Authors: Adam M. Pourcho, DO Jay Smith, MD Stephen J. Wisniewski, MD Jacob L. Sellon, MD

Osteoarthritis

Affiliations: From the Departments of Physical Medicine & Rehabilitation (AMP, JS, SJW, JLS) and Radiology and Anatomy (JS), Sports Medicine Center, Mayo Clinic, Rochester, MN.

Correspondence: All correspondence and requests for reprints should be addressed to: Jacob L. Sellon, MD, Department of Physical Medicine & Rehabilitation, Sports Medicine Center, Mayo Clinic, W14 Mayo Building, 200 1st St SW, Rochester, MN 55905.

Disclosures: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

0894-9115/14/9311(Suppl)-S108 American Journal of Physical Medicine & Rehabilitation Copyright * 2014 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000115

Intraarticular Platelet-Rich Plasma Injection in the Treatment of Knee Osteoarthritis Review and Recommendations ABSTRACT Pourcho AM, Smith J, Wisniewski SJ, Sellon JL: Intraarticular platelet-rich plasma injection in the treatment of knee osteoarthritis: review and recommendations. Am J Phys Med Rehabil 2014;93(Suppl):S108YS121. Intraarticular platelet-rich plasma (PRP) injection has emerged as a promising treatment for knee osteoarthritis. Studies to date, including multiple randomized controlled trials, have shown that PRP is a safe and effective treatment option for knee osteoarthritis. Intraarticular PRP is similar in efficacy to hyaluronic acid, and seems to be more effective than hyaluronic acid in younger, active patients with low-grade osteoarthritis. Treatment benefits seem to wane after 6Y9 mos. There are numerous PRP treatment variables that may be of importance, and the optimal PRP protocol remains unclear. Future investigations should control and analyze the effects of these variables in PRP treatment. High-quality randomized controlled trials are needed to optimize PRP treatment methods and better define the role of PRP in osteoarthritis management in the knee and, potentially, in other joints. Key Words:

Knee, Osteoarthritis, Platelet-Rich Plasma, Regenerative Medicine, Injections

BACKGROUND Osteoarthritis (OA), also known as degenerative arthritis or osteoarthrosis, involves mechanical and biologic abnormalities of the articular cartilage and subchondral bone.1 OA affects approximately 250 million people (nearly 27 million Americans), and the prevalence is expected to rise as life expectancy increases.2,3 OA causes moderate-to-severe disability in more than 43 million people globally, and nearly one in every two people may develop symptomatic knee OA by the age of 85 yrs.4,5 Once articular cartilage is damaged, healing potential is poor, leading to focal cartilage lesions and OA.6 Given the prevalence of OA and the morbidity associated with it, any treatment that may help alleviate the symptoms, improve function, and ideally reverse the damage and promote healing, is of interest to both patients and medical specialists. The ongoing search for effective nonoperative OA treatments has driven the interest in Bregenerative[ biologic therapies.7 In the last decade, intraarticular platelet-rich plasma (PRP) injection has emerged as a promising treatment option for OA.8

S108

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

PRP is most simply defined as a volume of plasma that has a platelet (PLT) count above baseline (BL) blood levels.9 PRP is an autologous blood product that can be injected into damaged areas to deliver PLT-derived growth factors (GFs) and promote healing.10 The autologous nature of PRP theoretically reduces the risk of potential side effects and makes it an attractive treatment option.11,12 Numerous studies have demonstrated PRP efficacy in the treatment of chronic tendinopathy and ligamentous injuries.13Y19 The most compelling data to date have been in elbow lateral epicondylitis (i.e., Btennis elbow[), for which multiple randomized controlled trials have demonstrated therapeutic benefit.20Y22 In the past several years, a growing body of evidence has accumulated examining PRP as a possible treatment of knee OA. This review outlines the many variables involved in the use of PRP, summarizes the currently available literature on its application in knee OA, and suggests avenues for further research.

TABLE 1 Variables in PRP treatment Preparation method Needle gauge for blood harvest and injection Platelet concentration Platelet granule secretion (e.g., GFs) Leukocyte (and subtype) concentration Platelet storage (vs. immediate injection) Anticoagulant use Platelet preactivation Local anesthetic use Palpation vs. image guidance Injection volume Injection frequency Preinjection and postinjection protocol (e.g., NSAID/ activity restriction) Type and severity of disease being treated Patient-specific factors (e.g., age, sex, platelet disorders)

theoretically provide more precision, but variation among systems complicates comparisons.23,26,27

Needle Gauge for Blood Harvest and Injection VARIABLES IN PRP TREATMENT When using PRP as a treatment for OA, there are many variables to consider (see Table 1).78 These include preparation method, needle gauge for blood harvest and injection, PLT concentration, PLT granule secretion variability, leukocyte (and subtype) concentration, PLT storage, anticoagulant use, PLT preactivation, local anesthesia use, image guidance use, injection volume, injection frequency, preinjection and postinjection protocol, severity of OA being treated, and other patient factors. An understanding of these variables is essential in critically analyzing the literature and deciding how to implement PRP treatment into clinical practice.

Needle gauge is another factor that may potentially affect PRP. Smaller gauge needles used in blood draws can cause premature activation of PLTs.28 Because PLTs release 90% of their GFs within 10 mins of activation, needle gauge may affect the timing of GF release.29 To avoid unintentional activation of PLTs, clinicians may consider using large bore needles (21-gauge or larger) and slow aspiration during blood harvest. It is unclear whether needle gauge is an important factor during PRP administration. Clearly, further research is needed to determine the effects of specific needle gauges on PLT activation in the context of PRP preparation and injection.

PLT Concentration Preparation Method The first variable to consider when using PRP is the method of preparation (Figs. 1AYC). Most methods use either a centrifuge or density gradient cell separator to separate whole blood into its cellular components.23,24 Typically, the initial Bspin[ separates the red blood cell and buffy coat/plasma (leukocyte and PLT) layers, whereas a second spin is used in some systems to further concentrate PLTs. Therefore, the number of centrifugations and centrifuge speed/timing has a major influence on the final PRP concentration of PLTs and leukocytes.25 Because of these variables, manual laboratory preparation can be technically demanding and difficult to precisely reproduce. Commercially available systems www.ajpmr.com

PLT concentration may be arguably one of the most important variables in PRP treatment. Mishra et al. 30 proposed a PRP classification system with subcategories of relatively high (95 BL) and low (G5 BL) PLT concentrations. However, PLT concentration in the published literature on knee OA has been variable and inconsistently reported. Some authors suggest that PRP PLT concentration should be at least two times the whole blood PLT concentration; however, concentrations up to eight times of blood levels have been reported with good results.23,31 There is in vitro evidence that PRP with higher PLT concentration (4.69) releases more GFs than PRP with lower concentration (1.99).32 Other laboratory studies have suggested a ceiling effect of PRP Injection as a Treatment for Knee OA

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S109

the anabolic effects of PLT concentration.33Y36 In practice, there is evidence that positive clinical outcomes in knee OA can be obtained with relatively low PLT concentrations (2Y3 BL).25,37Y40 Scientific evidence is currently limited with regard to optimal PRP PLT concentration for the treatment of knee OA and requires further investigation.

PLT Granule Secretion One of the most unpredictable variables in PRP injection is PLT granule secretion. PLT granules release a variety of GFs, including PLT-derived GF, transforming GF beta, insulin-like GF-1, and epidermal GF. The concentrations of these GFs may vary between patients and within the same patient at different times.10 These molecules are believed to be important in maintaining joint homeostasis, tissue healing, and tissue regeneration.10 In addition, PLT granules store substances such as adenosine diphosphate, adenosine triphosphate, histamine, dopamine, serotonin, cathespin D, cathespin E, elastases, and hydrolases, which are believed to play a complex role in tissue regeneration.10,12,41 The significance of variability in PLT granule secretion on PRP treatment is unknown and would be difficult to account for in clinical trials.

Leukocyte (and Subtype) Concentration The presence or absence of leukocytes and their subtypes may also play an important role in PRP treatment efficacy. Mishra et al’s30 PRP classification

defined leukocyte-rich (LR) as Bincreased over baseline[ and leukocyte-poor (LP) as Bminimal to no leukocytes.[ For most currently available PRP systems, leukocyte concentration is directly related to PLT concentration.26 Although there are a few exceptions, most systems produce either an LR-PRP with a relatively high PLT concentration (95 BL) or an LP-PRP with a relatively low PLT concentration (G5 BL). In vitro human and animal research has shown that LR-PRP yields higher GF concentrations than LP-PRP, but LR-PRP also contains more catabolic/inflammatory cytokines.32,42 In vivo research in various tissue types has shown that LR-PRP causes a significantly greater acute inflammatory response at 5 days after injection when compared with LP-PRP, with no significant difference in the inflammatory response or cellularity at 14 days.43 Studies of intraarticular PRP injections in arthritic knees have supported this finding.44 Interestingly, there is evidence that LR-PRP has both proinflammatory and anti-inflammatory properties.45 Intuitively, one could surmise that an LR-PRP product would be more beneficial in chronic conditions, which may benefit from some degree of inflammation, whereas an LP-PRP product would be more beneficial in acute or subacute conditions, where additional inflammation may be detrimental. With regard to knee OA, positive clinical results have been reported using both LR-PRP and LP-PRP intraarticular injections.25,38 One study comparing LR-PRP and LP-PRP yielded similar efficacy, although the LR-PRP group had a higher incidence of postinjection pain.25

FIGURE 1 PRP preparation: (A) typical PRP centrifuge. After harvest, autologous whole blood is centrifuged to separate and concentrate platelets. This particular single-spin PRP centrifuge can process four samples simultaneously in approximately 5 mins. (B) Top layer (PRP) is aspirated from the bottom syringe into the top syringe of a Bdouble syringe[ system. Unused bottom layer is rich in red and white blood cells. (C) On the left, the final PRP product is ready for injection. On the right, the unused remaining blood products remain in the bottom syringe.

S110

Pourcho et al.

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Therefore, it is unclear whether leukocyte concentration has a significant effect on PRP injection efficacy in knee OA. Regarding leukocyte subtypes, there is evidence that polymorphonuclear neutrophils (PMNs) may have a negative effect on cartilage.10,46 PMNs infiltrating injured tissue can exacerbate or increase the original tissue damage.47Y49 Theoretically, LPPRP products may be preferable in the treatment of knee OA because of their very low concentrations of PMNs. However, typically, LR-PRP is relatively low in PMNs, and some have postulated that these concentrations are not high enough to cause significant inflammatory reaction.26 Therefore, the optimal PMN level in PRP injection for knee OA is unknown.

PLT Storage The use of freeze-thawing to produce PLT releasate/lysate vs. the immediate injection of PRP after preparation is another point of contention. When serial PRP injections are performed, freezethawing provides the advantage of a single blood draw. However, many GFs have short half-lives, and there is some evidence that freeze-thawing lowers GF concentrations.27 Nevertheless, this technique has been used in multiple trials demonstrating clinical benefit in patients with knee OA.25,44,50,51 Therefore, the clinical implications of freezethawing on PRP injection efficacy are debatable.

Anticoagulant Use Anticoagulation of PRP is another potential treatment variable. Most commercial PRP systems recommend use of an anticoagulant to prevent premature clotting after harvest. One study found that acid citrate dextrose and citrate-theophyllineadenosine-dipyridamole were superior to heparin and sodium citrate in maintaining the integrity of PLT structures and preventing the PLT spontaneous activation.52 Furthermore, PRP prepared with acid citrate dextrose or citrate-theophyllineadenosine-dipyridamole released more transforming GF beta and enhanced proliferation of human marrow stromal cells compared with PRP prepared using heparin or sodium citrate as anticoagulants.52 Thus, the limited evidence to date suggests that acid citrate dextrose or citrate-theophylline-adenosinedipyridamole may be preferable anticoagulants for PRP preparation.

PLT Preactivation PRP preactivation is controversial. Preactivation is the administration of a substance to promote PLT www.ajpmr.com

release of GFs and other substances involved in the healing process. Clotting, although undesirable before injection, is vital for PLT degranulation after PRP delivery.52 Therefore, when using an anticoagulant, PLT activation is necessary for GF release. Commonly used preactivation agents include calcium chloride (CaCl2) and thrombin. Although studies suggest that CaCl2 provides sufficient PLT activation, there is some evidence that it causes differentiated GF release, possibly affecting outcomes.53,54 Preactivation with thrombin is also not without controversy. Animal models have shown that thrombin stimulates earlier GF release in the first 24 hrs compared with no preactivation.55 However, thrombin has also been shown to inhibit PRP osteoinductivity and, therefore, is possibly detrimental in knee OA.56 Notably, type 1 collagen alone can activate PLTs after injection, providing sustained release of anabolic cytokines.57 There is also evidence that PLTs without preactivation stimulate wound healing more efficiently than preactivated PLTs.58 Indeed, positive clinical results in knee OA have been reported in PRP injections both with and without PLT preactivation.25,40,44,50,51,59 To date, there are no clinical trials comparing different types of PRP activation.

Local Anesthetic Use The use of local anesthesia for PRP injections has also been debated. In vitro local anesthetics have been shown to decrease the positive effects of PRP.60 Furthermore, multiple studies have demonstrated the chondrotoxicity of local anesthetics.61Y63 Given the lack of clinical data on the subject, it is difficult to give a recommendation regarding the use of local anesthetics with PRP therapy. However, if local anesthesia is used before PRP intraarticular injection, it seems reasonable to avoid injection into the joint.

Palpation vs. Image Guidance Logically, one may expect PRP injection accuracy to affect knee OA clinical outcomes. It is notable that most PRP knee OA studies to date have used palpationguided injections with success.25,37Y40,44,50,51,59,64Y69 However, there is evidence that knee injection therapeutic outcomes improve with accuracy, and this may be more important with biologic agents such as PRP.70,71 Previous studies suggest that the accuracy of palpation-guided knee injections can be highly variable (50%Y93%).72,73 Furthermore, it has been shown that sonographically guided knee joint injections are more accurate than palpation-guided PRP Injection as a Treatment for Knee OA

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S111

injections.74 Therefore, the use of image guidance may enhance PRP injection efficacy for knee OA.

Injection Volume and Frequency PRP injection volume and frequency are widely varied among published knee OA studies, with no clear standardization yet proposed. Injection volume has ranged from as little as 3 ml to as high as 8 ml.37,44 Because the primary effects of PLT GFs occur during approximately 8 days, most authors have elected to perform multiple injections at weekly, biweekly, every-3-wk, or monthly intervals to maximize effects.11,37,40,50,64 Nevertheless, positive effects have been reported with a single injection, with one clinical trial showing equivalent benefits in one vs. two injections.38,59,65 The great variability of these factors in the current literature makes it difficult to derive specific recommendations.

Preinjection and Postinjection Protocol Many specialists recommend avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) before and after PRP treatment. NSAIDs have been shown to have a negative effect on PLT function and, theoretically, may reduce PLT GF release.75 Previous investigations have shown that NSAIDs slow the healing rate of various tissues, including the bone, tendon, and muscle.76 There are no data specifically examining NSAID use with PRP. However, considering the pharmacokinetics of most NSAIDs and the duration of the initial phase of tissue healing, it seems reasonable to recommend avoiding NSAIDs at least 5 days before and for 2 wks after PRP injection.77 It is unknown whether specific activity restrictions or rehabilitation after PRP knee joint injection affect treatment outcomes. In studies to date, postinjection activity recommendations have ranged from no restrictions to temporary restriction of activities with gradual return to full activity.37,51 Until further studies provide more guidance, it is difficult to provide specific postinjection activity recommendations.

S112

Patient-Specific Factors Other patient factors may also be important to recognize when considering PRP injection for knee OA. Several clinical studies have suggested that treatment efficacy may be decreased in older patients, although it is unclear whether this is simply related to a tendency toward higher grade OA or other yet unknown factors.25,44,50,51,59,69 Women have had less robust results in some studies, perhaps related to biochemical or biomechanical differences.44,50 Logically, one may deduce that PLT-related comorbidities, such as thrombocytopenia, may negatively affect PRP efficacy. The use of PRP in various knee OA patient populations requires further study, and potentially confounding patient factors should be accounted for in future investigations. Even though there are multiple studies showing potential benefit of PRP injection for knee OA, the numerous variables make study comparison difficult. High-quality randomized controlled trials that account for these factors are needed to optimize PRP treatment of knee OA.

CLINICAL STUDIES OF PRP INJECTION FOR KNEE OA A PubMed search was performed using key words Bplatelet-rich plasma or PRP or autologous conditioned plasma or ACP and cartilage or chondrocyte or chondrogenesis or osteoarthritis or osteoarthrosis or arthritis or growth.[ The search included original manuscripts and review articles from 1970 to September 2013. Case studies and original research that specifically mentioned the intraarticular use of PRP in knee OA were also included. Studies investigating PRP exclusively for osteochondral lesions were excluded. Sixteen publications were identified using this search and the selection criteria. For simplicity, the summary below is divided into case series, nonrandomized cohort studies, and randomized controlled trials (see Table 2).

Disease Type and Severity

Case Series

As with other knee OA treatments, the stage of disease may be an important variable in determining appropriate patient selection for PRP treatment. Studies to date have examined the effect of PRP on knees affected by chondromalacia/early OA to advanced OA, with varying results (as will be discussed later).25,38,67,68 Defining PRP efficacy in various stages of knee OA is essential to guide specialists in appropriate patient selection.

In 2010, Sampson et al.78 published a prospective case series of 14 patients with unclassified Bprimary and secondary OA[ of the knee. These patients were treated with three 3-ml sonographically guided injections of CaCl2- and thrombin-activated PRP with an unspecified leukocyte and PLT concentration, at 3-wk intervals. Patients were restricted from NSAID use 1 wk before treatment and 1 mo after treatment and were instructed to restrict the use

Pourcho et al.

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

of the treated leg for 24 hrs after each injection. Outcomes were measured at the 12-mo follow-up with the Brittberg-Peterson Visual Analog Pain, Activities and Expectations Scale, in addition to the Knee Injury and Osteoarthritis Outcome Score (KOOS). The authors also sonographically measured the trochlear cartilage thickness before injection and at 6 mos. Results indicated that PRP improved outcomes in all measures with no significant sonographic changes in cartilage thickness. In addition, in 2010, Kon et al.44 published a prospective case series on 91 patients (115 joints) with Kellgren-Lawrence grades 1Y4 of knee OA. Patients were treated with three 3-ml palpationguided injections of CaCl2-activated LR-PRP/lysate with a PLT concentration of 6 BL, at 3-wk intervals. After the procedure, patients were instructed to restrict the use of the leg, ice, and avoid NSAIDs/ steroids for 24 hrs. Thereafter, mild activity (light cycling/pool exercises) was allowed during the 42-day injection cycle period with subsequent gradual return to full activity. The International Knee Documentation Committee (IKDC) subjective and objective questionnaire and EuroQol Visual Analog Scale (EQ-VAS) were used to measure outcomes at 6 and 12 mos. Overall patient outcomes improved at 6 mos, with subsequent decline at 12 mos, although they remained improved from BL (P G 0.0005). Patients with higher OA severity showed less improvement (cartilage lesion 9 KellgrenLawrence 1Y3 9 Kellgren Lawrence 4). In addition, older patients (965 yrs), women, and those with a higher body mass index had less benefit, whereas previous knee surgery did not seem to influence results. The most common adverse reaction reported was postinjection pain and swelling that resolved spontaneously at 2 wks. In 2011, the same authors reported on this same patient population at 24 mos, with only one patient lost to follow-up (114 joints).50 All evaluated parameters worsened by 24 mos, although remained improved from BL (P = 0.0014). Median duration of beneficial effect was 9 mos. Younger patients, men, and patients with less severe OA (by Kellgren-Lawrence grading as above) had better results and a longer duration of benefit. Wang-Saegusa et al.64 in 2011 reported the results of their prospective case series on 261 patients (359 joints) with Outerbridge grades 1Y4 of knee OA. Patients in this study received three 5-ml palpation-guided injections of CaCl2-activated LPPRP with an unspecified PLT concentration, at 2-wk intervals. There were no postinjection physical activity or NSAID restrictions mentioned. Outcomes were measured with the VAS for Pain, Short Form www.ajpmr.com

(36) Health Survey (SF), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and Lequesne index at 6-mo follow-up. Similar to previous smaller studies, patients displayed statistically significant improvements in all pain and functional outcomes. In 2013, Halpern et al.65 published a case series of 17 patients (18 joints) with Kellgren grades 1Y2 of knee OA. Of the included joints, 15 had preinjection and postinjection magnetic resonance imaging. All knees were injected with a single 6-ml palpationguided injection of LP-PRP. There was no mention of PRP preactivation or specific PLT concentrations. Postinjection physical activity and NSAID restriction were also not specified. Outcomes were measured with VAS (pain, function, and activities of daily living) and WOMAC scores at 12 mos. Pain and function improved with statistical significance in all patients, with no magnetic resonance imaging changes in 73% of the patients at 1 yr.

Nonrandomized Cohort Studies In 2008, Sa´nchez et al.37 published the first study examining PRP in knee OA, a retrospective cohort study of 60 patients (two groups) with unilateral Ahlba¨ck grades 1Y4 disease. The first group of 30 patients was treated with three 6- to 8-ml palpation-guided injections of CaCl2-activated LPPRP with a PLT concentration of È2 BL, at 1-wk intervals. The second group of 30 patients was treated with three 2-ml injections of highmolecular-weight hyaluronic acid (HWHA), also at 1-wk intervals. NSAID or postprocedure activity restrictions were not specified. The WOMAC was used to assess clinical outcomes in pain, stiffness, and function. Treatment success rates (40% of decrease in WOMAC pain score) were also measured. Both groups showed statistically significant benefits in pain and function. However, the PRP group had a higher treatment success rate with greater pain and functional improvements at 5-wk follow-up, all with statistical significance. Although encouraging in demonstrating the feasibility and short-term safety of intraarticular PRP injections, this investigation was limited by its very short-term follow-up. In 2011, Kon et al.51 published a multicenter three-arm prospective cohort study of 150 patients with unilateral Kellgren grades 1Y4 OA. In this study, the clinical efficacy of PRP was compared with the efficacy of low-molecular-weight HA (LWHA) and HWHA. Patients in the PRP arm (50 joints) received three 5-ml palpation-guided injections of CaCl2-activated LR-PRP/lysate with PLT PRP Injection as a Treatment for Knee OA

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S113

S114

Pourcho et al.

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 120 Pts, 120 Jts

KL Gr 1Y3

Prospective cohort study

Spakova´ et al. (2012)66

Gobbi et al. (2012)40

1x PRP

3x PRP q 2 wk

3x PRP q 3 wk

NS

CaCl2

Grp A (60 Jts), 3x PRP q 1 wk Grp B (60 Jts), 3x HWHA q 1 wk

Grp A (72 Jts), 3x PRP q 3 wk Grp B (72 Jts), 3x PRP q 3 wk

NA

CaCl2

CaCl2

Ahlba¨ck Gr 1Y4 Grp A (30 Jts), CaCl2 3x PRP q 1 wk Grp B (30 Jts), NA 3x HWHA q 1 wk KL Gr 1Y4 Grp A (50 Jts), CaCl2 3x PRP q 2 wk Grp B (50 Jts), NA 3x HWHA q 2 wk Grp C (50 Jts), NA 3x LWHA q 2 wk Grp A (19 Jts), 3x PRP q 1 wk Calcium KL Gr 1Y3 Gluconate Grp B (15 Jts), Outerbridge Gr 1Y2 KL Gr 1Y3 2x PRP q 1 mo None

KL Gr 1Y2

Outerbridge Gr 1Y4

KL Gr 1Y4

Filardo et al. (2012)25

27 Pts, 34 Jts

Prospective Napolitano cohort study et al. (2012)39

Thrombin + CaCl2

a

CaCl2

Preact

Treatment

Primary and 3x PRP q 4 wk secondary OA

Disease

Prospective 50 Pts, 50 Jts cohort study (25 native and 25 operated knees) Prospective 144 Pts, 144 Jts KL Gr 1Y4 cohort study

150 Pts, 150 Jts

Prospective cohort study

Kon et al. (2011)51

17 Pts, 18 Jts

Case series

Halpern et al. (2013)65 60 Pts, 60 Jts

261 Pts, 359 Jts

Case series

Wang-Saegusa et al. (2011)64

Retrospective cohort study

90 Pts, 114 Jts

Case series

Kon et al. (2010)44 Filardo et al. (2011)50

Sa´nchez et al. (2008)37

14 Pts, 14 Jts

Subjects

Case series

Design

Sampson et al. (2010)78

Authors

TABLE 2 Clinical studies of PRP injection in the treatment of knee OA F/U

6 mos

2 ml

NA

6 mos

5 wks

EQ-VAS, IKDC

LR-PRP (PLT, È4.5 BL) NA

LP-PRP (PLT, È1.5 BL) LR-PRP/lysate (PLT, È4.7 BL)

LR-PRP (PLT, È2 BL)

2 ml

3 ml

6 mos Numeric Rating Scale (Pain), WOMAC

5 ml 12 mos VAS (Pain), IKDC, KOOS, Tegner, Marx 5 ml 12 mos EQ-VAS, IKDC, Tegner

LP-PRP È5 ml 6 mos Numeric Rating (PLT, È2.3 BL) Scale (Pain), WOMAC

2 ml

5 ml

2 ml

6Y8 ml

6 ml 12 mos

5 ml

24 mos

5 ml 12 mos

Results

(continued on next page)

Improved pain and functional outcomes in both native and operated knees. Both PRP Grps had equal improvement with better results in younger patients and OA. LR-PRP Grp had more transient swelling and pain. PRP Grp had greater pain and functional improvements than HA Grp.

PRP better than HA Grps in younger (G50 yrs old), more active, and low-grade OA patients. PRP/HA Grps showed equal improvements in older (950 yrs old) patients and high-grade OA. Both groups had improved pain and functional outcomes.

Improved pain and functional outcomes. No significant change in USFCT at 6 mos. IKDC, EQ-VAS Improved outcomes at 6 mos with decline at 12 mos but still above BL. All outcomes worsened between 12 and 24 mos. Median duration of improvement was 9 mos. Better results in younger and low-grade OA. VAS (Pain), All outcomes improved, ranging SF-36, WOMAC, from 36% to 73%. Lequesne VAS (Pain, Improved pain and functional Function, ADLs), outcomes. percent had no WOMAC worsening of OA on magnetic resonance imaging. WOMAC PRP Grp had better pain and functional outcomes than the HA Grp.

Outcome

È6 ml 12 mos BPVAS, KOOS, USFCT

Vol

LR-PRP/lysate (PLT, È6 BL) NA

LP-PRP (PLT, È2 BL) NA

LP-PRP

LP-PRP

LR-PRP/lysate, (PLT, È6 BL)

LR-PRP

PRP

www.ajpmr.com

PRP Injection as a Treatment for Knee OA

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S115

Randomized 120 Pts, 120 Jts controlled trial

Randomized 109 Pts, 109 Jts controlled trial

Randomized controlled trial

Cerza et al. (2012)68

Filardo et al. (2012)69

Patel et al. (2013)38

78 Pts, 156 Jts

Treatment

Ahlba¨ck Gr 1Y2

Grp A (52 Jts), 1x PRP Grp B (50 Jts), 2x PRP q 3 wks Grp C (46 Jts) 1x saline

Grp A (38 Jts), 1x PRP KL Gr 1 Grp B (36 Jts), KL Gr 2 Grp C (16 Jts), KL Gr 3 Ahlba¨ck Gr 1Y3 Grp A (89 Jts), 3x PRP q 1 wk Grp B (87 Jts), 3x HWHA q 1 wk KL Gr 1Y3 Grp A (60 Jts), 4x PRP q 1 wk Grp B (60 Jts), 4x LWHA q 1 wk KL Gr 1Y3 Grp A (54 Jts), 3x PRP q 1 wk Grp B (55 Jts), 3x HWHA q 1 wk

Disease

NA

CaCl2

CaCl2

NA

LP-PRP (È3 BL) LP-PRP (È3 BL) NA

LR-PRP/lysate (PLT, È5 BL) NA

NA

NA CaCl2

LP-PRP

NA

NA None

LP-PRP

LR-PRP

PRP

CaCl2

None

Preact

F/U

Outcome

È8 ml

2 ml

5 ml

2 ml

5.5 ml

2 ml

8 ml

WOMAC

All OA Grps had improved outcomes at 6 mos that deteriorated at 12 mos, but still above BL. Mean relapse time was 8.8 mos. Better and longer duration results in Gr 1 OA with mean relapse at 9.9 mos. PRP Grp had more pain responders than HA Grp. No statistical Grp differences in other WOMAC scores.

Results

PRP Grp with better and longer duration improvements compared with HA Grp. PRP equally effective in KL Gr 1Y3. 12 mos IKDC, EQ-VAS, Both Grps had improved outcomes, Tegner, KOOS with no statistical Grp differences. PRP Grp trend toward better IKDC scores in low-grade OA subgroup. PRP with more transient postinjection pain. 6 mos VAS (Pain), PRP one- and two-injection Grps had WOMAC equal pain and functional improvements. Both superior to saline placebo. Improvements slightly decreased at 6 mos. Better outcomes in lower grade OA.

6 mos

6 mos Responders (50% of pain reduction), WOMAC

3 ml 12 mos VAS (Pain), IKDC

Vol

Injection interval (i.e., 3x PRP q 4 wks = 3 PRP injections performed at 4-wk intervals). ADLs, activities of daily living; BPVAS, Brittberg-Peterson Visual Analog Pain, Activities, and Expectations Score; F/U, follow-up interval; Gr, grade; Grp, group; Jts, joints; KL, Kellgren-Lawrence; NA, not applicable; NS, not specified; Preact, preactivation; Pts, patients; SF-36, Short Form (36) Health Survey; USFCT, ultrasound femoral cartilage thickness; Vol, injection volume.

a

Randomized 176 Pts, 176 Jts controlled trial

Sa´nchez et al. (2012)67

65 Pts, 90 Jts

Prospective cohort study

Jang et al. (2013)59

Subjects

Design

Authors

TABLE 2 (Continued)

concentration of È6 BL, at 2-wk intervals. Both LWHA (50 joints) and HWHA (50 joints) treatment arms received three 2-ml palpation-guided injections of the respective viscosupplement at 2-wk intervals. Activity and NSAID restrictions were similar to other PRP studies by the same authors mentioned previously. Outcomes were measured with EQ-VAS and IKDC scores at 6 mos. Although all three groups improved, the PRP group showed statistically greater and longer-term improvements in pain and function than the two HA groups, especially in younger (G50 yrs old), more active patients with less severe OA. Older (950 yrs old) patients with high-grade knee OA showed more modest improvements that were similar among the PRP and both HA groups. Napolitano et al.39 in 2012 reported on a prospective cohort study of 27 patients (34 joints) with knee OA, separated into two groups based on disease classification. Nineteen joints had Kellgren-Lawrence grades 1Y3 OA, and 15 joints had Outerbridge grades 1Y2 of osteochondral lesions. All patients received three È5-ml palpation-guided injections of Ca-gluconate-activated LP-PRP with a PLT concentration of È2.3 BL, at 1-wk intervals. Patients were instructed to avoid NSAIDs and Bheavy[ physical activity for 2 wks after injection. Outcomes were measured at 1 wk after the last injection and at 6 mos using the Pain Numeric Rating Scale and WOMAC. Both the OA and osteochondral groups demonstrated improved pain and function scores at the 1-wk follow-up that were maintained at 6 mos, with no mention of significant differences between the groups. In 2012, Gobbi et al.40 published a prospective cohort study of 50 patients with unilateral OA separated into two groups with Kellgren-Lawrence grades 1Y3 of knee OA. The first group (25 patients) had nonoperated knees, and the second group (25 patients) were status-post either microfracture or cartilage shaving procedures. Both groups received two 5-ml palpation-guided injections of nonactivated LR-PRP with PLT concentrations of È2 BL, separated by 1 mo. After the procedure, patients were instructed to ice for 20 mins every 2Y3 hrs for 24 hrs and restrict Bvigorous activity[ for at least 48 hrs. There was no mention of NSAID restrictions. Outcomes at 12 mos were measured with the VAS for Pain, IKDC, KOOS, Tegner, and Marx scores. Both nonoperated and postsurgical patients demonstrated statistically significant improvements in all outcomes and returned to previous activities, including recreational sports. This study was unique in showing positive outcomes without PRP preactivation and in the treatment of postoperative knees.

S116

Pourcho et al.

In 2012, Filardo et al.25 reported a prospective cohort study comparing the efficacy of LR-PRP with LP-PRP in patients with knee OA. This trial investigated 144 patients with unilateral KellgrenLawrence grades 1Y4 of knee OA. One group of 72 patients received three 5-ml palpation-guided injections of CaCl2-activated LR-PRP/lysate with PLT concentrations of È4.7 BL and leukocyte concentrations of È1.4 BL, at 3-wk intervals. The other 72 patients received three 5-ml palpation-guided injections of CaCl2-activated LP-PRP with PLT concentrations of È1.5 BL and no leukocytes, also performed at 3-wk intervals. Patients followed the same postprocedure exercise and NSAID restrictions as in the previous studies from these authors. Outcomes were measured with the EQ-VAS, IKDC, and Tegner scores at 12 mos. Both treatment groups had similar statistically significant improvements in all outcomes at 2 mos with further improvement at 6 mos and stable results at 12 mos. Results again showed greater pain and function improvements in younger patients with a lower grade of knee OA. However, other factors, such as BMI, sex, bilateral disease, and previous surgery, did not influence the outcomes. Patients receiving LR-PRP did report a higher incidence of postinjection swelling and discomfort (P G 0.03), although this resolved spontaneously after a few days. With otherwise similar results between the LR-PRP and LP-PRP groups, the authors recommended choosing a system based on practical considerations (e.g., cost, time, technical difficulty). Spakova´ et al.66 in 2012 reported results on 120 patients with unilateral Kellgren-Lawrence grades 1Y3 of knee OA, comparing PRP and HA. One group of patients (60 joints) received three 3-ml palpationguided injections of CaCl2-activated LR-PRP with a PLT concentration of È4.5 BL and leukocyte concentration of È3.6 BL, at 1-wk intervals. The other group (60 joints) received three 2-ml palpation-guided injections of HWHA at 1-wk intervals. Patients were instructed to withhold use of NSAIDs for 5 days before the procedure and 1 wk after the procedure. There were no postprocedure exercise restrictions. WOMAC and Pain Numeric Rating Scale scores improved in both PRP and HA groups at 3 mos, with slight worsening at 6 mos that remained statistically better than before treatment. The PRP group had statistically superior outcomes. In 2013, Jang et al59 published a prospective cohort study on 65 patients (90 joints) with knee OA separated into three groups based on radiographic severity (Kellgren-Lawrence grades 1Y3). All groups receivedone3-mlpalpation-guidedinjection of LR-PRP

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

without preactivation. Specific PLT and leukocyte concentrations were unspecified. Patients were instructed to not use NSAIDs for 2 wks and avoid Bextensive use[ of the knee for several days after injection. Outcomes were measured with the VAS for Pain and IKDC at 12 mos. Statistically significant improvements were reportedin all groups with a mean relapse in pain at 8.8 mos. Patients with grade 1 knee OA had better and longer duration pain relief (mean, 9.9 mos), whereas those with grade 3 disease had less effective, shorter duration pain relief (mean, 5.6 mos). The presence of patellofemoral joint disease was also associated with a shorter duration of pain relief (mean, 7.9 vs. 10.2 mos, if not present).

Randomized Controlled Trials Four randomized controlled trials investigating the efficacy of PRP injection for knee OA have been published. In 2012, Sa´nchez et al.67 reported the first double-blinded, randomized controlled trial comparing the efficacy of LP-PRP with HWHA in 176 patients with unilateral Ahlba¨ck grades 1Y3 of knee OA. Eighty-nine patients received three 8-ml palpation-guided injections of CaCl2-activated LPPRP with unspecified PLT concentration, at 1-wk intervals. The other 87 patients received three 2-ml palpation-guided injections of HWHA, also at 1-wk intervals. Patients were not allowed to use NSAIDs during the 6-mo follow-up period, and there was no mention of postprocedure activity restrictions. Outcomes were measured with the WOMAC, using 50% pain reduction as the primary outcome. At 6 mos, the number of patients with level of pain relief was higher (P = 0.044) in the PRP group (38.2%) than in the HA group (24.1%). Regarding secondary WOMAC outcomes, both groups improved, with greater, although not statistically significant, improvements observed in the PRP group. In 2012, Cerza et al.68 compared PRP with HA in 120 randomized patients with unilateral KellgrenLawrence grades 1Y3 of knee OA. Sixty patients received four 5.5-ml palpation-guided injections of LP-PRP without preactivation and unspecified PLT/ leukocyte concentrations, at 1-wk intervals. The other 60 patients received four 2-ml palpationguided injections of LWHA, also at 1-wk intervals. There was no mention of NSAID or activity restrictions. The PRP group had statistically better WOMAC scores (combined pain, stiffness, and physical function subscales) than the HA group at the 1-, 3-, and 6-mo follow-up points. Whereas the HA group’s WOMAC scores worsened between 1 www.ajpmr.com

and 6 mos, the PRP group scores improved between 1 and 3 mos and remained stable through the 6-mo follow-up. With regard to OA severity, the PRP group showed similar WOMAC improvements among all grades, whereas the HA group had statistically less benefit in subjects with grade 3 knee OA. Filardo et al.69 in 2012 published a doubleblinded, randomized controlled trial in 109 patients with unilateral Kellgren-Lawrence grades 1Y3 of knee OA, again comparing efficacy of PRP with HA injections. Fifty-four patients received three 5-ml palpation-guided injections of CaCl2-activated LRPRP/lysate with a PLT concentration of È5 BL and leukocyte concentration of È1.2 BL, at 1-wk intervals. The second group of 55 patients received three 2-ml palpation-guided injections of HWHA, also at 1-wk intervals. NSAID and activity restrictions were similar to the aforementioned studies by these investigators. Patient outcomes were measured with the IKDC, EQ-VAS, Tegner, and KOOS at 2, 6, and 12 mos. Compared with BL, both PRP and HA groups showed statistically significant improvements in outcomes at all time points, with no significant differences between treatment groups. However, in a subanalysis of patients with lowgrade articular degeneration (Kellgren-Lawrence grades 1Y2), the PRP group had better IKDC subjective scores than the HA group at 6 and 12 mos; this difference nearly reached statistical significance (Ps = 0.07 and 0.08, respectively). The PRP group had a higher incidence of postinjection pain, but this was self-limiting within a few days. In 2013, Patel et al.38 published the first double-blinded, randomized controlled trial comparing PRP injection with a saline control. In their study of 78 patients (156 joints) with bilateral Ahlba¨ck grades 1Y2 of knee OA, patients were separated into three treatment arms. The first group (26 patients/52 joints) received one È8-ml palpationguided injection of CaCl2-activated LP-PRP with a PLT concentration of È3 BL (mean, 310  103/KL) and no leukocytes. The second group (25 subjects/50 joints) received two È8-ml palpation-guided injections of the same LP-PRP product, separated by 3 wks. The last group (23 subjects/46 joints) received one 8-ml palpation-guided injection of saline, establishing a placebo control. Patients were immobilized for 10 mins after injection, but otherwise, no activity restrictions were specified. NSAIDs were not allowed during the follow-up period. Outcomes were measured with the VAS for Pain and WOMAC at 6 wks and 3 and 6 mos. Both PRP groups showed statistically significant improvements in all outcomes PRP Injection as a Treatment for Knee OA

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S117

at all time points. There was a slight, but significant, decrease in benefit at 6 mos, but all outcomes remained significantly improved from BL. In contrast, the saline control group showed a gradual, slight worsening in all outcomes, which was statistically significant for the total WOMAC and pain scores. Interestingly, there was no significant difference in outcomes between the one- and two-injection PRP groups. Subjects with Ahlba¨ck grade 1 of knee OA had greater WOMAC improvements than those with grade 2 OA. Age, sex, and BMI were not correlated with treatment efficacy. Limitations included the use of only bilateral injections and a relatively small sample size (power analysis based on VAS for Pain). The small sample size may have reduced the ability to detect a potential difference between the one- and two- injection PRP groups. Nevertheless, the study was novel in its comparison of different PRP injection frequencies and use of a saline placebo group.

RECOMMENDATIONS AND FUTURE RESEARCH CONSIDERATIONS Despite the widespread use of PRP for orthopedic conditions, research on the use of PRP injection for knee OA is still in its infancy, and many questions remain unanswered.24 Until recently, the evidence primarily consisted of expert opinion and uncontrolled studies, with minimal accounting for variables.79 However, the quality of PRP research in knee OA has improved significantly with the emergence of randomized controlled trials. Although the optimal protocol for PRP injection in knee OA has not been defined, some general conclusions can be drawn from the current literature. First, intraarticular knee PRP, as applied in published studies, seems to be safe. Although some patients experience transient increases in pain or swelling, these symptoms typically resolve within 2Y3 days, and no long-term side effects have been reported within the available 1- to 2-year follow-up periods. Of note, transient postinjection pain and swelling seem to be more common with LR-PRP than LP-PRP.25 Second, PRP seems to be more efficacious than HA in younger (G50 yrs old) patients with mild disease and equally effective as HA in older patients with more severe OA.25,50,51,59,68,69 Finally, the clinical benefits of PRP with respect to pain and function seem to decline starting at 6Y9 mos after treatment, with further loss of benefit at 24 mos.44,50,59 Although PRP seems to be a safe and effective treatment of knee OA, there are still many questions

S118

Pourcho et al.

that future studies will hopefully answer. On the basis of the literature to date, the optimal PRP protocol remains unclear. Notably, the few studies to date comparing various PLT/leukocyte concentrations and injection frequencies have not demonstrated significant differences in PRP treatment efficacy.25,38 Nevertheless, there is a pressing need for future investigations to compare PRP protocols with different PLT concentrations, leukocyte/PMN concentrations, activation methods, and injection frequencies/volumes. Other factors that are of possible importance and warrant reporting in future studies include blood draw/injection needle gauge, anticoagulant method, local anesthetic use, and NSAID/activity restrictions. Although almost all studies to date have used palpation guidance for injections, future investigators should also consider the use of image guidance to minimize injection inaccuracy as a confounding factor.70Y74 Beyond optimizing PRP protocols, further research is also needed to define patient-specific prognostic factors to aid in identifying likely responders. Ideally, forthcoming investigations should be blinded, randomized controlled trials, with follow-up of at least 1 yr and accounting of the aforementioned variables (see Table 1). At this time, intraarticular PRP injection is not a standard treatment of knee OA. However, in patients who have not adequately responded to traditional nonoperative treatments, especially young patients with low-grade knee OA, PRP should be a treatment consideration. The available literature indicates that PRP is a better option than HA for many knee OA patients. Now, further research is needed to compare PRP with corticosteroid injection, which is the current first-line standard of care of injection therapy used in the treatment of knee OA.80,81 Until these data are available, PRP will remain a second-line treatment option. It seems likely that PRP will become increasingly more available and affordable for patients with early knee OA. Future studies will determine how PRP will fit in the knee OA treatment algorithm as well as its potential role in the treatment of OA affecting other joints. REFERENCES 1. Brandt KD, Dieppe P, Radin E: Etiopathogenesis of osteoarthritis. Med Clin North Am 2009;93:1Y24 2. Centers for Disease Control and Prevention: Prevalence of disabilities and associated health conditions among adults. Morb Mortal Wkly 2001;50:120Y5 3. Vos T: Years lived with disability for 1160 sequelae of 289 diseases and injuries 1990Y2010: A systemic

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163Y96 4. Murphy L, Schwartz TA, Helmick CG, Renner JB, et al: Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum 2008;59:1207Y13 5. Hootman JM, Helmick CG: Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 2006;54:226Y9 6. Mankin HJ: The response of articular cartilage to mechanical injury. J Bone Joint Surg Am 1982;64:460Y6 7. Kon E, Filardo G, Drobnic M, Madry H, et al: Nonsurgical management of early knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2012;20:436Y49 8. Fortier LA, Barker JU, Strauss EJ, McCarrel TM, et al: The role of growth factors in cartilage repair. Clin Orthop Relat Res 2011;469:2706Y15 9. Marx RE: Platelet-rich plasmaVEvidence to support it use. J Oral Maxillofac Surg 2004;62:489Y96 10. Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, et al: Platelet-rich plasma: From basic science to clinical applications. Am J Sports Med 2009;37: 2259Y72 11. Anitua E, Sa´nchez M, Nurden AT, Zalduendo MM, et al: Platelet-released growth factors enhance the secretion of hyaluronic acid and indue hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology (Oxford) 2007;46:1769Y72 12. Boswell SG, Cole BJ, Sundman EA, Karas V, et al: Platelet-rich plasma: A milieu of bioactive factors. Artroscopy 2012:429Y39 13. de Vos RJ, Weir A, van Schie HT, Bierma-Zeinstra SM, et al: Platelet-rich plasma injection for chronic Achilles tendinopathy: A randomized controlled trial. JAMA 2010;303:144Y9 14. Nin JR, Gasque GM, Azca´rate AV, Beola JD, et al: Has platelet-rich plasma any role in anterior cruciate ligament allograft healing? Arthroscopy 2009:1206Y13 15. Kalaci A, Cakici H, Hapa O, Yanat AN, et al: Treatment of plantar fasciitis using four different local injection modalities: A randomized prospective clinical trial. J Am Podiatr Med Assoc 2009;99:108Y13 16. Sys J, Weyler J, Van Der Zijden T, Parizel P, et al: Platelet-rich plasma in mono-segmental posterior lumbar interbody fusion. Eur Spine J 2011;20:1650Y7 17. Mishra A, Pavelko T: Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med 2006;34:1774Y8 18. Filardo G, Kon E, Di Matteo B, Pelotti P, et al: Plateletrich plasma for the treatment of patellar tendinopathy: Clinical and imaging findings at medium-term follow-up. Int Orthop 2013;37:1583Y9

autologous whole blood for the treatment of chronic lateral elbow epicondylitis: A randomized controlled clinical trial. Am J Sports Med 2011;39:2130Y4 21. Gosens T, Peerbooms JC, van Laar W, den Oudsten BL: Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: A double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med 2011;39:1200Y8 22. Mishra AK, Skrepnik NV, Edwards SG, Jones GL, et al: Platelet-rich plasma significantly improves clinical outcomes in patients with chronic tennis elbow: A double-blind, prospective, multicenter, controlled trial of 230 patients. Am J Sports Med 2013;42(2):463Y71 23. Dohan Ehrenfest DM, Rasmusson L, Albrektsson T: Classification of platelet concentrates: From pure platelet-rich plasma (P-PRP) to leucocyte- and plateletrich fibrin (L-PRF). Trends Biotechnol 2009;27(3): 158Y67 24. Tschon M, Fini M, Giardino R, Filardo G, et al: Lights and shadows concerning platelet products for musculoskeletal regeneration. Front Biosci (Elite Ed) 2011;3: 96Y107 25. Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, et al: Platelet-rich plasma intraarticular injections for cartilage degeneration and osteoarthritis: Singleversus double-spinning approach. Knee Surg Sports Traumatol Arthrosc 2012;20:2082Y91 26. Kevy SV, Jacobson MS: Comparison of methods for point of care preparation of autologous platelet gel. J Extra Corpor Technol 2004;36:28Y35 27. Wasterlain AS, Braun HJ, Dragoo JL: Contents and formulations of platelet-rich plasma. Oper Tech Orthop 2012;22:33Y42 28. Lippi G, Salvagno GL, Montagnana M, Poli G, et al: Influence of the needle bore size on platelet count and routine coagulation testing. Blood Coagul Fibrinolysis 2006;17:557Y61 29. Andia I, Sanchez M, Maffulli N: Tendon healing and platelet-rich plasma therapies. Expert Opin Biol Ther 2010;10:1415Y26 30. Mishra A, Harmon K, Woodall J, Vieira A: Sports medicine applications of platelet rich plasma. Curr Pharm Biotechnol 2012;13:1185Y95 31. Sa´nchez M, Azofra J, Anitua E, Andı´a I, et al: Plasma rich in growth factors to treat an articular cartilage avulsion: A case report. Med Sci Sports Exerc 2003; 35:1648Y52 32. Sundman EA, Cole BJ, Fortier LA: Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med 2011;39:2135Y40

19. Mautner K, Colberg RE, Malanga G, Borg-Stein JP, et al: Outcomes after ultrasound-guided platelet-rich plasma injections for chronic tendinopathy: A multicenter, retrospective review. PM R 2013;5:169Y75

33. Boswell SG, Schnabel LV, Mohammed HO, Sundman EA, et al: Increasing platelet concentrations in leukocyte-reduced platelet-rich plasma decrease collagen gene synthesis in tendons. Am J Sports Med 2014;42(1):42Y9

20. Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, et al: Platelet-rich plasma versus

34. Anitua E, Sa´nchez M, Zalduendo MM, de la Fuente M, et al: Fibroblastic response to treatment with different

www.ajpmr.com

PRP Injection as a Treatment for Knee OA Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S119

preparations rich in growth factors. Cell Prolif 2009; 42:162Y70 35. Mazzocca AD, McCarthy MB, Chowaniec DM, Dugdale EM, et al: The positive effects of different platelet-rich plasma methods on human muscle, bone, and tendon cells. Am J Sports Med 2012;40:1742Y9 36. Graziani F, Ivanovski S, Cei S, Ducci F, et al: The in vitro effect of different PRP concentrations on osteoblasts and fibroblasts. Clin Oral Implants Res 2006; 17:212Y9 37. Sa´nchez M, Anitua E, Azofra J, Aguirre JJ, et al: Intraarticular injection of an autologous preparation rich in growth factors for the treatment of knee OA: A retrospective cohort study. Clin Exp Rheumatol 2008; 26:910Y3 38. Patel S, Dhillon MS, Aggarwal S, Marwaha N, et al: Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: A prospective, double-blind, randomized trial. Am J Sports Med 2013;41:356Y64 39. Napolitano M, Matera S, Bossio M, Crescibene A, et al: Autologous platelet gel for tissue regeneration in degenerative disorders of the knee. Blood Transfus 2012;10:72Y7 40. Gobbi A, Karnatzikos G, Mahajan V, Malchira S: Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: Preliminary results in a group of active patients. Sports Health 2012;4:162Y72 41. Mishra A, Woodall J Jr., Vieira A: Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med 2009;28(1):113Y25 42. McCarrel TM, Minas T, Fortier LA: Optimization of leukocyte concentration in platelet-rich plasma for the treatment of tendinopathy. J Bone Joint Surg Am 2012;94:e143 43. Dragoo JL, Braun HJ, Durham JL, Ridley BA, et al: Comparison of the acute inflammatory response of two commercial platelet-rich plasma systems in healthy rabbit tendons. Am J Sports Med 2012;40:1274Y81

S120

49. Schneider BS, Tiidus PM. Neutrophil infiltration in exercise-injured skeletal muscle: How do we resolve the controversy? Sports Med 2007;37:837Y56 50. Filardo G, Kon E, Buda R, Timoncini A, et al: Platelet-rich plasma intraarticular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2011;19:528Y35 51. Kon E, Mandelbaum B, Buda R, Filardo G, et al: Platelet-rich plasma intraarticular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: From early degeneration to osteoarthritis. Arthroscopy 2011;27:1490Y501 52. Lei H, Gui L, Xiao R: The effect of anticoagulants on the quality and biological efficacy of platelet-rich plasma. Clin Biochem 2009;42:1452Y60 53. Textor JA, Tablin F. Activation of equine platelet-rich plasma: Comparison of methods and characterization of equine autologous thrombin. Vet Surg 2012;41:784Y94 54. Hamilton B, Tol JL, Knez W, Chalabi H: Exercise and the platelet activator calcium chloride both influence the growth factor content of platelet-rich plasma (PRP): Overlooked biochemical factors that could influence PRP treatment. Br J Sports Med 2013 [Epub ahead of print] 55. Fufa D, Shealy B, Jacobson M, Kevy S, et al: Activation of platelet-rich plasma using soluble type I collagen. J Oral Maxillofac Surg 2008;66:684Y90 56. Han B, Woodell-May J, Ponticiello M, Yang Z, et al: The effect of thrombin activation of platelet-rich plasma on demineralized bone matrix osteoinductivity. J Bone Joint Surg Am 2009;91:1459Y70 57. Harrison S, Vavken P, Kevy S, Jacobson M, et al: Platelet activation by collagen provides sustained release of anabolic cytokines. Am J Sports Med 2011;39:729Y34 58. Scherer SS, Tobalem M, Vigato E, Heit Y, et al: Nonactivated versus thrombin-activated platelets on wound healing and fibroblast-to-myofibroblast differentiation in vivo and in vitro. Plast Reconstr Surg 2012;129:46eY54e

44. Kon E, Buda R, Filardo G, Di Martino A, et al: Platelet-rich plasma: intraarticular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc 2010; 18:472Y9

59. Jang SJ, Kim JD, Cha SS: Platelet-rich plasma (PRP) injections as an effective treatment for early osteoarthritis. Eur J Orthop Surg Traumatol 2013;23:573Y80

45. Browning SR, Weiser AM, Woolf N, Golish SR, et al: Platelet-rich plasma increases matrix metalloproteinases in cultures of human synovial fibroblasts. J Bone Joint Surg Am 2012;94:e1721Y7

60. Carofino B, Chowaniec DM, McCarthy MB, Bradley JP, et al: Corticosteroids and local anesthetics decrease positive effects of platelet-rich plasma: An in vitro study on human tendon cells. Arthroscopy 2012;28:711Y9

46. Yuan M, Meng HY, Wang AY, Guo QY, et al: Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: A review. Osteoarthrits Cartilage 2013;21(11):1627Y37

61. Dragoo JL, Braun HJ, Kim HJ, Phan HD, et al: The in vitro chondrotoxicity of single-dose local anesthetics. Am J Sports Med 2012;40:794Y9

47. Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 2005;288:R345Y53

62. Lo IK, Sciore P, Chung M, Liang S, et al: Local anesthetics induce chondrocyte death in bovine articular cartilage disks in a dose- and duration-dependent manner. Arthroscopy 2009;25:707Y15

48. Pizza FX, McLoughlin TJ, McGregor SJ, Calomeni EP, et al: Neutrophils injure cultured skeletal myotubes. Am J Physiol Cell Physiol 2001;281:C335Y41

63. Piper SL, Kramer JD, Kim HT, Feeley BT: Effects of local anesthetics on articular cartilage. Am J Sports Med 2011;39:2245Y53

Pourcho et al.

Am. J. Phys. Med. Rehabil. & Vol. 93, No. 11 (Suppl), November 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

64. Wang-Saegusa A, Cugat R, Ares O, Seijas R, et al: Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg 2011; 131:311Y7 65. Halpern B, Chaudhury S, Rodeo SA, Hayter C, et al: Clinical and MRI outcomes after platelet-rich plasma treatment for knee osteoarthritis. Clin J Sport Med 2013;23:238Y9 66. Spakova´ T, Rosocha J, Lacko M, Harvanova´ D, et al: Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil 2012;91:411Y7 67. Sa´nchez M, Fiz N, Azofra J, Usabiaga J, et al: A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28:1070Y8 68. Cerza F, Carni S, Carcangiu A, Di Vavo I, et al: Comparison between hyaluronic acid and platelet-rich plasma, intraarticular infiltration in the treatment of gonarthrosis. Am J Sports Med 2012;40:2822Y7 69. Filardo G, Kon E, Di Martino A, Di Matteo B, et al: Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: Study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord 2012;13:229

72. Jones A, Regan M, Ledingham J, Pattrick M, et al: Importance of placement of intraarticular steroid injections. BMJ 1993;307:1329Y30 73. Sibbitt WL, Peisajovich A, Jr, Michael AA, Park KS, et al: Does sonographic needle guidance affect the clinical outcome of intraarticular injections? J Rheumatol 2009;36:1892Y902 74. Curtiss HM, Finnoff JT, Peck E, Hollman J, et al: Accuracy of ultrasound-guided and palpation-guided knee injections by an experienced and lessexperienced injector using a superolateral approach: A cadaveric study. PM R 2011;3:507Y15 75. Scharf RE: Drugs that affect platelet function. Semin Thromb Hemost 2012;38:865Y73 76. Su BO, O’Connor JP: NSAID therapy effects on healing of bone, tendon, and the enthesis. J Appl Physiol 2013;115:892Y9 77. Shi S, Klotz U: Clinical use and pharmacological properties of selective COX-2 inhibitors. Eur J Clin Pharmacol 2008;64:233Y52 78. Sampson S, Reed M, Silvers H, Meng M, et al: Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: A pilot study. Am J Phys Med Rehabil 2010;89:961Y9 79. Filardo G, Kon E: PRP: More words than facts. Knee Surg Sports Traumatol Arthrosc 2012;20:1655Y6

70. Berkoff DJ, Miller LE, Block JE. Clinical utility of ultrasound guidance for intraarticular knee injections: A review. Clin Interv Aging 2012;7:89Y95

80. Bellamy N, Campbell J, Robinson V, Gee T, et al: Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006;2

71. Sibbitt WL, Band PA Jr, Kettwich LG, ChavezChiang NR, et al: A randomized controlled trial evaluating the cost-effectiveness of sonographic guidance for intraarticular injection of the osteoarthritic knee. J Clin Rheumatol 2011;17:409Y15

81. Hochberg MC, Altman RD, April KT, Benkhalti M, et al: American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465Y74

www.ajpmr.com

PRP Injection as a Treatment for Knee OA Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S121