7 Use of Platelet-Rich Plasma for Patellar Tendon and Medial Collateral Ligament Injuries: Best Current Clinical Practice

10.1055/b-0035-123578

7 Use of Platelet-Rich Plasma for Patellar Tendon and Medial Collateral Ligament Injuries: Best Current Clinical Practice

Isabel Andia and Nicola Maffulli

7.1 Introduction

Patellar tendinopathy (PT), also named jumper’s knee, is an overuse injury characterized by activity-related anterior knee pain, most often showing lesions at the inferior pole of the patella, even though the midzone, paratenon, tibia tubercle or superior pole can also be affected.

PT is common among professional and recreational athletes ¹ involved in sports with high demand of the knee extensors, in particular volleyball and basketball. ² In this context, intrinsic risk factors such as patellar shape ³ and athlete’s age, or extrinsic risk factors involving playing at high level competition, hours of training per week, and training errors among others make athletes vulnerable to PT. ⁴ So far, most research involves professional and recreational athletes. The personal and economic burden of PT is high, because swelling and pain impairs performance with loss of function (jumping and kneeling), often leading athletes to abandon their career. ⁵

Several nonoperative treatment modalities can be used to manage PT, including a variety of injectable substances with different mechanisms of action such as corticoids, polidocanol or platelet-rich plasma (PRP). The effect of high volume injections to mechanically modify the tissue has been explored both in chronic PT ⁶ and recalcitrant medial collateral ligament (MCL) injuries. ⁷ In addition, physical therapies (mainly eccentric training) and extracorporeal shock wave therapy (ESWT) are used. While some evidence supports the efficacy of eccentric exercises, not enough data demonstrate the effectiveness of polidocanol injection or ESWT. ⁸ Their efficacy may depend on the phase of PT. Here, we review the available data on the efficacy of PRP injections in the management of PT.

Typical histopathological features of PT include collagen bundles separated by mucoid tissue, increased cellularity, extensive neovascularity, as well as clefts in collagen, and occasionally necrotic fibers suggesting microtears. ⁹ From a molecular point of view, alterations in the mechanical environment, that is, disintegrated collagen fibers and loss of cell attachment, modify the microenvironment ¹⁰ and affect a range of biological processes. The latter may be molecularly described as a dysregulation of inflammatory and angiogenic molecules, including prostaglandin E2, interleukin 6, interleukin 6 receptor, cyclooxygenase 2, vascular endothelial growth factor, oncostatin M, leukemia inhibitory factor, connective tissue growth factor ¹¹ as well as unbalanced anabolic/catabolic mediators. ¹² In this context, PRP therapy, a multimolecular approach influencing inflammation, angiogenesis, and cell metabolism, ¹³ is increasingly used to manage pathological tendons both in the upper and lower limb ¹⁴ with variable efficacy between tendons.

PRP therapies are easy to implement, and are considered safe because they are prepared through minimal manipulation of the patients’ own blood. But elucidating the effect of these therapies on patient outcomes requires careful analysis of PRP products and protocols, and methodological characteristics of the study to identify the most promising approaches. In this review, we examine clinical studies exploring the efficacy of PRP injections in PT and MCL injuries, seeking to identify under what conditions PRP works.

7.2 Methods

We searched for peer-reviewed original articles in the PubMed and Web of Science databases using the following keywords, and their different combinations: “platelet-rich plasma,” “jumper’s knee,” “patellar tendon,” “patellar tendinopathy,” and “medial collateral ligament” from January 2003 to January 2014. We also searched the authors own personal files. Only articles published in English were reviewed.

7.2.1 Study Selection and Data Collection

We have included all clinical studies, that is, case series, controlled nonrandomized and controlled randomized studies.

Extraction of data consists of study design, patient population, intervention, that is, type of PRP formulation, volume and number of injections and interval between injections, control treatment, outcome measurements, follow-up, and the reported results.

7.3 Results

7.3.1 Platelet-Rich Plasma Injections in Patellar Tendinopathy

PRP injections to manage PT were reported in a total of 226 patients, including three controlled studies ¹⁵ ^, ¹⁶ ^, ¹⁷ and eight case series studies ¹⁸ ^, ¹⁹ ^, ²⁰ ^, ²¹ ^, ²² ^, ²³ ^, ²⁴ ^, ²⁵ (Table 7.1). Two randomized clinical trials, one including 23 patients, ¹⁵ and the other, ¹⁶ 46 patients, have been published recently (2013–2014). In a randomized controlled trial (RCT) comparing one leukocyte and PRP (L-PRP) injection (n = 9 patients) and eccentric exercises with dry needling and eccentric exercise (n = 12 patients), Dragoo et al ¹⁵ showed significant improvement in clinical outcomes, in visual analog score (VAS) and Victoria Institute of Sport Assessment-patellar (VISA-P) at 12 weeks after treatment. Three patients failed treatment in the dry needling group and were rescued with PRP; their outcomes at the 26-week time-point were lost. Thus, the study is biased because patients were no longer in the treatment group they were allocated. Moreover, at 26-week follow-up the number of patients was low and there were no differences between dry needling (n = 9) and the PRP injection (n = 9). The authors interrupted recruitment because of clinically significant differences in favor of the PRP group at 12 weeks. However, these differences vanished over 26 weeks.

**Table 7.1** Platelet-rich plasma in the management of patellar tendinopathy
	Patellar tendon (conservative management)
Study (year) (Level of evidence)	Study design, N (patient population)	PRP (volume)	Intervention/ outcome measurements	Follow-up/results
Dragoo et al(2014) ¹⁵ (Level 1)	RCT, N = 23	6 mL L-PRP (Pit: 4–8x WBC: 6x), buffered pH: 7.4 No exogenous activation	Single injection PRP + eccentric vs. US-guided dry needling + eccentric/ VISA-P, VAS, Tegner, Lysholm, SF12	12 and 26 wks/VISA-P at 12 wks, VAS, Tegner, Lysholm, SF12 at 12 and 26 wks. Better PRP group at 1 2 wks but not at 26 wks. PRP accelerates the recovery but effect banishes over time No adverse effects
Vetrano et al(2013) ¹⁶ (Level 1)	RCT, N = 23 per group Athletes, chronic > 6 mo recalcitrant	2 mL pure PRP Pit: 3–5x	Two PRP injections, biweekly, US-guided vs. ESWT/VAS, VISA-P, Blazina scale	2,6, and 12 mo/VISA-P and VAS, PRP better at 6 and 12 mo, no differences at 2 mo; Blazina PRP better at 12 mo; PRP higher success rates (% responders) at 12 mo
Filardo et al (2010) ¹⁷ (Level III)	Nonrandomized study, PRP, N = 15 vs. physiotherapy N = 16 (matched for age, sex, and sport level) Chronicity > 3 mo and recalcitrant to conservative and surgical treatment only in PRP the group	5 mL L-PRP Blood bank: (Pit: 6x; WBC: ?) Activated Ca²⁺ mEq/ dose	Three blind injections/ biweekly + physical therapy Comparator: physical therapy/EQ-VAS, Tegner score	6 mo/No significant improvement in PRP group for EQ-VAS and pain level. Significant improvement in PRP group for Tegner score (+39 vs. 20%)
Charousset et al(2014) ¹⁸ (Level IV)	Case series, N = 28 athletes, 17 professional, 11 semiprofessional PT refractory	6 mL pure PRP (Pit: > 2x)	Three US-guided injections/VISA-P, VAS, Lysholm	2 year/21 athletes returned to presporting levels at 3 mo 57% patients recovered structural integrity, 7 treatment failures
Filardo et al (2013) ¹⁹ (Level IV)	Case series, N = 43, chronic	5 mL L-PRP Blood bank: (Pit: 6x; WBC: ?) Activated Ca²⁺ mEq/ dose	Three US-guided injections biweekly/ VISA-P, Blazina, EQ-VAS, Tegner, US	4y/VISA-P increased over time, 80% were satisfied and resume previous sport activities
van ArK et al (2012) ²⁰ (Level IV)	Case series, N = 5 patients, 6 tendons/ athletes, symptoms for over 12 mo VISA-P < 80, US hypoechogenicity, recalcitrant to at least 12 wks eccentric training	2–3 mL P-PRP Pit: 1.7x(ACP, Arthrex)	Single US-guided injection + physical therapy VISA-P, VAS during daily activities, functional test	6 mo/5/6 tendons showed an improvement of at least 30 points on the VISA-P after 6 mo
Gosens et al (2012) ²¹ (Level IV)	Case series N = 36, subgroups: refractory N = 14 vs. nonrefractory N = 22. Resistant to conservative and surgical treatment N = 14, resistant but no injections, no responders to eccentric	3 mL L-PRP (Pit: 4–8x WBC: 6x), buffered pH: 7.4 + bupivacaine/no activation	Single blind injection, one skin portal, and five penetrations of the tendon VISA-P, ADL, VAS	18 mo/clinical improvement in refractory and non-refractory patients, better results in the last group
Kon et al (2009) ²² (Level IV)	Case series N = 20 males Refractory tendinopathy	5 mL L-PRP Blood bank: (Pit: 6x; WBC: ?) Activated Ca²⁺ mEq/ dose	L-PRP and rehabilitation three injections, 2 wk interval between injections/Tegner, VAS, SF-36	6 mo/significant improvement in all scores after 6 mo. Six men complete recovery, eight men marked improvement, two men showed mild improvement and four men no improvement
Volpi et al (2007) ²³ (Level IV)	Case series N = 8 Young athletes, third proximal recalcitrant tendinopathy since at least 1 y	3 mL L-PRP (Pit: 4–8x WBC: 6x) buffered pH: 7.4/no activation	Single blind injection + rehabilitation/ VISA-P, M RI	4 mo/VISA improvement (91%)/ reduction in irregularity in 80% of treated tendons (MRI, 4 mo)
Ferrero et al (2012) ²⁴ (Level IV)^a	Case series 28 patellar tendons in 24 patients Competitive and recreational athletes, resistant to conservative treatments	Blood bank: 6 mL L-PRP Pit: 5x WBC: 6x/ thrombin activation	US-guided two injections and scarifications (3 wks interval)/ VISA-P, US/6 mo	VISA-P improvement at 6 mo/reduction in hypoechoic areas and tendon thickness after 6 mo. Intratendinous vascularity increased at 20 d and 6 mo
Volpi et al (2010) ²⁵ (Level IV)^a	Case series, patellar (N = 13 tendons), nine athletes, other recreational	3 mL L-PRP (Pit: 4–8x WBC: 6x) buffered pH: 7.4 no activation	PRP and rehabilitation Single US-guided injection	VISA-P, MRI//24 mo/ Improvement in VISA-P (+ 37) and reductions in abnormalities in 80% of treated tendons (MRI). The improvement of clinical symptoms is maintained for at least 2 y following treatment. Improvement less marked in Achilles
^aAchilles and patellar tendon examined in the same study. Abbreviations: ESWT, extracorporeal shock wave therapy; L-PRP, leukocyte-rich PRP; MRI, magnetic resonance imaging; Pit, platelets; PRP, platelet-rich plasma; PT, patellar tendon; RCT, randomized controlled trial; US, ultrasound; VISA-P, Victoria Institute of Sport Assessment-patellar; VAS, visual analog score; WBC, white blood cells; SF-12, health survey 12 questions; SF-36, health survey 36 questions.

Two randomized clinical trials, ¹⁶ each involving 46 patients, have compared two injections of pure PRP with ESWT. Clinical outcomes, as assessed by VAS, VISA-P, and Blazina scores, showed greater improvement at 6 and 12 months in the PRP group, and the percent of responders was significantly higher in PRP than in the ESWT group. ¹⁶ Given evident differences between experimental and control treatment these studies were blind merely for the outcome assessor.

In a nonrandomized controlled study, Filardo et al ¹⁷ showed that three injections of L-PRP 1 week apart were superior to physiotherapy as assessed by the Tegner activity score at 6 months. In this study, subjects treated with PRP had previously failed physiotherapy treatment.

Eight case series, ¹⁸ ^, ¹⁹ ^, ²⁰ ^, ²¹ ^, ²² ^, ²³ ^, ²⁴ ^, ²⁵ with a variable number of patients ranging from 5 to 43, have been published. Two ²⁴ ^, ²⁵ of these case series included both Achilles and PT.

Regarding procedural factors, most studies (6/8) used L-PRP ¹⁹ ^, ²¹ ^, ²² ^, ²³ ^, ²⁴ ^, ²⁵ ; the number of injections varied from a single injection (four studies), ²¹ ^, ²³ ^, ²⁴ ^, ²⁵ two injections with 3 weeks interval (one study), ²⁴ to three injections with 2 weeks interval (two studies). ¹⁷ ^, ¹⁸ All studies but one used the ultrasound (US) guidance for PRP delivery. ¹⁷ The VISA-P, a standardized and validated score that allows follow-up of chronic symptoms, was used in all studies except the study by Filardo et al. ¹⁷

Several studies evaluated the structural changes after treatment. ²³ ^, ²⁴ ^, ²⁵ Volpi et al ²³ reported structural improvement in 80% of the treated tendons, as assessed by magnetic resonance imaging (MRI) at 3 to 4 month post-treatment, while Ferrero et al ²⁴ reported significant changes in tendon thickness, reductions in hypoechoic areas, and decrease in intratendinous vascularity at 6 months posttreatment, but no changes at 20-day follow-up.

The effect of previous treatments and length of disease was examined in a prospective study involving 36 patients treated with one injection of buffered L-PRP. ²¹ Although, VAS and ADL (pain during daily activities) scores improved in both groups, patients with previous treatments (ethoxysclerol, cortisone and/or surgical treatment) did not show significant changes in VISA-P over time.

Whether the effects of PRP injections lasted or not was examined by Filardo et al ¹⁷ in a 4-year follow-up study including 42 male patients and 1 female patient. The VISA-P score was significantly higher 4 years after the treatment and 80% of patients resumed their sporting activities thus were satisfied with the treatment. Results were worst in patients with bilateral PT, and in those with longer history of the pathology.

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