available Simplex, the extrapolated low load fatigue lives of all materials were comparable. Conclusions Increased inhibition times at high temperature give longer predicted shelf-life whilst stability of mixed paste inhibition times is important for consistent clinical application. Increased volumetric stability, strontium release and apatite formation should encourage bone integration. Replacing TEGDMA by PPGDMA and increasing MCPM could therefore increase suitability of the above novel bone composites for vertebroplasty. Long fatigue lives of the composites may also ensure long-term durability of the materials.
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Study design: Retrospective cohort study. Purpose: To evaluate the incidence and risk factors for early adjacent vertebral fractures following balloon kyphoplasty (KP). Overview of literature: KP is a safe and effective treatment for pain alleviation in patients with osteoporotic vertebral compression fractures (OVCF). However, some studies have reported that the risk of newly developed fractures increases at the adjacent vertebra after KP. Methods: Total 123 consecutive patients with painful OVCF who underwent KP were enrolled from January 2009 to June 2016. Early adjacent vertebral fractures were defined as new fractures that had developed within 3 months after surgery. Sex, age, body mass index (BMI), bone mineral density (BMD), vertebral height, kyphotic angle, Visual Analog Scale score, cement amount, and leakage were evaluated as risk factors for adjacent vertebral fractures. Only cement leakage into the disc space was included in this study. Results: Early adjacent vertebral fractures were identified in 20 (16.2%) of the 123 patients. The mean time to diagnosis of fractures was 1.7±0.7 months after KP. The average patient age was 78.0±0.7 years, average BMI was 23.06±3.83 kg/m2 , and mean BMD was -3.61±1.22 g/m2 . Cement leakage was present in 16 patients, and fractures developed in 11 (68.7%). In contrast, fractures developed in nine patients (8.2%) without cement leakage. There were no significant differences in terms of age, BMI, BMD, kyphotic angle, or vertebral body height ratio between the fracture and control groups. Conclusions: Cement leakage into the disc increased the risk of early adjacent vertebral fractures after balloon KP.
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Background Image-guided elastoplasty is an innovative method for percutaneous vertebral augmentation with a silicone elastomeric material. Our aim was to evaluate its technical success, safety and efficacy as well as the rate of secondary fractures. Methods Nineteen patients (13 women and 6 men, age 72 ± 10 years, mean ± standard deviation) underwent elastoplasty between 2010 and 2016. A total of 33 vertebrae were treated. A total of 2–6 mL of silicone-based elastomeric polymer material (VK100) was used. Visual analogue scale (VAS) and Oswestry disability index (ODI) pain scores were used. Results In all cases, it was possible to complete the procedure (technical success 100%). No major complications occurred. In 6/19 (31.5%) patients, asymptomatic leakage of the material was observed during the procedure. Full pain recovery was obtained in 18/19 (94%) patients. One patient with a painful angioma did not experience any change in symptoms. VAS and ODI were significantly reduced after the procedure, from 7.9 ± 1.1 to 0.7 ± 1.4 and from 79.6 ± 12% to 9.9 ± 14% respectively (p < 0.001 for both comparisons). After vertebroplasty, 14 of 15 patients (93%) removed the brace and 16/19 (84%) completely stopped using any drugs for pain relief (p < 0.001 for both pre-procedure versus post-procedure comparisons). At a mean follow-up time of 26.5 ± 28.1 months (median 8.7 months, range 6–69 months), no secondary fracture occurred. Conclusion Taking into consideration the relatively small sample size, image-guided elastoplasty seems to be a safe procedure providing effective pain control over time.
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Background: Percutaneous vertebroplasty (PVP) is widely used to treat osteoporotic vertebral compression fractures (OVCFs). The influence of timing (early vs. late) of PVP on the development of adjacent vertebral fractures (AVF) has rarely been discussed. Objective: This study aimed to compare the incidence of AVF among patients who received early PVP (= 30 days after symptom onset, EPVP) or late PVP (> 30 days after symptom onset, LPVP) in the thoracolumbar region (T10 to L2) after a 1-year follow up. Study design: A retrospective cohort study. Setting: Department of Orthopedic, an affiliated hospital of a medical university. Methods: Patients who had single-level, T-score = -2.5 of lumbar bone mineral density (BMD), primary OVCF in the thoracolumbar region (T10 to L2) and who received PVP between July 2012 and June 2014 were included in the study. They were divided into early PVP and late PVP groups according to the interval between symptom onset and treatment. The risk factors associated with subsequent AVFs were analyzed. Results: Of the 225 patients reviewed, 124 met the criteria and were followed for a minimum of 1 year. Eleven patients (14.1%) in the EPVP group (n = 78) and 18 patients (39.1%) in the LPVP group (n = 46) experienced an AVF during the first year following vertebroplasty. Outcomes were significantly better in patients with higher bone mineral density, lower cement volume, and without cement leakage (P < 0.01). Cox regression indicated an increase risk for AVF for LPVP, with an adjusted hazard ratio of 6.08 (95% confidence interval: 2.50-14.81). Limitation: The incidence of AVFs could be over estimated due to this being a retrospective study with a small case number and lack of either biomechanical study of intra-vertebral cement distribution by times to support the result. Conclusions: Compared with later interventions, PVP performed within 30 days after fracture development may be associated with a lower risk of adjacent fractures in the thoracolumbar region. Key words: Percutaneous vertebroplasty, osteoporosis, osteoporotic vertebral compression fracture, adjacent vertebral fracture.
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Introduction: Over the last several decades, both kyphoplasty (PKP) and vertebroplasty (PVP) have been used for pain relief in patients with osteoporotic vertebral compression fractures (OVCF). The purpose of our study was to use citation analysis to identify and review the top 100 most-cited publications regarding PKP and PVP. Methods: All databases of the Web of Science were searched using the keywords "kyphoplasty" and "vertebroplasty". All publications with greater than 100 citations were identified and the results were ranked in descending order of citations. The 100 most-cited publications were included for analysis. Results: A total of 6,271 publications on PKP and PVP were identified. The number of citations of the 100 most-cited studies ranged from 735 to 109, with a mean of 225.3 citations per study. The most productive period was 2001-2010, which produced 79 out of the top 100 publications. Thirteen journals published these 100 studies, with the journal Spine publishing the largest number (23) of studies. Most of the identified papers originated in the United States, with France and Switzerland found to be the next most heavily represented countries of origin out of the eleven countries that produced them. Most of the studies focused on treatment of OVCF, followed by pathologic fractures caused by tumors. Conclusion: We identified the 100 most-cited publications on PKP and PVP and performed a bibliometric analysis characterizing distinguishing features of these studies. This list can help guide clinical decision-making and future research directions as clinicians and researchers continue to explore these controversial therapeutic techniques.
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Poly(methyl methacrylate) (PMMA) bone cement is used to anchor the majority of total joint replacements (TJRs). Many brands of cement are used, both with and without the addition of antibiotics to reduce the risk of infection. The present study involved determination of various parameters in tensile fatigue loading: (1) energy absorbed (U) vs number of loading cycles (N) and creep strain (ε) vs N, during fatigue tests on specimens of an antibiotic-containing cement (SmartSet GHV) and a plain cement (CMW1) and(2) crack length (a) vs fatigue loading cycles (N) and crack growth rate (da/dN) vs Mode I stress intensity factor range (ΔKI), during Fatigue Crack Propagation (FCP) tests. In the fatigue tests, four different sample types (round, machined; round, directly moulded; rectangular, machined, and rectangular, directly moulded) and tension-tension loading were used. In the FCP tests, compact tension specimens under tension-tension loading were used. It was found that there were limited effects of sample type, except at the highest stress levels, but that these two cements had different rates of crack propagation. These differences were reflected in the fracture surfaces with SmartSet GHV showing accumulation of opacifier around the particles and crack progression around the initial beads, while for CMW1 the opacifier was evenly distributed and the cracks went through the initial beads.
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Objectives: Balloon Kyphoplasty (BKP) for vertebral compression fractures (VCFs) in cancer patients is more challenging than for osteoporotic ones. Cord compressions are frequent and the incidence of complications ten-fold greater. Polymethylmetacrylate (PMMA) is the gold standard material for BKP but has disadvantages: exothermic reaction, short working time, rapid solidification, absence of osteoconduction. VK100 is a mixture of Dimethyl Methylvinyl siloxane and Barium Sulphate. It is elastic, adhesive to bone, leaves 30 min before solidification without exothermic reaction, and shows a stiffness close to the intact vertebrae. The surgical procedure, called elastoplasty, is similar to a BKP. Clinical results obtained with this new silicone in pathological VCFs have been investigated. Patients and methods: 41 cancer patients with symptomatic VCFs (70 vertebral bodies), underwent percutaneous and open elastoplasties. Post-operative leakages, pulmonary embolism (PE) and adjacent fractures were carefully evaluated with neuroimaging. KPS, VAS and Dennis Pain Score were calculated pre- post-operatively and at the last follow-up. Results: The mean volume of silicone inserted in each vertebra was 3.8 cc. Complications included seven leakages (17%), two asymptomatic PE (4.3%) and 3 post-operative adjacent fractures (7.3%). Median follow-up was 29 months. A significant improvement was observed in KPS, VAS and Dennis Pain Score (p < .0001). The 1-yr survival rate was 76.9%. Conclusions: Elastoplasty appears a safe and effective palliative treatment of VCFs in oncologic patients. Useful qualities of VK100 are the lack of exothermic reaction and the wider working window. The influence of biomechanical properties of silicone on reduction of adjacent level fractures requires further investigations.
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Statement of significance: The benefits of using linoleic acid to reduce the stiffness of poly(methyl methacrylate) bone cement has been demonstrated previously, with the in vitro and in vivo response of the modified cement in small animals reported as comparable to the base cement. However, biocompatibility evaluation of modified cement in large animal models for future clinical use has yet to be performed. In this study, modified and unmodified cements were injected into bone defects created in sheep. We showed that the inflammatory response of the modified cement was similar to the base cement, allowing remodelling of the bone surrounding the implant. This demonstrates the potential of low-modulus PMMA cement in the field of bone augmentation.