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Figure 1:

Figure 1

PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) flowchart of the systematic literature review.

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Abstract

Background

: The treatment of degenerative meniscal lesions usually consists of conservative measures such as physical therapy and/or knee injections. Recently, the use of orthobiologics, in the form of PRP and cell-based therapies, gained huge popularity in orthopedic practice.

Objectives

: The aim of the present systematic review is to summarize the available evidence concerning the use of orthobiologics in the treatment of degenerative meniscal lesions

Data sources

: A comprehensive search of PubMed, Google Scholar, Cochrane, and EMBASE was performed using various combinations of the following keywords: Meniscus AND (platelet OR BMAC OR bone marrow OR adipose OR stromal vascular fraction OR placental OR cord OR jelly).

Study eligibility criteria, participants, and interventions

: Articles were screened according to the following inclusion criteria: (i)clinical reports and/or randomized trials that included injections to treat degenerative meniscal lesions; (ii)written in the English language; (iii)published from 2012 to 2022.

Results

: 9 studies were finally included in the present systematic review: 8 for PRP and 1 for MFAT. All the studies reported clinical and functional improvements for degenerative meniscal lesions treated with orthobiologics.

Limitations

: Included studies highlight considerable heterogeneity in methodological approaches. Differences in product choice, outcome measures and follow up preclude the ability to generate definitive suggestions for application in the everyday clinical practice.

Conclusions and implications of key findings

: The literature suggests that the use of orthobiologics may offer a new effective therapeutic strategy for the treatment of degenerative meniscus lesions.

Systematic review registration number: Not applicable.

Background

Meniscal tears can be defined as interruptions in the continuity of the meniscal fibrocartilage.1x1Di Matteo, B, Moran, CJ, Tarabella, V et al. A history of meniscal surgery: from ancient times to the twenty-first century. Knee Surg Sports Traumatol Arthrosc. 2016; 24: 1510–1518https://doi.org/10.1007/s00167-015-3717-2

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Based on the etiology, meniscal tears can be classified as traumatic (tears that occur with trauma of sufficient energy and with sudden onset of knee pain) and degenerative (lesions with a slow progression and without a clear history of trauma).2x2Beaufils, P, Becker, R, Kopf, S et al. Surgical management of degenerative meniscus lesions: the 2016 ESSKA meniscus consensus. Knee Surg Sports Traumatol Arthrosc. 2017; 25: 335–346https://doi.org/10.1007/s00167-016-4407-4

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In terms of location, the most commonly affect zones are the body and posterior horn of the medial meniscus.3x3Metcalf, MH and Barrett, GR. Prospective evaluation of 1485 meniscal tear patterns in patients with stable knees. Am J Sports Med. 2004; 32: 675–680https://doi.org/10.1177/0095399703258743

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From a clinical point a view, degenerative meniscal tears present as knee pain without a clear history of recent trauma, often in patients over 40 years of age, possibly (but rarely) accompanied by the presence of mechanical symptoms (clicking, popping).4x4Wagemakers, HP, Heintjes, EM, Boks, SS et al. Diagnostic value of history-taking and physical examination for assessing meniscal tears of the knee in general practice. Clin J Sport Med. 2008; 18: 24–30https://doi.org/10.1097/JSM.0b013e31815887a7

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On physical examination, findings that point to the presence of a meniscal lesion are joint line tenderness, pain on deep knee flexion, positive meniscal provocation tests (McMurray, Apley, Childress, Thessaly, Steinman), and an audible click during range of motion. Knee effusion may be present, but it's more commonly observed with acute traumatic meniscal tears.5x5Howell, R, Kumar, NS, Patel, N, and Tom, J. Degenerative meniscus: Pathogenesis, diagnosis, and treatment options. World J Orthop. 2014; 5: 597–602https://doi.org/10.5312/wjo.v5.i5.597

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The imaging modality of choice to support a diagnosis of a degenerative meniscal lesion is Magnetic Resonance Imaging (MRI).6x6De Smet, AA. How I diagnose meniscal tears on knee MRI. AJR Am J Roentgenol. 2012; 199: 481–499https://doi.org/10.2214/AJR.12.8663

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On MRI, degenerative meniscal lesions appear as areas of linear hyperintensity contacting the posterior and most commonly inferior surface of the meniscus (horizontal tears) or areas of hyperintensity with multiple components (complex tears).7x7von Engelhardt, LV, Schmitz, A, Pennekamp, PH, Schild, HH, Wirtz, DC, and von Falkenhausen, F. Diagnostics of degenerative meniscal tears at 3-Tesla MRI compared to arthroscopy as reference standard. Arch Orthop Trauma Surg. 2008; 128: 451–456https://doi.org/10.1007/s00402-007-0485-6

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The treatment of degenerative meniscal lesions, in the absence of mechanical symptoms, constitutes primarily conservative measures,2x2Beaufils, P, Becker, R, Kopf, S et al. Surgical management of degenerative meniscus lesions: the 2016 ESSKA meniscus consensus. Knee Surg Sports Traumatol Arthrosc. 2017; 25: 335–346https://doi.org/10.1007/s00167-016-4407-4

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while arthroscopy8x8B, Di Matteo, Tarabella, V, Filardo, G, Viganò, A, Tomba, P, and Thomas, Marcacci M. Annandale: the first meniscus repair. Knee Surg Sports Traumatol Arthrosc. 2013; 21: 1963–1966https://doi.org/10.1007/s00167-013-2490-3

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should only be performed in the presence of knee locking or failure of conservative measures in the absence of knee osteoarthritis.9x9Hohmann, E, Angelo, R, Arciero, R et al. Degenerative Meniscus Lesions: An Expert Consensus Statement Using the Modified Delphi Technique. Arthroscopy. 2020; 36: 501–512https://doi.org/10.1016/j.arthro.2019.08.014

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This is based on a course of supervised physical therapy10x10Kise, NJ, Risberg, MA, Stensrud, S, Ranstam, J, Engebretsen, L, and Roos, EM. Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up. BMJ. 2016; 354: i3740https://doi.org/10.1136/bmj.i3740

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and/or knee injections.11x11Alessio-Mazzola, M, Felli, L, Trentini, R et al. Efficacy of Autologous Platelet-Rich Plasma Injections for Grade 3 Symptomatic Degenerative Meniscal Lesions: A 1-Year Follow-up Prospective Study. Sports Health. 2022; 14: 227–236https://doi.org/10.1177/19417381211011074

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These can consist of viscosupplementation with hyaluronic acid, corticosteroid injections, or “so-called” orthobiologic approaches (including autologous blood products such as PRP, and cell-based therapies)12x12Perdisa, F, Filardo, G, Di Matteo, B, Marcacci, M, and Kon, E. Platelet rich plasma: a valid augmentation for cartilage scaffolds? A systematic review. Histol Histopathol. 2014; 29: 805–814https://doi.org/10.14670/HH-29.805

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, which can be delivered intra-articularly or directly into meniscus tissue with the aid of ultrasound (ultrasound-guided intra-meniscal injection). The rationale behind the use of these products in the treatment of degenerative meniscal lesions is the presence in these products of growth factors and cells that may promote angiogenesis, cell proliferation, and cell differentiation13x13Sánchez-González, DJ, Méndez-Bolaina, E, and Trejo-Bahena, NI. Platelet-rich plasma peptides: key for regeneration. Int J Pept. 2012; 2012: 532519https://doi.org/10.1155/2012/532519

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,14x14Ghazi Zadeh, L, Chevrier, A, Farr, J, Rodeo, SA, and Buschmann, MD. Augmentation Techniques for Meniscus Repair. J Knee Surg. 2018; 31: 99–116https://doi.org/10.1055/s-0037-1602247

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, all characteristics that are beneficial for the healing of the torn meniscus.

While a number of studies have evaluated the literature concerning orthobiologics as an adjunct to meniscal repair15x15Jacob, G, Shimomura, K, Krych, AJ, and Nakamura, N. The Meniscus Tear: A Review of Stem Cell Therapies. Cells. 2019; 9: 92https://doi.org/10.3390/cells9010092

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,16x16Twomey-Kozak, J and Jayasuriya, CT. Meniscus Repair and Regeneration: A Systematic Review from a Basic and Translational Science Perspective. Clin Sports Med. 2020; 39: 125–163https://doi.org/10.1016/j.csm.2019.08.003

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or as a treatment in pre-clinical studies17x17Korpershoek, JV, de Windt, TS, Hagmeijer, MH, Vonk, LA, and Saris, DBF. Cell-Based Meniscus Repair and Regeneration: At the Brink of Clinical Translation?: A Systematic Review of Preclinical Studies. Orthop J Sports Med. 2017; 5: 2325967117690131https://doi.org/10.1177/2325967117690131

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,18x18Dai, TY, Pan, ZY, and Yin, F. In Vivo Studies of Mesenchymal Stem Cells in the Treatment of Meniscus Injury. Orthop Surg. 2021; 13: 2185–2195https://doi.org/10.1111/os.13002

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, we are not aware of any studies that have systematically reviewed the clinical literature concerning orthobiologics as a standalone treatment for degenerative meniscal lesions. The aim of the present systematic review is to summarize the available evidence concerning the use of orthobiologics to treat degenerative meniscal lesions.

Data sources

A comprehensive search of PubMed, Google Scholar, Cochrane, and EMBASE was performed using various combinations of the following keywords: Meniscus AND (platelet OR BMAC OR bone marrow OR adipose OR stromal vascular fraction OR placental OR cord OR jelly). The search was performed on 30th october 2022 with two reviewers evaluating included studies independently (U.V. and A.G.).

Study appraisal and synthesis methods

The present systematic review followed Preferred Reporting items for Systematic Reviews and Meta-analysis (PRISMA) guidelines19x19Liberati, A, Altman, DG, Tetzlaff, J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339: b2700https://doi.org/10.1136/bmj.b2700

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(flow chart shown in Figure 1). All articles identified by the initial literature search were screened according to the following inclusion criteria: (i) clinical reports and/or randomized trials that included injections to treat meniscal tears or degeneration; (ii) written in the English language; (iii) published from 2012 to 2022. Exclusion criteria were: (i) in vitro studies or review articles; (ii) pre-clinical studies or studies not performed on human subjects (iii) not evaluating treatment of with meniscal tears or degeneration; (iv) not written in the English language. All duplicate articles, articles from non-peer reviewed journals and articles lacking access to the full text were excluded. Conference presentations, narrative reviews, editorials and expert opinions were also excluded. Discrepancies between the two reviewers were resolved by discussion, and the final results were reviewed by the senior investigators.

Figure 1: Opens large image

Figure 1

PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) flowchart of the systematic literature review.

Results

Study selection

A total of 498 related records were identified in the initial database search. Following evaluation of titles and abstracts, 21 full-text manuscripts were included and further assessed for eligibility. As shown in the PRISMA flowchart (Figure1) 12 records were excluded for not meeting the inclusion criteria. A total of 9 studies dealing with orthobiologic injectable treatments for degenerative meniscal lesions were finally included in the present systematic review (Table 1).

Table 1List of the studies included in the systematic review.
PublicationStudy DesignPatients’

Characteristics
Meniscus

Disease
TreatmentOutcome

Measure
Follow-Up

(months)
Main Clinical FindingsAdditional findings
Di Matteo et al.21x21Di Matteo, B, Altomare, D, Garibaldi, R, La Porta, A, Manca, A, and Kon, E. Ultrasound-Guided Meniscal Injection of Autologous Growth Factors: A Brief Report. Cartilage. 2021; 13: 387S–391Shttps://doi.org/10.1177/19476035211037390

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Prospective12 (10M 2F)

Age: 51.7 ± 19.1
Medial degeneration

K-L 0-1
3 US guided IM and PM inj. of ACP (Arthrex, Naples, FL)IKDC, VAS6-12-18

IKDC* and VAS* improved

1 patient failed

No severe AEs
Negative correlation with duration of symptoms
Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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Prospective10 (7M 3F)

Age: 40.4 ± 13.6
Medial degeneration

No Knee OA
1 US guided IM and PM inj. of PRP (Hy-Tissue, PRP, FIDIA)KOOS, MRI, VAS, RTSKOOS 3-6

At 6 m MRI (7 pt)
KOOS* and VAS improved

60% response rate

80% pain <10 minutes
Stable lesions at MRI

100% RTS
Popescu et al.26x26Popescu, MB, Carp, M, Tevanov, I et al. Isolated Meniscus Tears in Adolescent Patients Treated with Platelet-Rich Plasma Intra-articular Injections: 3-Month Clinical Outcome. Biomed Res Int. 2020; 2020: 8282460https://doi.org/10.1155/2020/8282460

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Retrospective30 (9M 21F)

Age: 13.9 ± 1.43
Tear II

acc. Reicher
1 IA inj. of PRP (PRP kit not specified)

Lysholm, NRS3NRS* and Lysholm* improved77% had ‘’excellent’’ or ‘’good’’ outcomes
Özyalvaç et al.24x24Özyalvaç, ON, Tüzüner, T, Gürpinar, T, Obut, A, Acar, B, and Akman, YE. Radiological and functional outcomes of ultrasound-guided PRP injections in intrasubstance meniscal degenerations. J Orthop Surg (Hong Kong). 2019; 27: 2309499019852779https://doi.org/10.1177/2309499019852779

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Retrospective15 (6M 9F)

Age: 33.2 ± 8.2
Tear II

acc. Reicher

Ahlback 0-1
1 US guided IM inj. of PRP (T-LAB PRP kit, T-Biotechnology Laboratory, Istanbul, Turkey)Lysholm, MRIMean:31.9 ± 5.6 (19–39)Lysholm* improved

Correlation between Lysholm and MRI improvement
MRI improved*: 67% grade II to grade I regression
Blanke et al.23x23Blanke, F, Vavken, P, Haenle, M, von Wehren, L, Pagenstert, G, and Majewski, M. Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. Muscles Ligaments Tendons J. 2015; 5: 162–166https://doi.org/10.11138/mltj/2015.5.3.162

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Retrospective10 (6M 4F)

Age: 53.3 ± 13.9
Tear II

acc. Reicher
3 weekly fluoroscopy guided IM inj. of PRP (Arthrex ACP Double Syringe System)NRS, MRI, RTS6NRS* improved

60% RTS

40% MRI improvement

40% additional surgery
Medina-Porqueres et al.30x30Medina-Porqueres, I, Martin-Garcia, P, Sanz-De-Diego, S et al. Clinical and Functional Outcome of Meniscal Injuries Treated with Platelet-Rich Plasma: A Single-Center Case Series. Int J Environ Res Public Health. 2022; 19: 7118https://doi.org/10.3390/ijerph19127118

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Retrospective38 (30M 8F)

Age: 50.7 ± 9.65
Tear I-III

acc. Reicher
3 weekly IA and PM inj. of PRP (no specific PRP kit adopted)KOOS, NRS,

Tegner
Mean: 75.92 ± 31.7 days (39–190)KOOS*, NRS*, Tegner* improved

No AEs
100% satisfaction rate
Kaminski et al.20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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Prospective

RCT

Double blind
72 (41M 31F)

Age: control 46 (27-68) study 44 (18-67)
Chronic horizontal lesionControl: 1 US guided trephination with placebo

Study: 1 US guided trephination + PRP (no specific PRP kit adopted)

VAS, KOOS,

WOMAC, IKDC,

MRI
3-6-12

At 33° week (MRI)
PROMs improved in both groups

Higher VAS* and KOOS for symptoms* improvement in PRP group
MRI healing rate superior in PRP group

Arthroscopy free survival superior in PRP group*

Alessio-Mazzola et al.11x11Alessio-Mazzola, M, Felli, L, Trentini, R et al. Efficacy of Autologous Platelet-Rich Plasma Injections for Grade 3 Symptomatic Degenerative Meniscal Lesions: A 1-Year Follow-up Prospective Study. Sports Health. 2022; 14: 227–236https://doi.org/10.1177/19417381211011074

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Prospective69 (21M 48F)

Age: 52.1 ± 7.8
Medial grade III

acc. Crues

K-L 0-1
4 weekly IA inj. of PRP (no specific PRP kit adopted)Lysholm, VAS, ROM,

WOMAC, Tegner
1-3-6-12Lysholm, VAS, WOMAC improved

ROM improved

No AEs
Patients <50yo had better VAS*, Lysholm*, Tegner*, WOMAC*, ROM* improvements
Malanga et al.22x22Malanga, GA, Chirichella, PS, Hogaboom, NS, and Capella, T. Clinical evaluation of micro-fragmented adipose tissue as a treatment option for patients with meniscus tears with osteoarthritis: a prospective pilot study. Int Orthop. 2021; 45: 473–480https://doi.org/10.1007/s00264-020-04835-z

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Prospective20 (11M 9F)

Age: 59.8 ± 6.5
Atraumatic tears

Knee OA
1 US guided trephination

+ IM and IA inj. of MFAT (Lipogems® processing kit, Lipogems International SpA, Milan, Italy)
KOOS, NRS3-6-12NRS* and KOOS* improved

No severe AEs
AEs limited to adipose harvest procedure
View Table in HTML

Inj: injection; MFAT: micro-fragmented adipose tissue; IM: intra-meniscal; PM: peri-meniscal; IA: intra-articular; *: statistically significant (p< 0.05); AE: adverse events; RTS: return to sport; acc.: according to

Study characteristics

Of the 9 selected studies, only the one from Kaminski et al20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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was a randomized, double blind, controlled trial comparing placebo to PRP injections in the setting of percutaneous meniscal trephination. The remaining studies were retrospective (4) or prospective (4) single arm studies evaluating the injection of 2 different products: PRP was assessed in 7 studies while micro-fragmented adipose tissue (MFAT) was assessed in one study. The injection of the specific product was variably described as intra-meniscal, peri-meniscal or intra-articular in the different reports and the procedure was US-guided in the majority of those. Interestingly, Blanke et al.23x23Blanke, F, Vavken, P, Haenle, M, von Wehren, L, Pagenstert, G, and Majewski, M. Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. Muscles Ligaments Tendons J. 2015; 5: 162–166https://doi.org/10.11138/mltj/2015.5.3.162

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performed 3 weekly injections of PRP through a fluoroscopic-guided procedure stating that meniscal tissue was identified by increase and then loss of resistance.  As for the study protocol, relevant variability was observed: MFAT was injected in a single administration in the setting of meniscal trephination while PRP was either evaluated after a single injection (4 studies) or in 3 (3 studies) or in 4 multiple injections (1 study).

Similarly, different clinical outcomes were reported in the evaluated studies. Özyalvaç et al.24x24Özyalvaç, ON, Tüzüner, T, Gürpinar, T, Obut, A, Acar, B, and Akman, YE. Radiological and functional outcomes of ultrasound-guided PRP injections in intrasubstance meniscal degenerations. J Orthop Surg (Hong Kong). 2019; 27: 2309499019852779https://doi.org/10.1177/2309499019852779

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were the only group not reporting pain modifications (VAS or NRS) after the injective treatment and there were no clinical outcomes reported equally in all the 9 examined studies.  The most reported clinical outcome was the KOOS scale (4 studies), while Lysholm, IKDC, WOMAC, Tegner scales were described only in a small portion of the selected reports. Return to sport (RTS) was reported only by Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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and Blanke et al.23x23Blanke, F, Vavken, P, Haenle, M, von Wehren, L, Pagenstert, G, and Majewski, M. Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. Muscles Ligaments Tendons J. 2015; 5: 162–166https://doi.org/10.11138/mltj/2015.5.3.162

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for a total of only 20 patients. Mazzola et al.11x11Alessio-Mazzola, M, Felli, L, Trentini, R et al. Efficacy of Autologous Platelet-Rich Plasma Injections for Grade 3 Symptomatic Degenerative Meniscal Lesions: A 1-Year Follow-up Prospective Study. Sports Health. 2022; 14: 227–236https://doi.org/10.1177/19417381211011074

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were the only authors to report specific results on range of motion variation after treatment. The possible onset of treatment-related adverse effects was reported only in 5 studies out of the 9 examined.

Post-treatment MRIs were performed and evaluated in 4 studies for a total of 68 patients: Özyalvaç et al24x24Özyalvaç, ON, Tüzüner, T, Gürpinar, T, Obut, A, Acar, B, and Akman, YE. Radiological and functional outcomes of ultrasound-guided PRP injections in intrasubstance meniscal degenerations. J Orthop Surg (Hong Kong). 2019; 27: 2309499019852779https://doi.org/10.1177/2309499019852779

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performed MRIs with a 1.0T device at a mean of 32 months follow up while all other 3 groups used a 1.5T device at 6 months of follow up. Interestingly, Kaminski et al.20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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performed MRI arthrography and considered meniscal healing as the reduction of meniscal tissue contrast filling.

Study population

In the present systematic review, clinical data from 276 patients were retrieved for a total of 141 males and 135 females. The mean follow-up of the included studies was 12 months and the mean age of included patients was 44.4 years. Popescu et al.26x26Popescu, MB, Carp, M, Tevanov, I et al. Isolated Meniscus Tears in Adolescent Patients Treated with Platelet-Rich Plasma Intra-articular Injections: 3-Month Clinical Outcome. Biomed Res Int. 2020; 2020: 8282460https://doi.org/10.1155/2020/8282460

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examined a younger cohort of 30 adolescent aged 12 to 17 years presenting lesions that were classified as grade 2 according to Reicher27x27Reicher, MA, Hartzman, S, Duckwiler, GR, Bassett, LW, Anderson, LJ, and Gold, RH. Meniscal injuries: detection using MR imaging. Radiology. 1986; 159: 753–757https://doi.org/10.1148/radiology.159.3.3754645

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(intrasubstance meniscal degeneration, IMD). The Reicher classification was also used to classify meniscal lesions as ‘’degenerative’’ in 3 other studies. In contrast, the Crues classification28x28Crues, JV, Mink, J, Levy, TL, Lotysch, M, and Stoller, DW. Meniscal tears of the knee: accuracy of MR imaging. Radiology. 1987; 164: 445–448https://doi.org/10.1148/radiology.164.2.3602385

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was adopted by Alessio-Mazzola et al.11x11Alessio-Mazzola, M, Felli, L, Trentini, R et al. Efficacy of Autologous Platelet-Rich Plasma Injections for Grade 3 Symptomatic Degenerative Meniscal Lesions: A 1-Year Follow-up Prospective Study. Sports Health. 2022; 14: 227–236https://doi.org/10.1177/19417381211011074

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, the Stoller classification29x29Stoller, DW, Martin, C, Crues, JV, Kaplan, L, and Mink, JH. Meniscal tears: pathologic correlation with MR imaging. Radiology. 1987; 163: 731–735https://doi.org/10.1148/radiology.163.3.3575724

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by Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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while the remaining 3 studies generally described the lesions as ‘’degenerative meniscal lesions’’ without reporting a specific grading system.

Reported clinical results

Patients undergoing PRP and MFAT injections reported a statistically significant reduction in pain, evaluated with either an NRS or VAS scale, in all studies with the exception of the study be Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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where improvements in reported pain did not reach statistical significance. The mean decrease in pain from the pre-injection levels to final follow up in the considered studies was of 3.29 points (on a 1-10 scale). In the RCT conducted by Kaminski et al.20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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, a significant difference level in the percentage of patients who exceeded MCID for VAS score for PRP (65%) and placebo (39%) was detected (P = 0.046).

As previously mentioned, considerable variation in different functional scores was noted in this systematic review. Nevertheless, statistically significant improvements in patient reported knee function were found in all the 9 studies regardless of the patient reported outcome measure (PROM) adopted (KOOS, IKDC, Lysholm, WOMAC) and the type of treatment (MFAT, PRP).

In the only RCT available, patients treated with either PRP or placebo experienced an improvement in functional outcomes measured with IKDC, WOMAC and KOOS subscales. Furthermore, a statistically significant difference in the percentage of patients exceeding the MCID for KOOS for symptoms subscale in the PRP (76%) and placebo (48%) group was detected (P = 0.028).

Clinical results were generally reported up to 6 or 12 months follow up. However, Di Matteo et al.21x21Di Matteo, B, Altomare, D, Garibaldi, R, La Porta, A, Manca, A, and Kon, E. Ultrasound-Guided Meniscal Injection of Autologous Growth Factors: A Brief Report. Cartilage. 2021; 13: 387S–391Shttps://doi.org/10.1177/19476035211037390

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reported clinical outcomes at 18 months after percutaneous needling plus ACP injection in 12 patients: after a significant improvement in IKDC and VAS score from pre-treatment to 12 months follow up, both results appeared stable between 12 and 18 months suggesting a persistence of the clinical effect. Furthermore, a negative correlation was found between duration of symptoms and IKDC score: patients with a longer history of pain reported significantly lower IKDC values after injection (P = 0.035, Pearson correlation coeff: -0.54).  In addition, Özyalvaç et al.24x24Özyalvaç, ON, Tüzüner, T, Gürpinar, T, Obut, A, Acar, B, and Akman, YE. Radiological and functional outcomes of ultrasound-guided PRP injections in intrasubstance meniscal degenerations. J Orthop Surg (Hong Kong). 2019; 27: 2309499019852779https://doi.org/10.1177/2309499019852779

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examined the clinical results at a mean 32 months follow up and reported a statistically significant improvement in mean Lysholm score from 71.1 to 91.9 after PRP treatment.

Return to sport (RTS) rate after the injective treatment was described in two studies. Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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reported a 100% return to competition or training activities in the 6 patients that used to practice sports regularly before the treatment. Similarly, Blanke et al.23x23Blanke, F, Vavken, P, Haenle, M, von Wehren, L, Pagenstert, G, and Majewski, M. Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. Muscles Ligaments Tendons J. 2015; 5: 162–166https://doi.org/10.11138/mltj/2015.5.3.162

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stated that 60% of the patients in their cohort increased their sports activity compared to the pre-injection situation and returned to previous athletic levels.

In the study from Medina-Porqueres et al.30x30Medina-Porqueres, I, Martin-Garcia, P, Sanz-De-Diego, S et al. Clinical and Functional Outcome of Meniscal Injuries Treated with Platelet-Rich Plasma: A Single-Center Case Series. Int J Environ Res Public Health. 2022; 19: 7118https://doi.org/10.3390/ijerph19127118

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, 38 patients with stable meniscal injuries were treated with 3 weekly intra-articular and peri-meniscal injections of PRP. In addition to the aforementioned statistically significant improvement in KOOS score, all patients were either very satisfied or satisfied with the outcome and none of the patients were reported to state that they would not undergo the same procedure again. In the same cohort, there was a significant improvement in the Tegner scale indicating a moderate level of sports participation after the treatment, in accordance with the improvements in Tegner scale ratings reported by Alessio-Mazzola et al.11x11Alessio-Mazzola, M, Felli, L, Trentini, R et al. Efficacy of Autologous Platelet-Rich Plasma Injections for Grade 3 Symptomatic Degenerative Meniscal Lesions: A 1-Year Follow-up Prospective Study. Sports Health. 2022; 14: 227–236https://doi.org/10.1177/19417381211011074

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Of note, in the RCT from Kaminski et al.20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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, the rate of patients that underwent arthroscopy because of failure of the injective treatment was monitored. The authors stated that 10 patients (8 in the placebo group and 2 in the PRP group) underwent subsequent arthroscopic meniscectomy or meniscal repair, resulting in a statistically significant difference in the arthroscopy free survival rate in the two groups favoring PRP (P = 0.032).

Only 5 studies reported that they monitored possible adverse effects of the injective treatments. Malanga et al.22x22Malanga, GA, Chirichella, PS, Hogaboom, NS, and Capella, T. Clinical evaluation of micro-fragmented adipose tissue as a treatment option for patients with meniscus tears with osteoarthritis: a prospective pilot study. Int Orthop. 2021; 45: 473–480https://doi.org/10.1007/s00264-020-04835-z

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described minor complications in 52% of cases, all of which were related to morbidity at the adipose harvest site including an uncomplicated cellulitis successfully treated with antibiotics. Similarly, Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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described that 80% of patients reported pain immediately following US-guided intra-meniscal and peri-meniscal injection of PRP with a mean VAS of 50 ± 31. In all patients pain resolved within 10 minutes.

Reported radiological results

Only 4 studies, totaling of 68 patients, included a post-treatment MRI to evaluate possible meniscal healing. MRIs were performed at 6 months following treatment in 85% of the patients. All the studies including post treatment MRIs evaluated PRP injection while no MRI data was available on MFAT.

The biggest cohort of patients assessed using MRI were part of the RCT by Kaminski et al.20x20Kaminski, R, Maksymowicz-Wleklik, M, Kulinski, K, Kozar-Kaminska, K, Dabrowska-Thing, A, and Pomianowski, S. Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study. Int J Mol Sci. 2019; 20: 856https://doi.org/10.3390/ijms20040856

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: half of the 72 patients in the RCT were treated with a single PRP injection in the context of percutaneous meniscal trephination and compared to patients treated with placebo injection. In this specific study, MRI arthrography was performed at 33 weeks. The meniscal healing rate (defined as a reduction in meniscal tissue contrast filling), was reported to be superior in the PRP augmented group than in the control placebo-augmented group, although this did not reach statistical significance. Indeed, 60% of the menisci treated with PRP were considered either fully or partially healed on post-treatment MRI arthrography.

Özyalvaç et al.24x24Özyalvaç, ON, Tüzüner, T, Gürpinar, T, Obut, A, Acar, B, and Akman, YE. Radiological and functional outcomes of ultrasound-guided PRP injections in intrasubstance meniscal degenerations. J Orthop Surg (Hong Kong). 2019; 27: 2309499019852779https://doi.org/10.1177/2309499019852779

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performed MRIs at a mean 32 months follow up after a single intra-meniscal PRP injection in 15 patients with intrasubstance meniscal degeneration (IMD, grade II according to Reicher). Interestingly, they reported a significant regression of MRI grades of meniscal degeneration: ten patients changed from grade II to grade I IMD, four patients showed no radiological changes while only one patient progressed to a grade III lesion. Furthermore, a statistically significant correlation between the decrease in MRI grades and increase of Lysholm score was reported.

The 10 patients treated with 3 weekly injections of PRP by Blanke et al.23x23Blanke, F, Vavken, P, Haenle, M, von Wehren, L, Pagenstert, G, and Majewski, M. Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. Muscles Ligaments Tendons J. 2015; 5: 162–166https://doi.org/10.11138/mltj/2015.5.3.162

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had a similar evolution: four of them showed a decrease of meniscal lesion, four remained stable and two presented a progression of the baseline grade II lesions.

Lastly, Guenoun et al.25x25Guenoun, D, Magalon, J, de Torquemada, I et al. Treatment of degenerative meniscal tear with intrameniscal injection of platelets rich plasma. Diagn Interv Imaging. 2020; 101: 169–176https://doi.org/10.1016/j.diii.2019.10.003

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reported stability of the meniscal tears and similar Stoller grades in all the seven patients of their cohort that underwent MRI 6 months after a single injection of PRP.

As already mentioned, post treatment imaging data was limited to patients undergoing PRP injection while there was no available data evaluating the morphological effect of MFAT on degenerative meniscal lesions.

Limitations

The results of the present systematic review should be evaluated in the context of its limitations. Indeed, the use of orthobiologics intended as PRP and cell based therapies have gained tremendous popularity in multiple fields of medicine. 31x31Di Matteo, B, Vandenbulcke, F, Vitale, ND et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019; : 1735242https://doi.org/10.1155/2019/1735242 (2019)

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,32x32Anzillotti, G, Conte, P, Di Matteo, B, Bertolino, EM, Marcacci, M, and Kon, E. Injection of biologic agents for treating severe knee osteoarthritis: is there a chance for a good outcome? A systematic review of clinical evidence. Eur Rev Med Pharmacol Sci. 2022; 26: 5447–5459https://doi.org/10.26355/eurrev_202208_29413

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In vitro data indicates that autologous growth factors present in these preparations may contribute to lowering inflammation while inhibiting catabolic distress.32x32Anzillotti, G, Conte, P, Di Matteo, B, Bertolino, EM, Marcacci, M, and Kon, E. Injection of biologic agents for treating severe knee osteoarthritis: is there a chance for a good outcome? A systematic review of clinical evidence. Eur Rev Med Pharmacol Sci. 2022; 26: 5447–5459https://doi.org/10.26355/eurrev_202208_29413

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Factors with anabolic properties, present in autologous preparations of blood and fat, may promote cartilage anabolism, type II collagen deposition, and extracellular matrix remodeling justifying the rationale for the application of orthobiologics to the degenerative meniscus.14x14Ghazi Zadeh, L, Chevrier, A, Farr, J, Rodeo, SA, and Buschmann, MD. Augmentation Techniques for Meniscus Repair. J Knee Surg. 2018; 31: 99–116https://doi.org/10.1055/s-0037-1602247

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,33x33Di Matteo, B, Anzillotti, G, and Kon, E. Navigating around the Current Options to Preserve and Regenerate Meniscus: A Long Journey Still to Be Pursued. Int J Mol Sci. 2022; 23: 6057https://doi.org/10.3390/ijms23116057

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Despite this clear rationale, the clinical evidence for these strategies is limited to small studies with considerable variation in the treatments delivered and in the patients studied. Firstly, the definition of “degenerative meniscus” was heterogenous, with different classifications adopted, highlighting the need for consistency in classification systems applied. Secondly, the majority of the included studies adopted a single injection strategy (5 of 9 papers), three repeated the injection three times, one study performed four injections, with similar disparities in the follow up periods used. Moreover, the injection itself was subject to differences in terms of localization with injectate delivered inside the meniscus, in the perimeniscal region or simply within the joint space. It is intuitive that the location of delivery may critically influence effect, with delivery of factors locally to the damaged tissue potentially offering advantages over those simply injected intra-articularly where only a minimal fraction may reach the target tissue. To minimize inaccuracies in injection location, 5 out of 9 studies performed injections under ultrasound-guidance, with one study adopting a fluoroscopy-base technique. Studies on cadaveric human specimens have shown that the administration of substances through intrameniscal or perimeniscal approaches are feasible and do not require special equipment. As such this may be the primary choice of strategy when addressing a meniscus-only degenerative pathology.34x34Baria, MR, Sellon, JL, Lueders, D, and Smith, J. Sonographically Guided Knee Meniscus Injections: Feasibility, Techniques, and Validation. PM R. 2017; 9: 998–1005https://doi.org/10.1016/j.pmrj.2016.12.012

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,35x35Coll, C, Coudreuse, JM, Guenoun, D et al. Ultrasound-Guided Perimeniscal Injections: Anatomical Description and Feasibility Study. J Ultrasound Med. 2022; 41: 217–224https://doi.org/10.1002/jum.15700

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Heterogeneity in the data collected in the present systematic review precluded the ability to draw definitive conclusions from the data presented. Indeed, the small samples sizes of included studies and the different outcome measures adopted made it impossible to directly address the primary question as to whether the biologic agents would be of value in the treatment of degenerative meniscus lesions or not. Accordingly, the overall level of evidence of the studies is low, with almost half of the data collected retrospectively, and significantly different methodological approaches accompanied by the lack of control group. Conversely, only one of the studies conducted a prospective randomized analysis with a control group but the concurrent use of trephination, which may have a therapeutic effect itself, impedes a clear assessment of the contribution of the orthobiologic. Despite the abovementioned limitations, the data presented in the present systematic review indicate that orthobiologics may represent a valuable therapeutic strategy in the treatment of degenerative meniscal lesions. Studies with longer follow up, and more uniform methodology are needed to more definitively evaluate the value of these approaches in clinical practice.

Conclusions and implications of key findings

Orthobiologics injections are increasingly utilized in the treatment of degenerative meniscal lesions. Exisiting literature evaluating these approaches are limited to a small number of studies with significant methodological limitations, with inadequate reporting of factors that may critically influence outcome. Well designed prospective clinical trials with uniform methodological approaches are required to definitively evaluate the value of these approaches.

Authorship contributions

PC and GA wrote the draft of the paper. UV and AG conducted the literature review and contributed to the data collection and interpretation. BDM contributed to the conception of the manuscript and critically revised the draft of the manuscript. EK was responsible for the conception of the paper and critically revised the final draft of the manuscript. All authors read and approved the final manuscript.

Patient informed consent statement

Not applicable.

Disclaimer

Nothing to declare.

Funding

No funding relevant to the current study.

Declaration of competing interests

The authors declare no competing financial interests or personal relationships related to this paper.

References

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3These authors contributed equally to the article and should both be considered first authors.

 

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