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. 2022 Nov 7;49(2):723–745. doi: 10.1007/s00068-022-02155-y

Prognostic factors for the management of chondral defects of the knee and ankle joint: a systematic review

Filippo Migliorini 1,2,✉, Nicola Maffulli 3,4,5, Jörg Eschweiler 1, Christian Götze 6, Frank Hildebrand 1, Marcel Betsch 7
PMCID: PMC10175423  PMID: 36344653

Abstract

Purpose

Different surgical techniques to manage cartilage defects are available, including microfracture (MFx), autologous chondrocyte implantation (ACI), osteoarticular auto- or allograft transplantation (OAT), autologous matrix-induced chondrogenesis (AMIC). This study investigated the patient-related prognostic factors on the clinical outcomes of surgically treated knee and ankle cartilage defects.

Methods

This study followed the PRISMA statement. In May 2022, the following databases were accessed: PubMed, Google Scholar, Embase, and Scopus. All the studies investigating the outcomes of surgical management for knee and/or talus chondral defects were accessed. Only studies performing mesenchymal stem cells transplantation, OAT, MFx, ACI, and AMIC were considered. A multiple linear model regression analysis through the Pearson Product–Moment Correlation Coefficient was used.

Results

Data from 184 articles (8905 procedures) were retrieved. Female sex showed a positive moderate association with visual analogue scale at last follow-up (P = 0.02). Patient age had a negative association with the American Orthopaedic Foot and Ankle Score (P = 0.04) and Lysholm Knee Scoring Scale (P = 0.03). BMI was strongly associated with graft hypertrophy (P = 0.01). Greater values of VAS at baseline negatively correlate with lower values of Tegner Activity Scale at last follow-up (P < 0.0001).

Conclusion

The clinical outcomes were mostly related to the patients’ performance status prior surgery. A greater BMI was associated with greater rate of hypertrophy. Female sex and older age evidenced fair influence, while symptom duration prior to the surgical intervention and cartilage defect size evidenced no association with the surgical outcome. Lesion size and symptom duration did not evidence any association with the surgical outcome.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00068-022-02155-y.

Keywords: Chondral defect, Knee, Talus, Prognostic factors

Introduction

The treatment of articular cartilage defects of the lower extremities is challenging given the poor recruitment of regenerative cells into the defect, which results in a limited self-healing capacity of native cartilage tissue [1, 2]. Patients with full-thickness cartilage defects may experience significant pain, decrease in joint function and quality of life [3]. Cartilage defects result from trauma or repetitive shear and torsional forces applied to the cartilage surface [4]. If left untreated, cartilage lesions can progress to early osteoarthritis, joint pain, and mobility impairment [5, 6]. The previous studies estimated that the incidence of full-thickness cartilage lesions varies from 5% to 10% in knees of patients undergoing arthroscopy [7–9]. The prevalence of cartilage lesions in the ankle joint varies from 40% to 95% in patients with persistent pain after an ankle sprain with and without chronic ankle instability [10].

Microfracture (MFX) is considered the first-line treatment for cartilage defects, in both the knee and ankle joints, given the simplicity of the procedure, its low cost, minimal invasiveness, and satisfactory short-term clinical outcome [11, 12]. However, there have been concerns regarding the durability of MFX over time, since the clinical outcomes may worsen over time, in particular in larger lesions and more active patients [13–15]. To overcome limitations of the MFX technique, various forms of autologous chondrocyte implantation (ACI) and osteoarticular transfer system (OATS) have been introduced [16]. Although multiple techniques have been suggested to be effective in the management of articular cartilage defects, international recommendations and clear guidelines are missing. Moreover, it is also uncertain in which patient-dependent factors predict success after any of the above-mentioned cartilage treatment options.

Therefore, a systematic review was conducted to investigate whether patient characteristics at baseline exert an influence on surgical outcome in terms of patient-reported outcome reports (PROMs) and complications.

Materials and methods

Search strategy and data source

This systematic review is according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement [17]. The literature search was conducted independently by two authors (F.M. & J.E.). In May 2022, the following databases were accessed: PubMed, Google scholar, Embase, and Scopus. The following keywords were used in combination: chondral, cartilage, articular, damage, defect, injury, chondropathy, knee, pain, matrix-induced, periosteal, periosteum, collagen, autologous, chondrocyte, transplantation, implantation, MFX, microfractures, mosaicplasty, mACI, cACI, pACI, AMIC, OAT, osteochondral transplantation, allograft, autograft, membrane, therapy, management, surgery, outcomes, revision, hypertrophy, failure. Articles resulting from the literature search were screened by the same authors. The full text of the articles of interest was accessed. The bibliographies were also screened by hand for inclusion. Disagreements were solved by a third author (NM).

Eligibility criteria

All the studies investigating the outcomes of surgical management for knee and/or talus chondral defects were accessed. Only studies performing OAT, MFX, ACI or AMIC were considered. Given the authors language abilities, articles in English, German, Italian, French and Spanish were eligible. Studies with level I to IV of evidence, according to Oxford Centre of Evidence-Based Medicine [18], were considered. Abstracts, reviews, comments, editorial and opinion were not considered. Animals, biomechanics or in vitro studies were not considered. Studies enhancing the surgical procedures with stem cells were also eligible. Only studies that clearly stated the nature of the surgical intervention were included. Studies which included patients with large chondral and/or osteochondral lesions (>5 cm2) and obese (BMI > 30 kg/m2) were not included. Studies that reported data on patients with end-stage joint degeneration were not eligible. Only articles reporting quantitative data under the outcomes of interest were considered for inclusion. Missing data under the outcomes of interest warranted the exclusion from this study.

Outcomes of interest

Data extraction was performed separately by two authors (F.M. & J.E.). Data concerning author, year, journal, type of study and length of the follow-up were collected. The following data at baseline were collected: the number of patients, age, sex, mean BMI (kg/m2), size of the defect (cm2), and duration of symptoms (months). Data concerning the following scores were extracted at baseline and at last follow-up: visual analogic scale (VAS), American Orthopedic Foot and Ankle Score (AOFAS) [19], Tegner Activity Scale [20], Lysholm Knee Scoring Scale [21], and International Knee Documentation Committee (IKDC) [22] scores. Furthermore, rate of hypertrophy, failures, and revisions were also retrieved. The primary outcome was to investigate the association of baseline patient-specific characteristics on surgical outcomes following restorative cartilage procedures for the knee and ankle.

Methodology quality assessment

The methodological quality assessment was performed by two authors independently (F.M. & J.E.). The risk of bias graph tool of the Review Manager Software (The Nordic Cochrane Collaboration, Copenhagen) was used. The following risk of bias was evaluated: selection, detection, attrition, and other source of bias.

Statistical analysis

All statistical analyses were performed by one author (F.M.) using the software STATA/MP 14.1 (StataCorp, College Station, TX). The Shapiro–Wilk test was performed to investigate data distribution. For normal data, mean and standard deviation were calculated. For nonparametric data, median and interquartile range were calculated. The Student’s T test was used to assess significance for parametric data, while the Mann–Whitney U-test was used for nonparametric variables. Values of P < 0.05 considered statistically significant. A multivariate analysis was performed to assess associations between data of patients at baseline with the clinical scores at last follow-up and complications. A multiple linear model regression analysis through the Pearson Product–Moment Correlation Coefficient (r) was used. The Cauchy–Schwarz formula was used for inequality: + 1 is considered as positive linear association, while − 1 a negative one. Values of 0.1 <|r |< 0.3, 0.3 <|r |< 0.5, and |r |> 0.5 were considered to have weak, moderate, and strong association, respectively. The overall assessment of significance was performed using the χ2 test, with values of P < 0.05 considered statistically significant.

Results

Search result

The literature search resulted in 795 articles. Of them, 309 were duplicates. A further 302 articles were not eligible: surgical technique (N = 74), not focusing on knee or ankle (N = 41) study design (N = 140), not reporting quantitative data under the outcomes of interest (N = 19), other (N = 24), language limitations (N = 4). This left 184 articles for the present study. The literature search results are shown in Fig. 1.

Fig. 1.

Fig. 1

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Flowchart of the literature search

Methodological quality assessment

The risk of selection bias was judged as moderate. Indeed, 46.7% of studies (86 of 184) performed a retrospective analysis, while 38.0% (70 of 184) were prospective, and 15.2% (28 of 184) were randomized. Only few studies (35 of 184) performed assessor blinding; thus, the risk of detection bias was high. The risk of attrition and reporting bias were moderate, as was the risk of other bias. In conclusion, the overall review authors' judgements about each risk of bias item scored moderate, attesting to this study acceptable methodological assessment. The risk of bias graph is shown in Fig. 2.

Fig. 2.

Fig. 2

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Methodological quality assessment

Patient demographics

Data from 8905 procedures were retrieved. The median duration of symptoms before the index surgery was 36 (23.6–50.8) months. 41.7% (3713 of 8905) of patients were women. The mean age of the patients was 33.9 ± 6.9 years, while the mean BMI 25.6 ± 1.5 kg/m2. The mean defect size was 3.3 ± 2.3 cm2. The median follow-up time was 41.8 (24 to 60) months. Generalities and demographic data of the study are shown in Table 1.

Table 1.

Generalities and patient baseline of the included studies

Author, year Journal Study Design Follow-up (months) Place Type of treatment Procedures (n) Female (%) Mean age
Adams et al. 2011 [42] J Bone Joint Surg Retrospective 48.0 Talus OAT 8 62.5% 31.4
Adams et al. 2018 [43] Foot Ankle Int Prospective 55.0 Talus OAT 14 42.9% 40.0
Ahmad et al. 2015 [44] Foot Ankle Int Randomized 40.5 Talus OAT 16 37.5% 39.7
35.2 Talus OAT 20 45.0% 41.3
Akgun et al. 2015 [45] Arch Orthop Trauma Surg Prospective, randomized 24.0 Knee Syn-MSC 7 57.1% 32.3
Knee mACI 7 57.1% 32.7
Albano et al. 2017 [46] BMC Musculos Dis Retrospective 30.0 Talus AMIC 16 50.0% 42.6
Anders et al. 2012 [47] Int Orthop Prospective 63.5 Talus MACI 22 22.7% 23.9
Anders et al. 2013 [48] Open Orthop J Prospective, randomized 24.0 Knee AMIC 8 12.0% 35.0
Knee AMIC 13 23.0% 39.0
Knee MFX 6 33.0% 41.0
Apprich et al. 2012 [49] Osteoarthritis Cartilage Retrospective 48.0 Talus MACT 10 60.0% 31.0
59.6 Talus MFX 10 40.0% 32.4
Astur et al. 2018 [50] Rev Bras Orthop Prospective 12.0 Knee AMIC 7 14.3% 37.2
Aurich et al. 2010 [51] Am J Sports Med Retrospective 24.5 Talus MACI 19 27.8% 29.2
Bartlett et al. 2005 [52] J Bone Joint Surg Prospective, randomized 12.0 Knee cACI 44 40.7% 33.7
Knee mACI 47 33.4
Basad et al. 2010 [53] Knee Surg Sports Traumatol Arthrosc Prospective, randomized 24.0 Knee mACI 40 38.0% 33.0
Knee MFX 20 15.0% 37.5
Basad et al. 2015 [54] Knee Surg Sports Traumatol Arthrosc Prospective 60.0 Knee mACI 25 37.0% 32.0
Battaglia et al. 2011 [55] Knee Surg Sports Traumatol Arthrosc Retrospective 60.0 Talus MACI 20 30.0% 35.0
Baumfeld et al. 2018 [56] Foot Retrospective 10.8 Talus AMIC 17 47.1% 37.5
Baums et al. 2007 [57] J Bone Joint Surg Retrospective 63.0 Talus PACI 12 58.3% 29.7
Becher et al. 2015 [58] Arch Orthop Trauma Surg Prospective 21.0 Knee MFX 5 40.0% 27.0
Becher et al. 2017 [59] J Orthop Surg Res Prospective, randomized 36.0 Knee mACI 25 32.0% 33.0
Knee mACI 25 16.0% 34.0
Knee mACI 25 40.0% 34.0
Becher et al. 2018 [60] Knee Surg Sports Traumatol Arthrosc Retrospective 67.2 Talus MFX 16 56.3% 33.3
68.4 Talus AMIC 16 56.3% 32.4
Behrens et al. 2006 [61] Knee Prospective 34.5 Knee mACI 38 50.0% 35.0
Bentley et al. 2012 [62] J Bone Joint Surg Prospective, randomized 120.0 Knee pACI, cACI 58 43.1% 31.0
Knee Mosaicplasty 42 59.5% 32.0
Berruto et al. 2017 [63] Injury Prospective 162.0 Knee pACI 9 31.3% 31.6
Knee cACI 24
Bode et al. 2013 [64] Arch Orthop Trauma Surg Prospective 71.9 Knee cACI 19 40.2
Knee cACI 24 38.3
Brittberg et al. 2018 [65] Am J Sports Med Prospective, randomized 60.0 Knee mACI 65 38.0% 35.0
Knee MFX 63 33.0% 34.0
Browne et al. 2006 [66] Clin Orthop Rel Res Prospective 60.0 Knee pACI 100 35.0% 37.0
Buda et al. 2010 [67] J Bone Joint Surg Prospective 29.0 Knee BM- MSC 20 40.0%
Buda et al. 2015 [68] Int Orthop Retrospective 48.0 Talus MACI 40 37.5% 31.4
Talus BMC 40 32.5% 30.2
Buda et al. 2019 [69] Europ J Orthop Trauma Surg Retrospective 48.0 Knee BMAC 28 42.9% 38.0
Chan et al. 2018 [70] Cartilage Prospective 65.8 Talus pACI 24 41.7% 34.1
Chung et al. 2014 [71] Knee Surg Sports Traumatol Arthrosc Prospective 24.0 Knee MFX 12 83.3% 44.3
Knee AMIC 24 41.7% 47.4
Cole et al. 2011 [72] Am J Sports Med Prospective, randomized 24.0 Knee Control group
Knee MFX 9 44.0% 33.0
Cole et al. 2012 [72] Am J Sports Med Prospective 48.0 Knee pACI 32 25.0% 30.5
Cvetanovich et al. 2017 [73] Am J Sports Med Prospective 24.0 Knee pACI, cACI 12 22.0% 17.0
24.0 Knee mACI 11 22.0% 17.0
24.0 Knee mACI 14 22.0% 17.0
D'Ambrosi et al. 2017 [74] Arthroscopy Retrospective 27.0 Talus AMIC 17 52.9% 25.0
Talus AMIC 14 26.0% 47.0
D'Ambrosi et al. 2019 [75] Clin J Sport Med Retrospective 42.6 Talus AMIC 26 34.6% 33.7
de l’Escalopier et al. 2015 [76] Orthop Traumatol Sur Res Retrospective 76.0 Talus Mosaicplasty 37 33.0% 21.6
De Windt et al. 2017 [77] Stem Cells Prospective 12.0 Knee Allo-MSC 10 20.0% 26.0
De Windt et al. 2017 [78] Stem Cells Prospective 18.0 Knee Allo-MSC 35 31.0% 30.0
De Girolamo et al. 2019 [79] J Clin Med Prospective, randomized 100.0 Knee AMIC 12 38.0% 30.0
Knee AMIC 12 50.0% 30.0
Desando et al. 2017 [80] Cartilage Prospective 36.0 Talus MACI 7 42.9% 31.2
36.0 Talus MBMAC 15 33.3% 31.0
Dhollander et al. 2012 [81] Knee Surg Sports Traumatol Arthrosc Prospective 36.0 Knee cACI 32 31.0% 30.0
Dixon et al. 2011 [82] Foot Ankle Int Retrospective 44.4 Talus MACI 28 22.2% 41.0
Domayer et al. 2012 [83] Osteoarthritis Cartilage Retrospective 113.8 Talus MFX 10 55.6% 30.8
65.4 Talus MACT 10 77.8% 25.4
Duramaz et al. 2018 [84] Knee Surg Sports Traumatol Arthrosc Retrospective 28.9 Talus MFX 14 62.5% 34.6
Talus Control group
Ebert et al. 2011 [85] Am J Sports Med Prospective 60.0 Knee mACI 44 48.0% 39.0
Ebert et al. 2012 [86] Arthroscopy Prospective 24.0 Knee mACI 20 50.0% 34.0
Ebert et al. 2015 [87] Am J Sports Med Prospective 24.0 Knee mACI 10 20.0% 39.0
Knee mACI 13 7.0% 36.0
Knee mACI 9 66.0% 38.0
Knee mACI 15 53.0% 37.0
Ebert et al. 2017 [88] Am J Sports Med Prospective 60.0 Knee mACI 31 51.0% 35.0
Efe et al. 2011 [89] Am J Sports Med Prospective 24.0 Knee mACI 15 60.0% 26.0
El-Rashidy et al. 2011 [90] J Bone Joint Surg Retrospective 37.7 Talus OAT 38 42.1% 44. 2
Emre et al. 2012 [91] J Foot Ankle Surg Retrospective 16.8 Talus Mosaicplasty 32 9.4% 27.5
Enea et al. 2013 [92] Knee Retrospective 22.0 Knee AMIC 9 45.0% 48.0
Enea et al. 2015 [93] Knee Retrospective 29.0 Knee AMIC 9 44.0% 43.0
Espregueira-Mendes et al. 2012 [94] Knee Surg Sports Traumatol Arthrosc Prospective 110.0 Knee OAT 31 29.0% 30.0
Ferruzzi et al. 2008 [95] J Bone Joint Surg Prospective 60.0 Knee pACI 48 38.0% 32.0
Knee mACI 50 28.0% 31.0
Filardo et al. 2011 [96] Am J Sports Med Prospective 84.0 Knee mACT 62 23.0% 28.0
Filardo et al. 2014 [26] BMC Musculos Dis Prospective 84.0 Knee mACT 131 35.0% 29.0
Fraser et al. 2016 [97] Knee Surg Sports Traumatol Arthrosc Retrospective 70.8 Talus OAT 36 3.3% 31.0
Galla et al. 2019 [98] Knee Surg Sports Traumatol Arthrosc Retrospective 33.5 Talus AMIC 23 34.8% 35.6
Gaul et al. 2018 [99] Foot Ankle Int Retrospective 116.4 Talus OAT 20 47.0% 34.7
Gaul et al. 2018 [100] Foot Ankle Int Retrospective 123.6 Talus OAT 20 55.0% 43.6
Gautier et al. 2002 [101] J Bone Joint Surg Retrospective 24.0 Talus OAT 11 66.5% 32.0
Georgiannos et al. 2016 [102] Knee Surg Sports Traumatol Arthrosc Retrospective 66.0 Talus OAT 48 19.5% 36.0
Giannini et al. 2008 [103] Am J Sports Med Retrospective 36.0 Talus mACI 46 37.0% 31.4
Giannini et al. 2009 [104] Am J Sports Med Retrospective 119.0 Talus PACI 10 50.0% 25.8
Giannini et al. 2014 [105] Knee Surg Sports Traumatol Arthrosc Retrospective 87.2 Talus mACI 46 36.9% 31.4
Giannini et al. 2017 [106] Injury Retrospective 121.0 Talus OAT 48 25.0% 36.0
Gille et al. 2013 [107] Arch Orthop Trauma Surg Prognostic study 24.0 Knee AMIC 57 33.0% 37.0
Giza et al. 2010 [108] Foot Ankle Int Retrospective 24.0 Talus MACI 10 50.0% 40.2
Gobbi et al. 2006 [109] Arthroscopy Prospective 53.0 Talus MFX 10 40.0% 24.0
Talus Control group
Talus OAT 12 33.3% 27.8
Gobbi et al. 2009 [110] Am J Sports Med Prospective 60.0 Knee mACI 34 32.0% 31.0
Gobbi et al. 2011 [111] Cartilage Prospective 24.0 Knee cACI 15 33.0% 48.0
Gobbi et al. 2014 [112] Am J Sports Med Prospective 41.0 Knee cACI 25 36.0% 47.0
Gobbi et al. 2017 [113] Knee Surg Sports Traumatol Arthrosc Prospective 48.0 Knee cACI 20 50.0
Knee mACI 20 37.0
Gomoll et al. 2014 [114] Am J Sports Med Prospective 48.0 Knee pACI 110 64.0% 33.0
Gooding et al. 2006 [115] Knee Prospective, randomized 24.0 Knee pACI 33 51.0% 31.0
Knee cACI 35
Gottschalk et al. 2017 [116] J Foot Ankle Surg Retrospective 60.0 Talus AMIC 21 38.1% 37.0
Gudas et al. 2006 [117] Knee Surg Sports Traumatol Arthrosc Prospective, randomized 37.1 Knee MFX 28 42.9% 24.3
Knee OAT 29 34.5% 24.6
Gudas et al. 2009 [118] J Pediatr Orthop Prospective, randomized 24.0 Knee OAT 25 40.0% 15.0
Knee MFX 22 40.0% 14.0
Gudas et al. 2012 [119] Am J Sports Med Prospective, randomized 120.0 Knee OAT 28 32.0% 25.0
Knee MFX 29 41.0% 24.0
Gudas et al. 2018 [120] J Orthop Surg Retrospective 54.0 Knee AMIC 15 33.0% 31.0
Gül et al. 2016 [121] Foot Ankle Surg Retrospective 30.5 Talus OAT 15 33.3% 32.6
28.9 Talus OAT 13 830.0% 36.7
Guney et al. 2016 [122] Knee Surg Sports Traumatol Arthrosc Prospective 47.3 Talus MFX 19 37.4% 47.4
40.4 Talus MFX & PRP 22 43.9% 50.0
30.1 Talus Mosaicplasty 13 37.6% 15.4
Haleem et al. 2010 [123] Cartilage Retrospective 12.0 Knee pACI 5 20.0% 25.0
Haleem et al. 2014 [124] Am J Sports Med Retrospective 93.0 Talus OAT 14 50.0% 42.8
85.3 Talus OAT 28 39.3% 44.1
Haasper et al. 2007 [125] Arch Orthop Trauma Surg Retrospective 24.0 Talus Mosaicplasty 14 57.1% 24.8
Hahn et al. 2010 [126] Foot Ankle Int Retrospective 47.9 Talus OAT 13 61.5% 30.4
Hangody et al. 1997 [127] J Bone Joint Surg Retrospective 19.0 Talus Mosaicplasty 11 25.1
Hangody et al. 2001 [128] Foot Ankle Int Retrospective 50.4 Talus Mosaicplasty 36 27.0
Hoburg et al. 2019 [129] Orthop J Sports Med Prospective 63.0 Knee mACI 29 48.0% 16.0
48.0 Knee mACI 42 29.0% 27.0
Horas et al. 2003 [130] J Bone Joint Surg Prospective 24.0 Knee pACI 20 60.0% 31.4
Knee OAT 20 25.0% 35.4
Imhoff et al. 2011 [131] Am J Sports Med Retrospective 84.0 Talus OAT 26 46.2% 33.0
Jackson et al. 2019 [132] Foot Ankle Surg Retrospective 21.0 Talus OAT 31 9.7% 33.6
Kim et al. 2019 [133] Foot Ankle Int Retrospective 47.3 Talus MFX 64 26.6% 40.5
Knutsen et al. 2016 [134] J Bone Joint Surg Prospective, randomized 180.0 Knee pACI 40
Knee MFX 40
Koh et al. 2016 [135] Arthroscopy Prospective, randomized 27.0 Knee MFX 40 65.0% 38.0
Knee MFX 40 60.0% 39.0
Kon et al. 2009 [136] Am J Sports Med Prospective 60.0 Knee mACT 40 17.0% 29.0
Knee MFX 40 32.0% 31.0
Kon el al. 2011 [137] Am J Sports Med Prospective 61.0 Knee mACT 22 32.0% 46.0
58.0 Knee mACI 39 35.0% 45.0
Kretzschmarr et al. 2015 [138] Eur Radiol Prospective Talus AMIC 25 32.0% 38.0
Kreulen et al. 2018 [139] Foot Ankle Spec Prospective 84.0 Talus MACI 9 55.6% 45.8
Kreuz et al. 2005 [140] Am J Sports Med Retrospective 48.9 Talus Mosaicplasty 35 48.6% 30.9
Kubosch et al. 2016 [33] Int Orthop Retrospective 39.5 Talus AMIC 17 47.1% 38.8
Kwak et al. 2014 [141] Am J Sports Med Retrospective 70.0 Talus PACI 29 48.3% 34.0
Lahner et al. 2018 [142] Biomed Res Int Prospective 14.7 Knee AMIC 9 48.0
Lee et al. 2003 [143] Foot Ankle Int Retrospective 36.0 Talus Mosaicplasty 18 5.6% 22.7
Li et al. 2017 [144] BMC Musculos Dis Retrospective 21.2 Talus OAT 11 63.6% 55.4
Lim et al. 2012 [12] Clin Orthop Rel Res Prospective, randomized 60.0 Knee MFX 30 40.0% 33.0
Knee OAT 22 45.0% 30.0
Knee pACI 18 44.0% 25.0
Liu et al. 2011 [145] Foot Ankle Int Prospective 36.3 Talus OAT 16 37.5% 33.9
Liu et al. 2019 [146] Foot Ankle Soc Retrospective 18.0 Talus OAT 14 21.4% 29.6
Lopez-Alcorocho et al. 2018 [147] Cartilage Prospective 24.0 Knee mACI 50 30.0% 35.0
López-Alcorocho et al. 2019 [148] Cartilage Prospective 24.0 Talus HD-ACI 26 41.7% 31.0
Macmull et al. 2011 [149] Int Orthop Prospective 66.0 Knee pACI, cACI 24 29.0% 16.0
Knee mACI 7
Macmull et al. 2012 [150] Am J Sports Med Prospective 45.0 Knee cACI 25 80.0% 35.0
35.3 Knee mACI 23 61.0% 35.0
Magnan et al. 2012 [151] Advance Orthop Retrospective 45.0 Talus MACI 30 50.0% 28.9
Marlovits et al. 2012 [152] Am J Sports Med Prospective 60.0 Knee mACI 24 12.0% 35.0
McNickle et al. 2009 [153] Am J Sports Med Prospective 52.0 Knee pACI 140 42.0% 30.0
Mehl et al. 2019 [154] Knee Retrospective 78.0 Knee pACI, cACI 78 59.0% 32.0
Meyerkort et al. 2014 [155] Knee Surg Sports Traumatol Arthrosc Prospective 60.0 Knee mACI 23 42.0
Micheli et al. 2001 [156] Clin J Sport Med Prospective 36.0 Knee pACI 50 26.0% 36.0
Minas et al. 2014 [157] Clin Orthop Rel Res Prospective 120.0 Knee pACI 210 46.0% 36.0
Moseley et al. 2010 [158] Am J Sports Med Prospective 110.0 Knee pACI 72 39.0% 37.0
Murphy et al. 2019 [159] Knee Surg Sports Traumatol Arthrosc Retrospective 36.7 Talus MAST 38 31.2% 35.0
Nam et al. 2009 [160] American Journal Sports Med Retrospective 37.5 Talus PACI 11 54.5% 33.5
Nawaz et al. 2014 [161] J Bone Joint Surg Retrospective 74.0 Knee pACI, cACI 827 40.0% 34.0
Knee mACI
Nehrer et al. 2011 [162] Cartilage Prospective 61.0 Talus pACT, MACT 17 58.8% 28.0
Nejadnik et al. 2010 [163] Am J Sports Med Retrospective 24.0 Knee mACI 36 50.0% 43.0
Knee MFX 36 44.0% 44.0
Nguyen et al. 2019 [164] Am J Sports Med Retrospective 44.7 Talus OAT 38 0.0% 26.0
Niemeyer et al. 2008 [165] Arch Orthop Trauma Surg Retrospective 38.0 Knee pACI 95 34.0
Knee mACI
Niemeyer et al. 2010 [166] Arthroscopy Prospective 37.0 Knee cACI 59 37.0
Niemeyer et al. 2014 [167] Am J Sports Med Prospective 131.0 Knee pACI 70 64.0% 33.0
Niemeyer et al. 2016 [168] Am J Sports Med Prospective, randomized 12.0 Knee mACI 25 33.0% 33.0
Knee mACI 25 16.0% 34.0
Knee mACI 25 40.0% 34.0
Niemeyer et al. 2019 [169] Orthop J Sports Med Prospective, randomized 24.0 Knee mACI 52 36.0% 36.0
Knee MFX 50 44.0% 37.0
Ogura et al. 2017 [170] Am J Sports Med Prospective 240.0 Knee pACI 24 30.0% 35.0
Ogura et al. 2019 [171] Orthop J Sports Med Prospective 24.0 Knee pACI, cACI 15 20.0% 31.0
Orr et al. 2017 [172] Foot Ankle Spec Retrospective 28.5 Talus OAT 8 0.0% 34.4
Pagliazzi et al. 2018 [173] Foot Ankle Surg Retrospective 87.2 Talus MACI 20 30.0% 35.0
Park et al. 2018 [174] American Journal Sports Med Retrospective 71.4 Talus OAT 18 41.6%
Talus OAT 28
Park et al. 2020 [175] Bone Joint Journal Retrospective 22.0 Talus OAT 25 40.0% 19.6
Paul et al. 2012 [176] Am J Sports Med Retrospective 60.0 Talus OAT 131 38.2% 31.0
Peterson et al. 2010 [177] Am J Sports Med Retrospective 154.0 Knee pACI 224 33.0
Polat et al. 2016 [178] Knee Surg Sports Traumatol Arthrosc Retrospective 121.3 Talus MFX 82 41.5% 35.9
Quirbach et al. 2009 [179] Skeletal Radiol Retrospective 19.8 Talus MACT 12 33.3% 32.8
Randsborg et al. 2016 [180] BMC Musculos Dis Prospective, randomized 24.0 Knee cACI 82
Knee Control group
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Syn-MSC synovial mesenchymal stem cell; BMAC bone marrow aspirate concentrate; BM-MSC bone marrow-derived mesenchymal stem cells; Allo-MSC allogenic mesenchymal stem cell

Outcomes of interest

Female sex evidenced moderate association with greater VAS at last follow-up (r = 0.3; P = 0.02). Patient’s age evidenced negative association with the AOFAS score (r =  − 0.2; P = 0.04) and Lysholm Knee Scoring Scale (r =  − 0.4; P = 0.03). Greater BMI was moderately associated with the rate of graft hypertrophy (r = 0.6; P = 0.009). VAS, IKDC, AOFAS, and Tegner Activity Scale at baseline were positively associated with themselves at last follow-up: VAS (r = 0.9; P < 0.0001), IKDC (r = 0.5; P = 0.007), AOFAS (r = 0.6; P = 0.0002), Tegner Activity Scale (r = 0.4; P = 0.009). The VAS score at baseline was inversely associated with the Tegner Activity Scale (r =  − 0.8; P < 0.0001) at last follow-up. No further statically significant associations were evidenced. The results of each of the pairwise correlation is shown in greater detail in Table 2.

Table 2.

Overall results of the multivariate analyses

Demographic data at baseline
Endpoint at last FU Sex Age BMI Defect size Symptoms Duration VAS Tegner Lysholm AOFAS IKDC
r P r P r P r P r P r P r P r P r P r P
VAS 0.2 0.02 0.0 0.9 0.0 0.7 0.0 0.7 0.3 0.1 0.9 < 0.0001 0.3 0.2  − 0.3 0.2  − 0.3 0.2 0.1 0.7
Tegner  − 0.2 0.07 0.0 0.9  − 0.2 0.3 0.2 0.1  − 0.0 0.8  − 0.8 < 0.0001 0.4 0.009 0.0 0.9  − 0.0 0.9  − 0.1 0.5
AOFAS 0.1 0.4  − 0.2 0.04 0.0 0.7 0.0 0.9  − 0.1 0.7  − 0.1 0.4  − 0.1 0.9 0.6 0.0002
Lysholm  − 0.3 0.05  − 0.3 0.03 0.3 0.2 0.0 0.7 0.2 0.6  − 0.1 0.5  − 0.4 0.05 0.2 0.1 0.3 0.3
IKDC  − 0.2 0.08 0.0 0.8  − 0.2 0.4 0.3 0.05  − 0.3 0.2 0.0 0.8 0.1 0.5 0.0 0.8 0.4 0.0007
Hypertrophy 0.2 0.2 0.0 0.8 0.6 0.009  − 0.1 0.4 0.1 0.5  − 0 0.1 0.0 0.9 0.1 0.7 0.1 0.7 0.0 0.9
Failure 0.0 0.5 0.0 1 0.2 0.2 0.0 0.5 0.0 0.6  − 0.0 0.9  − 0.2 0.3  − 0.2 0.4  − 0.2 0.4  − 0.0 0.9
Revision 0.0 0.5 0.0 0.8 0.2 0.2 0.1 0.1 0.3 0.1 0.2 0.2 0.0 0.9  − 0.4 0.1  − 0.4 0.1  − 0.2 0.4
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Values of 0.1 <|r |< 0.3, 0.3 <|r |< 0.5, and |r |> 0.5 were considered to have weak, moderate, and strong association, respectively

FU follow-up

Discussion

The management of articular cartilage defects still presents a major challenge. Therefore, identification of prognostic factors would allow to predict the outcome of various surgical techniques in multiple joints, and it would help to educate patients on the success (or not) of their surgical intervention. Older age was associated with lower values of the AOFAS and Lysholm scores at last follow-up, while women evidenced a positive association with VAS. Given the weak associations between these endpoints, the role of sex and age still remain not fully defined. BMI evidenced a moderate positive association with the rate of graft hypertrophy. VAS, IKDC, AOFAS, and Tegner scores at baseline were associated among themselves at last follow-up, demonstrating that the final outcome is influenced by the pre-operative performance status of the patients. Interestingly, symptom duration prior to the surgical intervention and cartilage defect size did not show any significant association with the surgical outcome.

Neri et al. analyzed 48 patients who underwent microfractures of knee cartilage defects at a mean follow-up of 5.7 years [23]. Patients’ age, BMI, time from diagnosis to surgery, and size of the cartilage lesion were negatively associated with the functional outcome. Differences between these findings and our results may be explained by the fact that Neri et al. only included 48 patients treated for knee articular cartilage defects with a longer follow-up, while we included 8905 procedures including various treatment options with a variable follow-up. Similar findings were reported by Andriolo et al. in 113 patients with knee cartilage defects treated with matrix-assisted autologous chondrocyte implantation [24]. Older age, female sex, degenerative lesions, longer symptoms duration, and previous surgery were negatively associated with outcome.

Age has been identified as one of the most important factors for success in the treatment of cartilage defects [25, 26]. A study comparing microfracture to ACI or OATS showed better clinical outcomes for patients younger than 30 years compared to those older than 30 years, unrelated to treatment type [27, 28]. Robb et al. were able to identify age as a prognostic factor for lower clinical outcomes after treatment [29]. The structure and composition of the matrix molecules as well as the synthetic function of chondrocyte change with age, may explain the lower functional outcomes after cartilage defect management in older patients [30, 31]. These previous findings confirm our results of age being negatively associated with AOFAS and Lysholm scores.

Previously, it was also shown, in particular for the ankle joint, that patients’ BMI is a negative prognostic factor [32], with worse clinical outcomes for patients with a BMI > 30 kg/m2 [33, 34]. Jaiswal et al. found similar results showing an influence of BMI on the Modified Cincinnati Score after anterior cruciate ligament reconstruction and matrix-assisted autologous chondrocyte implantation [35]. The poorer results following cartilage repair in obese patients may be explained by an increase in mechanical forces across the joint leading to cartilage breakdown.

There was evidence of weak association between female sex and VAS. Females have lower femoral and retropatellar cartilage volumes than males, and this decreases with age [36]. These findings might explain the higher risk for knee osteoarthritis in women compared to men. Kreutz et al. studied 52 patients after ACI showing worse outcomes in women compared to men [37]. Furthermore, higher complication rates in cartilage repair surgery were found in women 24 months after surgery, which might be related to lower satisfaction levels in women, possibly resulting in more postoperative complaints [38–40].

Interestingly, cartilage defect size, in both the knee and ankle joints, is not associated with negative outcome. This was previously confirmed in studies highlighting that defect size does not predict the clinical outcome after treatment of cartilage defects, confirming that functional outcome seems to be independent of cartilage defect size [25, 41].

This study identified prognostic factors for successful cartilage repair management in the knee and ankle joints, regardless of the surgical procedure. However, there are also some limitations that need to be addressed. Although we followed established guidelines for the preparation of systematic reviews, the risk of bias of the included studies was only moderate, with acceptable methodological assessment. Given the lack of quantitative data, primary and revision settings could not be analyzed separately. To increase the pooling data, the sex of the patients, mean age and BMI, defect size, and mean length of prior symptoms duration were not analyzed separately according to the body location (knee and ankle). Furthermore, we considered only the most common surgeries strategy for chondral repair, potentially increasing the risk of selection bias. Given their uncertain results, less common or more innovative procedures were not considered. Given the lack of data, surgical indications were not considered separately for analysis. Patients with larger chondral and/ or osteochondral lesions (>5 cm2) and obese (BMI > 30 kg/m2) were not considered, as the surgical outcomes are strongly negatively influenced by these variables [33–35]. Large lesions require challenging surgery, with transplants and unpredictable outcome. Similarly, in obese patients, the articular cartilage is subjected to high loads, and lesions may not heal properly. Further clinical investigations are required to establish the proper management of chondral defects. Results from the present study should be considered in the light of these limitations. Further high-quality investigations should validate the results of the present study in a clinical setting.

Conclusion

Our results suggest that the clinical outcomes were mostly related to the patients’ performance status prior surgery and that greater BMI could be associated with greater rate of hypertrophy. Female sex and older age evidenced fair influence on outcome, while symptom duration prior to the surgical intervention and cartilage defect size evidenced no association with the surgical outcome. These results should be interpreted in the light of the limitations of the present study, and further investigations are needed to validate them in a clinical setting.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 65 KB) (64.5KB, doc)

Acknowledgements

None

Abbreviations

MFx

Microfracture

ACI

Autologous chondrocyte implantation

OAT

Osteoarticular auto- or allograft transplantation

AMIC

Autologous matrix-induced chondrogenesis

PROMs

Patient-reported outcome reports

VAS

Visual analogic scale

AOFAS

American Orthopedic Foot and Ankle Score

BMI

Body mass index

IKDC

International Knee Documentation Committee

FU

Follow-up

Author contributions

FM contributed to literature search, data extraction, methodological quality assessment, statistical analyses, writing; NM contributed to supervision, revision, final approval; JE contributed to literature search, data extraction, methodological quality assessment; CG, FH contributed to supervision; MB contributed to writing.

Funding

Open Access funding enabled and organized by Projekt DEAL. No external source of funding was used.

Availability of data and materials

The data underlying this article are available in the article and in its online supplementary material.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Contributor Information

Filippo Migliorini, Email: migliorini.md@gmail.com.

Nicola Maffulli, Email: n.maffulli@qmul.ac.uk.

Jörg Eschweiler, Email: joeschweiler@ukaachen.de.

Christian Götze, Email: christian.goetze@muehlenkreiskliniken.de.

Frank Hildebrand, Email: fhildebrand@ukaachen.de.

Marcel Betsch, Email: marcel.betsch@gmx.de.

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