Knee Surgery, Sports Traumatology, Arthroscopy

, Volume 26, Issue 4, pp 1223–1229 | Cite as

Biophysical stimulation improves clinical results of matrix-assisted autologous chondrocyte implantation in the treatment of chondral lesions of the knee

  • Marco Collarile
  • Andrea Sambri
  • Giada Lullini
  • Matteo Cadossi
  • Claudio Zorzi
Knee
  • 205 Downloads

Abstract

Purpose

The purpose of the present study was to evaluate the effects of pulsed electromagnetic fields (PEMFs) on clinical outcome in patients who underwent arthroscopic matrix-assisted autologous chondrocyte implantation (MACI) for chondral lesions of the knee.

Methods

Thirty patients affected by grade III and IV International Cartilage Repair Society chondral lesions of the knee underwent MACI. After surgery, patients were randomly assigned to either experimental group (PEMFs 4 h per day for 60 days) or control group . Clinical outcome was evaluated through International Knee Documentation Committee (IKDC) subjective knee evaluation form, Visual Analog Scale, Short Form-36 (SF-36) and EuroQoL before surgery and 1, 2, 6, and 60 months postoperative.

Results

Mean size of chondral lesion was 2.4 ± 0.6 cm2 in the PEMFs group and 2.5 ± 0.5 cm2 in the control one. No differences were found between groups at baseline. IKDC score increased in both groups till 6 months, but afterward improvement was observed only in the experimental group with a significant difference between groups at 60 months (p = 0.001). A significant difference between groups was recorded at 60 months for SF-36 (p = 0.006) and EuroQol (p = 0.020). A significant pain reduction was observed in the experimental group at 1-, 2- and 60-month follow-up.

Conclusion

Biophysical stimulation with PEMFs improves clinical outcome after arthroscopic MACI for chondral lesions of the knee in the short- and long-term follow-up. Biophysical stimulation should be considered as an effective tool in order to ameliorate clinical results of regenerative medicine. The use of PEMFs represents an innovative therapeutic approach for the survival of cartilage-engineered constructs and consequently the success of orthopaedic surgery.

Level of evidence

II.

Keywords

Osteochondral lesions Pulsed electromagnetic fields Autologous chondrocyte transplantation Regenerative medicine 

Introduction

Matrix-assisted autologous chondrocyte implantation (MACI), generally offers good clinical outcomes in the treatment of osteochondral lesions in the knee with a good safety profile [1, 2, 3, 4]. However, approximately 15% failures were reported within 2 years from surgery. Histological characteristics of failed grafts obtained from biopsy during second-look arthroscopy, showed fibrous tissue with incomplete integration with the surrounding cartilage [5].

Transplanted chondrocyte destiny may be influenced by several factors such as pro-inflammatory and anti-inflammatory cytokines, growth factors and mechanical stimulation. The imbalance between catabolic and anabolic factors may jeopardize the survival of the cartilage tissue construct thus promoting fibrous tissue formation [6, 7].

The joint microenvironment is modified following a local surgical procedure. Increased interleukin-1beta (IL-1β) synovial fluid concentration has been documented after joint surgery, and its levels have been found to correlate with the severity of cartilage damage and C-reactive protein [8]. In the presence of an inflammatory environment, prostaglandin E2 (PGE2) is released thus promoting chondrocyte apoptosis [9].

Biophysical stimulation with specific physical parameters of pulsed electromagnetic fields (PEMFs) has been shown to promote anabolic chondrocyte activity and to stimulate proteoglycan synthesis [10]. Moreover, it has been shown to reduce the release of the most relevant pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8 and PGE2 by immune cells including; T-cells, B-cells and macrophages that infiltrate the inflamed synovium, while stimulating the release of the anti-inflammatory cytokine IL-10 [10, 11, 12, 13, 14, 15]. The effects of these PEMFs are partially mediated by the activation of A2A and A3 adenosine receptors, potent endogenous inhibitors of inflammatory processes associated with joint diseases [16, 17, 18]. The therapeutic efficacy of PEMFs has been demonstrated after arthroscopic treatment of cartilage injuries: after micro-fractures in the knee [19] and bone marrow derived cells transplantation in osteochondral lesions of the talus [20].

Based on these results, transplanted chondrocytes with MACI technique may benefit from the proper joint microenvironment control by PEMFs effects. PEMFs can play a fundamental role in the success of tissue engineering surgery by controlling the microenvironment for cartilage regeneration.

The hypothesis of this study was that PEMFs may improve the clinical outcome of patients who underwent arthroscopic MACI for chondral lesions of the knee. The aim of this trial was to assess the effect of PEMFs used within 1 week after MACI on functional recovery evaluated by International Knee Documentation Committee (IKDC) subjective evaluation score at long-term follow-up.

Materials and methods

Institutional review board (IRB)

Ethical approval (with Document Prot.3005-H) was obtained at the ethical committee of “Ospedale Sacro Cuore Don Calabria”, Negrar (Vr), and patients enrolled in this trial signed a specific informed consent.

Study population

Inclusion criteria were: (1) patients aged between 18 and 50; (2) focal chondral knee defects grade III to IV according to International Cartilage Repair Society (ICRS) classification; (3) chondral knee defects involving either femoral condyle or patella assessed with magnetic resonance imaging (MRI); (4) clinical symptoms of pain, swelling, locking or giving way [21, 22].

Exclusion criteria were: (1) co-existing knee pathologies such as tibiofemoral axial malalignment on full-length weight-bearing radiographs [23] or patellofemoral mal-tracking; (2) knee instability evaluated both clinically and by MRI; (3) kissing lesions; (4) previous knee surgery; (5) radiographic signs of osteoarthritis (Kellgren-Lawrence grade 0–1); (6) other medical conditions (e.g. rheumatoid arthritis, autoimmune diseases, systemic diseases, malignancy and BMI higher than 30 kg/m2).

From October 2010 to July 2011, 30 patients were enrolled in this study (21 males and 9 females) with a mean age of 40 ± 6 years. Before surgery, patients were randomly assigned by a sealed envelope technique to the experimental group (15 patients) or to the control group (15 patients).

Patients were normally distributed by age in the whole cohort and in single groups.

Three patients were lost to follow-up (Fig. 1).
Fig. 1

Flow diagram showing the randomization of included patients

Outcome assessment

Function and pain were assessed with: IKDC, Visual Analog Scale (VAS), Short Form-36 (SF-36) and EuroQoL at baseline, 1, 2, 6 and 60 months postoperative. Through a phone call interview, Tegner scale was performed at 12 months in order to investigate activity level. Resumption of physical activity was defined as initiation of any work/sport activity with a minimum level of the pre-symptoms level minus 1 point at the Tegner scale, maintained for at least 30 days.

The patients’ characteristics did not differ between 2 groups at enrolment; nevertheless, the difference in VAS score between groups was close to being statistically significant (p = 0.0504) (Table 1).
Table 1

Preoperative patients’ characteristics in the stimulated and in the control group

 

Control n = 15

PEMFs therapy n = 15

p value

Sex

5 females, 10 males

4 females, 11 males

n.s.

Age

38.8 ± 7.4

41.6 ± 3.7

n.s.

BMI

25.4 ± 1.9

27.1 ± 3.6

n.s.

Pre-op IKDC

40 ± 6

37 ± 12

n.s.

Pre-op VAS

6.2 ± 1.2

5.1 ± 2.3

0.050

Pre-op SF-36

43 ± 10

43 ± 6

n.s.

Pre-op EuroQoL

0.56 ± 0.20

0.51 ± 0.24

n.s.

Interventions

The surgical technique consisted of 2 steps.

The cells were arthroscopically harvested from articular cartilage in the lateral or medial margin of the femoral trochlea and were expanded in a monolayer cell culture system for 3–5 weeks. A few days before implantation, the expanded chondrocytes were seeded onto a biodegradable purified and cell-free porcine collagen scaffold Carticel® (Genzyme Biosurgery, Cambridge, Massachusetts, USA).

Patients underwent the second-stage procedure [24] through standard arthroscopy 3–5 weeks after the biopsy.

The lesion was measured by its area with a millimetre-marked probe as recommended by ICRS [25] in order to properly shape the scaffold. Chondral defects’ characteristics are reported in Table 2.
Table 2

Cartilage lesions’ characteristics in the stimulated and in the control group

 

Control n = 15

PEMFs therapy n = 15

p value

Side

10 right, 5 left

10 right, 5 left

n.s.

Location

12 femurs, 3 patellae

11 femurs, 4 patellae

n.s.

ICRS grade

3 grade III, 12 grade IV

2 grade III, 13 grade IV

n.s.

Area (cm2)

2.5 ± 0.5

2.4 ± 0.6

n.s.

Etiology

3 post-traumatic, 12 degenerative*

6 post-traumatic, 9 degenerative*

n.s.

* Negative anamnesis for knee trauma

A one-side open cannula was inserted through the arthroscopic access closer to the lesion. No more saline fluid was used for joint distension, and the residue liquid was aspirated.

A circular area with regular margins for graft implantation was prepared with a specially designed cannulated low profile drill.

The bioengineered tissue was pushed out of the delivery device and positioned precisely within the defect, where it remained tightly fixed to the subchondral bone due to its adhesive properties. A further fixation was achieved with a minimal amount of fibrin glue.

Under arthroscopic control, the stability of implanted stamps was evaluated, before and after tourniquet release, and also during cyclic bending of the knee.

After surgery, all patients underwent the same rehabilitation protocol: early active and passive mobilization of the knee and no weight bearing for 6 weeks; after a 4-week partial weight-bearing phase, total weight bearing was finally allowed.

Patients in the experimental group were instructed to use PEMFs (I-ONE® Therapy, IGEA S.p.A. Carpi, MO, Italy) for 4 h per day for 60 days, starting within 3 days after surgery. The coil, placed on the operated knee but not in direct contact with the skin, was powered by the PEMF generator system, which produces a pulsed signal of 1.5 mT peak magnetic field intensity and a frequency of 75 Hz (Fig. 2). PEMFs generators produced the same signal of that well characterized in previous in vitro and in vivo studies [16, 17, 26]. The patient could wear the battery-operated device during day or night and was instructed to interrupt treatment in case of adverse events. The devices were fitted with a clock to record the actual use of the device.
Fig. 2

a PEMF exposure: waveform of the induced voltage (top) and waveform of the magnetic field (bottom), b I-ONE® device

Statistical analysis

We considered a 10 point difference of the IKDC subjective evaluation score as clinically relevant.

As reported by Cadossi et al. [20, 27] and Servodio Iammarrone et al. [28], the smallest difference in 100 points-based questionnaires considered clinically important was at least 10 points. We also used this assumption in absence of other relevant results available in literature concerning this kind of research. The sample power calculation was made on the hypothesis that the score would be superior at 60 months in the intervention group of 12 units with a standard deviation for the population of 12 units. If the alpha value was 0.05 and the statistical power was set to 80%, the sample size for each sample was 13 per group.

Considering a dropout percentage of about 10%, the resulting sample size was 15 per group.

Statistical analysis was conducted with Statistical Packages for Social Sciences software (SPSS Inc, Chicago, IL, USA). Normal distribution of continuous variables was confirmed by Kolmogorov–Smirnov test. Mean values and standard deviation were calculated to continuous variables. Comparison between groups was performed by heteroscedastic two-tail Student t test, while comparison among follow-up visit on the same patients of each group was performed by coupled two-tail Student t test. Categorical variables were compared between groups by contingency tables and Chi-square test.

Results

Four patients were not compliant (total amount of stimulation: 0, 5, 23, 29 h, respectively) and were excluded from per-protocol analyses. These patients were considered in the intention-to-treat evaluation. Among the 11 compliant patients, biophysical stimulation was performed for a mean of 4.5 ± 1.4 h per day.

Clinical outcomes and significant differences between groups in per-protocol analysis are reported in Table 3.
Table 3

Clinical outcome measures at baseline and at all follow-up for compliant PEMFs patients and controls

 

IKDC

VAS

SF-36

EuroQoL

Control

PEMFs

p value

Control

PEMFs

p value

Control

PEMFs

t test

Control

PEMFs

p value

Baseline

40 ± 6

38 ± 12

n.s.

6.2 ± 1.2

4.4 ± 2.3

0.015

43 ± 9

45 ± 5

n.s.

0.56 ± 0.20

0.50 ± 0.27

n.s.

1 month

34 ± 11

47 ± 9

0.001

5.7 ± 1.3

3.9 ± 2.2

0.018

35 ± 6

40 ± 6

0.023

0.53 ± 0.17

0.59 ± 0.14

n.s.

2 months

53 ± 11

63 ± 15

0.041

4.9 ± 1.1

3.5 ± 2.3

0.043

47 ± 11

57 ± 18

n.s.

0.66 ± 0.14

0.74 ± 0.17

n.s.

6 months

64 ± 15

76 ± 17

0.053

4.4 ± 1.9

3.0 ± 2.3

n.s.

67 ± 20

77 ± 14

n.s.

0.82 ± 0.20

0.89 ± 0.19

n.s.

60 months

64 ± 16

83 ± 15

0.001

3.1 ± 1.6

1.5 ± 1.5

0.011

66 ± 24

81 ± 12

0.006

0.82 ± 0.16

0.95 ± 0.12

0.020

A different trend between groups in IKDC score was observed over time (Fig. 3). Patients in the PEMFs group achieved a better clinical outcome up to 60-month follow-up.
Fig. 3

Mean IKDC score trend in PEMFs (red line) and in control group (blue line), respectively

Resumption of physical activity at 12-month follow-up was 91% in the PEMFs group and 67% in the control group (n.s.).

An additional intention-to-treat analysis was carried out. Mean IKDC score at 60 months was 80 ± 7; nevertheless, it remained still significantly higher compared to control group (p = 0.003).

PEMFs therapy was still effective in pain reduction; however, the difference in VAS score between the 2 groups became statistically significant at 2- and 6-month follow-up (p = 0.043, p = 0.039 respectively).

Physical activity resumption occurred in 87% of PEMFs patients according to intention-to-treat analysis.

Discussion

The most important findings of the present study confirm the positive effect of biophysical stimulation with PEMFs after MACI in terms of knee function, pain reduction and quality of life.

A mean difference in IKDC score of 19 points in favour of PEMFs compliant patients was observed at final follow-up. In addition, IKDC score in the control group was similar to that reported in a recent study by Kon et al. [29] for a matched patient population in terms of lesion size, ICRS grade, age and BMI who underwent MACI technique. This finding emphasizes that the improved clinical outcome observed in the PEMFs group can be attributed to biophysical stimulation. Similar benefits were reported in previous clinical studies using PEMFs [19, 30].

The effect of PEMFs therapy on pain reduction was significantly relevant in the first 2 months after surgery and at long-term follow-up (60 months). This result may reflect the effectiveness of biophysical stimulation on pain control during more intense rehabilitation phases: weight bearing and initial sport resumption. Pain reduction could enhance a proper adherence to a specific rehabilitation protocol thus leading to a better functional outcome [28]. Nevertheless, it should be noted that at baseline, the difference in VAS score between groups was not statistically significant. When only compliant patients were analysed, this difference became statistically significant and may have partially overestimated the PEMFs effect on pain relief.

No statistically significant difference between groups was detected in physical activity resumption. It should be noted that a good clinical outcome does not always reflects activity resumption as reported in the previous study by Kon et al. [29]. Moreover, the inclusion criteria did not select a specific population involved in regular sport activity.

When dealing with a therapy requiring several hours of daily treatment, patient’s compliance is crucial. In this study, 4 out of 15 patients showed an insufficient compliance to the prescribed treatment, less than 30 min of stimulation per day. Previous experience indicates that less than 1 h of stimulation per day does not significantly enhance chondrocytes anabolic activity [10].

Therefore, intention-to-treat analysis best reflects the attended benefits of biophysical stimulation in clinical practice. Patient counselling is therefore of paramount importance in order to increase compliance and to achieve the expected results.

This study had limitations. First, there is a lack of placebo devices in the control group. A placebo effect can be observed in patients who are involved in their own recovery when using a device [31]. In the present study, a placebo effect might have played a role among patients in the experimental group. However, we believe it is extremely unlikely that this effect was still present 58 months after biophysical stimulation was over. Due to the lack of placebo devices, patients were not blinded regarding the treatment; nevertheless, all the clinical evaluation scales were self-administered.

Second, the small number of patients included, even if the power analysis performed and the study design was adequate to verify the primary endpoint. Considering the small sample size and the three patients in the control group who were lost to follow-up, we set the Level of Evidence of this study at Level II, according to Wright et al. [32]. Further studies with larger samples should confirm our results.

Third, Carticel® according to FDA should be reserved to those patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, micro-fracture, drilling/abrasion arthroplasty or osteochondral allograft/autograft) [33]. In our patient population, previous knee surgery was an exclusion criterion thus MACI technique was proposed as a first treatment option. This specific trial setting may have overestimated the positive results of this technique, both in control and PEMFs group. Despite minor differences in patient selection, surgical technique or type of scaffold, MACI is currently performed with positive results [34, 35, 36]. We believe that biophysical stimulation with PEMFs can be effective in further improving the clinical outcome even in these slightly different situations.

Fourth, our patients did not have a second-look arthroscopy for histological analysis of the repaired tissue or biochemical characterization of the joint microenvironment. This data could confirm the relationship between inhibition of pro-inflammatory cytokines, preservation of the bioengineered tissue and ultimately the positive clinical outcome. Even though these analyses may have provided a more complete understanding of the effects of biophysical stimulation on MACI, we considered a second-look arthroscopy inappropriate for patients with a positive clinical outcome.

Conclusions

Biophysical stimulation with PEMFs should be considered as an effective tool to ameliorate clinical outcome after MACI technique. This improvement is maintained at 60 months from surgery. It is of paramount importance to properly select compliant patients in order to maximize the effects of PEMFs.

Notes

Compliance with ethical standards

Conflict of interest

Dr. Matteo Cadossi owns 10% of IGEA SpA shares, the manufacturer of devices used in the present study. All other authors declare not to have any conflict of interest.

Funding

There was not outside funding or grants received that assisted in this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individuals included in the study.

Author contribution

MC and CZ carried out data collection; AS and GL performed the statistical analysis. MC, GL and CZ conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

References

  1. 1.
    Ebert JR, Robertson WB, Lloyd DG, Zheng MH, Wood DJ, Ackland T (2010) A prospective, randomized comparison of traditional and accelerated approaches to postoperative rehabilitation following autologous chondrocyte implantation: 2-year clinical outcomes. Cartilage 1:180–187CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ebert JR, Robertson WB, Woodhouse J, Fallon M, Zheng MH, Ackland T et al (2011) Clinical and magnetic resonance imaging-based outcomes to 5 years after matrix-induced autologous chondrocyte implantation to address articular cartilage defects in the knee. Am J Sports Med 39:753–763CrossRefPubMedGoogle Scholar
  3. 3.
    Marlovits S, Aldrian S, Wondrasch B, Zak L, Albrecht C, Welsch G et al (2012) Clinical and radiological outcomes 5 years after matrix-induced autologous chondrocyte implantation in patients with symptomatic, traumatic chondral defects. Am J Sports Med 40:2273–2280CrossRefPubMedGoogle Scholar
  4. 4.
    Siebold R, Suezer F, Schmitt B, Trattnig S, Essig M (2017) Good clinical and MRI outcome after arthroscopic autologous chondrocyte implantation for cartilage repair in the knee. Knee Surg Sports Traumatol Arthrosc. doi: 10.1007/s00167-017-4491-0 Google Scholar
  5. 5.
    Peterson L, Brittberg M, Kiviranta I, Akerlund EL, Lindahl A (2002) Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med 30:2–12CrossRefPubMedGoogle Scholar
  6. 6.
    Bosnakovski D, Mizuno M, Kim G, Takagi S, Okumura M, Fujinaga T (2006) Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells (MSCs) in different hydrogels: influence of collagen type II extracellular matrix on MSC chondrogenesis. Biotechnol Bioeng 93:1152–1163CrossRefPubMedGoogle Scholar
  7. 7.
    Longobardi L, O’Rear L, Aakula S, Johnstone B, Shimer K, Chytil A et al (2006) Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res 21:626–636CrossRefPubMedGoogle Scholar
  8. 8.
    Schmal H, Mehlhorn A, Stoffel F, Kostler W, Sudkamp NP, Niemeyer P (2009) In vivo quantification of intraarticular cytokines in knees during natural and surgically induced cartilage repair. Cytotherapy 11:1065–1075CrossRefPubMedGoogle Scholar
  9. 9.
    Lima EG, Tan AR, Tai T, Bian L, Stoker AM, Ateshian GA et al (2008) Differences in interleukin-1 response between engineered and native cartilage. Tissue Eng Part A 14:1721–1730CrossRefPubMedGoogle Scholar
  10. 10.
    De Mattei M, Fini M, Setti S, Ongaro A, Gemmati D, Stabellini G et al (2007) Proteoglycan synthesis in bovine articular cartilage explants exposed to different low-frequency low-energy pulsed electromagnetic fields. Osteoarthr Cartil 15:163–168CrossRefPubMedGoogle Scholar
  11. 11.
    Benazzo F, Cadossi M, Cavani F, Fini M, Giavaresi G, Setti S et al (2008) Cartilage repair with osteochondral autografts in sheep: effect of biophysical stimulation with pulsed electromagnetic fields. J Orthop Res 26:631–642CrossRefPubMedGoogle Scholar
  12. 12.
    De Mattei M, Pellati A, Pasello M, Ongaro A, Setti S, Massari L et al (2004) Effects of physical stimulation with electromagnetic field and insulin growth factor-I treatment on proteoglycan synthesis of bovine articular cartilage. Osteoarthr Cartil 12:793–800CrossRefPubMedGoogle Scholar
  13. 13.
    Jahns ME, Lou E, Durdle NG, Bagnall K, Raso VJ, Cinats D et al (2007) The effect of pulsed electromagnetic fields on chondrocyte morphology. Med Biol Eng Comput 45:917–925CrossRefPubMedGoogle Scholar
  14. 14.
    Ongaro A, Varani K, Masieri FF, Pellati A, Massari L, Cadossi R et al (2012) Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol 227:2461–2469CrossRefPubMedGoogle Scholar
  15. 15.
    Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P et al (1998) T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clin Diagn Lab Immunol 5:430–437PubMedPubMedCentralGoogle Scholar
  16. 16.
    De Mattei M, Varani K, Masieri FF, Pellati A, Ongaro A, Fini M et al (2009) Adenosine analogs and electromagnetic fields inhibit prostaglandin E2 release in bovine synovial fibroblasts. Osteoarthr Cartil 17:252–262CrossRefPubMedGoogle Scholar
  17. 17.
    Varani K, De Mattei M, Vincenzi F, Gessi S, Merighi S, Pellati A et al (2008) Characterization of adenosine receptors in bovine chondrocytes and fibroblast-like synoviocytes exposed to low frequency low energy pulsed electromagnetic fields. Osteoarthr Cartil 16:292–304CrossRefPubMedGoogle Scholar
  18. 18.
    Varani K, Vincenzi F, Ravani A, Pasquini S, Merighi S, Gessi S, et al. (2017) Adenosine receptors as a biological pathway for the anti-inflammatory and beneficial effects of low frequency low energy pulsed electromagnetic fields. Mediat Inflamm 2017. doi: 10.1155/2017/2740963
  19. 19.
    Zorzi C, Dall’Oca C, Cadossi R, Setti S (2007) Effects of pulsed electromagnetic fields on patients’ recovery after arthroscopic surgery: prospective, randomized and double-blind study. Knee Surg Sports Traumatol Arthrosc 15:830–834CrossRefPubMedGoogle Scholar
  20. 20.
    Cadossi M, Buda RE, Ramponi L, Sambri A, Natali S, Giannini S (2014) Bone marrow-derived cells and biophysical stimulation for talar osteochondral lesions: a randomized controlled study. Foot Ankle Int 35:981–987CrossRefPubMedGoogle Scholar
  21. 21.
    Filardo G, Kon E, Di Martino A, Iacono F, Marcacci M (2011) Arthroscopic second-generation autologous chondrocyte implantation: a prospective 7-year follow-up study. Am J Sports Med 39:2153–2160CrossRefPubMedGoogle Scholar
  22. 22.
    Outerbridge RE, Dunlop JA (1975) The problem of chondromalacia patellae. Clin Orthop Relat Res (110):177–196Google Scholar
  23. 23.
    Colebatch AN, Hart DJ, Zhai G, Williams FM, Spector TD, Arden NK (2009) Effective measurement of knee alignment using AP knee radiographs. Knee 16:42–45CrossRefPubMedGoogle Scholar
  24. 24.
    Marcacci M, Zaffagnini S, Kon E, Visani A, Iacono F, Loreti I (2002) Arthroscopic autologous chondrocyte transplantation: technical note. Knee Surg Sports Traumatol Arthrosc 10:154–159CrossRefPubMedGoogle Scholar
  25. 25.
    International Cartilage Repair Society evaluation package. http://www.cartilage.org/_files/contentmanagement/ICRS_evaluation.pdf
  26. 26.
    Ciombor DM, Aaron RK, Wang S, Simon B (2003) Modification of osteoarthritis by pulsed electromagnetic field–a morphological study. Osteoarthr Cartil 11:455–462CrossRefPubMedGoogle Scholar
  27. 27.
    Cadossi M, Chiarello E, Savarino L, Tedesco G, Baldini N, Faldini C et al (2013) A comparison of hemiarthroplasty with a novel polycarbonate-urethane acetabular component for displaced intracapsular fractures of the femoral neck: a randomised controlled trial in elderly patients. Bone Joint J 95-B(5):609–615CrossRefPubMedGoogle Scholar
  28. 28.
    Servodio Iammarrone C, Cadossi M, Sambri A, Grosso E, Corrado B, Servodio Iammarrone F (2016) Is there a role of pulsed electromagnetic fields in management of patellofemoral pain syndrome? Randomized controlled study at one year follow-up. Bioelectromagnetics 37:81–88CrossRefPubMedGoogle Scholar
  29. 29.
    Kon E, Filardo G, Condello V, Collarile M, Di Martino A, Zorzi C et al (2011) Second-generation autologous chondrocyte implantation: results in patients older than 40 years. Am J Sports Med 39:1668–1675CrossRefPubMedGoogle Scholar
  30. 30.
    Benazzo F, Zanon G, Pederzini L, Modonesi F, Cardile C, Falez F et al (2008) Effects of biophysical stimulation in patients undergoing arthroscopic reconstruction of anterior cruciate ligament: prospective, randomized and double blind study. Knee Surg Sports Traumatol Arthrosc 16:595–601CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Rossini M, Viapiana O, Gatti D, de Terlizzi F, Adami S (2010) Capacitively coupled electric field for pain relief in patients with vertebral fractures and chronic pain. Clin Orthop Relat Res 468:735–740CrossRefPubMedGoogle Scholar
  32. 32.
    Wright JG, Swiontkowski MF, Heckman JD (2003) Introducing levels of evidence to the journal. J Bone Joint Surg Am 85-A(1):1–3CrossRefPubMedGoogle Scholar
  33. 33.
  34. 34.
    Niethammer TR, Pietschmann MF, Horng A, Rossbach BP, Ficklscherer A, Jansson V et al (2014) Graft hypertrophy of matrix-based autologous chondrocyte implantation: a two-year follow-up study of NOVOCART 3D implantation in the knee. Knee Surg Sports Traumatol Arthrosc 22:1329–1336CrossRefPubMedGoogle Scholar
  35. 35.
    Zak L, Albrecht C, Wondrasch B, Widhalm H, Vekszler G, Trattnig S et al (2014) Results 2 years after matrix-associated autologous chondrocyte transplantation using the Novocart 3D scaffold: an analysis of clinical and radiological data. Am J Sports Med 42:1618–1627CrossRefPubMedGoogle Scholar
  36. 36.
    Zaslav K, Cole B, Brewster R, DeBerardino T, Farr J, Fowler P et al (2009) A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defect of the knee: results of the study of the treatment of articular repair (STAR) clinical trial. Am J Sports Med 37:42–55CrossRefPubMedGoogle Scholar

Copyright information

© European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA) 2017

Authors and Affiliations

  1. 1.Ospedale Sacro Cuore Don CalabriaNegrarItaly
  2. 2.Istituto Ortopedico RizzoliBolognaItaly

Personalised recommendations