Clinical therapy of hyaluronic acid combined with platelet‑rich plasma for the treatment of knee osteoarthritis

WENXING YU, PENG XU, GUILING HUANG and LIN LIU

Department of Orthopedics, Hong-Hui Hospital, Xi’an Jiangtong University College of Medicine, Xi’an, Shaanxi 350021, P.R. China

Received December 19, 2016; Accepted August 23, 2017 DOI: 10.3892/etm.2018.6412

 

Abstract. Knee osteoarthritis is the most common degenera- tive disease of the joints caused by articular cartilage injury, degradation of the joint edge and subchondral bone hyper- plasia. Various treatments are used to alleviate the symptoms of patients with knee osteoarthritis, including analgesics and intra-articular injections. Platelet-rich plasma (PRP) is an autologous and multifunctional platelet concentrate of the blood, which stimulates the cartilage healing process and improves the damage caused by articular disease. Hyaluronic acid (HA) is an effective treatment for patients with knee osteoarthritis. In the current study, the effectiveness of PRP and HA combination therapy administered via intra-articular injections for patients with knee osteoarthritis was analyzed. A total of 360 patients with knee osteoarthritis were randomized into four different treatment groups as follows: Double-blind treatment with PRP (2-14 ml); double-blind treatment with HA (0.1-0.3 mg); combination therapy of PRP and HA; and placebo groups. Following treatment, all patients were evalu- ated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Common Toxicity Criteria. The most common treatment-emergent adverse events were hypertension and proteinuria. The current study demonstrated that PRP and HA treatment significantly improved arthralgia, and PRP treatment was determined to be significantly more effective than HA treatment using the WOMAC pain score (P<0.05). PRP and HA combination treatment significantly improved arthralgia, reduced humoral and cellular immune responses and promoted angiogenesis, which improved the patients’ histological parameters compared with PRP or HA treatment alone. These results suggested that PRP and HA combination treatment may be a potential treatment option for patients with knee osteoarthritis in the future.

Introduction

Osteoarthritis is a degenerative disease with clinical mani- festations, including joint pain, tenderness, stiffness, joint swelling, restricted movement and joint deformities (1). In recent years, the incidence of osteoarthritis has increased and presents as a serious threat to human health and quality of life (2-4). The causes of osteoarthritis are complex, therefore it is difficult to develop a comprehensive classification system and its pathogenesis remains unclear (5). Osteoarthritis is divided into primary and secondary osteoarthritis depending on the presence of local and systemic risk factors, including high bone mass and metabolic disorders (6). It is frequently diagnosed in the clinic as rheumatoid arthritis and anky- losing spondylitis (7). Previous studies have demonstrated that rheumatoid arthritis is the most common manifestation of osteoarthritis in patients; however, an effective treatment strategy for rheumatoid arthritis remains unknown (8,9). Thus, further investigations into efficient treatments for osteoarthritis with minimal side effects are required.

Platelet-rich plasma (PRP) is a multifunctional platelet concentrate of the blood that may be used for the treatment of the manifestations of osteoarthritis, including osteonecrosis of the femoral head, cartilage injury and rheumatoid arthritis (10). It has been demonstrated previously that PRP improves the repair of articular cartilage injury in patients with joint disease by removing harmful inflammation factors (11). It was also demonstrated that PRP reduces the level of inflammatory factor synovial fluid in rheumatoid arthritis without exhibiting side effects (12). Treatment-emergent adverse events of PRP have not been previously reported. The isolation of PRP, including blood product rich in cytokines, growth factors and other bio-active molecules from autologous peripheral blood mononuclear cells, is an efficient and innovative treatment strategy (13). Furthermore, Sadabad et al (14) investigated the efficiency of PRP vs. hyaluronic acid (HA) for the treatment of knee osteoarthritis and Khoshbin et al (15) conducted a systematic review of PRP as a therapeutic intervention in the management of symptomatic knee osteoarthritis. These reports demonstrated that intravenous injection of PRP repaired the damage to the tendon and articular bone and reduced inflam- mation, which may serve a key function in maintaining the morphology, collagen microarchitecture and mechanical properties of the injected vein.

HA is a high molecular weight glucosamine (5-7×106 kD) synthesized by chondrocytes, fibroblasts and synovio- cytes (16). It is responsible for viscoelasticity and lubricance in the synovial fluid and extracellular matrix (17). It has been demonstrated that there is a higher concentration of HA (2.5-4.0 mg/ml) in the synovial fluid, while there is     a decreased concentration level in patients with osteoar- thritis (18). Therefore, the concentration of HA is an indicator of the prognosis of patients with osteoarthritis. The efficacy of HA treatment in improving osteoarthritis symptoms has been widely studied and the clinical outcomes for patients with osteoarthritis are positive (19-21).

The current study investigated the efficacy and outcomes of PRP and HA combination treatment in patients with knee osteoarthritis aged 22-68 years. The clinical data demon- strated that intra-articular injections of PRP were more successful in recovering articular function, alleviating symp- toms and reducing arthralgia and body pain compared with HA treatment. PRP and HA combination treatment signifi- cantly improved arthralgia, reduced humoral and cellular immune responses and promoted angiogenesis, which led to an improvement in histological parameters, compared with PRP or HA injections alone. These results suggest that PRP and HA serve a critical therapeutic role in knee osteoarthritis progression and highlights their potential for the treatment of knee osteoarthritis in the future.

 

Materials and methods

Patients. Patients with knee osteoarthritis (age, 22-72 years; 170 females and 190 males) with a Karnofsky performance status of ≥80% (patients have difficulty walking by themselves and have knee pain) (22) were randomly divided into four groups and once-weekly, double-blind trials were conducted in Xi’an Jiangtong University College of Medicine (Xi’an, China). The inclusion/exclusion criteria, and allocation method are described in previously published studies (23,24). Patients with knee osteoarthritis received PRP (2, 4, 8, 10, 12  and 14 ml, Sigma-Aldrich; Merck KGaA, Darmstadt, Germany), HA (0.10, 0.15, 0.20, 0.25 and 0.30 mg, Sigma-Aldrich; Merck KGaA), combination treatment or placebo (normal saline, Sigma-Aldrich; Merck KGaA) through intralesional injec- tions as referenced previously (23). The current phase-III study (XAJT006999781) was carried out in strict accordance with the recommendations in the Guide for Xi’an Jiangtong University College of Medicine between February 2009 and October 2014 (25). All patients were required to review trial protocols, amendments and provide informed consent. Ethical approval was granted by the Ethics Committee of Xi’an Jiangtong University College of Medicine (24).

Study design. The double-blind study was carried out in three phases: Baseline stage, the double-blind treatment phase (4-week  dose-titration treatment, PRP,  2,  4,  8,  10,  12 and

14  ml, HA, 0.10,  0.15,  0.20, 0.25 and 0.30 mg) and  52-week

post-treatment (PRP, 8ml, HA, 0.2 mg) for patients with knee osteoarthritis who volunteered to complete the ongoing exten- sion study. Patients were randomly sorted into groups where they underwent once-weekly, double-blind treatment with HA (n=88),  PRP (n=104),  combination therapy of  HA and PRP (n=96) or a placebo (n=72). Patients with knee osteoarthritis continued treatment with PRP (8 ml), HA (0.20 mg), combi- nation (PRP: 8 ml, HA: 0.20 mg) or placebo throughout the maintenance period (52 weeks).

Outcomes measures. A Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire (26) for pain, two items for stiffness and 17 items for assessing functional limitation and the function of patients with knee osteoarthritis. The data was recorded and the degree of lesion was calculated.

ELISA. Plasma samples were prepared immediately using centrifugation at 2,000 x g at 4˚C for 10 min. Serum levels of TNF-α (cat no. MBS6080, Thermo Fisher Scientific, Inc., Waltham, MA, USA), IL-1β (cat no. MBS700340, Thermo Fisher Scientific, Inc.), IL-6 (cat no. MBS3205, Thermo Fisher Scientific, Inc.), IL-17A (cat no. DY-5194, Bio-Rad Laboratories, Inc., Hercules, CA, USA), RANKL (cat no. DY626, Bio-Rad Laboratories, Inc.), PD-ECGF (cat no. DY229-05, Bio-Rad), VEGF (cat no. DVE00, Bio-Rad Laboratories, Inc.) and IL-10 (cat no. MBS910284, Thermo Fisher Scientific, Inc.) were analyzed using ELISA kits according to the manufacturer’s protocol. The serum concentration levels of these cytokines were measured using micro-plate reader at a wavelength of 570 nm.

Efficacy and safety assessments. Efficacy assessments, including WOMAC scores or Karnofsky performance were analyzed in patients with knee osteoarthritis at baseline, during the 52-week and double-blind period in  the  PRP (8 ml), HA (0.20 mg), combination (PRP: 8 ml, HA: 0.20 mg) or placebo treatment groups. In addition, the overall safety and pharmacokinetic analysis were conducted according to previous clinical studies (25-27). Safety assessments of the most frequent treatment-emergent adverse events were evalu- ated in all randomized patients who received the study drug and had undergone at least one post-dose safety assessment. Dose-response analysis was conducted at the time of the last drug injection. Common Toxicity Criteria grades for hyperten- sion and proteinuria were determined by the National Institute Common Terminology Criteria (28).

Statistical analysis. Data are expressed as the mean ± standard deviation. Statistical analysis was performed using a Student’s t-test for unpaired data. Comparisons of data between multiple groups were performed using one-way analysis of variance followed by a Dunnett’s t test. Treatment effect was presented as median reduction in knee osteoarthritis over the treatment period. Robust nonparametric Responder rates and treat- ment-emergent adverse events were analyzed using a χ2 test. P<0.05 was considered to indicate a statistically significant difference.

Results
Patient characteristics. There were 360 patients with knee osteoarthritis (mean age, 48 years) who were candidates for intra-articular injection in the present study. All patients were randomly divided into four groups and treated with HA (n=88),

 

Table I. Patient characteristics.

Table II. Treatment-emergent adverse events following platelet-rich plasma (PRP) treatment.

PRP (n=104), combination therapy of HA and PRP (n=96) or a placebo (n=72). The numbers of male and female patients were approximately equal. The characteristics of patients with knee osteoarthritis are presented in Table I. Overall, 277 (75%) patients with knee osteoarthritis completed the maintenance period of the phase III study, the other 25% stopped the study due to side effects.

Duration of treatment, dose‑limiting toxicities and maximum tolerated dose. Median overall duration of PRP and HA treatments was 8 weeks. Patients underwent treatments with at least one of the following doses: 2, 4, 8, 10, 12 and 14 ml

for PRP; and 0.10, 0.15, 0.20, 0.25 and 0.30 mg for HA. The data presented in Table II demonstrated that 12 ml PRP once  a week was identified as the maximum tolerated dose (MTD) and 16 ml of PRP once a week was identified as dose-limiting toxicity (DLT) (29). Doses of 0.25 and 0.30 mg HA were identified as the MTD and DLT, respectively (Table III). The common treatment-emergent adverse events of PRP or HA injection were hypertension, diarrhea, vomiting, rash, protein- uria, fatigue, constipation, hypertriglyceridemia and edema peripheral. A total of 60 patients with knee osteoarthritis required a reduction in drug dose for cumulative toxicity following treatment with MTD dose. Therefore, most patients were enrolled at a dose of 8 ml PRP and 0.20 mg HA for further examination of the tolerability and therapeutic effects of patients with knee osteoarthritis.

Treatment‑emergent  adverse  events  of  PRP,  HA  and combination treatment. Patients with knee osteoarthritis who received at least one dose of study therapy with a post-baseline safety evaluation were included in the safety population. Following the last dose of PRP, it was observed that the most common treatment-emergent adverse events of PRP, HA and combination treatment (PRP, 8 ml; HA, 0.20 mg) were hypertension and proteinuria (≥10% each; Table IV). The data for the 12 ml (n=28) and 14 ml (n=18) PRP doses are not shown as there were more side effects, including hypertension, proteinuria, constipation and diarrhea and few patients were treated at these dose levels. Of the 360 patients enrolled in the current study, 118 patients with knee osteo- arthritis completed the overall maintenance period of the phase III study.

Efficacy of combination PRP and HA treatment. The clinical outcomes of combination treatment of PRP and HA were analyzed. Preliminary clinical analyses indicated that pain was markedly improved in drug-treatment groups compared with the placebo group. Pain was reduced more in patients who received PRP treatment compared with patients who received HA treatment in the 52-week observation (P<0.01). Combination treatment of PRP and HA improved pain, physical function, stiffness and total WOMAC score compared with PRP treatment or HA treatment alone compared to the baseline (Table V). These clinical outcomes indicate that

Table III. Treatment-emergent adverse events following hyaluronic acid (HA) treatment.

Table IV. Common Toxicity Criteria grades for hypertension and proteinuria.

Table V. WOMAC scores during the study period.v

 

 

PRP (8 ml) and HA (0.20 mg) combination therapy improves
the clinical features of knee osteoarthritis.
PRP and/or HA treatments was then measured. Plasma concentration levels of interleukin (IL)-17A, tumor necrosis factor-α,
IL-1β and receptor activator of nuclear factor κ-B ligand were
downregulated in patients with knee osteoarthritis following
treatment with PRP or HA and further downregulated following
combination treatment with PRP and HA (all P<0.01; Figs. 1-4).
The plasma concentration of platelet derived-endothelial cell
growth factor, IL-6, vascular endothelial growth factor and
IL-10 were upregulated in patients with knee osteoarthritis
following treatment with PRP or HA and were further upregulated following combination treatment with PRP and HA (all
P<0.01; Figs. 5-8). These results suggest that combination PRP
and HA treatment inhibits inflammation for patients with knee
osteoarthritis.

Discussion
Reports have indicated that inflammatory cytokines serve a
critical function in the induction and development of osteoarthritis (30,31). PRP is an autologous and multifunctional
platelet concentrate of the blood that contains highly
concentrated platelets and high levels of cell growth factors.
PRP promotes synovial cell proliferation and differentiation,
and promotes recovery of cartilage morphology. Clinically,
Battaglia et al (32) has demonstrated the efficacy of ultrasound-guided intra-articular injections of PRP vs. HA for hip
osteoarthritis. Laudy et al (33) has suggested that PRP injections are beneficial to patients with knee osteoarthritus based
on a reduction in pain, improvement in function, global assessment and changes regarding joint imaging. Meheux et al (34)
demonstrated that treatment with PRP injection significantly
improved validated patient-reported outcomes in patients
with symptomatic knee osteoarthritis at 6 and 12 months
post-injection, and indicated similarities and differences in
outcomes based on the PRP formulations used in the analyzed
studies. These clinical reports suggest that PRP exhibited a
potential efficacy for treating osteoarthritis.
HA is responsible for the viscoelastic and lubricant capabilities of the synovial fluid in joints. It serves a key function
in metabolism in the joints and mechanical support, which
stimulates chondrocyte metabolism and cartilage matrix
components synthesis as well as inflammatory processes (35).
Clinical research has indicated that intra-articular HA injections in patients with knee osteoarthritis are associated with
pain relief, quality of life, survival time, clinical effect and a
longer period of time prior to the onset of knee arthroplasty (16).
In addition, the efficacy and safety of HA in the management
of osteoarthritis has been investigated using real-life setting
trials and surveys (17). However, single intra-articular HA
injections did not achieve the ideal therapeutic effect for
patients with osteoarthritis.
Previous studies have compared the clinical efficacy
of PRP vs. HA for treatment of knee osteoarthritis and
determined that PRP presented more notable improvements
in physical function, stiffness and total WOMAC (14,36).
Coincidentally, Kon et al (37) investigated PRP intra-articular
injection vs. HA viscosupplementation in treatments for cartilage pathology from early degeneration to osteoarthritis, and
outcomes suggested that PRP was superior to HA treatment
for patients with cartilage pathology. However, the efficacy
and safety of combination treatment with PRP and HA for
patients with knee osteoarthritis remains unknown.
In the present study, the clinical efficacy of combination
treatment with PRP and HA for patients with knee osteoarthritis was investigated in a phase-III clinical study. Following
an 8-week baseline period, patients with knee osteoarthritis
were randomized into groups undergoing once-weekly,
double-blind treatment with PRP, HA, combined therapy or
a placebo. Although previous studies indicated that patients
with knee osteoarthritis treated with PRP or HA exhibited
regulated plasma concentrations of inflammatory factors and
pro-angiogenic factors, the clinical outcomes of combined
PRP and HA have not been investigated (27,38). The current
study was performed to evaluate the clinical application
of combination treatment with PRP and HA. Responses to
treatment were assessed by median percent reduction in
arthralgia, which was improved with PRP and/or HA treatments compared with the placebo group. Hypertension and
proteinuria were the treatment-emergent adverse events
with the highest incidence following treatment with PRP
or HA alone. The results demonstrated that PRP and/or
HA alleviated knee osteoarthritis and reduced the humoral
and cellular immune responses, which subsequently led to
beneficial effects on histological parameters. The clinical
outcomes revealed a significant improvement in all the variables of WOMAC following combination treatment with PRP
and HA

In conclusion, although the direct effects of different drugs
on knee osteoarthritis have been demonstrated previously, it
is critical that the overall role of PRP and HA in affecting
entire joint cytokines homeostasis is investigated (39). Clinical
outcomes of the current study demonstrated that PRP and HA
are potential novel therapeutic options for treating knee osteoarthritis and an increasing number of clinical reports continue
to indicate promising results. Of note, the results of the current
study suggest that pharmacokinetic interactions of PRP and
HA are important determinants in optimizing therapies for
treating knee osteoarthritis. Therefore, clinicians are required
to monitor clinical responses and tolerability when patients are
treated with PRP and HA. The results indicate that patients
with knee osteoarthritis treated with PRP and HA exhibited
beneficial effects on body pain, and alleviated arthralgia,
cartilage destruction and bone damage.

Competing interests
The authors declare that they have no competing interests

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platelet Rich Plasma Rehabilitation Guidelines

What is tendinopathy?
Tendons are strong bands of connective tissue comprised primarily of a
substance called collagen. Mechanically,
tendons connect muscle to bone and transmit the force to generate
movement. Muscle and tendon injuries account for a significant percentage of the over 100 million physician visits
in the US per year and this number will continue to rise as our population ages and remains active1. Previously, tendon injuries and disorders were almost always considered tendonitis. Tendonitis is an inflammatory process,
but recent research has shown that most of the more chronic tendon problems do not have any inflammatory cells. The primary problem in these cases appears to be a breakdown of the structural properties of the tendon collagen. Thus the correct terminology for this problem is tendinopathy, as opposed to tendonitis.
Tendinopathy results from overstressing a tendon. This can be from a singular acute bout of activity, or more often, from repetitive and sustained stresses over many months or even years. It
is possible for different areas of the tendon to be in different stages of injury or disorder2. Tendinopathy can ultimately lead to chronic degradation of the tendon, and rarely, to the point of tearing or rupture. There are many current treatment options for this condition including, but not limited to,
rest, anti-inflammatory medications (e.g., ibuprofen, naproxen), steroid injections, physical therapy, shock wave therapy, dry needling, and surgery.
Recent advancements in regenerative (restoration and growth) medicine have led to the development of platelet-rich plasma (PRP) injections as a viable treatment for various tendinopathies.

What is platelet-rich plasma (PRP)?
PRP is the concentration of platelets derived from the plasma portion of one’s own blood3. While platelets are widely known to play a large role
in clotting processes, their use in the treatment of tendon disease is due to their abundance of enzymes and growth factors related to the healing
process4,5. Tendons have a poor blood supply, meaning it is difficult for these tissues to receive the nutrients needed to stimulate repair1,4,6. An injection of PRP to the injured site provides the tendon tissue with healing growth factors that are otherwise difficult for the body
to deliver because of the poor blood supply. Similar mechanisms have been theorized for the treatment of ligament injuries such as medial collateral ligament sprains of the knee or cartilage deterioration, such as osteoarthritis of the knee7. The injection can also restart a healing inflammatory process, which is why patients are often given initial activity restrictions. Subsequent referrals
to physical therapy are often made so that patients may be taught to load the tissue in an appropriate fashion to rebuild strength and flexibility.

What does the PRP procedure involve?
PRP begins by collecting blood from the individual, usually by using a syringe and needle at the arm, similar to a clinical laboratory blood draw. The amount of blood needed is determined by the size of the area to be treated and the concentration of platelets desired3. The blood is then placed in
a centrifuge where the rapid spinning process separates the blood into 3 components—the plasma or water portion of the blood, the PRP layer, and the cellular layer containing red and white blood cells. The PRP layer is
then available for use in the clinic. After applying a local anesthetic (numbing medicine) to the site of the injection, the PRP is injected into the injured tissue. Sometimes the injection is performed in the radiology department so that the radiologist physician
may view the area under ultrasound guidance to ensure accurate placement of the injection. The patient is educated about activity restrictions and is often given devices that limit the amount of movement in the area for the next few days. The patient is encouraged to rest the area for a few weeks, avoiding any beginning the rehabilitation process two weeks following the procedure. The patient is typically seen by the physician in the clinic for a routine follow-up about 1 month after the injection.

Do I need to do physical therapy and rehabilitation after PRP?

A quality post-procedure rehabilitation program helps facilitate a successful outcome. Initial rehabilitation will focus on protection for healing and gentle

range of motion. After the early phases, strengthening and neuromuscular control exercises are emphasized throughout the affected extremity. In the final stages of rehabilitation, the focus will be on progressive dynamic extremity control and stability during sport-specific movements, such as change of direction and rotational movements.

The UW Health Sports Medicine rehabilitation guidelines below are presented in a criterion based progression. General time frames are given for reference to the average, but individual patients will progress at different rates depending on their age, associated injuries, pre-injury health status, rehabilitation compliance, and injury severity. These guidelines are presented in reference to tendon-related procedures, but general guidelines and concepts apply with the treatment of ligamentous, joint, and muscle pathologies.

 

Phase i (0 to 3 days after the procedure)

Phase ii (3 to 10-14 days after the procedure)

 

Phase iii (~14 days after procedure to 6-8 weeks after procedure)

Phase iv (begin after meeting phase iii criteria, usually no sooner than 6-8 weeks after procedure)

These rehabilitation guidelines were developed collaboratively between Ken Krogman, MSPT, ATC, Marc Sherry, PT, DPT LAT, CSCS, Dr. John Wilson and the UW Sports Medicine physician group.

References

  1. Mishra A, et al. Treatment of Tendon and Muscle Using Platelet-Rich Plasma. Clin Cports Med 2009; 28:113-125.
  2. Cook JL, et al. Is Tendon Pathology a Continuum? A Pathology Model to Explain the Clinical Presentation of Load-Induced Tendinopathy. Br J Sports Med 2009; 43:409-416.
  3. Soomekh DJ, et al. Current Concepts for the Use of Platelet-Rich Plasma in the Foot and Ankle. Clin Podiatr Med Surg 2011; 28:155-170.
  4. Van Ark M, et al. Injections Treatments for Patellar Tendinopathy. Br J Sports Med. 2011; 45:1068-1076.
  5. De Vos RJ, et al. Autologous Growth Factor Injections in Chronic Tendinopathy: A Systematic Review. British Medical Bulletin 2010; 95:63-77.
  6. Sanchez M, et al. Platelet-Rich Therapies in the Treatment of Orthopedic Sport Injuries. Sports Med 2009; 39(5):345-354.
  7. Nguyen RT, et al. Applications of Platelet- Rich Plasma in Musculoskeletal and Sports Medicine: An Evidence-Based Approach. PM R 2011; 3:226-250.

Autologous platelet-rich plasma injection in tennis elbow and plantar fasciitis

S.K.Venkatesh Gupta, MS (Ortho) Prof and HOD and Divya Bandari, Post Graduate Department of Orthopaedics, Mamata Medical College/General Hospital, Khammam, Telangana, India

INTRODUCTION

The introduction of platelet-rich plasma (PRP) as a possible adjunct to conservative and operative treatment has motivated significant research into this topic.1 PRP is

 

Financial Disclosure: The authors have no disclosures and report no conflicts of interest.

Correspondence to Divya Bandari, Post Graduation, Mamata Medical College, Khammam, Telangana, India

Tel: þ 917799578082; fax: þ 91 8742 234206;

e-mail: [email protected]m.

1940-7041 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

promoted as an ideal autologous biological blood-derived product that can be exogenously applied to various tissues where it releases high concentrations of platelet-derived growth factors that enhance wound, bone, and tendon healing.2 Platelets present in PRP function as a tissue sealant, initiating wound repair.3 Whereas fibrin matrix acts as a drug delivery system slowly releasing various platelet-derived bioactive factors4 such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-b1, insulin-like growth factor (IGF) and platelet derived growth factor (PDGF),5,6 PRP platelets are initially activated by thrombin and collagen, releasing growth factors that attract undifferentiated cells into the newly formed matrix and trigger cell division.7 PRP can inhibit cytokine release from macrophages, improving tissue healing and regeneration by limiting the inflammation,8 can promote new capillary growth,9 and can accelerate epithelialization4 in chronic wounds.

Platelet rich plasma has found its application in various orthopaedic conditions like tendinopathies (i.e., lateral epicondylitis,2,8,10–12 patellar tendinopathy,13–15 Achilles tendinopathy,16,17 shoulder impingement syndrome,18 ro- tator cuff tear,17 osteoarthritis knee,19–21 and avascular necrosis of femoral head).22 We have emphasized two conditions in this article, tennis elbow and plantar fasciitis. Probably one of the most common overuse syndromes is related to excessive wrist extension and is commonly referred to as tennis elbow or lateral epicondylitis. It does not show signs of inflammation but rather angiofibroblas- tic degeneration and collagen disarray. On a histological level, light microscopy reveals both an excess of fibroblasts and blood vessels that are consistent with neo-

angiogenesis.23

Chronic plantar fasciitis is probably the most common cause of foot complaints, making up 11% to 15% of the midfoot and hindfoot symptoms, requiring  professional care among adults.24 The underlying condition that causes plantar fasciitis is a degenerative tissue condition that occurs near the site of origin of the plantar fascia at the medial tuberosity of the calcaneus.25

MATERIALS AND METHODS

The protocol of this study has been approved by the relevant ethical committee related to our institution in which it was performed. All subjects gave full informed consent to participate in this study. During October 2013 to March 2015,100 patients 60 diagnosed with tennis elbow and 40 diagnosed with plantar fasciitis, visiting our center with

failed conservative treatment involving a trial of non- steroidal antiinflammator drugs (NSAIDs) and physiother- apy were treated with PRP and results were evaluated with Visual Analog Score (VAS), Disability of Arm Shoulder and Hand (DASH), and Foot Health Status Questionnaire (FHSQ).

 

Clinical Assessment

Among 100 patients, 60 patients of both sexes and over the age of 18 yr diagnosed as having tennis elbow and 40 diagnosed as having plantar fasciitis were selected based on following:

 

Inclusion Criteria for Tennis Elbow

  1. Pain and tenderness over the lateral aspect of the elbow.
  2. One of the following tests being positive: wrist extension (Cozen’s test), Mill’s maneuver, jar lifting test, wringing test, broom, or stir frying test.

 

Inclusion Criteria for Plantar Fascitis

  1. Pain in the inferior aspect of heel that is usually worse with their first steps in the morning or after a period of inactivity (with maximal tenderness over the anterome- dial aspect of the inferior heel).
  2. Increased pain on passive dorsiflexion of foot.

 

Overall Exclusion Criteria

  1. Patients with history of anemia (hemoglobin < 7.0 g/dL).
  2. Thrombocytopenia (platelets < 150 103 mL).
  3. Pregnancy.
  4. Local malignancy.
  5. Local corticosteroid injections for lateral epicondylitis in previous 1 mo.
  6. Rheumatoid disease and previous surgery or elbow dislocation.
  7. Diabetes mellitus.

In both tennis elbow and plantar fasciitis NSAID’s were avoided for 1 wk before and after the procedure.

 

Method of Data Collection

Data were collected by verbal communication with patients, including their informed consent when the clinical exami- nation was done. Blood investigations like complete blood picture (CBP), clotting time (CT), bleeding time (BT), and random blood sugar (RBS) were done. Written documenta- tion of pain (VAS) and evaluation of limitation of function (DASH and FHSQ) was done before and after the procedure.

 

Preparation of PRP

Blood was drawn from the patient in a syringe (10 mL) preloaded with citrate phosphate dextrose (CPD) and later centrifuged in two spins. The first spin was at 1800 rpm for 15 min to separate erythrocytes and white blood cells from other blood components and a second spin was at 3500 rpm for 10 min for further concentration of platelets. About 2 to 3 mL of platelet rich plasma was pipetted out and injected into the affected site. In our study we found an increase of platelets to three to five times from baseline.

 

 

FIGURE 1. Tennis elbow participants (24 men and 36 women).

 

Procedure

The patient is placed supine and the site is palpated for maximal point of tenderness before giving a local anaes- thetic. Under strict aseptic precautions local anaesthetic (2% xylocaine) followed by PRP is then injected into the affected site with a 18-guage needle, and patient is advised to rest in the outpatient block for approximately 1 hr.

In cases of tennis elbow, the affected hand of the patient is immobilized in elastic crepe bandage and cuff and collar for 48 to 72 hr and the patient is strictly advised not to lift weights or participate in activities that involve wrist extension. In cases of plantar fasciitis, a crepe bandage is applied, and the patient is advised to use micro-cellulose rubber footwear and avoid sports and athletic activities for 48 to 72 hr. After 3 days, the crepe bandage is removed, and the patient is allowed to do daily activities. After the procedure, the patient is prescribed broad spectrum antibiotics (cephalosporins) for 3 days. All NSAIDS are strictly avoided for 7 days after the procedure.

Patients with tennis elbow and plantar fasciitis were evaluated at 1 mo, 2 mo, 3 mo, and 6 mo after injection using the VAS and DASH scores (for tennis elbow) and VAS and FHSQ scores (for plantar fasciitis). One month after injection of PRP, the patients were assessed and if there was no sign of improvement (less than 25% reduction in VAS, DASH AND FHSQ score),10 PRP injection was repeated twice with a gap of 1 mo between each. If no improvement was seen, after a period of 6 mo from the third injection, surgery was considered.

RESULTS

The mean age of the tennis elbow group was 40.5 ± 15.5 yr, and it included 24 men and 36 women and plantar fasciitis group was 42.5 ± 17.5 yr and it included 16 men and 24

women (Figures 1 and 2).

Table 1 compares the mean VAS (Figure 3) and DASH (Figure 4) scores in tennis elbow patients during their first visit and at 1 mo, 2 mo, and 3 mo. Highly significant results

 


FIGURE 2. Plantar fasciitis participants (16 men and 24 women).

 

were observed between the scores at first visit and later
visits, i.e., 4 wk and after 8 wk (P < 0.001).
Table 2 compares the mean VAS (Figure 3) and FHSQ
(Figure 4) scores in plantar fasciitis during the first visit and
at 1 mo, 2 mo, and 3 mo. Highly significant results were
observed between the scores at first visit and later visits, i.e.
4 wk and 8 wk (P < 0.001).
There were four cases of tennis elbow and two cases of
plantar fasciitis that were not successful after 1 mo of
injection. Out of these, two patients with tennis elbow
and one with plantar fasciitis injection had repeated
injections and results were successful. The other three
patients did not agree to have a second injection.

DISCUSSION
The current study strongly suggests that local injection of
PRP is a novel form of treatment that provides significant
relief of pain and improvement in function in both tennis
elbow and plantar fasciitis. Moreover, it is possibly a safer
option for patients than steroid use and surgery. The
proposed mechanism of action of autologous PRP is
improvement of early neotendon properties26 and improvement of tissue healing by enhancing cellular chemotaxis,
proliferation and differentiation, removal of tissue debris,
angiogenesis and laying of extracellular matrix.27
Relative to tennis elbow, our results are similar to those
described by Mishra and Pavelko28 who reported a significant
improvement of symptoms after 8wk in 60% of the patients
treated with PRP. At the end of 6mo, patients treated with PRP
noted 81% improvement in their VAS pain scores (P¼ 0.0001).
Our results also are in agreement with that observed by
Peerbooms et al.10 who reported that 24 of the 49 patients
(49%) in the corticosteroid group and 37 of the 51 patients (73%)
in the PRP group were successful (P< 0.001). Furthermore, in
their study based on improvement on the DASH scores, 25 of the
49 patients (51%) in the corticosteroid group and 37 of the 51
patients (73%) in the PRP group were successful (P¼ 0.005); both
these studies offer encouraging results of an alternative minimally invasive treatment that addresses the pathophysiology of
tennis elbow for which traditional nonsurgical modalities failed.
In our study, we observed highly significant differences
between VAS and DASH scores before and after injection
(P < 0.001); after 4 to 8 wk after injection, 75% patients had
excellent VAS score improvement (> 50% reduction) and
around 62% had reduction of DASH score (> 50%).
Relative to plantar fasciitis, Martinelli et al.29 demonstrated at 12 mo follow-up excellent results in 9 of 14
(64.3%) patients with chronic plantar fasciitis who received
three injections of PRP into the plantar fascia, good results
in two (14.3%), acceptable results in two (14.3%), and a poor
result in one (7.1%) according to the Roles and Maudsley
score. VAS for pain was significantly decreased from 7.1 ± 1.1
before treatment to 1.9 ± 1.5 at the last follow-up (P < 0.01)29
In another study conducted by Barret et al.30 in which PRP
injection was given under ultrasound guidance, complete
pain relief was seen up to 1 yr in 77.8% of patients, and
reduced thickness was observed.
In our study, significant results were observed when VAS and
FHSQ were compared before and after injection (P< 0.003);
82% patients had a decrease in VAS score (> 50%) and around
60% had improvement in FHSQ score (> 50%).
In conclusion, local injection of autologous PRP appeared
to be a promising form of therapy for tennis elbow and
plantar fasciitis. It is both safe (avoiding surgical complications) and effective in relieving pain and improving
function. It is a cost effective procedure for the patients.
The current available data support that repeated steroid
injections are deleterious and may lead to serious consequences, and our study demonstrates a newer, safer, and
better alternative for patients. However sustained efficacy of
this promising and safer therapeutic option should be
further evaluated in long-term follow-up studies that
include a larger number of patients.

REFERENCES
1. Geaney LE, Arciero RA, DeBerardino TM, et al. The effects of
platelet-rich plasma on tendon and ligament: basic science and
clinical application. Op Techn Sports Med. 2011; 19:160–164.
2. Edwards SG, Calandruccio JH. Autologous blood injections for
refractory lateral epicondylitis. J Hand Surg. 2003; 28:272–278.
3. Eppley BL, Woodell JE, Higgins J. Platelet quantification and
growth factor analysis from platelet-rich plasma: implications
for wound healing. Plast Reconstr Surg. 2004; 114:1502–1508.
4. Everts PA, Knape JT, Weibrich G, et al. Platelet-rich plasma and
platelet gel: a review. J Extracorp Tech. 2006; 38:174.
5. Weibrich G, Kleis WK, Hafner G, et al. Growth factor levels in
platelet-rich plasma and correlations with donor age, sex, and
platelet count. Journal of Cranio-Maxillofacial Surgery. 2002; 30:97–102.
6. Landesberg R, Roy M, Glickman RS. Quantification of growth
factor levels using a simplified method of platelet-rich plasma
gel preparation. Journal of Oral and Maxillofacial Surgery. 2000;
58:297–300.
7. Bhanot S, Alex JC. Current applications of platelet gels in facial
plastic surgery. Facial Plast Surg. 2002; 18:27–34.
8. Mishra A, Woodall J, Vieira A. Treatment of tendon and muscle
using platelet-rich plasma. Clin Sports Med. 2009; 28:113–125.
9. McAleer JP, Sharma S, Kaplan EM, et al. Use of autologous
platelet concentrate in a nonhealing lower extremity wound.
Adv Skin Wound Care. 2006; 19:354–363.
10. Peerbooms JC, Sluimer J, Bruijn DJ, et al. Positive effect of an
autologous platelet concentrate in lateral epicondylitis in a
double-blind randomized controlled trial: platelet-rich plasma
versus corticosteroid injection with a 1-year follow-up. Am J
Sports Med. 2010; 38:255–262.
11. Connell DA, Ali KE, Ahmad M, et al. Ultrasound-guided
autologous blood injection for tennis elbow. Skeletal Radiol.
2006; 35:371–377.
12. Gani N, Butt MF, Dhar SA, et al. Blood injection in the treatment
of refractory tennis elbow. Internet Journal of Orthopedic Surgery.
2007; 6(4):5473.
13. Filardo G, Kon E, Della Villa S, et al. Use of platelet-rich plasma
for the treatment of refractory jumper’s knee. Int Orthop. 2010;
34:909–915.
14. James SL, Ali K, Pocock C, et al. Ultrasound guided dry needling
and autologous blood injection for patellar tendinosis. Br J
Sports Med. 2007; 41:518–521. discussion 522.
15. Kon E, Filardo G, Delcogliano M, et al. Platelet-rich plasma: new
clinical application: a pilot study for treatment of jumper’s
knee. Injury. 2009; 40:598–603.
16. de Vos RJ, Weir A, van Schie HT, et al. Platelet-rich plasma
injection for chronic Achilles tendinopathy: a randomized
controlled trial. JAMA. 2010; 303:144–149.
17. Randelli PS, Arrigoni P, Cabitza P, et al. Autologous platelet rich
plasma for arthroscopic rotator cuff repair. A pilot study. Disabil
Rehabil. 2008; 30:1584–1589.
18. Everts PA, Devilee RJ, Brown Mahoney C, et al. Exogenous
application of platelet-leukocyte gel during open subacromial
decompression contributes to improved patient outcome. A
prospective randomized double-blind study. Eur Surg Res. 2008;
40:203–210.
19. Kon E, Buda R, Filardo G, et al. Platelet-rich plasma: intraarticular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc.
2010; 18:472–479.
20. Sanchez M, Azofra J, Anitua E, et al. Plasma rich in growth
factors to treat an articular cartilage avulsion: A case report. Med
Sci Sports Exerc. 2003; 35:1648–1652.
21. Sa´nchez M, Anitua E, Azofra J, et al. Intra-articular injection of
an autologous preparation rich in growth factors for the
treatment of knee OA: a retrospective cohort study. Clin Exp
Rheumatol. 2008; 26:910–913.
22. Ibrahim V, Dowling H. Platelet-rich plasma as a nonsurgical
treatment option for osteonecrosis. PM&R. 2012; 4:1015–1019.
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exercise, corticosteroid injection, or wait and see for tennis
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of diagnosis and therapy. Am Fam Physician. 2005; 72:2237–2242.
25. Buchbinder R. Plantar fasciitis. N Engl J Med. 2004; 350:
2159–2166.
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improves Achilles tendon repair in rats. Acta Orthop Scand.
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27. Sanchez AR, Sheridan PJ, Kupp LI. Is platelet-rich plasma the
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buffered platelet-rich plasma. Am J Sports Med. 2006; 34:1774–1778.
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plantar fasciitis? Podiatry Today. 2004; 17:1045–7860

 

Regression of Melasma with Platelet-Rich Plasma Treatment

Ann Dermatol. 2014 Jun; 26(3): 401-402.
PMCID: PMC4069656
Published online 2014 Jun 12. doi: 10.5021/ad.2014.26.3.401
PMID: 24966645
Regression of Melasma with Platelet-Rich Plasma Treatment
2
Mutlu Çayırlı, Ercan Çalışkan,Gürol Açıkgöz,Ahmet Hakan Erbil,and Güneş Ertürk
Dermatology Service, Mevki Military Hospital, Ankara, Turkey.
1Department of Dermatology, Gulhane School of Medicine, Ankara, Turkey.
2MD Dermatology Clinic, Istanbul, Turkey.
Corresponding author.
Corresponding author: Mutlu Çayırlı, Mevki Military Hospital, Dermatology Service, Dışkapı- Altındağ, 06290 Ankara, Turkey. Tel:
90-537-620-76-79, Fax: 90-312-311-46-09, [email protected]
Received 2013 Apr 3; Revised 2013 May 11; Accepted 2013 May 29.
Copyright © 2014 The Korean Dermatological Association and The Korean Society for Investigative Dermatology
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/3.0/ ) which permits unrestricted non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
This article has been cited by other articles in PMC.
Dear Editor:
Platelet-rich plasma (PRP) treatment is performed via the autologous injection of high concentration of
platelets in a small volume of plasma1.
A 27-year-old woman presented at our dermato-cosmetology department for skin rejuvenation, as she
had epidermal hyperpigmentation over the cheeks, perioral region, and forehead for about 5 years. PRP
treatment was initiated and her face was injected with autologous PRP prepared by using RegenKit®
(Regen Lab., Le Montsur-Lausanne, Switzerland). Before the treatment sessions, 8 ml of blood was
collected from the patient into a special tube containing a separation gel and an anticoagulant. The tube
was then centrifuged for 8 minutes at 3,500 rpm, and PRP was obtained from the upper part of the buffy
coat. A 32-G needle was used for superficial microinjections via the mesotherapy technique, and the
injections were administered in to the papillary dermis (1.5~2.0 mm deep). Approximately 1.5 ml of
PRP was injected in to the dermis of the face at each session with 15-day intervals. At the end of the
third session of PRP treatment, >80% reduction in epidermal hyperpigmentation was observed (Fig. 1,
2). We did not provide any other treatment or post treatment care besides prescribing the use of a sun-
screen product. There has been no recurrence of melasma for 6 months now.
Fig. 1
Hyperpigmentation over the cheeks, perioral region, and forehead.
Fig. 2
Significant regression in epidermal hyperpigmentation.
PRP is commonly used in dermatology and plastic surgery, especially for treating chronic wounds,
ulcers, and burns. In recent years, PRP has also started to be used in the field of cosmetology1.
Volumetric filling, skin rejuvenation, acne scars, and alopecia are the main targets of PRP application in
cosmetology1.
The most important contents of platelets are contained in the α-granules. There are >30 bioactive
substances in these granules2. Some of the bioactive substances present in the α-granules include
platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β1, 2, epidermal growth
factor, and mitogenic growth factors such as platelet-derived angiogenesis factor and fibrinogen3. To
our knowledge, only TGF-β1 has been investigated about its relation with melanogenesis.
Kim et al.investigated the effects of TGF-β1 on melanogenesis by using a spontaneously immortalized
mouse melanocyte cell line, and asserted that TGF-β1 significantly inhibits melanin synthesis in a
concentration-dependent manner. They declared that TGF-β1 decreases melanogenesis via delayed
extracellular signal-regulated kinase activation.
The pigmentary improvement that occurs with PRP treatment may be associated with the increase in
skin volume. PDGF has a significant role in blood vessel formation and in the synthesis of collagen and
components of the extracellular matrix, including hyaluronic acid. Hyaluronic acid has been shown to
increase skin tone and volume, resulting in providing a more ‘glowing skin’5.
Although, it is not possible to reach a definitive conclusion, we consider the regression of melasma after
PRP treatment as an interesting finding. Controlled clinical trials are needed to confirm this preliminary
observation.
References
Go to:
1. Kim DH, Je YJ, Kim CD, Lee YH, Seo YJ, Lee JH, et al. Can platelet-rich plasma be used for skin
rejuvenation? Evaluation of effects of platelet-rich plasma on human dermal fibroblast. Ann Dermatol.
2011;23:424-431. [PMC free article] [PubMed]
2. Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: a review of biology and applications in
plastic surgery. Plast Reconstr Surg. 2006;118:147e-159e. [PubMed]
3. Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, et al. 2009 Platelet
Colloquium Participants. Platelet functions beyond hemostasis. J Thromb Haemost. 2009;7:1759-1766.
[PubMed]
4. Kim DS, Park SH, Park KC. Transforming growth factor-beta1 decreases melanin synthesis via
delayed extracellular signal-regulated kinase activation. Int J Biochem Cell Biol. 2004;36:1482-1491.
[PubMed]
5. Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: a key molecule in skin aging.
Dermatoendocrinol. 2012;4:253-258. [PMC free article] [PubMed]
Articles from Annals of Dermatology are provided here courtesy of Korean Dermatological Association and
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