Funded an important Regenerative Medicine Research Paper

At Alliance Spine, we are committed to helping move forward the science behind regenerative medicine. We recently funded a research paper: “Combined administration of platelet-rich plasma and
autologous bone marrow aspirate concentrate for spinal
cord injury: a descriptive case series”.

By Joseph A. Shehadi, Steven M. Elzein, Paul Beery, M. Chance Spalding,
Michelle Pershing.

 

This is a copy of the article:

NEURAL REGENERATION RESEARCH|Vol 16|No.××|×× 2021|1
Combined administration of platelet rich plasma and
autologous bone marrow aspirate concentrate for spinal
cord injury: a descriptive case series
Joseph A. Shehadi1, *, Steven M. Elzein2, Paul Beery3, M. Chance Spalding3,
Michelle Pershing4
Abstract
Administration of platelet rich plasma (PRP) and bone marrow aspirate concentrate (BMAC)
has shown some promise in the treatment of neurological conditions; however, there is
limited information on combined administration. As such, the purpose of this study was to
assess safety and functional outcomes for patients administered combined autologous PRP
and BMAC for spinal cord injury (SCI). This retrospective case series included seven patients
who received combined treatment of autologous PRP and BMAC via intravenous and
intrathecal administration as salvage therapy for SCI. Patients were reviewed for adverse
reactions and clinical outcomes using the Oswestry Disability Index (ODI) for up to 1 year,
as permitted by availability of follow-up data. Injury levels ranged from C3 through T11, and
elapsed time between injury and salvage therapy ranged from 2.4 months to 6.2
years. Post-procedure complications were mild and rare, consisting only of self-limited
headache and subjective memory impairment in one patient. Four patients experienced
severe disability prior to PRP combined with BMAC injection, as evidenced by high (>
48/100) Oswestry Disability Index scores. Longitudinal Oswestry Disability Index scores
for two patients with incomplete SCI at C6 and C7, both of whom had cervical spine
injuries, demonstrated a decrease of 28–40% following salvage therapy, representing an
improvement from severe to minimal disability. In conclusion, intrathecal/intravenous coadministration
of PRP and BMAC resulted in no significant complications and may have
had some clinical benefits. Larger clinical studies are needed to further test this method of
treatment for patients with SCI who otherwise have limited meaningful treatment options.
This study was reviewed and approved by the OhioHealth Institutional Review Board (IRB
No. 1204946) on May 16, 2018.
Key Words: bone marrow aspirate concentrate; cell-based therapy; neural regeneration;
Oswestry Disability Index; platelet rich plasma; spinal cord injury; stem cells
Chinese Library Classification No. R456; R471; R605
https://doi.org/10.4103/
Received: February 23, 2020
Peer review started: February 26, 2020
Accepted: May 21, 2020
Published online: 2020
Introduction
Spinal cord injury (SCI) is associated with long-term, permanent
disability as a direct result of damage to the nervous
structures as well as by complex inflammatory and scar-forming
events that reduce regenerative capacity (Kjell and Olson,
2016; Shende and Subedi, 2017). Unlike the peripheral
nervous system, the central nervous system (CNS) shows
little inherent ability to regenerate due to: 1) the presence of
inhibitory factors present in myelin and scar tissue; 2) the intrinsic
state of CNS neurons, which show limited upregulation
of regeneration-associated genes; and 3) the physical barrier
incurred by the presence of scar tissue (Huebner and Strittmatter,
2009). Altogether, the CNS has limited intrinsic ability
to regenerate that is further exacerbated by complex post-injury
sequelae. Due to these limitations, treatment for SCI has
traditionally sought to minimize progressive damage through
rapid administration of medications such as corticosteroids to
reduce swelling and early surgical decompression of neural
elements via fixation and stabilization of the bony spine.
The more recent discovery that CNS neurons may be
prompted to regenerate through alteration of the local environment
(Benfey and Aguayo, 1982; Huebner and Strittmatter,
2009) has resulted in interest and enthusiasm in regenerative
therapies that promote structural and functional recovery
through cell and tissue replacement (Abbaszadeh et al., 2018).
Cell transplantation in SCI has been explored with a variety of
cell types that may minimize tissue loss and support axonal regrowth,
most commonly Schwann cells, olfactory ensheathing
cells, and progenitor and stem cells (Tsintou et al., 2015; Gabel
et al., 2017). These cell transplantation therapies have shown
promise in a number of in vitro and animal studies; however,
there has been only minor observed functional benefit in patients
with SCI, and growing evidence suggests that functional
recovery following SCI will not be possible with a single therapeutic
strategy.
1Section of Neurosurgery at OhioHealth Grant Medical Center, Cedar Stem Cell Institute, Columbus, OH, USA; 2The Ohio State University College of Medicine,
Columbus, OH, USA; 3Division of Trauma and Acute Care Surgery, OhioHealth Grant Medical Center, Columbus, OH, USA; 4OhioHealth Research Institute,
Columbus, OH, USA
*Correspondence to: Joseph A. Shehadi, MD, joseph@drshehadi.com.
https://orcid.org/0000-0002-9692-371X (Joseph A. Shehadi)
Funding: This study was funded by Alliance Spine, San Antonio, TX, USA.
How to cite this article: Shehadi JA, Elzein SM, Beery P, Spalding MC, Pershing M (2021) Combined administration of platelet rich plasma and autologous bone
marrow aspirate concentrate for spinal cord injury: a descriptive case series. Neural Regen Res 16(0):000-000.
Research Article
2 |NEURAL REGENERATION RESEARCH|Vol 16|No.×× |×× 2021
Compared to other cell-based therapies, bone marrow aspirate
concentrate (BMAC) may be preferable based on its lower
immunogenicity, wide availability, and absence of ethical concerns
(Li et al., 2015). BMAC can be a rich source of stem cells
(e.g., hematopoietic and mesenchymal stromal cells), other
progenitor cells, white blood cells, platelets and a variety of
growth factors (Chahla et al., 2016; Sugaya et al., 2018). Precise
mechanisms of action for BMAC as a regenerative therapy
have not been fully elucidated, but may include the ability of
mesenchymal stromal cells (MSCs) within the aspirate to secrete
trophic factors and cytokines (Joyce et al., 2010; Dasari
et al., 2014). Few studies have been conducted in humans;
although intrathecal administration of autologous bone marrow-
derived stem cells (BMDCs) every 4 weeks for 12 weeks
(Bansal et al., 2016) and administration of BMAC once intrathecally
or intralesion (Chhabra et al., 2016) corresponded to
improved functional outcomes in small cohorts of patients.
While there is evidence of the effectiveness of bone marrow
mesenchymal cells and/or aspirate concentrate for use in SCI
(Park et al., 2010), there are limitations associated with cell
delivery and integration when BMAC is delivered alone, potentially
because of variable ability for the transplanted cells
to integrate with tissue in the areas of interest (Kador and
Goldberg, 2012; Lee et al., 2015; Zhang et al., 2015; Kim et al.,
2018). Recent evidence suggests that regenerative capacity
is improved when stem or stromal cells are co-administered
with growth and differentiation factors (Steinert et al., 2012)
and/or tissue scaffolds. One promising avenue of current
research is the co-administration of stem cells with PRP. PRP
contains high concentrations of growth factors, which have
been shown to promote axonal growth in spinal cord tissues
(Takeuchi et al., 2012; Salarinia et al., 2017) and act as a tissue
scaffold (Shen et al., 2009; Lubkowska et al., 2012). In fact,
co-administration of PRP and BMAC yielded positive healing
effects in a rat model of SCI, as evidenced by astrocyte migration
and axonal remyelination (Zhao et al., 2013).
Given the evidence that cell-based therapies such as mesenchymal
stem cells and BMDCs show better results when
combined with PRP in various animal models (Cho et al., 2010;
Lian et al., 2014; Hosni Ahmed et al., 2017), we propose that
PRP in combination with BMAC may be a viable treatment
option for patients with SCI. However, there is a relative paucity
in the literature of studies utilizing both PRP and BMAC to
treat SCI, and further exploration is warranted. The purpose
of this case series is to describe the characteristics of patients
that have received PRP combined with BMAC for SCI and to
describe the clinical outcomes of these patients, including
change in Oswestry Disability Index (ODI) and the occurrence
of post-procedure complications.
Subjects and Methods
Study population
This retrospective case series included all patients (n = 7)
who received PRP plus BMAC for SCI. All procedures were
performed by a single physician (JAS) at Cedar Stem Cell Institute,
Columbus, OH, USA, between January 2015 and August
2017. Follow-up data, when available, was obtained through 1
year following the procedure. There are no exclusion criteria;
all patients who received PRP plus BMAC for any type of SCI
are included in this case series. This study was reviewed and
approved by the OhioHealth Institutional Review Board (IRB
No. 1204946) on May 16, 2018 with a waiver of the informed
consent requirement.
PRP and BMAC preparation
Patients were placed in a lateral position on a clinic table. A
large bore intravenous line was started using normal saline at
150 mL/h rate. Then, 60 mL of peripheral blood was drawn
from the upper extremity to collect PRP. This blood was then
mixed with 10 mL of anticoagulant citrate dextrose solution
and processed and centrifuged using the double spin technique
and the Cyclone® Concentrating System (Alliance Spine,
San Antonio, TX, USA). In brief, this technique consists of a
first spin at 2237 × g for 1.5 minutes, followed by aspiration
of the plasma supernatant and subsequent second spin of the
supernatant at 2237 × g for 5 minutes. This yielded on average
approximately 7–8 mL of PRP.
To obtain BMAC, the patient’s right posterior iliac crest region
was prepared and draped using sterile technique. The
skin was anesthetized with an average of 5–10 mL of 2% lidocaine
without epinpherine. Next, a JamshidiTM bone marrow
biopsy needle (Ranfac Corporation, Avon, Massachusetts,
USA) was introduced through the skin and past subcutaneous
tissues into the right posterior iliac crest. A 60-mL locking syringe
was used to slowly aspirate bone marrow, turning the
needle 90 degrees following every 10 mL of aspirate. This
bone marrow aspirate was then processed using the EmCyte®
bone marrow concentrating system (EmCyte Corporation,
Fort Myers, FL, USA). In brief, this consisted of evenly dividing
approximately 50 mL of bone marrow into two 30 mL syringes
along with 1000 units/mL of heparin per syringe. This mixture
was then filtered and centrifuged at 2008 × g for 10 minutes
to yield an average of 17 mL of BMAC. The PRP was mixed
with BMACs in a larger sterile syringe, resulting in a ratio of
approximately 1:2 (PRP:BMACs).
PRP and BMAC infusion
First, a standard lumbar puncture was performed using sterile
technique. Approximately 8 mL of cerebrospinal fluid was
removed and discarded. Next, between 7 and 9 mL of the
combination PRP and BMAC mixture were slowly injected
intrathecally. Then, all of the remaining PRP + BMAC volume
was given back to the patient intravenously via the proximal
sideport of the intravenous line. Lastly, we allowed for a gentle
normal saline bolus of approximately 500 mL given slowly.
Patients remained supine for 30–45 minutes following treatment
and were monitored in the office for 90 minutes prior
to discharge to home. Patients were instructed to call at any
time with complications and six of seven patients returned to
the treating physician’s outpatient office 2 months post-treatment
for routine follow-up. One patient was lost to in-person
follow-up but did not report any complications to the treating
physician. On average, patients received 8–9 mL intrathecally
and 12–18 mL intravenously (IV), except for case #2, for whom
the IV dose was discarded due to lack of IV access in an office
setting.
Study variable collection and outcome assessment
Study data were collected and managed using Research Electronic
Data Capture (REDCap) electronic data capture tools
hosted at OhioHealth (Harris et al., 2009). REDCap is a secure,
web-based application designed and provided by Vanderbilt
University, Nashville, Tennessee, USA to support data capture
for research studies, providing 1) an intuitive interface for validated
data entry; 2) audit trails for tracking data manipulation
and export procedures; 3) automated export procedures for
seamless data downloads to common statistical packages; and
4) procedures for importing data from external sources. Data
were copied from Cedar Stem Cell Institute medical records to
REDCap by an independent clinical research coordinator from
the OhioHealth Research Institute.
Data collected included patient demographics, injury information,
types of therapies (surgical and non-surgical) prior to
receiving PRP plus BMAC treatment, procedure-related complications
at 90 minutes post-treatment and 2 month routine
follow-up, and functional outcomes (ODI) for up to 1 year
following the procedure when available. ODI is a measure of
functional disability, on a scale of 0% to 100%, where higher
scores represent higher disability (Fairbank and Pynsent, 2000;
Davidson and Keating, 2002). ODI scores were tabulated utilizing
a standard survey covering the following ten categories:
pain intensity, personal care, lifting, walking, sitting, standing,
Research Article
NEURAL REGENERATION RESEARCH|Vol 16|No.×× |×× 2021|3
sleeping, sex life, social life, and traveling. Patient responses to
each category are assigned a point value from 0 (no disability
due to injury) to 5 (maximum disability due to injury), and
aggregate scores are divided by the total possible score of 50
to yield a percentage of functional disability. Data were summarized
using descriptive statistics (mean, standard deviation,
median, range for continuous data and frequency/percentage
for categorical data).
Results
Table 1 summarizes demographics and characteristics for the
seven SCI patients who underwent PRP plus BMAC treatment,
including functional outcomes when available and post-procedure
complications.
Patient demographics and injury characteristics
The mean age of patients treated was 43.7 ± 16.9 years (median
46 years; range 22–65 years) and the majority (n = 5) were
male. Five patients suffered cervical injuries (C3 to C7) while
the remaining two patients had thoracic injuries (T4 or T11).
Patients received the PRP plus BMAC treatment between 2.4
months and 6.2 years following the initial injury (mean: 2.5 ±
2.33 years; median: 2.1 years), and all patients had at least two
interventions (surgery and physical therapy) prior to undergoing
PRP plus BMAC therapy. Prior surgery types included laminectomy,
corpectomy, fusion, anterior cervical discectomy and
fusion and/or spinal cord stimulator placement. In addition to
the above, two patients also engaged in occupational therapy
prior to undergoing PRP plus BMAC injections.
Procedure-related side effects and complications
Aside from a single patient who could not receive the IV dose
due to lack of venous access, procedure-related complications
were limited to a single patient who had a self-limiting headache
(1–3 days) and self-reported difficulty with recall.
Clinical outcomes
ODI assessment results showed that with the exception of a
single patient with minimal disability, remaining patients had
significant functional disability (range: 48% to 68%) prior to
PRP plus BMAC treatment.
Two patients (28.6%) provided baseline ODI scores with one
or more follow-up evaluations. Both patients improved from
“severe disability”, where activities of daily living were affected
to “minimal disability”, where the patient can cope with most
daily living activities (Table 1). Patient 5, who had a chronic
phase C7 injury level, exhibited a 40% improvement in disability
score at the 12-month follow-up. Patient 7, who had an
acute-phase C6 injury, exhibited a 28% improvement in disability
score at 2-month follow-up.
Discussion
In this study, we assessed the safety and effectiveness of a
combined mixture of adult autologous PRP and autologous
BMAC uniquely administered via both intrathecal and intravenous
routes in SCI patients. Our patient population consisted
primarily of individuals with chronic SCI who had undergone
at least two prior interventions including surgery and physical
therapy. In our cohort, one patient could not receive intravenous
treatment due to lack of venous access in the office
setting. Only one patient reported procedure-related complications,
namely a self-limiting headache and subjective recall
difficulty. Longitudinal ODI scores were obtained from two of
the seven patients and demonstrated improved scores from
“severe disability” to “minimal disability” for both.
Traumatic damage to the spinal cord is highly complex at the
cellular level. It consists of hypoxia, ischemia, necrosis, excess
production of pathological inflammatory factors, the accumulation
of excitatory amino acids, the influx of large amounts
of calcium ions, and significant amounts of oxygen free radicals
and nitric oxide which induce apoptosis of neurons and
neuroglia and disturb neurological function. Considering this
cascade of events, the challenge of interventional therapies
for SCI is to intervene at one or more of these levels to avoid
further cellular apoptosis and to promote axonal regeneration
and improve patient functionality.
One therapy that has shown promise for SCI rehabilitation
in pre-clinical studies is PRP (Takeuchi et al., 2012; Salarinia
et al., 2017; Chen et al., 2018). The enhancing effect of PRP is
based on the premise that a large number of platelets in PRP
release significant quantities of growth factors that aid the
healing process. These factors include platelet-derived growth
factor, transforming growth-factor beta, insulin-like growth
factor, vascular endothelial growth factor, epidermal growth
factor, fibroblast growth factor, keratinocyte growth factor,
connective tissue growth factor, and interleukin-8 (Fernandes
and Yang, 2016). Salarinia et al. (2017) demonstrated benefits
of PRP using a rat SCI model simulating blunt trauma and cord
contusion. They demonstrated functional motor recovery as
well as axonal regeneration following intrathecal PRP injection
24 hours post-lesion. Chen et al. (2018) directly injected PRP
into rat spinal cords and examined the effect of PRP on normal
and injured spinal cord. In normal spinal cords, PRP induced
microglia and astrocyte activation. In the SCI rats, PRP enhanced
locomotor recovery and spared white matter, promoted
angiogenesis and neuronal regeneration, and modulated
blood vessel size. While the exact mechanisms remain elusive,
Takeuchi et al. (2012) showed that human PRP promoted axon
growth in neonatal rat cerebral cortex and spinal cord co-culture
in an insulin-like growth factor-1- and vascular endothelial
growth factor-dependent manner.
Another therapy that has gained traction for SCI treatment
is transplantation of BMDCs obtained from BMAC. BMDCs
have been associated with functional locomotor recovery, preserved
axons, increased myelin sparing, reduced scar tissue
formation (Nakajima et al., 2012), preserved spinal ultrastructure
and hind limb motor recovery (Karaoz et al., 2012), and
reduced inflammatory reaction (Park et al., 2005) in rat models
of spinal cord contusion. In clinical trials, both the safety
of autologous BMDC treatment (Callera and do Nascimento,
2006; Yoon et al., 2007) and capacity for functional improvement
(Park et al., 2005; Dai et al., 2013) in SCI patients have
been demonstrated. While it is known that bone marrow-derived
MSCs possess tropism for damaged tissue sites, including
in chronic SCI patients (Callera and de Melo, 2007), the
exact mechanisms by with BMDC promote healing from SCI
is unknown and may lie within spinal cord neuroneogenesis
Table 1 | Patient demographics, injury characteristics, functional
outcomes, and complications
Demographics Injury information
Complications or
Patient Age (yr) Sex adverse events
Highest
level
Complete (C) or
incomplete (I)
Years postinjury
1 46 F C3 I 6.2 Self-limiting
headache; patientreported
memory
impairment
2 22 F C4 C 0.7 No intravenous
dose administered
due to lack of
intravenous access
3 65 M T11 C 0.5 None
4 33 M C7 C 2.1 None
5 55 M C7 I 3.2 None
6 59 M T4 I 4.9 None
7 26 M C6 I 0.2 None
Patient 5: Oswestry Disability Index (ODI) scores improved from 60 at time of
treatment to 20 at 12 months post-treatment. Patient 7: ODI scores improved
from 48 at time of treatment to 20 at 2 months post-treatment. F: Female; M:
male.
4 |NEURAL REGENERATION RESEARCH|Vol 16|No.×× |×× 2021
(Corti et al., 2002).
One unique aspect of the present study is the combination
treatment of both PRP and autologous BMAC for SCI patients.
While PRP and BMAC have been proven safe and in many cases
effective in treating SCI in preclinical and clinical models,
their synergistic effects are much less studied. Positive synergistic
effects of PRP combined with BMAC treatment have
been demonstrated via improved bone healing in distraction
osteogenesis of the tibia (Lee et al., 2014), rehabilitation of rotator
cuff injury (Liu et al., 2019), and facial nerve repair in an
acute nerve injury model (Cho et al., 2010). In a rat model of
spinal cord hemisection, Zhao et al. (2013) demonstrated that
a combination of PRP scaffolds with brain derived neurotrophic
factor- overexpressing BMDCs resulted in a synergistic effect
promoting astrocyte migration and axonal remyelination.
Ammar et al. (2017) utilized a combination of hematopoietic
stem cells and PRP along with a fibrin coating in SCI patients.
This study demonstrated motor and objective sensory improvement
in one patient, subjective sensory improvement in
two other patients, and no improvement in one patient who
received combination treatment. Of note, none of the patients
demonstrated adverse effects and MRI studies proved
non-migration of the inserted scaffolds 2–3 years following
treatment. While interesting, this study drew BMDCs from peripheral
blood rather than bone marrow itself, likely resulting
in a substantial proportion of hematopoietic stem cells with
controversial neuronal differentiation capability as opposed
to mesenchymal stem cells with the proven capability to mature
into neurons (Ullah et al., 2015). Additionally, this study
involved heavily invasive treatment methods including laminectomy
and dural- and spinal cord- dissection under general
anesthesia.
Another unique aspect of the current study is the multi-focal
administration of PRP plus BMAC therapy to SCI patients.
In our study, PRP plus BMAC combination treatment was administered
both intrathecally via lumbar puncture and intravenously
for all patients except one who lacked optimal intravenous
access. In addition to avoiding injection directly into the
SCI site, which may potentiate previous damage, this unique
multi-focal treatment method allows for multiple avenues of
regeneration and potentially bypasses obstacles associated
with either intrathecal or intravenous administration in any
one particular patient. Syková et al. (2006) compared intra-arterial
versus intravenous administration of bone marrow cells
in subacute- and chronic-SCI patients, noting partial improvement
in sensory and motor impairment scores and evoked
potentials in all four subacute SCI patients who received
intra-arterial injection and in one out of four who received intravenous
injection. While their group concluded that implantation
of bone marrow cells intra-arterially or intravenously
was safe and without complications, conclusions on functional
improvement as a result of the treatment were unable to be
drawn. Geffner et al. (2008) demonstrated that administration
of bone marrow stem cells into acute and chronic SCI patients
via multiple routes, including simultaneous administration
directly into the spinal cord, directly into the spinal canal, and
intravenously was safe, feasible, and had the capability to improve
quality of life scores for SCI patients. In their cohort of
25 SCI patients with 3-month comprehensive follow-up, while
most patients avoided adverse events, they do note transient
lack of erection or ejaculation in four patients, sweating on
one half of the body in two patients, and spinal cord canal fistula
in one patient.
One potential limitation of the current study lies in the
number of patients enrolled. Seven total SCI patients, ranging
from 2 months to 6.2 years post-injury, were treated under
our unique treatment protocol. This study is also limited due
to loss of regular patient follow-up post-treatment, which
limits our ability to make inferences about long-term changes
in sensory or motor impairment and overall functional recovery.
Of the seven patients treated, immediate adverse events
were noted in only one patient and were mild – a self-limiting
headache and patient-reported memory impairment. Patients
were monitored for an average of 90 minutes post-treatment,
during which time the other six reported no complications.
Although not significant enough to draw conclusions, one
patient’s ODI score improved from 60 at time of treatment
to 20 at 12 months post-treatment, while another patient’s
improved from 48 at time of treatment to 20 at 2 months
post-treatment. Future studies involving more patients and
regular, uninterrupted follow-up will be necessary in order to
further determine the safety, feasibility, and efficacy of combined
intrathecal and intravenous PRP plus BMAC treatment
for SCI.
Conclusions
While PRP and BMAC are commercially available and considered
safe and effective for numerous medical conditions,
they are not yet United States Food and Drug Administration
approved for SCI. Through our preliminary investigations, a
combination treatment of PRP and BMAC appears to be safe
and has the potential additive benefit of stem cells from bone
marrow combined with the more ideal milieu of PRP, which is
known to have potent growth hormones and cytokines. This
therapeutic combination shows great potential for recovery
from SCI and further studies are warranted to evaluate this
cutting-edge treatment modality.
Author contributions: Study design: JAS, PB, MCS, MP; data analysis: MP,
SME. All authors approved the final version of this study and contributed
to the preparation of the manuscript.
Conflicts of interest: Dr. Shehadi’s work has been funded by Alliance
Spine, the manufacturer of the kits utilized for the patients described in
this case series. He has also consulted for Alliance Spine and received
compensation. These conflicts of interest were minimized by OhioHealth
Research Institute, which provided independent personnel for data
collection and analysis. Dr. Beery, Dr. Spalding, Dr. Pershing, and Mr. Elzein
declare no potential conflict of interest.
Financial support: This study was funded by Alliance Spine, San Antonio,
TX, USA. The funding body played no role in the study design, in the
collection, analysis and interpretation of data, in the writing of the paper,
and in the decision to submit the paper for publication.
Institutional review board statement: The study was approved by the
OhioHealth Institutional Review Board (IRB No. 1204946) on May 16,
2018 with a waiver of the informed consent requirement.
Declaration of patient consent: This study is a retrospective case series,
for which the informed consent requirement is waived by the institutional
review board.
Reporting statement: This study followed the STrengthening the
Reporting of OBservational studies in Epidemiology (STROBE) statement.
Biostatistics statement: The statistical methods of this study were
reviewed by the biostatistician of OhioHealth Research Institute, USA.
Copyright license agreement: The Copyright License Agreement has
been signed by all authors before publication.
Data sharing statement: De-identified individual participant data that
underlie the results reported in this article will be available immediately
after study publication through 3 years to anyone who wishes to access
the data. De-identified data will be stored by the OhioHealth Research
Institute for 3 years following publication, then it will be destroyed per
institutional policy. If requested, study protocols and outputs of statistical
analysis will be available. All data sharing will occur following execution
of data sharing agreements as required by OhioHealth Research Institute.
Plagiarism check: Checked twice by iThenticate.
Peer review: Externally peer reviewed.
Open access statement: This is an open access journal, and articles are
distributed under the terms of the Creative Commons Attribution-Non-
Commercial-ShareAlike 4.0 License, which allows others to remix, tweak,
and build upon the work non-commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
Research Article
NEURAL REGENERATION RESEARCH|Vol 16|No.×× |×× 2021|5
References
Abbaszadeh HA, Niknazar S, Darabi S, Ahmady Roozbahany N, Noori-Zadeh A,
Ghoreishi SK, Khoramgah MS, Sadeghi Y (2018) Stem cell transplantation
and functional recovery after spinal cord injury: a systematic review and
meta-analysis. Anat Cell Biol 51:180-88.
Ammar AS, Osman Y, Hendam AT, Hasen MA, Al Fubaish FA, Al Nujaidi DY, Al
Abbas FM (2017) A method for reconstruction of severely damaged spinal
cord using autologous hematopoietic stem cells and platelet-rich protein as
a biological scaffold. Asian J Neurosurg 12:681-690
Bansal H, Verma P, Agrawal A, Leon J, Sundell IB, Koka PS (2016) Autologous
bone marrow-derived stem cells in spinal cord injury. J Stem Cells 11:51-61.
Benfey M, Aguayo AJ (1982) Extensive elongation of axons from rat brain into
peripheral nerve grafts. Nature 296:150-152.
Callera F, de Melo CM (2007) Magnetic resonance tracking of magnetically
labeled autologous bone marrow CD34+ cells transplanted into the
spinal cord via lumbar puncture technique in patients with chronic spinal
cord injury: CD34+ cells’ migration into the injured site. Stem Cells Dev
16:461‐466.
Callera F, do Nascimento RX (2006) Delivery of autologous bone marrow
precursor cells into the spinal cord via lumbar puncture technique in
patients with spinal cord injury: a preliminary safety study. Exp Hematol
34:130-131.
Chahla J, Dean CS, Moatshe G, Pascual-Garrido C, Serra Cruz R, LaPrade RF
(2016) Concentrated bone marrow aspirate for the treatment of chondral
injuries and osteoarthritis of the knee: a systematic review of outcomes.
Orthop J Sports Med 13:2325967115625481.
Chen NF, Sung CS, Wen ZH, Chen CH, Feng CW, Hung HC, Yang SN, Tsui KH,
Chen WF (2018) Therapeutic effect of platelet-rich plasma in rat spinal cord
injuries. Front Neurosci 12:252
Chhabra HS, Sarda K, Arora M, Sharawat R, Singh V, Nanda A, Sangodimath
GM, Tandon V (2016) Autologous bone marrow cell transplantaion in acute
spinal cord injury – an Indian pilot study. Spinal Cord 54:57-64.
Cho HH, Jang S, Lee SC, Jeong HS, Park JS, Han JY, Lee KH, Cho YB (2010) Effect
of neural-induced mesenchymal stem cells and platelet-rich plasma on
facial nerve regeneration in an acute nerve injury model. Laryngoscope
120:907-913.
Corti S, Locatelli F, Donadoni C, Strazzer S, Salani S, Del Bo R, Caccialanza M,
Bresnolin N, Scarlato G, Comi GP (2002) Neuroectodermal and microglial
differentiation of bone marrow cells in the mouse spinal cord and sensory
ganglia. J Neurosci Res 15:721-733.
Dai G, Liu X, Zhang Z, Yang Z, Dai Y, Xu R (2013) Transplantation of autologous
bone marrow mesenchymal stem cells in the treatment of complete and
chronic cervical spinal cord injury. Brain Res 1533:73-79.
Dasari VR, Veeravalli KK, Kinh DH (2014) Mesenchymal stem cells in the
treatment of spinal cord injuries: A review. World J Stem Cells 6:120-133.
Davidson M, Keating JL (2002) A comparison of five low back disability
questionnaires: reliability and responsiveness. Phys Ther 82:8-24.
Fairbank JC, Pynsent PB (2000) The Oswestry Disability Index. Spine 15:2940-
2952.
Fernandes G, Yang S (2016) Application of platelet-rich plasma with stem cells
in bone and periodontal tissue engineering. Bone Res 13:16036
Gabel BC, Curtis El, Marsala M, Ciacci JD (2017) A review of stem cell therapy
for spinal cord injury: Large animal models and the frontier in humans.
World Neurosurg 98:438-443.
Geffner LF, Santacruz P, Iurieta M, Flor L, Maldonado B, Auad AH, Montenegro
X, Gonzalez R, Silva F (2008) Administration of autologous bone marrow
stem cells into spinal cord injury patients via multiple routes is safe and
improves their quality of life: comprehensive case studies. Cell Transplant
17:1277-1293.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research
electronic data capture (REDCap)–a metadata-driven methodology and
workflow process for providing translational research informatics support. J
Biomed Inform 42:377‐381.
Hosni Ahmed H, Rashed LA, Mahfouz S, Elsayed Hussein R, Alkaffas M,
Mostafa S, Abusree A (2017) Can mesenchymal stem cells pretreated with
platelet-rich plasma modulate tissue remodeling in a rat with burned skin?
Biochem Cell Biol 95:537-548.
Huebner EA, Strittmatter SM (2009) Axon regeneration in the peripheral and
central nervous systems. Results Probl Cell Differ 48:339-351.
Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA (2010) mesenchymal
stem cells for the treatment of neurodegenerative disease. Regen Med
5:933-946.
Kador KE, Goldberg JL (2012) Scaffolds and stem cells: delivery of cell
transplants for retinal degenerations. Expert Rev Ophthalmol 7:459-470.
Karaoz E, Kabatas S, Suruksu G, Okcu A, Subasi C, Ay B, Msluman M, Civelek E
(2012) Reduction of lesion in injured rat spinal cord and partial functional
recovery of motility after bone marrow derived mesenchymal stem cell
transplantation. Turk Neurosurg 22:207-217.
Kim SJ, Kim EK, Kim SJ, Song DH (2018) Effects of bone marrow aspirate
concentrate and platelet-rich plasma on patients with partial tear of the
rotator cuff tendon. J Orthop Surg Res 13:1. Kjell J, Olson L (2016) Rat
models of spinal cord injury: from pathology to potential therapies. Dis
Model Mech 1:1125-1137.
Lee DH, Ryu KJ, Kim JW, Kang KC, Choi YR (2014) bone marrow aspirate
concentrate and platelet-rich plasma enhanced bone healing in distraction
osteogenesis of the tibia. Clin Orthop Relat Res 472:3789-3797.
Lee S, Choi E, Cha MJ, Hwang KC (2015) Cell adhesion and long-term survival
of transplanted mesenchymal stem cells: a prerequisite for cell therapy.
Oxid Med Cell Longev 2015:632902.
Li XC, Zhong CF, Deng GB, Liang RW, Huang CM (2015) efficacy and safety
of bone marrow-derived cell transplantation for spinal cord injury: a
systematic review and meta-analysis of clinical trials. Clin Transplant
29:786-795.
Lian Z, Yin X, Li H, Jia L, He X, Yan Y, Liu N, Wan K, Li X, Lin S (2014) Synergistic
effect of bone marrow-derived mesenchymal stem cells and platelet-rich
plasma in streptozotocin-induced diabetic rats. Ann Dermatol 26:1-10.
Liu F, Meng Q, Yin H, Yan Z (2019) Stem cells in rotator cuff injuries and
reconstructions: A systematic review and meta-analysis. Curr Stem Cell Res
Ther 14:683-697.
Lubkowska A, Dolegowska B, Banfi G (2012) Growth factor content in PRP and
their applicability in medicine. J Biol Regul Homeost Agents 26:3S-22S.
Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, Yoshida
A, Long G, Wright KT, Johnson We, Baba H (2012) Transplantation of
mesenchymal stem cells promotes an alternative pathway of macrophage
activation and functional recovery after spinal cord injury. J Neurotrauma
29:1614-1625.
Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, Park HS (2005) Treatment
of complete spinal cord injury patients by autologous bone marrow cell
transplantation and administration of granulocyte-macrophage colony
stimulating factor. Tissue Eng 11:913-922.
Park WB, Kim SY, Lee SH, Kim HW, Park JS, Hyun JK (2010) The effect of
mesenchymal stem cell transplantation on the recovery of bladder and
hindlimb function after spinal cord contusion in rats. BMC Neurosci 11:119.
Salarinia R, Sadeghnia HR, Alamdari DH, Hoseini SJ, Mafinezhad A, Hosseini M
(2017) Platelet rich plasma: Effective treatment for repairing of spinal cord
injury in rat. Acta Orthop Traumatol Turc 51:254‐257.
Shen YX, Fan ZH, Zhao JG, Zhang P (2009) The application of platelet-rich
plasma may be a novel treatment for central nervous system diseases. Med
Hypotheses 73:1038-1040.
Shende P, Subedi M (2017) Pathophysiology, mechanisms and applications
of mesenchymal stem cells for the treatment of spinal cord injury. Biomed
Pharmacother 91:693-706.
Steinert AF, Rackwitz L, Gilbert F, Nöth U, Tuan RS (2012) Concise review:
the clinical application of mesenchymal stem cells for musculoskeletal
regeneration: current status and perspectives. Stem Cells Transl Med
1:237-247.
Sugaya H, Yoshioka T, Kato T, Taniguchi Y, Kumagai H, Hyodo K, Ohneda O,
Yamazaki M, Mishima H (2018) Comparative analysis of cellular and growth
factor composition in bone marrow aspirate concentrate and platelet-rich
plasma. Bone Marrow Res 2018:1549826.
Syková E, Jendelová P, Urdziková L, Lesný P, Hejcl A (2006) Bone marrow stem
cells and polymer hydrogels–two strategies for spinal cord injury repair.
Cell Mol Neurobiol 26:1113-1129.
Takeuchi M, Kamei N, Shinomiya R, Sunagawa T, Suzuki O, Kamoda H, Ohtori S,
Ochi M (2012) Human platelet-rich plasma promotes axon growth in brainspinal
cord coculture. Neuroreport 23:712-716.
Tsintou M, Dalamagkas K, Seifalian AM (2015) Advances in regenerative
therapies for spinal cord injury: A biomaterials approach. Neural Regen Res
10:726-742.
Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells – current
trends and future prospective. Biosci Rep 35:e00191.
Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR,
Min B-H, Kim EY, Choi BH, Park H, Ha Y (2017) Complete spinal cord injury
treatment using autologous bone marrow cell transplantation and bone
marrow stimulation with granulocyte macrophage-colony stimulating
factor: Phase I/II clinical trial. Stem Cells 25:2066-2073.
Zhang J, Huang X, Wang H, Liu X, Zhang T, Want Y, Hu D (2015) The challenges
and promises of allogeneic mesenchymal stem cells for use as a cell-based
therapy. Stem Cell Res Ther 6:234.
Zhao T, Yan W, Xu K, Qi Y, Dai X, Shi Z (2013) Combined treatment with
platelet-rich plasma and brain-derived neurotrophic factor-overexpressing
bone marrow stromal cells supports axonal remyelination in a rat spinal
cord hemi-section model. Cytotherapy 15:792-804.
C-Editors: Zhao M, Li CH; T-Editor: Jia Y