International Orthopaedics (SICOT)

DOI 10.1007/s00264-016-3178-3

REVIEW ARTICLE

Intradiscal platelet-rich plasma (PRP) injections for discogenic

low back pain: an update
Michael Monfett 1 & Julian Harrison 1 & Kwadwo Boachie-Adjei 1 & Gregory Lutz 1

Received: 17 February 2016 / Accepted: 27 March 2016

# SICOT aisbl 2016

Abstract Introduction
Purpose The aim of this article is to provide an overview of
clinical and translational research on intradiscal platelet-rich Throughout the world, low back pain (LBP) is a common and
plasma (PRP) as a minimally invasive treatment for often complex problem for patients and physicians. As the
discogenic low back pain. most common cause of disability among Americans between
Methods A literature review of in vitro, in vivo, and clinical 45 and 65 years of age [1], LBP affects approximately 80 % of
studies was performed. adults, who will experience at least one episode of LBP during
Results There is strong in vitro evidence that supports the use their lifetime [2]. Furthermore, LBP imposes a significant eco-
of intradiscal PRP for discogenic low back pain. There are nomic burden on the US healthcare system [3], amounting to
also promising findings in select preclinical animal studies. the most costly musculoskeletal problem in the nation [4].
A clinical study of 29 participants who underwent intradiscal Most cases of LBP are self-limited; however, approximately
PRP injections for discogenic low back pain found statistically 20 % recur within six months of the initial episode and a subset
and clinically significant improvements in pain and function of patients experience chronic symptoms thereafter [4]. This
through two years of follow-up. subset of patients—which is often left with the difficult deci-
Conclusions Intradiscal PRP is a safe and a possibly effective sion of either living with the pain or undergoing major spinal
treatment for discogenic low back pain. Future studies are surgery—that may be candidates for intradiscal PRP therapy.
warranted to determine the best candidates for this treatment, LBP can have many varied underlying aetiologies. Of all the
what the optimal injectate is and what relationships exist be- causes, intervertebral disc (IVD) degeneration is one of the
tween patient-reported outcomes and radiological findings. most prevalent, accounting for ≥40 % of chronic LBP [4].
The IVD plays an important role in maintaining mobility and
stability of the adult spine [5]. Structurally, it comprises an
Keywords Biologic . Disc . Treatments inner nucleus pulposus (NP) and an outer fibrocartilaginous
ring, named the annulus fibrosus (AF). The NP, composed of
mainly water and proteoglycans, can bear heavy compressive
* Gregory Lutz loads due to its intrinsic hydrostatic pressure. The AF, com-
[email protected] posed of an extracellular matrix (ECM) mixed with both type
Michael Monfett I and II collagen, can resist heavy tensile stresses [5, 6]. The
[email protected] adult IVD is the largest avascular structure in the human body.
Julian Harrison Small branches of the metaphyseal arteries around the outer
[email protected]; [email protected] annulus comprise its limited vasculature, and therefore, the
Kwadwo Boachie-Adjei
IVD must rely on passive diffusion from adjacent endplate
[email protected] vessels for nutrition [7]. Unlike bone, which has an adequate
blood supply with great ability to repair and regenerate, the
1
Department of Physiatry, Hospital for Special Surgery, 429 E 75th IVD has no intrinsic capacity for remodeling and repair. This
Street, 3rd Floor, New York, NY 10021, USA limited vascular supply and largely indirect access to nutrition
 International Orthopaedics (SICOT)

results in poor inherent healing potential. IVD degeneration efficient, minimally invasive, sustainable, safe and readily
usually accompanies normal aging and is characterisd by a loss available, and is supported by well-designed clinical studies.
of IVD homeostasis. This results in degradation and dehydra- There is mounting evidence suggesting that intradiscal in-
tion of the NP, followed by breakdown of the collagenous fibre jections of platelet-rich plasma (PRP) may help injured or
bundles in the AF. Due to the homeostatic imbalance of the degenerative discs. PRP is an autologous injectate derived
IVD, annular fissures develop, allowing for migration of NP from patients’ own whole blood which is centrifuged to yield
contents into the outer AF. A variety of pro-inflammatory cy- injectates concentrated with platelets and several biologically
tokines have been implicated in this process, including active soluble mediators of IVD homeostasis. The theory
interleukin-1 beta (IL-1β) and tumor necrosis factor alpha supporting the use of PRP in treating various musculoskeletal
(TNF-α). Upregulation of these cytokines can lead to chemical conditions is based on the concept of reparative healing. In
sensitisation of the rich network of nerve fibres that reside in the this context, growth factors are considered essential in the
outer AF [8–10]. The combination of these events, with the healing process and tissue formation [21]. It is believed that
inability of the IVD to heal after injury because of its limited in the earlier stages of DDD, the remaining functional cells
vascular supply, lead to chronic pain characterised by the con- within the IVD, when exposed to varied growth factors, re-
dition referred to as degenerative disc disease (DDD) [4]. spond with proliferation and extracellular matrix (ECM) ac-
Currently, the most common treatments available for cumulation, which helps to restore and preserve the structure
DDD range from conservative strategies (physical therapy and function of the degenerated IVDs [22]. PRP is considered
and anti-inflammatory medications) to minimally invasive extremely rich in these growth factors, which are contained
interventional techniques (epidural injections and ablation within the platelet alpha granules. Of particular interest in the
techniques) to surgical options [11, 12]. Each of these strat- context of pain-generating IVDs are the high concentrations of
egies aims to provide symptomatic relief from clinical symp- fibrin, transforming growth factor beta (TGF-β), insulin-like
toms associated with DDD, but none actually target the spe- growth factor-1 (IGF-1), basic fibroblast growth factor
cific underlying pathophysiology itself or reverse the degen- (bFGF), platelet-derived growth factor-BB (PDGF), and vas-
erative process. Historically, the two most commonly cular endothelial growth factor (VEGF) [23–26]. Recently,
employed techniques considered to be minimally invasive there has been considerable interest in the utility of PRP in
options were intradiscal electrothermal therapy (IDET) and the treatment of degenerative IVB disease.
nucleoplasty. Evidence for IDET reports short-term improve- The objective of this article was to discuss and summarise
ments in pain relief at six months of 40–75 % and long-term the most recent literature, including in vitro, in vivo and clin-
relief between 16 and 75 % [13–17]. The evidence for ical trials, focusing on the use PRP injectate in the setting of
intradiscal electrothermal therapy (IDET) is considered lumbar IVD-derived pain.
strong for short-term and moderate for long-term relief in
managing chronic discogenic LBP [18]. With regards to In vitro
nucleoplasty, the evidence largely consists of prospective
evaluations yielding limited evidence for nucleoplasty as a In vitro investigations on the regenerative potential of PRP on
treatment option for lumber discogenic pain. Open IVD cells report consistent results. Chen et al. [27] assessed
discectomy and microdiscectomy were recently evaluated PRP in a 2D culture of human NP cells to determine the pro-
by Cook et al., who found that less than half of 1,108 pa- teoglycan accumulation and antiapoptotic effects demonstrated
tients achieved at least 50 % improvement with regards to by NP cells. They reported that NP cell proliferation increased
pain and disability outcomes following the procedure. 7–11 times compared with controls, along with upregulated
Radicular pain greater than LBP was observed to be a strong proteoglycan content. Around the same time, Akeda et al.
prognostic indicator for discectomy [19]. Accordingly, in the [28] assessed the effects of PRP on porcine IVD ECM and
absence of conspicuous morphologic deformity, indications found that IVD tissues cultured in PRP lead to upregulated
for surgical intervention appear less substantiated. synthesis of proteoglycans and collagen. Kim et al. [29] sought
Reoperation after lumbar disc surgery was recently to understand what role PRP has in suppressing IL-1- and
discussed by Cheng et al., who found that there was also TNF-α-induced inflammation in human-derived NP cells and
still a notable population requiring reoperation and/or revi- found that PRP leads to both a downregulation of proinflam-
sion following primary operations targeting lumbar disc her- matory cytokines and upregulated ECM synthesis. Similarly,
niation [20]. With such variable results in treatments for Liu et al. [30] found that immortalised human NP cells previ-
IVD degeneration, studies involving other viable options ously exposed to lipopolysaccharides (LPS) underwent upreg-
focused on preventing, treating and possibly reversing the ulation of chondrogenic markers and downregulation of inflam-
degenerative disc process, are ongoing. The ideal treatment matory mediators and matrix-degrading enzymes following
option would not be harmful or destructive to tissue but would culture with PRP. More recently, Pirvu et al. [31] investigated
repair and/or regenerate the injured tissue. It would be cost the regenerative potential of PRP and platelet lysate (PL) on
International Orthopaedics (SICOT)

bovine AF cells and concluded that both induced proliferative significantly reduced apoptotic NP cells [33]. Using a percu-
effects on AF cells and upregulation of ECM synthesis. taneous annulus puncture-induced DDD rat model, Gullung
et al. [34] found that discs treated with PRP had higher pres-
In vivo ervation of normal morphology, fewer inflammatory cells and
higher fluid content, as evidenced by T2 MRI compared with
While results collected in vitro are relatively consistent, the in sham at four weeks post-injection. Hou et al. [35] found that
vivo evidence for the effect of PRPs on disc degeneration bone morphogenic protein-2 (BMP-2) transduced bone mar-
appears more variable. Nagae et al. initially reported in 2007 row mesenchymal stem cells when combined with a PRP gel
[32] that autologous PRP embedded in gelatin microspheres scaffold could survive 12 weeks in vivo when injected into the
found via immunohistochemical staining that IVD proteogly- injured discs of rabbits. They also demonstrated ECM resto-
can content was enhanced in a suction-induced DDD rabbit ration and preservation of NP histologic structures. Obata
model at eight weeks following intradiscal administration of et al. [36] found that at eightweeks post-injection, rabbit discs
PRP. Two years later, the same group found that discs injected injected with PL activated with calcium chloride had signifi-
with PRP had significantly higher water content determined cantly higher disc height and number of NP cells than those
by magnetic resonance imaging (MRI), which corresponded injected with phosphate-buffered saline. While the PRP lysate
with increased intradiscal proteoglycan content, upregulated group exhibited normalised T2 relaxation times that were con-
messenger RNA (mRNA) precursors for type II collagen and sistently higher compared with saline controls at 8 weeks, this

Fig. 1 Two-year longitudinal Numeric Rating Scale: pain results foof participants who received intradiscal platelet-rich plasma (PRP)
 International Orthopaedics (SICOT)

difference lacked statistical significance. The results of the (SF-36) and the modified North American Spine Society
study conflict with those reported by Chen and colleagues (NASS) Outcome Questionnaire. Participants were randomised
[37], but as Obata et al. explain, this can likely be attributed into PRP versus control groups after provocative discography,
to the use of a chymopapain-induced DDD model and PL and data was collected at baseline, one week, four weeks,
prepared using thrombin, which has been shown to degrade eight weeks, six months and one year. Of note, participants
cartilage tissues [38]. A more recent in vivo investigation who did not improve at eight weeks were offered the option to
using a rabbit AF puncture model found that intradiscal injec- cross over to receive PRP treatment and were subsequently
tion of PRP significantly hindered the progression of DDD as followed. At eight weeks, the authors found there were statisti-
determined using modified Pfirmann criteria [39]. However, cally significant improvements in those who received the
as the MRI evaluators in that study were unblinded, the ob- intradiscal PRP compared with the control groups with regards
jectivity of these findings is unclear. Overall, variable meth- to pain (NRS best pain), function (FRI) and patient satisfaction
odologies in preclinical animal studies demonstrate a range of (NASS Outcome Questionnaire.) At the eigh tweek time point,
histologic and radiological changes that warrant further inves- 68.2 % of control patients requested to be unblinded from the
tigation both in translational and clinical settings. control arm of the study and received the PRP treatment. These
participants were longitudinally followed as a separate arm after
Clinical trials eight weeks. PRP and control group outcomes were not com-
pared beyond the eight week time point. Longitudinal analysis
The utility of intradiscal PRP as a treatment for DDD was was conducted on participants of the original PRP group at
demonstrated recently in the clinical setting by Tuakli- six months and one and two years. The authors found that there
Wosornu et al. [26]. They performed a DBRCT comprising was improvement at each time point with regards to NRS best
47 participants with DDD whose treatment group received pain, FRI function, and SF-36 (both pain and function) in the
single injections of autologous PRP versus the control group, PRP arm. Most impressively, there was clinically significant im-
who received contrast agent alone into symptomatic degener- provement sustained at two years post-injection for NRS worst
ative IVDs. The participants were analysed in terms of both pain −2.12 points (p < .01), FRI function −25.81points (p < .01)
pain and function using the Functional Rating Index (FRI), and SF-36 pain +23.99 (p < .01) and SF36 function 18.04
Numeric Rating Scale (NRS) for pain, the pain and physical (p < .01) (Figs. 1, 2, and 3). Throughout the course of the trial,
function domains of the 36-item Short Form Health survey there were no adverse events of disc-space infection, neurologic

Fig. 2 Two-year longitudinal Functional Rating Index results for participants who received intradiscal platelet-rich plasma (PRP)
International Orthopaedics (SICOT)

Fig. 3 Two-year longitudinal Short Form 36 pain and function results for participants who received intradiscal platelet-rich plasma (PRP)

injury or progressive herniation reported following the injection Clinical case

of PRP. With clinically significant and positive data through
104 weeks, the authors concluded that PRP is a safe and sustain- Dr. Gregory Lutz and his team at the Hospital for Special
able treatment option for discogenic pain. The authors encour- Surgery in New York have been using PRP for DDD for the
aged further studies to look at ways to optimise the PRP injectate past six years and provided us with a case example of the typical
to potentially produce even better clinical results. patient who responds to this type of therapy. The patient was a

Fig. 4 Axial and sagittal T2

magnetic resonance images
(MRI) of the patient prior to
intradiscal platelet-rich plasma
(PRP) injection. Arrows highlight
left L4-5 disc protrusion, with
visible high-intensity zone
 International Orthopaedics (SICOT)

Fig. 5 Sagittal and

anteroposterior fluoroscopic
images of the patient undergoing
L3-4 and L4-5 provocative
discography. An annular fissure is
visible at L4-5 in the
anteroposterior view

54-year-old woman with severe, chronic, LBP and left L4 radic- questions regarding its use. Just as Cooke et al. had described
ular pain from a small left-sided foraminal disc protrusion the presence of possible predictive factors for determining
(Fig. 4a, b). She reported trialing anti-inflammatory medications, surgical outcome measures and optimal surgical candidates,
physical therapies and even several interventional procedures at further research is needed to discover characteristics that
outside clinics. After two years of failed therapies and refractory would suggest a nonsurgical intradiscal PRP interventional
pain, she underwent a two-level discogram, which was normal route may be a more favorable option in the setting of lumbar
at L3-4 but al L4-5 provoked concordant pain (Fig. 5a, b), disc disease [19]. If an algorithm can be achieved to positively
showing evidence of annular fissure. Postdiscography computed predict whether a surgical or nonsurgical route would best
tomography (CT) scan images (Fig. 6a, b) revealed a grade IV suite each patient, then not only would patient and physician
annular tear. The patient had received 1.5 ml of autologous PRP satisfaction improve, but also a large economic burden may be
at the time of discography and four weeks post-procedure, lifted from the healthcare system in general. Illien-Junger et al.
reporting near complete pain relief. At that time, the patient suggest that there may also be a role for injectable regenerative
was re-enrolled in comprehensive physical therapy and followed therapies used to augment surgical treatments at the time of
in the clinic. At 18 months post-procedure, she continued to intervention and serve as a protective tool against post-
report sustained improvement in both pain and function procedural degeneration for the IVD tissues [40]. The litera-
(Fig. 7a, b). ture to date suggests that intradiscal PRP has the potential to
not only fill this role but to prevent surgery in many patients.
Future clinical trials should focus on determining optimal can-
Discussion didates to receive such treatments, optimal PRP concentration
and composition, effects of receiving multiple injections,
The pre-clinical and clinical studies summarised in this man- whether cellular physiology responsible for IVD regeneration
uscript support intradiscal PRP as a safe and possibly thera- can be targeted to optimise the therapeutic effect, whether any
peutic agent for this disabling condition, as well as being a biomarkers or MRI variations exist that could serve as prog-
sustainable cost-efficient treatment option. These procedures nostic indicators and if there exists a role for augmenting
can be performed in the outpatient setting in about 30 minutes surgical interventions with intra-operative PRP.
and are about one tenth the cost of a spinal fusion. However, We believe we are at the onset of a paradigm shift in how
further research is needed to elucidate the many unanswered patients with degenerative disc disease will be managed in the

Fig. 6 Axial and anteroposterior

computed tomography (CT)
imaging of the study participant
following provocative
discography and injection of PRP
at L4-5. A grade IV fissure with
circumferential spread of contrast
in the periphery of the annulus
fibrosus is visible in the axial
view
International Orthopaedics (SICOT)

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Acknowledgments The platelet-rich plasma preparation kits used in chronic low back pain in active-duty soldiers: 2- year follow-up.
the clinical study included in this review were donated by Harvest Spine J 3:502–509
Technologies. 18. Boswell MV, Trescot AM, Datta S, Schultz DM, Hansen HC, Abdi
S, Sehgal N, Shah RV, Singh V, Benyamin RM, Patel VB,
Compliance with ethical standards Buenaventura RM, Colson JD, Cordner HJ, Epter RS, Jasper JF,
Dunbar EE, Atluri SL, Bowman RC, Deer TR, Swicegood JR,
Conflict of interest Dr. Gregory Lutz is the Chief Medical Advisor for Staats PS, Smith HS, Burton AW, Kloth DS, Giordano J,
Biorestorative Therapies, LLC. The authors have no other financial inter- Manchikanti L (2007) American Society of Interventional Pain
ests to disclose. Physicians. Interventional techniques: evidence-based practice
guidelines in the management of chronic spinal pain. Pain
Physician 10(1):7–111
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