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Background: Millions of patients suffer chronic neck
pain, headaches, interscapular pain, and radiating arm pain from degenerated
cervical discs. Operative options include cervical disc fusion or cervical
artificial disc replacement. Patients with more than two degenerated discs have
minimal surgical options.
Study Design: This is a prospective nonrandomized study of
the two-year follow-up results of injecting bone marrow concentrate (BMC) into
symptomatic degenerated cervical discs.
Methods: There were 182 patients (97 male, 85 female)
with an average age of 54.5 (range 18 to 80). The 30-minute procedure involved
aspirating 55ml of bone marrow from the iliac wing, concentrating this via
centrifugation to a volume of 3ml, and then injecting 0.5ml of the bone marrow
concentrate into each abnormal cervical disc. The procedure was performed with
IV sedation. Number of levels injected was: one level = 33 patients, two levels
= 60 patients, three levels = 45 patients, and four levels = 44 patients.
Average number of levels injected was 2.44. Pre-procedure Neck Disability Index
(NDI) was 44.5 (range 12-100) and Visual Analog Scale (VAS) was 62 (range
10-100).
Results: Six-month follow-up NDI and VAS were 17.4 and
22.5. One-year NDI and VAS were 15.8 and 21.4. Two-year follow-up NDI and VAS
were 16.5 and 20.7. All scores had a P-value of less than 0.001. There was no
difference in the clinical results comparing one, two, three, or four disc
levels injected. There were no injection complications and no patient had
surgery during the study.
Conclusions: These results indicate a bone marrow concentrate
injection may be a reasonable non-surgical option for patients with symptomatic
degenerated cervical discs.
INTRODUCTION
Millions of patients in the United States suffer from chronic
complaints of neck pain, pain in between their scapulae, radiating pain
producing headaches, and radiating pain into the arms. Epidemiologic studies
have found the incidence in the general population to range from 7% to 13.8%
[1,2]. Cervicogenic headaches are considered the most common etiology for
chronic headaches [3].
Patients suffering these symptoms have often developed degenerative
changes in the discs of their cervical spine. Plain radiographs often show a
loss of disc space and development of osteophytes posteriorly which can
protrude into the spinal canal producing nerve compression or anteriorly
impinging the esophagus. MRI scanning can verify the loss of disc space and
spinal cord and exiting nerve compression.
Non-operative treatments for patients who have degenerative discs in
their cervical spine with associated neck pain, headaches, pain in between
their shoulder blades, and radiating arm pain can include traction,
chiropractic care, physical therapy, acupuncture, epidural steroid injections,
intermittent use of a soft collar, and ergonomic pillows for sleeping. Patients
who continue to suffer serious symptoms may be candidates for a surgical
approach to their problem.
The standard surgical treatment for degenerative conditions of the cervical spine is an anterior cervical fusion [4-8]. One inherent problem with any fusion of the spine is the permanent loss of spine motion and development of adjacent level abnormalities [9-12]. Research has indicated the development of adjacent level abnormalities leading to additional surgery is between 3% and 5% per year after an anterior cervical fusion [13]. Several review articles of the literature indicate the clinical success rates of anterior cervical fusion at one level are about 70% with a reoperation rate at the two-year follow-up of 10% [14]. The clinical results of anterior cervical discectomy and fusion (ACDF) decreases the more levels that are fused [15,16]. Another inherent problem with anterior cervical fusion is the failure of the fusion to heal. This results in what is called a pseudoarthrosis or failure of fusion. Half the patients with this situation generally require a second surgery in an attempt to obtain a fusion [17,18].
Cervical artificial disc replacement has become a preferred surgical
option. This procedure underwent FDA testing beginning around 2005. McAfee, et
al, published a metanalysis comparing outcomes of cervical artificial disc
versus anterior cervical fusion at one level. This metanalysis reported
superior reports with the use of an artificial disc versus a fusion at a single
level when considering adjacent level degeneration [19]. Recently, an
artificial disc has been approved for two levels and the prospective randomized
study supporting this also indicated superior results with an artificial disc
versus fusion at two levels [20]. There have been numerous papers published
indicating the clinical superiority of cervical artificial disc over fusion
subsequent to 2005 [21-27]. One persistent problem, however, is that many
patients have degenerative changes at more than two levels, which is a
prognostic indicator of poorer outcomes in surgical procedures.
Patients who have three or more degenerated discs in the cervical spine
present a very difficult surgical treatment situation. The surgical results of
three- and four-level anterior cervical fusions are certainly less than the 70%
success rate reported with fusion at a single level. Thus, patients with more
than two levels of degenerative changes in their neck have very poor surgical
options [15,16]. Performing cervical artificial disc replacements at more than
two levels is unusual and would very rarely be covered under insurance
benefits.
The use of biologics to treat disc abnormalities is a possible
non-surgical option which potentially can bridge the gap between traditional
non-surgical treatments for cervical degenerative disc abnormalities and
surgery. There is mounting evidence to support the use of biologic and cell
based therapy for chronic discogenic low back pain, a condition with similar
etiology [28,29]. The authors of this paper have published both one and
two-year follow-up from a study assessing the safety and efficacy of bone
marrow concentrated cells as an alternative to surgery for discogenic back pain
at one or two levels [30,31]. There have been numerous studies utilizing
mesenchymal stem cells to enhance tissue repair and decrease inflammatory
damage in both in vitro lab studies and in vivo clinical models [32-36]. It is
known that bone marrow aspirate concentrate (BMAC/BMC), the treatment used in
this study, contains mesenchymal stem cells as well as a number of other cell
types including but not limited to: hematopoietic stem cells, endothelial
progenitor cells, and platelets. Studies have shown both the mesenchymal stem
cell population and other nucleated cell types have healing properties and may
contribute in a synergistic fashion to the healing seen in studies on the
lumbar spine [37-44].
This is the first study to evaluate the potential of intradiscal bone
marrow concentrate to treat patients who have symptomatic degenerated cervical
discs and associated chronic axial neck pain, headaches, and radiating arm pain.
MATERIALS
AND METHODS
Study Design
This study is a prospective open-label non-randomized evaluation of
patients having an injection of bone marrow concentrate (BMC) into symptomatic
cervical discs. The patients enrolled as subjects in this study presented
clinically with symptomatic moderate to severe chronic axial neck pain. Axial
neck pain was also associated with interscapular pain, headaches, and radiating
arm pain. Abnormalities were present on cervical MRI scanning and plain
radiographs. These abnormalities include anterior and posterior osteophyte
formation, disc space narrowing on plain radiographs, and nucleus pulposus
desiccation on MRI scanning.
Pre-treatment baseline neck disability index (NDI) was a minimum of
30mm/100mm and pre-treatment baseline axial neck pain was at least 40mm/100mm
on visual analog scale (VAS) pain scores. The patients were required to sign
and fully comprehend an informed consent document before participating in the
study. All patients underwent a pre-injection medical history and physical
examination along with the neck disability index and visual analog scale pain
scores. These questionnaires were repeated at six weeks, three months, six
months, 12 months, and 24 months post injection of bone marrow concentrate. The
patients’ primary physical complaint in this study was one of axial neck pain
with associated interscapular and headaches and may or may not have included
radicular arm pain. Standard exclusion criteria included evidence of a
symptomatic herniated disc. Patient demographics are listed in Table 1.
Bone Marrow
Collection and Processing
Bone marrow aspirate (BMA, 55ml) was collected
over acid citrate dextrose-anticoagulant (ACD-A, 5ml) from the patient’s
posterior iliac crest. The procedure was performed with IV sedation consisting
of Versed and Fentanyl. Positioning of the Jamshidi needle in the iliac wing
was confirmed by fluoroscopy. BMA was collected in a 60ml syringe in a series
of discrete pulls on the plunger (targeting a collection of 5-10ml per pull)
with repositioning of the needle tip between pulls based on the reported
enrichment of progenitor cells by (Hernigou et al 2013) [45]. The BMA was
processed using the ART21 system (Celling Biosciences, Austin, TX) to produce a
bone marrow concentrated cell preparation. The 55ml of BMA were centrifuged for
12 minutes to produce 3ml of BMC. The 3ml of BMC were drawn from the processed
device and then 0.175 cc of 50% glucose and 0.175cc of bicarbonate were added
to the 3ml of BMC which was then immediately transferred to the physician for
injection [46].
Interdiscal
Injection
With the patient in a supine position, the skin overlying the disc to
be injected was anesthetized with 1% buffered Lidocaine. Bone marrow
concentrate was percutaneously injected into the symptomatic cervical discs
through the standard anterolateral approach on the patient’s right side of the
cervical spine. Digital pressure was utilized to separate the carotid sheath
and sternocleidomastoid laterally and trachea and esophagus medially and then a
20-gauge needle was placed into the disc space and centered on the anterior
posterior and lateral fluoroscopy. Approximately 0.5ml of bone marrow
concentrate was used per symptomatic cervical disc. The entire procedure
averaged less than 45 minutes.
Patients were prescribed pain medication to be used as needed for three
days and put on restricted physical activity for two weeks.
RESULTS
Pre-procedure neck disability index (NDI) was
44.5 (range 12-100) and visual analog scale (VAS) was 62 (range 10-100).
Six-month follow-up NDI and VAS were 17.4 and 22.5. One-year NDI and VAS were
15.8 and 21.4. Two-year follow-up NDI and VAS were 16.5 and 20.7. All scores
had a p-value of less than 0.001. This represents a 63% improvement in NDI and
a 67% improvement in VAS at the two year follow up. There was no difference in
the clinical results comparing one, two, three, or four disc levels injected.
There were no injection complications and no patient was made worse from the
procedure. No patient had surgery during the study. Figure One details the
pre-procedure and post-procedure changes in NDI through two-year follow-up.
Notice there was no difference in NDI improvement comparing the number of disc
levels treated. Figure Two details the pre-procedure and post-procedure changes
in VAS through two-year follow-up. Notice there was no difference in VAS
improvement comparing the number of disc levels treated. The results in figure
one and two represent all 182 patients.
Analysis of the Bone
Marrow Concentrate
This section is included from a previously published paper to detail
the BMC cell analysis expected in these patients [30]. The paper
involved a prospective study of 26 patients with discogenic low back pain. The
demographics of those patients was similar to this study of patients with the
same diagnosis in the cervical spine. This information is included to detail
the method of cell analysis and MSC cell counts expected in this group of 182
patients.
Cell analysis and characterization of 20 out of the 26 patients’ BMC
samples were performed. An aliquot (1ml) of each subject’s BMC was packed in a
shipping container with 5°C cold packs and shipped overnight to the cell
analysis laboratory (Celling Biosciences, Austin, TX). The samples were
received and processed immediately to determine total nucleated cell (TNC)
count and viability using a NucleoCounter NC-100 (Chemometec, Denmark). The BMC
was diluted in phosphate buffered saline (PBS, Invitrogen, Grand Island, NY)
with 2% fetal bovine serum (FBS, HyClone human mesenchymal grade, Thermo
Scientific, Waltham, MA) and subjected to a Ficoll-Paque (GE Healthcare Life
Sciences, Piscataway, NJ) gradient separation (1:1 cell solution to Ficoll
ratio by volume) in order to deplete red blood cells. Analysis of the recovered
cells included performing colony-forming unit-fibroblast and osteogenic (CFU-F
and CFU-O, respectively) assays and phenotypic analysis by flow cytometry. For
phenotype analysis, fresh (noncultured) BMC cells were stained with a series of
rabbit anti-human monoclonal antibodies for a hematopoietic lineage-committed
(nonprogenitor) panel of markers including CD2, 3, 8, and 11b (APC-Cy7), CD34
(PE), CD90 (FITC), and CD105 (APC) as well as appropriate isotype controls.
Isotype, single color stain, and four-color stain samples were analyzed by a
Guava EasyCyte 8HT (Millipore, Billerica, MA). The CFU-F assay was performed by
creating a dilution series (in culture medium with 5% FBS and 1% antibiotics)
of each cell preparation at concentrations of 50,000-500,000 TNC per well in
standard 12-well plates. The plates were placed in an incubator at 37°C, 5% CO2,
and 100% humidity for 72 hours when the medium was replaced. Medium was
replaced every 3 days. After 9 days in culture, wells were gently washed with
PBS, fixing the colonies/cells with methanol, staining the attached cells with
Crystal Violet, rinsing with water, and air-drying the plates. Visualization
and counting of the colonies were done with an inverted microscope. Colonies
containing 20 or more cells were scored as a CFU-F. The CFU-O assay was
performed identically as CFU-F, but after 9 days the medium was changed to an osteogenic
induction medium (Advance STEM Osteogenic Differentiation Kit, HyClone, Logna,
UT) for an additional 9 days with complete medium change every 3 days. On day
18, the wells were washed with PBS, then fixed for 15 minutes in 2% formalin
solution, and costained for alkaline phosphatase activity (Vector Blue ALP,
Vector Labs, Burlingame, CA) and calcified extracellular matrix (0.5% Alizarin
Red solution, Sigma-Aldrich, St. Louis, MO).
Outcome Assessment
and Analysis
There were no serious complications from harvesting the bone marrow
concentrate or the disc injections. The most common events were transient pain
at the harvest site and discomfort at the injection site, both of which
typically resolved within 48 hours of treatment. Not every patient improved
significantly, but no patient reported increases in visual analog scale or neck
disability index from pre-treatment scores. Patient follow up outcomes were
obtained by independent reviewers who were not investigators with the study.
The reviewers were paid senior pre-med students. Univariable data comparisons
of baseline to follow-up were analyzed using a two-tailed student’s t-test with
a 95% confidence interval (Alpha=0.05, Microsoft Excel). Demographic
comparisons were done using paired sample t-tests (www.socscistatistics.com).
Several human studies have recently been published documenting the
clinical results of utilizing biologics to treat symptomatic chronic lumbar
discogenic pain. The Coric, Pettine study was an FDA phase one evaluation of
utilizing expanded juvenile cartilage cells to treat discogenic low back pain
[47]. Fifteen patients were injected at one lumbar level with 10 million cells
and followed for one year. ODI went from 53.3 to 20.3 (p-value<0.0001) and
SF-36 improved from 35.3 to 46.9 (p-value<0.0002). MRI improvement of at
least one Pfirrmann grade was observed in 77% of patients. No patient had
surgery. Pettine, et al, have published one- and two-year follow-up studies on
26 patients injected with bone marrow concentrate (the same as this study) for
discogenic low back pain. Average improvement in ODI was 64% and VAS was 71%.
Only five of the 26 patients had surgery [30,31].
This study is a prospective non-randomized open label evaluation of 182
patients followed for two years to obtain preliminary data on the safety and
efficacy of utilizing BMC to treat symptomatic cervical degenerated discs.
The results in this group of 182 patients undergoing a single injection
of BMC into 1 to 4 discs in the cervical spine was unexpected. The two-year
follow-up showed an average improvement in NDI of 63% and VAS of 67%
(p<0.001). No patient was made worse and no patient underwent surgery during
the follow up.
Limitations of this study include: no randomized control, no follow-up
MRI scan data, and no cell count data. The author has published MRI follow-up
data and cell count data in a similar group of patients in the lumbar spine [30,31].
CONCLUSION
Patients with more than two levels of symptomatic discogenic cervical
pain have limited treatment options. There is minimal literature reporting the
long-term efficacy of any non-operative treatment and these patients basically
have minimal surgical options. Two-year follow-up data in treating multilevel
discogenic cervical pain with the BMC showed an improvement in NDI of 63%
(p<0.001) and VAS of 67% (p<0.001). No patient was made worse from the
procedure and there were no complications from the percutaneous injection of
BMC into the disc. Utilizing MSCs derived from BMC, based on these preliminary
results, may offer patients with multilevel discogenic cervical pain a viable
treatment option.
I would like to acknowledge the help of Dylan Merideth and Nick Collins
in obtaining patient follow up.
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