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The Journal of Craniomandibular & Sleep Practice
ISSN: 0886-9634 (Print) 2151-0903 (Online) Journal homepage: http://www.tandfonline.com/loi/ycra20
Liquid platelet-rich fibrin injections as a treatment
adjunct for painful temporomandibular joints:
preliminary results
Jonathan B. Albilia DMD, MSc, Carlos Herrera- Vizcaíno DDS, Hillary
Weisleder BSc, Joseph Choukroun MD & Shahram Ghanaati MD, DMD, PhD
To cite this article: Jonathan B. Albilia DMD, MSc, Carlos Herrera- Vizcaíno DDS, Hillary
Weisleder BSc, Joseph Choukroun MD & Shahram Ghanaati MD, DMD, PhD (2018): Liquid
platelet-rich fibrin injections as a treatment adjunct for painful temporomandibular joints: preliminary
results, CRANIO®, DOI: 10.1080/08869634.2018.1516183
To link to this article: https://doi.org/10.1080/08869634.2018.1516183
Published online: 20 Sep 2018.
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Liquid platelet-rich fibrin injections as a treatment adjunct for painful
temporomandibular joints: preliminary results
Jonathan B. Albilia DMD, MSca, Carlos Herrera- Vizcaíno DDSb, Hillary Weisleder BScc, Joseph Choukroun MDd
and Shahram Ghanaati MD, DMD, PhDe
Private Practitioner and Attending, Division of Oral and Maxillofacial Surgery, Department of Dentistry, Jewish General Hospital, Montreal,
Canada; bDepartment for Oral, Cranio-Maxillofacial and Facial Plastic Surgery. FORM (Frankfurt Orofacial Regenerative Medicine) Lab,
University Hospital Frankfurt Goethe University, Frankfurt am Main, Germany; cFormerly Department of Anatomy and Cell Biology, McGill
University, Montreal, QC, Canada; Currently, MD Candidate, New York Medical College, New York, NY, USA; dPrivate Practitioner, Pain
Therapy Center, Nice, France; eDepartment for Oral, Cranio-Maxillofacial and Facial Plastic Surgery, FORM (Frankfurt Orofacial Regenerative
Medicine) Lab, University Hospital Frankfurt Goethe University, Frankfurt am Main, Germany
Objective: To evaluate the clinical benefits of liquid platelet-rich fibrin (PRF) in patients with
temporomandibular joint (TMJ) pain and dysfunction.
Methods: Forty-eight TMJs in 37 patients with painful internal derangement (ID) (Wilkes’ I–V)
were included. Patients were injected with 1.5–2cc of PRF within the superior joint space at 2week intervals. Pain and subjective dysfunction were recorded using a visual analog scale.
Statistical analyses were done using the ANOVA test.
Results: Thirty-three of 48 TMJs (69%) showed significant reduction in pain at 8 weeks, and at 3,
6, and 12 months (Responders). Fifteen of 48 TMJs (31%) did not improve (Non-responders). The
best Responders to liquid PRF injections were ID stages Wilkes’ IV (78.5%) and V (100%),
compared to Wilkes’ I (0%), II (47%), and III (33%). A non-significant, but notable decrease in
dysfunction was found.
Conclusion: Preliminary findings support that liquid PRF exhibits long-term analgesic effects in
most patients with painful TMJ ID.
Arthritis; TMJ internal
derangement; liquid
platelet-rich fibrin; tissue
engineering; pain; i-PRF;
LSCC; low-speed
centrifugation concept
The temporomandibular joint (TMJ) is a key component in the functioning of the stomatognathic system,
and as a system, derangement of components due to
external or internal articular overloading, e.g., parafunctional habits, altered occlusion or degenerative
pathologies, can cause a continuous cycle of reactions
leading to structural joint deterioration [1]. TMJ internal derangement is one of the most common forms of
TMJ disorders, affecting 10% of the population worldwide, with a higher prevalence in young females [2].
The term denotes a disruption in the relation between
the articular eminence, the articular disc, and the condyle, which in turn interferes with joint nutrition,
waste removal, lubrication and stabilization, blood supply, and local delivery of systemic medications [1,3,4].
Internal derangement of the TMJ includes conditions
like anchored disc phenomenon and disc displacement
with and without reduction [2]. These variations in the
disc-condyle relation can cause an increase in the physiological internal articular pressure (IAP) of the TMJ
and collapse of blood perfusion [5], which leads to
erosion of the synovial membrane and increases
hypoxic-reoxygenation cycles. Such cycles are associated with non-enzymatic release of highly reactive
oxidative species (superoxide anions and hydroxyl
anions) that trigger a rapid chemical reaction
(Fenton’s reaction) [6], causing damage to key biomolecules in the synthesis of hyaluronic acid (HA) and
synovial fluid (SF). The reduced viscosity of the SF
increases joint friction, adherence, and rupture of
articular surfaces, thus initiating a state of chronic
inflammation, synovitis, capsulitis, and ultimately,
fibrous adhesions [1,3,7,8] (Figure 1).
The tendency of non-invasive treatments to painful
or degenerative TMJ internal derangements seeks to
cut the cycle of deterioration by the intraarticular
administration of various drugs, like long-lasting antiinflammatories, such as tenoxicam or etodolac, which
CONTACT Dr. Shahram Ghanaati
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ycra.
© 2018 Informa UK Limited, trading as Taylor & Francis Group
Figure 1. Pathophysiological cycle of temporomandibular joint (TMJ) deterioration after excessive loading and the establishment of
a degenerative pathology.
are non-steroidal anti-inflammatory drugs (NSAIDs),
or like corticosteroids, that function by means of reducing the biosynthesis of prostaglandins through direct
inhibition of cyclo-oxygenase (COX), and consequently, reduce inflammation [9–11]. Although this
category of drugs remains effective insofar as immediate analgesia is concerned, their effect on cartilage
metabolism and viability raises concerns [12,13]. The
term viscosupplementation, introduced in the 1970s,
indicates the restoration of the properties of SF (viscosity, shock absorbing, elasticity, and nutrition [14]) by
intraarticular injections of a high or low molecular
weight elastoviscous solution of hyaluronan, also called
HA [15]. Even though numerous studies report many
benefits, HA preparations possess short half-lives, and
when compared to other drugs, these have not shown
significant advantages [10,15,16]. The two previous
drugs described do not possess intrinsic reparative
biological features; however, biological effects have
been described. These effects are likely due to the
restoration of the joint environment, but the literature
lacks an explanation as to the long-term clinical benefits observed. Biosupplementation is the latest trend in
the field; the term indicates a restoration of joint rheology, anti-inflammatory, and anti-nociceptive effects,
the normalization of endogenous HA synthesis, and
cartilage regeneration [17].
Platelet-rich plasma (PRP) is a first-generation platelet concentrate from centrifuged blood with a weak
fibrin network in a liquid or gel form used after activation by thrombin and calcium. PRP has been described
as a biosupplement for TMJ derangement with properties including anti-inflammatory, analgesic, and antibacterial. PRP is also thought to restore intraarticular
HA properties, glycosaminoglycan synthesis by chondrocytes, balance joint angiogenesis, and it has also been
postulated to provide a scaffold for stem cell migration.
PRP was introduced in 1998, emphasizing the growth
factor content following platelet degranulation [18].
Due to the content of growth factors in PRP, there has
been an increase in the use of these concentrates in the
last decade in the maxillofacial surgery and orthopedic
disciplines. Nevertheless, PRP developers aimed at
removing leukocytes from blood concentrates, even
though it has been shown that they play an important
role in growth factor release and in different phases of
wound healing [19]. Furthermore, PRP can carry
numerous complications (coagulopathies, antibodies to
factors V and XI), and its tedious preparation renders its
use impractical in many outpatient clinical settings. In
2001, a second-generation blood concentrate was developed and termed platelet-rich fibrin (PRF), with numerous advantages and without the need for anticoagulants
or clotting activators (Figure 2). The developed PRF is
characterized by a strong three-dimensional fibrin
matrix in a coagulated state, which serves as a medium
for the slow and sustained release of growth factors, as
well as a scaffold for angiogenesis [22].
In 2017, the low-speed centrifugation concept
(LSCC) was introduced as a means of optimizing the
content and distribution of cells and growth factors
found within PRF matrices [23]. By lowering the relative centrifugation force (RCF) and maintaining a centrifugation time of 8 min, a liquid PRF matrix was
generated, with an even higher concentration of
immune cells, platelets, and growth factors, e.g.,
VGEF and TGF-β1, compared to previously described
solid PRF matrices [23,24]. Based on these results, the
influence of the RCF on the liquid PRF matrices was
analyzed using a stepwise decrease of the RCF (966–
60 g-force) with a lower centrifugation time of 3 min.
The results highlight a significantly higher number of
inflammatory cells, platelets, and significantly higher
growth factor/cytokine release in the low-RCF liquid
PRF preparation (700 rpm; 60 g for 3 min) [25].
Furthermore, in the clinical setting, the physiologic
coagulation of the liquid PRF formulation allows for
an easier handling and optimization of bone substitutes, highlighting its biological activity [26–30]. As a
result of its biological potential, this study introduces
this naturally-derived matrix for the first time as an
alternative or adjunct for treating painful internal
derangements of the TMJ. The aim of this preliminary
study is to evaluate to what extent liquid PRF improves
subjective pain and dysfunction in patients with painful
TMJ internal derangement.
Materials and methods
A level II prospective case study with a 12-month
follow-up was designed through a multicenter collaboration. This study followed the Declaration of
Helsinki on medical protocol and ethics. Patients
were informed about the treatment protocol, and a
written consent was signed by all participants. All
voluntarily-enrolled patients were also offered the
more conventional treatment for their disease state,
e.g., arthroscopic lysis and lavage, disc plication, discectomy, etc. Some study patients had ongoing splint
therapy; however, no patients began splint therapy or
other adjunctive therapy during the injection protocol
or post-treatment follow-up period. The study took
place at the Natix Oral Surgery Clinic in Montreal,
Canada between April 2015 and October 2016.
Patients were selected according to the following inclusion and exclusion criteria:
Figure 2. Characteristics and differences between platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). PRP requires platelet
activation by thrombin and calcium chloride during its preparation[20]; on the other hand, PRF is obtained through a one-step
centrifugation protocol without the requirement of an additive. The development of PRP is aimed to exclude the presence of white
blood cells (WBCs) and increase the content of platelets and fibrin. Conversely, the latest developed “Low-speed centrifugation
concept” introduced new PRF matrices with a higher content of white blood cells, platelets, and release of growth factors. A higher
content of white blood cells has been shown to play an important role in wound healing[19]. The released measurements of growth
factors increased in the liquid PRF when it was centrifuged using a low relative centrifugation force [21].
Inclusion criteria: Any degree of TMJ internal
derangement and localized TMJ pain.
● Exclusion criteria: Autoimmune diseases, major
mechanical obstruction to mouth opening, acute
capsulitis, benign or malignant TMJ lesions, neurologic disorders, blood discrasias, and myofascial
pain and dysfunction.
Thirty-seven patients fulfilled the inclusion criteria,
and 48 TMJs in total were classified and treated independently. Clinical evaluation was used for the classification of the TMJ internal derangement according to
Wilkes’ classification and confirmed by MRI in the
majority of cases [31] (Table 1). Patients’ gender, previous treatments and pain/dysfunction were recorded
(unilateral or bilateral). Pain and dysfunction were
recorded using a 10-cm visual analog scale (VAS) ranging from a 0 value, representing no subjective sensation of pain/dysfunction to a 10 value, representing the
worst imaginable pain/dysfunction. All assessments
and recordings were carried out by one evaluator pretreatment and afterwards at each time point prior to
any repeat injection. Only non-responders to the PRF
injection(s) received further interventions, such as
arthroscopic lysis and lavage or open surgery.
Liquid platelet-rich fibrin preparation
Blood was collected from the antecubital vein through
an aseptic technique of blood collection, using commercially-available butterfly needle sets and vacutainer
Table 1. Wilkes’ classification system for internal derangement
of TMJ [31].
Clinical findings
Radiographic findings
Painless clicking, No locking Slight forward displacement, good
anatomical contour of disc and
passive incoordination
Occasional painful clicking, Slight forward displacement, slight
intermittent locking,
thickening of posterior edge of
Frequent pain, joint
Anterior displacement with
tenderness, locking,
significant anatomical
restricted motion
deformity/prolapse of disc
Chronic pain, headaches,
Increase in severity, moderate
restricted motion with
degenerative remodeling hardcrepitus
tissue changes
Variable pain, joint crepitus Anterior displacement, perforation
with simultaneous filling of
upper and lower compartments,
filling defects.
tubes (sterile uncoated plastic tubes) without additive
(9-mL i-PRF tubes, Process for PRF, Nice, France) and
immediately centrifuged. The low speed centrifugation
protocol used to obtain liquid PRF was 60 (g) for 3 min
[25]. (Table 2). For liquid PRF, only two layers are
obtained after centrifugation: the red blood cells at the
bottom and the liquid PRF at the top of the tube, with an
approximate relation of 7:2, respectively. For each TMJ,
1.5–2 cc of liquid PRF was withdrawn into a 3 mL or 5mL syringe using a 21G needle by carefully penetrating
the rubber top on the vacutainer tube (Figure 3).
Injection technique
All injections were performed by the same oral and maxillofacial surgeon (JBA). The skin surface of the preauricular region was disinfected with antiseptic solution,
and a reference line was traced between the lateral
canthus and tragus. An auriculotemporal nerve block
was performed with 0.5–1.0 cc of 3% mepivacaine. The
articular fossa (AF) as the point of injection was confirmed by manual palpation of its lateral edge (deepest
concavity), about 10 mm anterior to the tragus and 2 mm
below the canthal-tragal line [32]. A 30G needle was
inserted in the TMJ capsule, 1.5-mL of liquid PRF was
deposited into the superior joint space (SJS), and 0.5 mL
was distributed in the retrodiscal tissue (RT) and pericapsular area (maximum of 2 mL/joint). The correct
location of the needle was verified by confirming the
ensuing ipsilateral open bite caused by the joint insufflation [33,34]. After the first injection, patients were interrogated and self-evaluated their pain/dysfunction
progress every two weeks on a VAS. The protocol was
continued only if there was a positive response
(Responders) in comparison to the previously recorded
values for pain on the VAS and was repeated until the
pain-VAS value was zero (0) or reached a subjectivelydetermined satisfactory level. For patients who did not
respond favorably to the treatment (Non-responders), the
protocol was immediately discontinued (Figures 4 and 5).
Statistical analysis
Patients’ VAS results were averaged (mean ± SD). The
mean values of the pain and dysfunction scores obtained
at each time point were statistically compared to the preinjection value. All statistical analyses, tables, and figures
Table 2. Low-speed centrifugation protocol for liquid platelet-rich fibrin (PRF).
PRF protocol
Liquid matrix
Rotation (rpm)
Time of
centrifugation (min)
Radius-Max (mm)
Centrifuge machine
Duo centrifuge
Figure 3. The yellow liquid-layer fraction represents the liquid platelet-rich fibrin (PRF) after centrifugation. 1.5–2 cc of liquid PRF
was withdrawn into a 3-mL syringe without manipulating the red blood cell fraction.
were graphed using Prism Version 6 (GraphPad Software
Inc., La Jolla, CA, USA). Data are expressed as mean
± standard deviation. The significance of differences
among means of data were analyzed using two-way analysis of variance (ANOVA) and a Tukey’s multiple comparison post-hoc test. Thereby, statistical differences were
marked as significant if p-values were less than 0.05
(*p < 0.05), and highly significant if p-values were less
than 0.01 (**p < 0.01) or 0.001 (***p < 0.001).
The study sample consisted of 48 TMJs in 37 patients,
with a female to male ratio of 5.2:1. Thirty-three TMJs
(69%) showed improvement to liquid PRF injections
(Responders). Fifteen TMJs (31%) did not respond to
the treatment (Non-responders) (Figure 6, 7, and 8).
Among the Non-responders, 11/15 TMJs required invasive surgery. When all 48 TMJ samples were analyzed, no
statistically significant improvement in pain, dysfunction,
or maximal mouth opening (MMO) could be determined, although notably favorable trends for all these
variables were observed (Table 3). However, when
Responders were analyzed, statistically significant reductions in pain scores were noted at 8 weeks, and at 3, 6, and
12 months; dysfunction and MMO also showed highly
favorable trends (Table 4). The mean number of injections required to obtain a 0 or a satisfactory value of pain
in the VAS according to the Wilkes’ classification were:
stage II 3.16 ± 0.98; stage III 2.5 ± 0.70; stage IV
2.75 ± 1.13, and stage V 3.3 ± 1.56 (Figure 9).
Twenty-six patients were treated unilaterally (70%)
and 11 bilaterally (30%). There were no injection-related
complications reported throughout the study. Eight TMJs
(17%) had failed prior treatment of different types, and
seven of those TMJs responded positively to liquid PRF
injections (arthroscopy = 5 TMJs, corticosteroid injection = 2 TMJs). In relation to the pathological status of
the TMJ derangement, 59% of TMJs treated were Wilkes
intermediate-late or late stage (stages IV and V), and
Figure 4. Injectable platelet-rich fibrin (i-PRF) injection protocol for TMJ derangement. Patients were interrogated before initiating
the treatment protocol and before each injection. The visual analog scale (VAS) was used to register subjective sensation of pain
and dysfunction (scale: no pain: 0; worst imaginable pain: 10). Treatment was continued only when the patients responded
positively (responders) and was discontinued when higher VAS values were recorded (non-responders).
Figure 5. Injection technique. An imaginary line (yellow) from the tragus to the lateral canthus and the manual palpation of the
deepest concavity of the articular fossa (AF) guide the clinician to the site of injection. Liquid platelet-rich fibrin (PRF) is infiltrated
into the superior joint space (SJS), the retrodiscal tissue (RT), and the pericapsular area.
these responded the best to the tested treatment (78.5%
and 100%, respectively) (Table 5). In four different
patients, it was not possible to determine the stage of
the internal derangement, due to ambiguous clinical
symptoms and the absence of MRI.
The non-surgical management of pain and dysfunction of
TMJ derangements has been effective in improving the
quality of life of many patients but inefficient in providing
a treatment to stop or reverse the cycle of deterioration of
the TMJ structures, and hence, explains the diversity of
drugs available. Regenerative therapeutics are encompassed by the term biosupplementation, and this group
of therapeutics aims to restore normal structure and
function above and beyond symptomatic relief [35]. The
objective of this preliminary investigation was to test a
new autologous therapeutic protocol for painful TMJ
internal derangement. A treatment protocol is proposed,
consisting of intraarticular injections of liquid PRF every
two weeks, provided the patient continues to report
improvement (Figure 4). This shorter interval, compared
Figure 6. Mean values recorded from all patients using the visual analog scale (VAS) for pain evaluation and maximal mouth
opening (MMO) to evaluate dysfunction progression. Follow-up appointments are expressed in weeks (W) and months (M).
Figure 7. Mean values recorded from all patients using the visual analog scale (VAS) for pain evaluation during follow-up in the
Responder’s group.
to two to four weeks, as reported by authors using PRP
[17,36–38], aims at benefiting from the cumulative physiological effects from the precedent blood concentrate
Understanding the cycle of deterioration has led
researchers to study not only the biomechanics of the
TMJ but also the biochemistry involved in the pathophysiology of arthralgia and joint inflammation. The
lack of waste removal and blood supply generates a
higher concentration of pain mediators (substance P
[SP], serotonin, bradykinin, leukotriene B4 [LTB4],
and prostaglandin E2 [PGE2]) and pro-inflammatory
cytokines (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and IL-8) within the SF, which in
chorus, results in vasodilation, extravasation, activation
of immune cell–cell communication and differentiation, chemotaxis, and activation of nociceptive neurons
[8,11,39]. The chronic presence of pain mediators and
pro-inflammatory cytokines has been related to bone
remodeling as well as to proteoglycan degradation,
impairing cartilage elasticity [6,40].
There are two groups of patients in this study:
“Responders” to the treatment and “Non-responders.”
A rapid positive response in the “Responders” was
observed as early as five days after the first and subsequent injections (69%). This suggests that PRF
requires several days for its positive physiological
effects to take place. This can be explained by liquid
PRF’s spontaneous clotting (± 15 min) (Figure 10),
which preserves its contents (cells and growth factors)
in the articular space for a prolonged release [24]. This
benefit generates a progressive return of functional
activity and reduction in pain, due to restoration of
the TMJ bio-environment. The slow release of growth
Figure 8. Mean values recorded from all patients using the visual analog scale (VAS) for pain evaluation during follow-up in the
non-responder’s group.
Table 3. Pain, dysfunction and MMO in all samples expressed as Mean ± SD (statistical significance when p-value < 0.05).
Pain score (VAS 1–10)
12 M
Mean ± SD
5.67 ± 2.47
3.62 ± 2.41
3.2 ± 2.57
2.90 ± 2.99
3.28 ± 3.17
2.40 ± 2.99
2.98 ± 3.13
1.73 ± 3.13
(0–50 cm)
Dysfunction (VAS 1–10)
p > 0.05 (0.2967)
p > 0.05(0.1302)
p > 0.05 (0.1044)
p > 0.05 (0.3912)
p > 0.05 (0.0695)
p > 0.05 (0.6326)
p > 0.05 (0.1992)
5.26 ± 2.70
4.22 ± 2.80
3.46 ± 3.08
3.06 ± 3.40
3.87 ± 3.49
2.57 ± 3.08
2.31 ± 3.28
1.63 ± 3.08
p > 0.05 (0.9532)
p > 0.05 (0.5564)
p > 0.05 (0.445)
p > 0.05 (0.9229)
p > 0.05 (0.2719)
p > 0.05 (0.5218)
p > 0.05 (0.3031)
32.11 ± 7.47
33.68 ± 7.74
33.86 ± 7.76
33.5 ± 7. 81
33.07 ± 7.10
33.37 ± 6.80
35.2 ± 4.32
39.4 ± 6.35
SD, standard deviation; MMO, maximal mouth opening; W, weeks; M, months; VAS, visual analog scale.
Table 4. Pain, dysfunction and MMO among responders expressed as mean ± SD (statistical significance when p-value < 0.05).
Pain score (VAS 0–10)
12 M
5.65 ± 2.58
3.09 ± 2.09
2.65 ± 2.14
1.71 ± 2.20
1.55 ± 1.49
0.51 ± 0.61
2.63 ± 3.36
0.76 ± 1.21
Dysfunction (VAS 0–10)
p > 0.05(0.1814)
p > 0.05(0.0749)
p < 0.01(0.0084)
p < 0.05(0.0253)
p < 0.01(0.0019)
p > 0.05(0.6171)
p < 0.05(0.0454)
5.33 ± 2.64
4.03 ± 2.79
2.93 ± 2.84
1.92 ± 2.59
2.37 ± 2.95
0.76 ± 1.19
1.96 ± 3.74
0.65 ± 0.93
p > 0.05(0.923)
p > 0.05(0.3222)
p > 0.05(0.0642)
p > 0.05(0.3188)
p < 0.05(0.0124)
p > 0.05(0.4896)
p > 0.05(0.0731)
MMO (0–50 cm)
33.18 ± 6.53
34.75 ± 7.13
35.12 ± 7.69
34 ± 7.53
33.73 ± 6.36
33.73 ± 6.36
35.2 ± 4.32
39 ± 8.71
SD, standard deviation; MMO, maximal mouth opening; W, week(s); M, months; VAS, visual analog scale.
factors from solid PRF matrices was previously demonstrated in vitro [23]. In addition, it is noteworthy that
Responders showed a sustained reduction in pain and
dysfunction up to 12 months (Figure 7) and beyond
(observed but not reported), further supporting the
likelihood that liquid PRF possesses the ability to
restore joint homeostasis.
The results of this investigation are comparable to
those applying PRP to the TMJ [17,32,41,42], but without an arthroscopic intervention. It is thus plausible to
believe that in some patients, liquid PRF (produced by
the LSCC) can induce a natural lavage of SF by its
immediate delivery of immune cells for debridement
[24] of joint debris and repair (neutrophilic granulocytes) following restitution of the synovium’s capillary
network [43–45].
Non-responders (31%) showed an overall early
improvement that was not sustainable beyond eight
weeks, as seen in (Figure 8), and in some cases, invasive
treatment was the alternative (11/48 TMJs required
arthroscopic or open surgical interventions). Although
some of these Non-responders may have improved
Figure 9. Mean number of injections required to reach a zero
or satisfactory pain level. The pathological condition of the
participants was scaled using the Wilke’s classification [I–IV].
Table 5. Response to treatment based on Wilkes’ classification.
Wilkes’ classification
Responders (%)
Non-responders (%)
6 (47%)
2 (33%)
11 (78.5%)
10 (100%)
4 (100%)
1 (100%)
7 (53%)
4 (67%)
3 (21.5%)
spontaneously at a later follow-up, this could not be
attributed to the proposed therapeutic effects of liquid
PRF. As such, Non-responders with similar signs and
symptoms as at the pre-injection time point were
offered conventional surgical treatment as soon as
their Non-responder status was determined.
It is important to note that no adverse effects or
acute negative responses were recorded during or after
liquid PRF injections throughout the study. Patients
either improved or remained status quo as to their
pain and dysfunction scores. No complications were
observed related to blood immunology reactions or
pain exacerbation. Among Responders, pain improvement during treatment appears to be correlated with
the severity of the pathology. The higher the stage, the
greater the number of liquid PRF injections were
needed to reach the study goals in Wilkes’ stages III–
V patients (Figure 9). If a patient missed a follow-up
appointment, they returned with increased pain, but
not with a VAS pain score as high as at the initial
evaluation, in which case, treatment was continued.
Although not statistically significant, it is noteworthy
that MMO was inversely proportional to pain and
dysfunction values (Figure 6).
It is generally accepted that there are two categories
of patients with TMJ internal derangement (ID): those
Figure 10. Spontaneous (physiological) coagulation of liquid
platelet-rich fibrin (PRF) (working time of 10–15 min).
who adapt and those who do not adapt to the ID. The
patients who show adaptive remodeling to the ID will
progress to Wilkes’ IV or even V, without major symptoms in the initial stages. It is noteworthy that the best
Responders to liquid PRF injections were TMJ
derangements Wilkes’ IV (78.5%) and Wilkes’ V
(100%), compared to 0–47% for cases Wilkes’ I–III.
This suggests that patients who have the capacity to
adapt to the different stages of ID may benefit the most
from local administration of therapeutics, including
liquid PRF. This finding is consistent with that of
other minimally invasive interventions (such as arthroscopy, PRP, HA), being highly beneficial in patients
with Wilkes’ IV–V ID [46–49], treatments that essentially modify the bio-environment of the joint and
allow the body’s immune and repair mechanisms to
take over.
The benefits of intraarticular injections of liquid PRF
appear to result from a combination of its cellular, biochemical, and angiogenic properties [50]. Hypotheses are
as follows: first, that each PRF injection is causing a
mechanical tear of adhesions through a hydraulic distension and expansion of the superior articular space,
thereby eliminating the vacuum effect present in
osteoarthritis (OA); and second, that the physiologically
coagulated PRF improves SF viscosity and nutrition of
the intracapsular structures [51,52] (Figure 10). The prolonged release of cytokines and growth factors (IL-1β, IL8, IL-4, VEGF, EGF, TGF-β1 and PDGF-AB [53]) plays
an important role in providing a supportive environment
for debridement by circulating macrophages and type A
synoviocytes, followed by repair by chondrocytes and
type B synoviocytes, as precursors to these cell types
have been shown to be highly responsive to PRF
[54,55]. Only now, following a shift from a catabolic
state to an anabolic state, can remodeling of damaged
synovial, cartilage, and bone surfaces (condylar lipping,
osteophyte formation, subchondral cyst formation, irregular articular surfaces) occur [6,56]. Previous studies
have associated IL-1β, TNF-α, IL-6 and IL-8 with pain
and TMJ ID [57–59]. The high concentration of IL-4, an
anti-inflammatory cytokine found in PRF, modulates
inflammation by inhibiting MMP 1–3 and neutralizing
all transduction pathways from IL-1β, TNF-α and prostaglandins [60] (Figure 11).
Many clinical studies have reported the use of a single
drug to treat TMJ internal disorders [1,9]. Although the
combination of injectable therapeutics together with
adjunctive therapy was described to provide improved
benefits, the synergy requires further research [61,62]. In
this study, patients were treated only with liquid PRF
injections, irrespective of ongoing splint therapy.
Additionally, study patients were not permitted to begin
splint therapy, physical therapy, or other adjunctive
therapies during the treatment and follow-up period.
While external agents causing TMJ ID is outside the
scope of this article, it is believed that the management
of TMJ derangements should involve the management of
external causes (extracapsular pathologies or systemic
diseases) and internal causes (ID with or without OA)
to achieve positive and long-lasting results. As such, a
similar study taking into consideration adjunctive therapies, such as the wearing of an orthotic, concomitant,
Botox injections to the elevator muscles, systemic antiinflammatories, or physical therapies, could be interesting insofar as determining the benefits of a combination
therapy with liquid PRF injections.
The strength of this preliminary investigation is limited,
due to the absence of a control group using commonly
accepted therapies or using normal saline. The regenerative capabilities of PRF require validation involving a
higher number of patients, imaging follow-up, arthroscopic views, as well as preclinical animal models of OA
with histopathologic analysis to further understand the
Figure 11. The benefits of liquid platelet-rich fibrin (PRF) as a therapeutic agent for painful synovial joints.
mechanism of regeneration related to the use of PRF.
Further studies are underway to reproduce and validate
the long-term findings and to test various PRF matrices as
a carrier for various therapeutics specifically to joints.
This preliminary investigation demonstrates that
intraarticular injections of liquid PRF appear to have
significant analgesic effects lasting over 12 months in
patients with localized painful internal derangement of
the TMJ, which is only one of many synovial joint
disorders. Although the results herein are preliminary
(absence of a control group), patients suffering from
Wilkes’ stage IV (intermediate-late) and stage V (late)
respond the best to this specific second-generation
blood concentrate. Patients with pain and dysfunction
related to Wilkes’ stages I-III are better managed using
conventional methods, such as arthroscopic or open
surgical interventions, in order to treat the mechanical
anomaly or diseased tissue in cases where nonsurgical
methods have proven ineffective.
This study was only partially funded, after completion of
study, by the Research and Development Department of the
Canada Revenu Agency.
Conflict of interest
No authors, except Joseph Choukroun, possess financial
interest in Process for PRF®, Nice, France. This study was
not funded or supported by Process for PRF® in any way.
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