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An ex-vivo model for the
biomechanical assessment of
cement discoplasty
Salim Ghandour
1
, Konstantinos Pazarlis
2
,
3
, Susanne Lewin
1
,
Per Isaksson
4
, Peter Försth
2
and Cecilia Persson
1
*
1
Division of Biomedical Engineering, Department of Materials Science and Engineering, Uppsala
University, Uppsala, Sweden,
2
Department of Surgical Sciences, Uppsala University Hospital, Uppsala,
Sweden,
3
Stockholm Spine Center, Stockholm, Sweden,
4
Division of Applied Mechanics, Department
of Materials Science and Engineering, Uppsala University, Uppsala, Sweden
Percutaneous Cement Discoplasty (PCD) is a surgical technique developed to
relieve pain in patients with advanced degenerative disc disease characterized
by a vacuum phenomenon. It has been hypothesized that injecting bone
cement into the disc improves the overall stability of the spinal segment.
However, there is limited knowledge on the biomechanics of the spine
postoperatively and a lack of models to assess the effect of PCD ex-vivo.
This study aimed to develop a biomechanical model to study PCD in a
repeatable and clinically relevant manner. Eleven ovine functional spinal
units were dissected and tested under compression in three conditions:
healthy, injured and treated. Injury was induced by a papain buffer and the
treatment was conducted using PMMA cement. Each sample was scanned with
micro-computed tomography (CT) and segmented for the three conditions.
Similar cement volumes (in %) were injected in the ovine samples compared to
volumes measured on clinical PCD CT images. Anterior and posterior disc
heights decreased on average by 22.5% and 23.9% after injury. After treatment,
the anterior and posterior disc height was restored on average to 98.5% and
83.6%, respectively, of their original healthy height. Compression testing
showed a similar stiffness behavior between samples in the same group. A
decrease of 51.5% in segment stiffness was found after injury, as expected. The
following PCD treatment was found to result in a restoration of
stiffness—showing only a difference of 5% in comparison to the uninjured
state. The developed ex-vivo model gave an adequate representation of the
clinical vacuum phenomena in terms of volume, and a repeatable mechanical
response between samples. Discoplasty treatment was found to give a
restoration in stiffness after injury. The data presented confirm the
effectiveness of the PCD procedure in terms of restoration of axial stiffness
in the spinal segment. The model can be used in the future to test more
complex loading scenarios, novel materials, and different surgical techniques.
KEYWORDS
spine, mechanical properties, discoplasty, bone cement, disc degeneration, papain, ex-
vivo
OPEN ACCESS
EDITED BY
Dennis E. Anderson,
Beth Israel Deaconess Medical Center,
United States
REVIEWED BY
Rizwan Arshad,
Royal Military College of Canada,
Canada
Chloé Techens,
Institut Mines-Télécom, France
*CORRESPONDENCE
Cecilia Persson,
cecilia.persson@angstrom.uu.se
SPECIALTY SECTION
This article was submitted to
Biomechanics,
a section of the journal
Frontiers in Bioengineering and
Biotechnology
RECEIVED 09 May 2022
ACCEPTED 27 July 2022
PUBLISHED 02 September 2022
CITATION
Ghandour S, Pazarlis K, Lewin S,
Isaksson P, Försth P and Persson C
(2022), An ex-vivo model for the
biomechanical assessment of
cement discoplasty.
Front. Bioeng. Biotechnol. 10:939717.
doi: 10.3389/fbioe.2022.939717
COPYRIGHT
© 2022 Ghandour, Pazarlis, Lewin,
Isaksson, Försth and Persson. This is an
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Frontiers in Bioengineering and Biotechnology frontiersin.org01
TYPE Original Research
PUBLISHED 02 September 2022
DOI 10.3389/fbioe.2022.939717
Introduction
Approximately 70%–80% of all adults will suffer from back
pain at some point in their lifetime (Frymoyer, 1988;Andersson,
1998). Degenerative disc disease is a common source of back pain
(Marcolongo et al., 2017;Wilke and Volkheimer, 2018).
Depending on the severity, it can also lead to degenerative
scoliosis and spinal stenosis (Pritchett and Bortel, 1993;
Ploumis et al., 2007). While some patients can be treated by
non-surgical means such as physiotherapy, others need surgical
intervention to reduce pain and restore functionality for daily
living (Rubin, 2007).
Spinal fusion is the gold standard surgical technique for
treating degenerative disc disease (Phillips et al., 2013). In the
United States, around 455,500 fusion procedures were conducted
in 2018, with an increasing procedure count each year (Martin
et al., 2019;McDermott and Liang, 2021). It is considered the
most costly operating room procedure in the United States
totaling $14.1 billion in aggregated costs (McDermott and
Liang, 2021). The procedure involves the use of
instrumentation such as screws, rods, and cages to fixate the
adjacent vertebrae and thus promote bony fusion (Marcolongo
et al., 2017). However, for certain patient groups with underlying
comorbidities, the risks of the procedure may outweigh the
potential benefits (Sola et al., 2018). This is especially the case
for elderly patients with advanced degenerative disc disease and
associated deformity where the surgical option, a lengthy
instrumented fusion, carries a risk of adverse events of 60%—
resulting in increased risks for the patient’s well-being (Scheufler
et al., 2010;Sola et al., 2018).
For the reasons above, a low-cost, minimally invasive option
to spinal fusion has been sought-after for high-risk patients. The
use of a minimally invasive procedure typically translates to less
blood loss, tissue damage, and risk of infection-related
complications and rapid mobilization (Jaikumar et al., 2002;
Uddin et al., 2015;Varga et al., 2015). Injection of bone
cement into the disc was indeed performed and studied in the
last half of the 20th century as a means for low-cost spinal fusion;
particularly in the cervical spine (Hamby and Glaser, 1959;Grote
et al., 1970;Böker et al., 1989;Van Den Bent et al., 1996).
However, it was shown through randomized clinical trials that
the use of bone cement in the disc does not yield better fusion
results as opposed to keeping the disc space hollow in anterior
cervical discectomy with fusion (ACDF). Thus, bone cement for
spinal fusion was no longer recommended (Van Den Bent et al.,
1996). Recently, Yamada et al. (2016) and Varga et al. (2015) have
reported on similar minimally invasive procedures in
degenerative deformities, commonly referred to as
percutaneous cement discoplasty (PCD) (and in some cases
percutaneous intervertebral-vacuum polymethylmethacrylate
injection (PIPI) (Yamada et al., 2016;Yamada et al., 2021)).
This procedure is based on injecting bone cement into a
degenerated disc in the lumbar spine but with a different
objective. PCD does not aim to fuse the vertebrae, but rather
to treat patients who cannot undergo spinal fusion surgery due to
the associated risks of the procedure, with the aim of providing
pain relief and improved functionality. PCD can be performed in
advanced degeneration of the disc when characterized by a
vacuum phenomenon (VP) (Figure 1)(Camino Willhuber
et al., 2020a). Vacuum phenomenon is commonly associated
with advanced degeneration of the disc and has been reported in
20-35% (Resnick et al., 1981;Morishita et al., 2008) or even as
high as 50% (Gohil et al., 2014) of elderly patients, with
increasing prevalence with age (Lardé et al., 1982;Gohil et al.,
2014). At present, two methods for the introduction of the
Jamshadi needle have been developed; either through the
Kambin's triangle (Figure 1A), or a transpedicular approach
from the lower vertebra (Figure 1B). So far, the cement
employed for this procedure is polymethylmethacrylate
(PMMA), otherwise used in the spine for vertebroplasty and
kyphoplasty, i.e., percutaneous cement injection for stabilization
of vertebral fractures. The cement components are mixed in the
surgical theatre and injected into the disc with the aid of
fluoroscopy. PCD has been shown to provide a consistent
pain relief (Camino-Willhuber et al., 2021;Yamada et al.,
2021). This pain relief is hypothesized to be the result of
increased stability of the spinal segment and partial
restoration in disc height after bone cement injection (Kiss
et al., 2019). Additionally, PCD allows for a higher degree of
motion preservation of the segment compared to spinal fusion,
thus there may be a lower risk of accelerated degeneration in
adjacent segments (Park et al., 2004).
Since the introduction of PCD, several cohort and case studies
have been published on cement injection into the disc in elderly
patients with degenerative lumbar scoliosis (DLS). These report
significant improvement in patient disability, pain, and quality of
life. Yamada et al. reported on mean improvements in Visual
Analog Scale (VAS) scores of –55.3 (n= 100) for patients who
opted for PIPI and –1.9 (n= 61) for patients who chose
conservative treatments, at 1-month follow-up. Similarly,
improvements in American Academy of Orthopedic Surgeons
MODEMS version of the Oswestry Disability Index (mODI)
(Fairbank and Pynsent, 2000) were –22.7 and –0.6 for PCD
and conservative treatments, respectively. These improvements
remained consistent at the 2-years follow-up where mean VAS
scores were –52.2 (n=91)and–4(n= 53) and mODI were
–20.7 and –1 for PIPI and conservative patients, respectively. A few
complications (n= 3) were reported where slight cement leakage
was observed causing pain, however no major complications
occurred (Yamada et al., 2016). PCD has shown similar positive
results in a case study conducted by Sola et al. (2018). Another
study by Camino Willhuber et al. (2020b) with 82 patients
(205 levels) presented a 1-year follow-up with significant
improvement to the Oswestry Disability Index (ODI) (Fairbank
and Pynsent, 2000) from 62 ± 7.12 preoperative to 36.2 ± 15.47 at
1-year post-operation There were no cardiac-, pulmonary- or
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thromboembolic complications. However, four patients (7%)
needed subsequent decompressive surgery within 90 days
because of continued or new radicular pain. There was one
patient with a deep surgical site infection and one with fracture
of an adjacent vertebra that was treated with vertebroplasty.
Moreover, after minimum 2 years follow-up, significant and
continued improvement to both VAS and ODI scores of
approximately 45% and 25% respectively (n=156)was
observed (Camino-Willhuber et al., 2021). Yamada et al. (2021)
reported on the long-term effects of PIPI in a single center. Both
ODI and VAS scores were significantly improved for PIPI patients
as opposed to the control group. VAS and ODI improvement for
PIPI patients (n=80)atfinal follow up of 63.7 ± 32.4 months was
72.5% and 57.5% respectively while the control group with non-
operative treatment (n= 53) had a minor improvement of 5.7%
and 17.0% respectively.
While the clinical data seems promising, further
investigation into the biomechanics of the treated spinal
segments is deemed required to support future
advancement of PCD. Techens et al. (2020) outlined the
need for a biomechanical model of PCD to study the effects
of the procedure on the spine. A porcine model of a
degenerated disc construct was developed, using functional
spinal units (FSU) comprised of two adjacent vertebra and the
intervertebral disc in between. The FSUs were tested with a
bending moment of 5.4 Nm using a force offset, and the
authors found no significant effect on the mechanical
behavior of the segment from treating the injured segments
with cement. However, nucleotomy was used to simulate VP,
i.e., complete removal of the nucleus pulposus, and no void/
vacuum volumes were reported, nor other types of loading.
Eltes et al. (2021) developed a volumetric method to study the
effectiveness of PCD in terms of decompression, i.e., the
volume increase of the neuroforamen that is responsible for
relieving the nerves from pressure. It was concluded that after
PCD there was an increase in the neuroforaminal canal and a
significant positive correlation (p=0.001)betweenthevolume
of cement injected and increase in neuroforaminal canal
volume. A finite element study exploring different PMMA
cements for discoplasty showed a decrease in stresses exerted
on the endplates with softer cements (Lewin et al., 2022). The
study also advocates for a validation model with consideration
to the clinical setting.
The relationship between PCD, the stability of the spinal
segment, and disc height differences have not been clearly
established yet, therefore the effect of PCD on patients from a
biomechanical perspective and whether or not pain relief is a
result of that effect is not clarified. Hence, there is a need for a
clinically relevant model to investigate new materials and the
biomechanical effects of PCD in a controlled setting. The aim
of this study was to develop an ex-vivo model to enable
biomechanical evaluation of PCD in a repeatable and
clinically relevant manner. To this end, a papain enzyme
buffer was used to produce a repeatable void size in ovine
vertebral FSU segments, which were compared to clinical
computed tomography (CT) data to ensure clinical
relevance. The FSUs were mechanically tested under
compression before and after injury, as well as after PCD
to measure stiffness, which directly correlates to the stability
of the segment. It was hypothesized that a clinically relevant
injury with vacuum voids would decrease the stiffness of the
vertebral segments, and that the stiffness would be increased
after discoplasty. This model could enable a deeper
understanding of the biomechanics of discoplasty and serve
as a basis for further investigation of the procedure, including
evaluation of new biomaterials.
FIGURE 1
Schematic showing different entry methods to the disc for cement discoplasty. (A) entry from Kambin’s triangle; (B) transpedicular approach.
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Materials and methods
A summary of the procedure can be found in Figure 2.Inbrief,
FSUs were dissected from fresh ovine spines. They were then
submerged in PBS +1%vol pen-strep for 12 h before each step in
the procedure. Each FSUs was mechanically tested non-destructively
as harvested (healthy), after papain induced VP (injured), and after
discoplasty treatment (treated). The samples were scanned with
micro-CT before and after tests to ensure no macro fractures were
present in the adjacent bone. The VP was produced using a papain
solution that was injected into the disc. Micro-CT images were used
to assess void and cement volume as well as disc morphology. The
segments were then treated using PCD. The following sections
present the different steps in more detail.
Sample preparation
The spines originated from Leicester crossbreed female sheep
(adult sheep above the age of 2.5 years) from the Uppland region
in Sweden. It has previously been shown that ovine spine possess
similar biomechanical properties as human spine in terms of
range of motion (Wilke et al., 1997a) and are commonly used in
biomechanical evaluations of spinal treatments (Wilke et al.,
1997a;Wilke et al., 1997b;Reid et al., 2002). The spines were
harvested and dissected fresh in the lab where they were rinsed
and divided into individual FSUs. Clinically, PCD has been
performed on the lower thoracic and lumbar spinal segments,
thus similar segments were considered for the experiments (T11-
L6). All spinal processes were cut off to ensure the forces were
transmitted purely in the disc during mechanical testing. The
purpose of the mechanical testing was to test the performance of
the material in the disc, preserving other ligaments and joints
that exert forces may mask issues related with the implant
(Berger-Roscher et al., 2017). This also facilitated micro-CT
analysis. The caudal vertebra was submerged in PMMA, and
an impression of the top endplate was created using a separate
PMMA mould. The segments were then stored in −20°C for later
use. A total of 12 FSUs were dissected and used for this study.
This process is outlined in Figure 3.
Injury method
Voids were induced in the disc using a 60 U/ml papain buffer
containing 55 mM sodium citrate, 150 mM sodium chloride,
5 mM ethylenediaminetetraacetic acid (EDTA), and 77 mM
cysteine-hydrochloride (all purchased from Sigma-Aldrich,
FIGURE 2
Key steps in the study including different checkpoints for mechanical testing. 1) Dissection and preparation of the spinal segment. 2) Injecti on of
the papain. 3) Incubation of the sample to lead to injured disc. 4) Performing discoplasty on sample. 5) A treated sample with PMMA.
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Darmstadt, Germany). Papain buffers have previously been
shown to induce disc degeneration by digesting disc tissue
(Roberts et al., 2008;Chan et al., 2013;Malonzo et al., 2015).
Preliminary tests were conducted to establish the protocol for
injection and inspection of the samples. Doses of 50 μl were
injected to control the damage and monitor the VP evolution.
The FSU was scanned in a Skyscan 1172 micro-CT (Bruker
Corporation, Massachusetts, United States) to measure the
distance between the anterior and center of the disc. The
distance was recorded and marked on the needle to ensure
proper injection from the anterior of the sample. After
injection, the FSU was subsequently incubated in humid
conditions at 60°C for 16 h to allow the papain to digest the
disc (Malonzo et al., 2015). The FSU was scanned again, and the
void size and morphology was assessed. Reinjection was required
under two conditions: if the void size was too small to be injected
with cement or if the void did not extend to one (type 2A) or both
(type 3A) endplates (Camino Willhuber et al., 2020a). The
sample was discarded if the papain injection had created a
hole in the annulus visible by eye or micro-CT.
Imaging
Screening, fracture assessment, injury morphology, and cement
morphology assessments were conducted using micro-CT
reconstructions. For screening and preliminary macro fracture
assessment visual inspection of the images was conducted. The
total time for each scan was approximately 20 min. A voxel size of
27.16 µm was used to have maximum field of view. The source
voltage and current were set at 100 kV and 100 µA respectively and
the samples were exposed for 1600 ms per image. Two frame
averages were used to reduce some noise, a rotation step of 1°,
and 180°rotation to keep scanning time to a minimum. It was
crucial to keep the scanning time low in order not to lose any
information after compression of the samples. An Aluminum +
Copper filter was used as it captured both soft tissue and hard tissue
with good detail. All samples were scanned with the same settings to
ensure an unbiased comparison in segmentation.
Injury and cement morphology were analyzed using open-
source software, 3D Slicer (Fedorov et al., 2012), where image
segmentation of the void, disc and cement injected was
conducted. Void and disc tissue were segmented using
“growth from seed”method which identified changes in
average voxel greyscale from markers that were manually
input in the system. Using an iterative method of marking for
each individual scan, the volumes were established. A similar
procedure was performed for the clinical CT images provided.
Anonymized CT images of spines pre- and post-operation were
provided by a collaborating hospital for 3 patients. As the method
is semi-automatic it was verified by an independent researcher.
Three random void volume percentages were assessed by this
FIGURE 3
Procedure for the dissection and preparation of ovine FSUs for mechanical testing.
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independent researcher and compared with the results from the
study, giving a margin of error of approximately 1%. For the
cement volumes, the segmentation was done using an automatic
threshold method as it could be differentiated using the
histogram (Otsu, 1979).
Fluoroscopy was used while performing the PCD. A Philips
BV Endura C-arm was operated by the surgeon (KP) and used to
guide the needle into the disc and monitor cement injection
(Figure 4). ‘Head/Back’optimized settings were used on the
machine, 45 kV and a range of 0.198–0.475 mA was used.
Exposure time was kept to a minimum. On average, each
sample was exposed to a dose of 1 µGy.
Cement discoplasty procedure
The FSUs were handled by the surgeon carrying out the
discoplasty. The transpedicular approach was favoured to
prevent physical damage to the annulus fibrosis—highlighting
the advantage of using papain injection instead of nucleoplasty.
Further, it reflects the protocol that is conducted at the
collaborating hospital. As sheep have a higher bone density, a
tabletop drill was employed to create a hole from the posterior
pedicles into the void. Once an appropriate hole was drilled, it
was verified using fluoroscopy and the needle was placed using
light tapping (Figure 4A). When the position of the needle was
considered appropriate, radio opaque liquid (Omnipaque, GE
Healthcare, United States) was injected to confirm the void
morphology. The liquid was then retracted, and PMMA
cement V-steady (G21 s.r.l, San Possidonio, Italy) was mixed
according to manufacturer’s instructions and injected until the
void was filled (Figure 4B). This is a cement designed for
vertebral body augmentation, containing e.g., a higher amount
of radiopacifier for enhanced visibility, which is typically the type
of PMMA used for PCD (Sola et al., 2018;Camino Willhuber
et al., 2021). Finally, the needle was retracted while some cement
was injected to fill up the space displaced by the needle.
Mechanical testing
Compression testing was done using an MTS 858 Mini
Bionix T/II (MTS Systems Corporation, Minnesota,
United States) to assess the stiffness of the FSUs. The stiffness
of the FSU in compression directly correlates to the stability of
the segment. A displacement rate of 5 mm/min, or an average
strain rate of 0.017%/s, was used and a maximum displacement
of one third of the minimum disc height was chosen. This was
calculated by finding the minimum distance parallel to the
vertical direction between the vertebra using reconstructed
micro-CT scans. Previously used strain rates for testing
human intervertebral disc tissue are in the range of
0.01–0.8%/s (Newell et al., 2017), and a strain rate in the
lower end was chosen to capture sufficient data for estimating
stiffness. The displacement limit was determined by pilot studies
and allowed for standardization of the displacement cycles as
each sample had a unique geometry. A preload of 25 N was set
and five compression cycles were performed per sample where
the last three cycles were used for stiffness measurements. Initial
investigations showed that 25 N was the minimum force where
the entire assembly is in contact (i.e., the superior vertebra is
conformed to the impression on the PMMA), and three cycles
were sufficient for preconditioning the samples and the last three
cycles were nearly identical (shown in Supplementary Material
S1). The setup featured a ball on plate setup to ensure the
actuated force is exerted in the center, vertically at a single
FIGURE 4
Fluoroscopy procedure for conducting PCD on an L3-L4 FSU. (A) verifying the position of the needle (B) after injection of PMMA cement.
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point, and reduce bending moments as the top plate pivots freely
(Figure 5). The bottom PMMA holder was fixed using screws and
the sample was positioned so that the center of the top endplate
was aligned with the actuator. The stiffness of each segment was
estimated in the linear range, corresponding also to human disc
axial strains during physiological loading (2%–5%) (Tsantrizos
et al., 2005;Tavana et al., 2021).
Statistical analysis
Statistical analysis was done using SPSS Statistics Version 28
(IBM Corp., Armonk, NY, United States). Sample size was
calculated using G*Power 3.1.9.7 (Erdfelder et al., 2009). Since
there were no previous studies with a similar method, estimating
the effect size for clinical relevance proved to be difficult. The
sample size was calculated after the experiment was conducted to
ensure conclusive results and significance of the statistics. The
number of samples calculated was 6 from both the stiffness’and
disc height’s effect size, given by a partial eta squared (η2
p)of
0.576 and a power of 95%. The partial eta squared was calculated
using multivariance analysis on SPSS based on the means of the
three health groups. A repeated measure analysis of variance
(ANOVA) was used, as the same specimens were used in each
group. Normality of the data was established using Shapiro-
Wilk’s normality test. All groups showed significance above 0.05.
Further, the repeated-measures ANOVA was validated using
Mauchly’s sphericity test. For testing correlations, Pearson’s
correlation coefficient was used, and a two-tailed test was
employed to test for significance. Significance was considered
for p<0.05.
Results
Void and cement volumes
The segmentation results showed that ovine samples had
15.4% ± 7.4% void volume and 15.5% ± 5% cement volume (n=
11) and clinical data showed 6.6% ± 2.2% (n= 3) void and
12.4% ± 4.4% cement volume (n= 6). Three of the voids could
not be measured accurately due to excessive compression, i.e., not
enough slices were available to give an accurate volumetric
representation. An example of the segmentation is found in
Figure 6. The region of cement analyzed was the cement
found inside the disc and does not include cement residue or
cement found in the vertebral body.
Eleven out of twelve samples successfully passed inspection
after inducing VP. The rejected sample showed penetration
through the annulus and separation of the endplate from the
vertebral body due to weakening in the growth plate from
excessive papain digestion. A total of approximately
100–150 µL of papain buffer solution was injected into each
disc. Variations were found between ovine FSU samples
(Table 1). However, all samples had type 2A (n= 1) and type
3A (n= 10) vacuum sizes as prescribed by a vacuum classification
study conducted by Willhuber et al. (Camino Willhuber et al.,
2020a). Eleven out of eleven samples successfully passed
inspection after PCD. No cement leakage was observed
through the annulus. Six samples had the void filled
(Figure 7A) while 3 samples had more cement volume than
void. This may be due to delamination of the annulus and high
injection pressure (Figure 7C). Two samples had less cement
volume than void volume due to large air bubbles. This could not
be spotted while using fluoroscopy and thus they were somewhat
underfilled (Figure 7B).
Disc height measurements
All samples were scanned pre and post mechanical testing.
An example of the difference of disc height between a tested and
untested sample is shown in Figure 8. Due to this difference, all
disc height measurements presented are post mechanical testing
to simulate muscle and tendon load. The percentage differences
were normalized to the healthy disc height for each sample.
A significant difference was observed in the evolution of the
anterior (p<0.001) and posterior (p= 0.004) disc heights. It was
measured that on average, both posterior and anterior disc height
FIGURE 5
Schematic of the mechanical testing setup.
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FIGURE 6
CT images of ovine and human spine segments before (top row) and after (bottom row) PCD. (A) Sagittal view of ovine FSU with papain induced
void; (B) Sagittal view of ovine FSU after PCD; (C) Segmentation of ovine FSU featuring void and disc tissue; (D) Segmentation of ovine FSU featuring
cement injected and disc tissue; (E) Frontal view of human spine with degenerated disc; (F) Frontal view of post-op image of human spine after PCD
surgery; (G) Segmentation of human spine featuring void and disc tissue; (H) Segmentation of human spine featuring cement injected and disc
tissue. Green = disc tissue; blue = void; yellow = PMMA cement.
TABLE 1 Volume Percentage of void and PMMA relative to the volume of the disc. Vacuum classification from Camino Willhuber et al. (2020a).
Sample Void (% of disc) Vacuum classification Cement (% of disc)
Sh1 L1-L2 12.3 3A 14.48
Sh1 L3-L4 3.56 2A 9.43
Sh1 T12-T13 20.17 3A 20.38
Sh2 L3-L4 15.6 3A 16.09
Sh2 L5-L6 13.37 3A 11.1
Sh2 T12-T13 12.68 3A 13.86
Sh3 L1-L2 19.4 3A 16.3
Sh3 L3-L4 23.54 3A 24.2
Sh3 L5-L6 30.72 3A 20.4
Sh3 T11-T12 10.27 3A 16.2
FIGURE 7
Axial cross-sectional micro-CT slices of a well-filled void (A), under-filled (B), and over-filled (C) ovine spine discs. Red arrows indicate bubbles
of air trapped in the cement.
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after injury were reduced to 76.1% (decrease of 23.9%) and 77.5%
(decrease of 22.5%) respectively (Figure 9). In addition, the
anterior disc height on treated samples was restored to 98.5%
(increase of 22.4%) while the posterior height regained to only
83.6% (increase of 6.1%) of its healthy disc height.
Mechanical testing
Eleven out of eleven samples passed all three mechanical
tests. Force-displacement curves for each individual sample can
be found in the Supplementary Material S1.Figure 10 shows the
force displacement curves of each sample in the different groups.
All curves showed an increase of stiffness with strain. This trend
is similar for all investigated specimens. The increase in stiffness
is a result of complex stress stiffening of the discs predominantly
at higher levels of compression. It can be noted that the injured
segments had a lower stiffness on average than the healthy
segments throughout the entire cycle. Furthermore, most
treated samples (n= 9) showed a similar response to the
healthy segments.
The stiffness derived from the linear regression of each
sample is reported in Figure 11.
A decrease in stiffness after injury was found for each sample
except one (L1-L2 FSU from sheep 2). However, all treated
segments had a higher stiffness than the injured segments.
The average stiffness for each group is shown in Figure 12.
The average stiffness for the healthy discs was 0.767 ± 0.271 kN/
mm. A decrease of stiffness was observed to 0.400 ± 0.184 kN/
mm in the injured discs. After treatment, the stiffness of the discs
increased to 0.806 ± 0.228 kN/mm.
The stiffnesses differences between the groups was
statistically significant (p<0.001). To emphasize the
differences, a comparison between the different groups of the
samples is shown in Figure 13. Between healthy and injured
groups, the stiffness decreased by 51.5% on average while a
significant restoration of stiffness is shown when comparing
injured and treated groups. Healthy and treated groups show
only a difference of 5% stiffness confirming the restoration
stiffness observed in Figure 12.
Excluding the outlier in the study, all samples had a decrease
in stiffness between healthy and injured. A statistically significant
negative correlation (p= 0.034) was observed between void
volume size and stiffness (Figure 14A). Likewise, all samples
had a stiffness increase as a result of cement discoplasty.
However, a statistically significant correlation could not be
confirmed between cement volume injected and stiffness at
the chosen significance level (p= 0.054) (Figure 14B).
Discussion
The objective of cement discoplasty is twofold. Firstly, to
relief patients from LBP caused by the narrowing of the
neuroforamen space and decrease in disc height (Varga et al.,
FIGURE 8
Before (A) and after (B) mechanical testing of an L1-L2 ovine sample showing posterior disc height (PDH) and anterior disc height (ADH)
differences.
FIGURE 9
Posterior and anterior disc heights for the different health
groups immediately after mechanical testing. Error bars = 95%
Confidence Interval. Statistical differences was observed in both
anterior (p<0.001) and posterior disc height (p= 0.004)
between health groups.
Frontiers in Bioengineering and Biotechnology frontiersin.org09
Ghandour et al. 10.3389/fbioe.2022.939717
2015) or endplate lesions (Yamada et al., 2016). Secondly, to
provide stability to the spinal segment (Varga et al., 2015;Sola
et al., 2018;Camino Willhuber et al., 2020b). This study
presented a procedure to induce a repeatable injury resulting
in the clinically observed vacuum phenomenon, and reported on
the mechanical properties of healthy, injured and PCD treated
ovine functional spinal units. X-ray imaging techniques were
employed to non-destructively assess void volume, cement
volume, posterior and anterior disc height.
Choosing an appropriate animal model for testing
discoplasty was an essential first step in developing this
method. Depending on the objective, different animal models
have been employed, where the most common are ovine, rabbit,
bovine and porcine (Reitmaier et al., 2017). To our knowledge,
the only other study on the biomechanical properties of
discoplasty used a porcine model (Techens et al., 2020).
However, an ovine model was chosen for this study for
several reasons. It possesses similar gross anatomical and
biomechanical representation to human lumbar spine (Wilke
et al., 1997a,1997b;Reid et al., 2002), a small form factor, and was
more accessible in this study relative to porcine. Further, ovine
intervertebral discs have been shown to have similar water
content in the discs relative to human spine, which directly
FIGURE 10
Force-displacement curves of ovine segments as healthy, treated, and injured. The displacement is given as a percentage of minimum disc
height for each sample. Curves in red represent the average cycle for each health group.
FIGURE 11
Stiffness of each segment for the different health group: healthy, injured and treated with cement.
FIGURE 12
Mean stiffness values for the different groups with 95%
confidence interval. Significant difference was observed between
health groups (p<0.001).
Frontiers in Bioengineering and Biotechnology frontiersin.org10
Ghandour et al. 10.3389/fbioe.2022.939717
affects the mechanical properties of the disc (Reid et al., 2002). As
long as the loads and implant (i.e., the bone cement volume) are
scaled down, a study on ovine samples can be assumed to give a
good approximation to how discoplasty would affect human
discs. The smaller form factor enabled the use of equipment such
as the employed micro-CT, which could not be used with a larger
FSU such as porcine.
A vacuum phenomenon needs to be present in order to apply
PCD. For the objective of this study, producing a repeatable and
clinically appropriate void size in the disc was necessary, but the
bone density and quality was not considered as relevant, thus an
animal model was used. One of the important advantages of
using papain was inducing minimal penetration damage at the
point of injection. Therefore, the present void model can be
considered more similar to the clinical vacuum situation as
opposed to performing a nucleoplasty, which was done in the
only previously reported model of discoplasty (Techens et al.,
2020). Additionally, the location of the void can be controlled by
the injection site. Using CT images as a guide, markers could be
set, and injection depth recorded making the procedure
repeatable. Over 90% of samples passed the exclusion criteria
and all voids were type 2A and 3A, which are within the
recommended void type for discoplasty treatment (Camino
Willhuber et al., 2020a) making the model suitable for clinical
comparison.
The stiffness of the healthy ovine spine could not be directly
validated due to the lack of literature on ovine FSUs without facet
joints and ligaments. The stiffness decrease after injury was
expected, as a result of the digestion of the nucleus pulposus.
The reduction of hydrostatic pressure in the disc results in
segment instability and a reduced capacity to carry load.
Moreover, Chan et al. (2013) have shown that papain also
FIGURE 13
Percentage difference in stiffness of the different health groups. The box indicates the values between 25-75% and the label indicates mean
value. (Sh2 L1-L2 excluded).
FIGURE 14
Correlation between stiffness vs. void volume (p= 0.034) (A) and cement injected (p= 0.054) (B).
Frontiers in Bioengineering and Biotechnology frontiersin.org11
Ghandour et al. 10.3389/fbioe.2022.939717
influences the annulus fibrosis fiber composition by observing a
decrease of rotational stiffness in their samples.
The stiffness of the treated samples was similar to the healthy
samples on average (Figures 12,13), although variations were
found within a sample (Figure 11). The mechanical properties of
disc tissue and PMMA are very different, however the behaviour
of the FSUs in the 2%–5% range was similar (Figure 10). In both
cases, it can be assumed that the majority of the displacement was
occurring inside the disc space as cortical bone (E = 15–25 GPa)
(Grant et al., 2014) is much stiffer than PMMA (E = 1.5–3.7 GPa)
(Kurtz et al., 2005;Boger et al., 2008;Hernandez et al., 2008) and
disc tissue (Casaroli et al., 2017). It is worth noting that in most
cases, the bone cement was in contact with both endplates thus
carrying most of the load in the treated segments. This was
supported by the fact that the FSUs showed an increase in
stiffness regardless of the amount of cement injected
(Figure 11). Overfilling and underfilling of voids has not been
studied in a clinical setting as clinical CT scanner resolution is
limited. It may be the case that this occurs also in a clinical setting
but it is not observed.
To the authors’knowledge, only one other ex vivo study
has reported on the biomechanics of cement discoplasty
(Techens et al., 2020). The study presents different loading
cases such as moment bending but no compression testing.
Therefore, the findings from both this study and Techens et al.
could complement each other to portray the overall
performance of cement discoplasty. Techens et al. (2020)
found no statistically significant differences in rotational
stiffness in flexion-extension and lateral bending between
healthy, injured and treated groups. From a clinical point
of view, this is promising, since it would indicate that patients
maintain their range of motion of the treated segment while
restoring stiffness in compression.
Disc height restoration is also an important outcome from
PCD. The procedure is hypothesized to remove pressure on the
spinal nerves by increasing the disc height (Kiss et al., 2019).
From a clinical point of view, this raised concerns regarding how
to expand the disc space during injection, and Varga et al. (2015)
recommends using a high viscosity cement. In the present study,
a cement described as high-viscosity cement was used, and while
anterior disc height was fully restored, the posterior was not
(Figure 7). Nevertheless, an increase of 22.4% in the anterior disc
height and 6% in the posterior disc height directly increases the
intervertebral foramen, which should result in reduced pressure
on the spinal nerves. Eltes et al. (2021) drew similar conclusions
when measuring the neuroforamen volume in pre- and
postoperative CT scans. Similarly, Techens et al. (2020)
observed similar disc height trends to this study in their
porcine nucleoplasty model—confirming the effectiveness of
PCD in that regard. With the present model, different
cements with various viscosities and material properties can
be tested to assess disc height restoration and validate
simulation studies.
Segmentation of the samples was key to compare with clinical
data and further the understanding of discoplasty. Techens et al.
(2020) compared the volume of cement injected between patients
and their samples however no attempt in measuring correlation
was performed. Absolute volumes could not be compared as a
different animal model was used in this study. Moreover, due to
natural variation of animal models the percentage cemented may
be a more adequate measure to compare with clinical data. This
was addressed herein by the segmentation of micro-CT scans and
clinical CT data provided by the hospital. It was shown that
similar percentages of cement were injected in both ovine
samples and patients. The void volumes were however not
similar, which could be explained by the difference in loading
scenario in a patient compared to our model. Moreover, the
resolution of the clinical CT scans is limited.
One of the limitations of this study was the use of an animal
model. While being more accessible, ovine spine has a higher
bone mineral density compared to humans. Additionally, all
ligaments and processes were removed, altering the
biomechanics of the FSUs. Therefore, adjacent vertebral
fracture risks in relation to loads experienced and materials
used were difficult to assess using this model. Hence, in the
case of transferring this model to a human cadaver case retaining
ligaments and processes should be considered. Further, due to
the time constraint between individual microCT scans, the noise
and artefacts produced could not be eliminated for all samples.
Another disadvantage was that measuring the exact volume of
papain injected into the disc was not possible due to the pressure
in the disc. It is recommended that the papain is administered
through more than one dose to possess better control over the VP
location and size. Delamination of the annulus tissue observed in
this study (Figure 7C) was not an expected outcome from the
papain injection. Although it did not affect the results, weaker
annulus tissue such as from elderly human cadaver FSUs may be
affected more severely than healthy ovine FSUs, and therefore
papain dose must be minimized. It was observed that injection of
papain as the needle was retracted promoted delamination. It is
important to note that applying this method on other cadaver
models requires some preliminary investigation to measure the
volume required per dose and location of injection.
In summary, the method outlined in this study could be used
to explore different aspects of discoplasty. Material optimization
for the technique is a topic for further investigation. As
previously discussed, there is a risk of vertebral facture in
PCD (Camino Willhuber et al., 2020b). PMMA has the
advantage of conforming to the geometry of the void.
Therefore, if the PMMA is conformed to the endplates, there
is less risk of concentrated stresses and movement of the PMMA.
Osteoporotic patients possess a higher risk for vertebral fractures
Frontiers in Bioengineering and Biotechnology frontiersin.org12
Ghandour et al. 10.3389/fbioe.2022.939717
and have been excluded from some studies (Yamada et al., 2021)
or advised to be treated pre-operatively to reduce the risk (Sola
et al., 2018). Optimizing the modulus of PMMA could prove to
be useful in this case. Low-modulus PMMA was previously
proposed for spinal applications (López et al., 2011,2014;
Holub et al., 2015;Persson et al., 2015) and could be
beneficial in PCD, particularly for osteoporotic patients. This
method could also serve as a screening phase where different
surgical advancements can be evaluated without putting patients
at risk. The two entry methods could be compared to further the
understanding of PCD. Further, different loading scenarios and
multiple level discoplasty could also be tested using this method.
Conclusion
In this study, a methodology to evaluate discoplasty in an ex
vivo ovine model was established. Papain was used to induce
clinically relevant voids, as established by percentage void
volume of the disc in comparison to clinical data. The injury
significantly decreased the stiffness of the FSUs, as expected. An
increase in stiffness was found for the specimens treated with
PCD as compared to the injured ones. Injected cement volumes
were found to be comparable to those of clinical treatments. The
anterior disc height was restored to its healthy state while the
posterior disc height was not fully restored after treatment.
Compression tests indicated support for PCD as an alternative
procedure to fusion for patients with painful disc degeneration
with vacuum phenomena, as based on the stiffness and disc
height restoration possibilities.
Data availability statement
Ovine microCT images, reconstructions, and mechanical
testing data is available via Zenodo using the following DOI:
10.5281/zenodo.6514285. Further inquiries can be directed to the
corresponding author.
Ethics statement
Ethical review and approval was not required for the study on
human participants in accordance with the local legislation and
institutional requirements. Written informed consent for
participation was not required for this study in accordance
with the national legislation and the institutional
requirements. Ethical review and approval were not required
for the animal study because ovine spines were collected from
local butchers. The lab where experiments were conducted
possess approval from Jordbruksverket to use animal bi-
products for research and diagnosis (that include adult sheep
spines). Registration number: SE 841713.
Author contributions
All authors contributed to conception of the project and
design of the study. SG conducted majority of sample
preparation, experimental testing, and data analysis. SG and
KP conducted surgical experimentation. SG, SL, KP, and PF
contributed to material and equipment allocation. SG drafted the
manuscript. SG, SL, PI, and CP contributed to result evaluation
and interpretation. All authors contributed to manuscript
revision, read, and approved the submitted version.
Funding
This research has received funding from EIT Health
(SOFTBONE, project nr 20519), supported by EIT, a body of
the European Union and from the European Union’s Horizon
2020 research and innovation programme under the Marie
Skłodowska-Curie grant agreement No 812765.
Acknowledgments
Prof. Dr. Benjamin Gantenbein and Andrea Oberli are
gratefully acknowledged for their assistance on the papain
recipe. Assoc. Prof. Caroline Öhman Mägi is gratefully
acknowledged for assisting in image segmentation protocols.
Dr. Alejandro Lopez and Rachel Stokes are also thanked for
their contribution in pilot testing.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fbioe.2022.
939717/full#supplementary-material
Frontiers in Bioengineering and Biotechnology frontiersin.org13
Ghandour et al. 10.3389/fbioe.2022.939717
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