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Bilateral knee chondral defects can be treated in one or two surgical acts.
Objectives
To study clinical outcome of patients with bilateral knee chondral defects treated with High-Density Autologous Chondrocyte Implantation (HD-ACI) during the same surgery.
Methods
Study on eight patients (4 women and 4 men) with chondral defects in both knees treated with HD-ACI during the same surgical act. Patients were evaluated 2, 6, 12 and 24 months post-op for treatment safety and efficacy: visual analogic scale (VAS) for pain, International Knee Documentation Committee (IKDC) for subjective patient's perception of both knees and EuroQol five-dimensional five-level questionnaire (EQ-5D-5 L) for quality of life. Integrity of neoformed tissue at 12 and 24-month follow-up was assessed by the magnetic resonance observation of cartilage repair tissue (MOCART) score.
Results
VAS decreased from baseline to 24 months from a median of 8 (6 – 9) to a median of 0 (0 – 5) (P < .001). IKDC increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a median of 83.7 (24.0 – 98.0) in the 24-month visit (P < .001). EQ-5D-5 L decreased at 2 months post-op and increased throughout the follow-up visits thereafter, needing 24 months after surgery to reach a value higher than the basal one. Median MOCART at 12 months was 80.3 (58.0 – 89.7) and 81.3 (54.0 – 89.9) at 24 months.
Conclusions
Treatment of both knees with HD-ACI during the same surgical act in patients with bilateral chondral lesions is a safe procedure, providing good clinical results.
Articular cartilage lesions are relatively common since this tissue has to withstand the high compressive forces exerted in everyday life. In the knee, trauma and osteochondritis dissecans are responsible for most cartilage lesions.
Although knee cartilage lesions are mainly located in one limb, some patients have bilateral injuries. There is little information published about bilateral knee cartilage. In this sense, prevalence of bilateral juvenile knee osteochondritis dissecans and associated risk factors was published in 2015 by Cooper et al.
Limited healing capacity of articular hyaline cartilage, related to the lack of cell progenitors and growth factors due to the lack of blood and lymphatic vessels, has been extensively demonstrated.
If left untreated, cartilage injuries may progress to osteoarthritis, a clinical entity that limits people's life. Cell therapy and regenerative medicine techniques, especially autologous chondrocyte implantation (ACI) are nowadays considered the best option to treat chondral lesions, providing good clinical outcome by regeneration of hyaline cartilage tissue in the defect area.
This technique is indicated to treat unstable symptomatic knee chondral lesions of more than 1–2 cm2 in size. The technique has been developed from the first publication of ACI, in which cells were implanted in liquid medium under a periosteal flap,
Although this last alternative, as well as the other ACI variants, is a two-step technique implying two surgeries (a first surgery to take a biopsy of healthy cartilage as a cell source and a second one to implant cultured chondrocytes), it has been successfully used to treat knee or talus chondral defects.
Treatment of bilateral lesions in the knee represents a challenge and no publications concerning this topic can be found in scientific literature. Whether to operate one limb after the other in separate procedures under different anesthesia or both limbs during the same surgical act using the same anesthesia is a decision that surgeons have to take depending on the patient's situation. In the present work, we describe the clinical outcome of 8 patients with bilateral knee lesions of different etiology treated with HD-ACI on the same surgical act.
Patients and methods
Eight patients (4 women and 4 men) with a median age of 25.5 years (16 – 48 years) and chondral defects in both knees (16 damaged knees) evidenced by MRI, were included in this retrospective study. Inclusion criteria were: Outerbridge grade III-IV cartilage lesion in both knees diagnosed by an imaging test (X-ray, magnetic resonance or arthro-resonance), 1 – 4 lesions of a minimum of 1 cm2 in size and an age ranged from 16 to 55 years. The exclusion criteria of the study were: arthrosis, specular lesions (femoral condyle and tibial plateau from the same side), misalignment of the limb (more than 10° varus or valgus), meniscal lesions, allergy to penicillin and/or streptomycin, hypersensitivity to bovine-derived products, active infection, tumoral pathology, and systemic disease as rheumatoid arthritis or other autoimmune diseases with articular affectation. MRI revealed grade III (1 patient) and grade IV chondral defects in both knees according to the Outerbridge classification. All patients agreed to participate in the study and signed the provided informed consent form. In all cases, clinical diagnosis was the same in both knees: osteochondritis dissecans (OD) in four cases, osteonecrosis in one case, and in 3 cases the origin of chondral lesions was unclear and which is why they were diagnosed with idiopathic chondropathy. Three patients with OD had previously undergone arthroscopic surgeries in order to extract loose bodies and to clean one knee in one case and both knees in the remaining two. Regarding other previous treatments for cartilage damage, two of the patients diagnosed as having idiopathic chondropathy underwent platelet-rich plasma (PRP) infiltrations in both knees.
Chondral lesions were treated with high-density autologous chondrocyte implantation (HD-ACI). HD-ACI is a two-step technique: during the first arthroscopic surgery in one of the knees, a sample of healthy cartilage, similar to 3 or 4 rice grains in size, was taken from the upper-medial area of the femoral trochlea. Each sample was placed in a tube with 25 ml of Dulbecco's Modified Eagle's Medium (DMEM) (Lonza Group Ltd., Basel, Switzerland) and immediately processed in a Good Manufacturing Practices (GMP) certified laboratory, authorized by the Spanish Health Authority for the culture of autologous chondrocytes for the treatment of articular cartilage lesions. The culture process was performed as previously described.
In a second surgery, both legs were operated, one after the other, under the same anesthesia. Chondral lesions were debrided and HD-ACI was carried-out following the previously published procedure.
Cells resuspended in culture medium were seeded onto a porcine type I/III collagen membrane (Chondro-Gide, Geistlich Biomaterials, Wolhusen, Switzerland) at a rate of 5 million cells per cm2 of lesion. After waiting for 10 min, the cells were adsorbed onto the membrane, and the membrane was then sutured to the adjacent bone and sealed to the injury using Tissucol (Baxter, Madrid, Spain).
Patients were kept under non weight-bearing conditions, performing flexion-extension exercises for 8 weeks. After the 8th week, patients started active physical therapy, with progressive hold up of both limbs with the aim of regaining any lost range of motion. From the 24th to the 36th week, patients were instructed to perform exercises to gain quadriceps strength: walking in swimming-pool, elliptical treadmill, bicycle (sitting-down). Five out the eight patients practiced recreational sports and were allowed to practice low-intensity sports one year after surgery.
Patients were evaluated 2, 6, 12 and 24 months after surgery to check for treatment safety and efficacy. Pain was assessed with the visual analogic scale (VAS) and International Knee Documentation Committee (IKDC) scale was used to evaluate patient's subjective perception of both knees. Established minimal clinically important difference (MCID) of VAS and IKDC were considered according to Jones et al.
Overall health of patients was evaluated with the EuroQol five-dimensional five-level questionnaire (EQ-5D-5 L) and Visual Analogic Scale for health included in the questionnaire.
At baseline and at each time point of follow-up, biomechanical evaluation of knees was checked by testing mobility (flexion and extension). Adverse events and possible relationship with surgery were also recorded. Magnetic resonance images were performed at baseline, 12 and 24 months, Neo-formed tissue integration at 12 and 24-month follow-up was assessed by the magnetic resonance observation of cartilage repair tissue (MOCART) score.
Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: determination of interobserver variability and correlation to clinical outcome after 2 years.
Statistical analysis was performed using IBM® SPSS® Statistics Version 22.0.0.0 software. Continuous variables were expressed as the median as central tendency measure, and minimum and maximum as dispersion measure. Distribution of continuous variables at different time points of evaluation (basal, 2, 6, 12 and 24 months) was contrasted using Friedman's one-way repeated measures analysis of variance by ranks test. Median difference values of pain and IKDC at 12 and 24 months with respect to baseline was compared with established MCID using one-sample Wilcoxon signed rank test. Kruskall-Wallis test was used to study distribution of pain and IKDC improvement at 12 and 24 months in the different categories of a factor. Non-parametric Spearman correlation was used to study the existence of any relationship between variables. All comparisons were two-sided and a P value < .05 was considered statistically significant.
Results
Location of bilateral chondral lesions of patients included in this work is depicted in Table 1. In 6 patients injuries were located in the patellas of both knees: in 3 of them diagnosis was OD while in the remaining 3 diagnosis was idiopathic chondropathy. As shown in Table 1, in 1 patient, injuries were located in both medial femoral condyles and diagnosis was OD. In the remaining patient, the medial femoral condyle of one knee and the lateral femoral condyle of the other knee were affected and diagnosis was osteonecrosis. Median of chondral defect surface area was 302 mm2 (minimum – maximum: 150 mm2 – 756 mm2). Median elapsed time between sampling and implantation surgery was 6 weeks (4 – 7 weeks).
Pain, evaluated with VAS, significantly decreased from a median value of 8 (6 – 9) in the basal evaluation to a median score of 0 (0 – 5) at 24 months post-op (P < .001) (Fig. 1A). Subjective perception of knee function measured by the IKDC score, significantly increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a median score of 83.7 (24.0 – 98.0) at the 24-month visit (P < .001) (Fig. 1B). In Figure 2, median differences between baseline and 12 and 24 months after surgery in VAS (Fig. 2A) and IKDC (Fig. 2B), are depicted. In both cases, improvement showed a statistically significant higher value than published MCID = 2.7 for VAS (P = .001 at 12 and 24 months) and MCID=16.7 for IKDC (P = .001 at 12 and 24 months). Median IKDC improvement at 12 and 24 months did not reach MCID in the two knees diagnosed as having osteonecrosis (11.8 at 12 months and 7.8 at 24 months). No statistical differences were found in VAS and IKDC improvement with respect to location or lesion size. Statistically significant negative correlations between age and IKDC improvement at 12 months (Spearman's Rho = −0.721; P =.002) and 24 months (Spearman's Rho = −0.655; P = .006) were found.
Fig. 1Box-plot representation of pain (A) and subjective perception of knee function (B) evolution, measured by the Visual Analogic Scale (VAS) and International Knee Documentation Committee (IKDC), respectively. Statistical significant differences were found in the evolution of both parameters (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test ). Pairwise comparisons : *P < .05 level; **P < .001 level.
Fig. 2Box-plot graph representing differences at 12 and 24 months with respect to baseline, of pain (A) measured by the Visual Analogic Scale (VAS) and subjective perception of knee function (B) assessed by International Knee Documentation Committee (IKDC). Blue horizontal line represents the Minimal Clinically Important Difference (MCID) value established for VAS and IKDC. VAS and IKDC improvements at 12 and 24 months were statistically higher than MCID (P = .001 in all one-sample comparisons, one-sample Wilcoxon signed rank test).
Figure 3A shows EQ-5D-5 L score evolution throughout the study period in the 8 patients included. In all patients, EQ-5D-5 L decreased at 2 months post-op compared with basal value and score increased throughout the follow-up visits thereafter, reaching a higher value at 24 months after surgery than at the basal point. In pairwise comparisons, statistical significant differences were found when basal EQ-5D-5 L score was compared with 12-month (P = .027) and 24-month (P < .001) scores (Fig. 3A). A similar behavior was observed in Visual Analogic Scale for health included in EQ-5D-5 L questionnaire (Fig. 3B), and statistically significant differences with basal value at 12-month (P = .001) and 24-month (P < .001) follow-ups were found. No correlations with defect size or location and previous surgeries were observed. With respect to graft integration, median MOCART at 12 months was 80.3 (58.0 – 89.7) and 81.3 (54.0 – 89.9) at 24 months (Fig. 4). No statistical differences in MOCART value between 12 and 24 months were observed. No correlations with diagnostic, previous surgeries and defect size or location were observed. Osteophytes or bone edema were no observed in any case.
Fig. 3Evolution of EQ-5D-5 L score (A) and visual analogic scale for health (B) from basal visit to 24 months post-op in the 8 patients included in the study. Statistically significant differences of score evolution were found (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test). Pairwise comparisons: *P < .05 level; **P < .001 level.
Fig. 4MRI corresponding to the right (A) and left (B) knees from the same patient in the basal visit (A1, B1) and 24 months after HD-ACI (A2, B2). Chondral lesions are indicated with arrows.
Figure 5 shows biomechanical evaluation, consisting in checking extension (Fig. 5A) and flexion (Fig. 5B) values of operated knees. Although percentage of knees with complete extension increased from basal visit to 24 months after surgery, differences were not statistically significant.
Fig. 5Extension (A) and flexion (B) degrees of operated knees.
No swelling was observed in any knee after surgery and no adverse events occurred in any patient.
Discussion
The main finding in this work is that patients with bilateral cartilage defects in whom both knees have been treated with HD-ACI in the same surgical act under the same anesthesia have a satisfactory clinical outcome, with a quality of life improvement with respect to their situation before surgery. Deciding whether to operate both legs during the same surgical act or to operate them in different surgical acts is mainly based on the time that patients need to be able to return to previous activities after recovery from either option. Both decisions have pros and cons. If considering to operate each knee in turn, after recovering from the first surgery, patients will probably spend more time to return to previous activities, because they have to recover from two surgeries, but in contrast, one leg is immobilized after each surgery, so patients may have less mobility limitations during their recovery time. If both legs are simultaneously operated, patients only have to recover from one surgery but they have the inconvenience of having both legs immobilized. Bilateral chondral lesions are relatively infrequent and, to the best of our knowledge, there are no publications mentioning the treatment of bilateral chondral lesions with ACI during the same surgical act.
In this work, clinical outcome for 8 patients with bilateral chondral defects treated with HD-ACI is reported. In our patients, the patella was the most frequent location of chondral injuries. In some patient series, medial femoral condyle is the main chondral lesion location,
but we do not have a clear explanation for their prevalence in the patella in bilateral defects. Patellar cartilage injuries may also show a high prevalence while they may be better tolerated than medial femoral condyle lesions or could be asymptomatic and would not be detected if an image test is finally not performed.
Clinical outcome of operated patients at 12 and 24 months was satisfactory in terms of pain (measured with VAS and subjective perception of knee function assessed by IKDC). Both parameters significantly improved from basal to 12 and 24 months follow-up, reaching a value that was significantly higher than published MCID.
These results indicate that improvement in pain and knee function is perceived by patients as a real improvement, indicating a satisfactory clinical outcome in these patients. In the case of unilateral lesions, improvement in clinical parameters is accompanied by good integration of the implant in the surrounding cartilage measured by MOCART score, as demonstrated by several authors.
All-arthroscopic hydrogel-based autologous chondrocyte transplantation in the knee joint: good clinical and magnetic resonance imaging outcome after 24 months.
Similar events took place for patients with bilateral lesions studied in the present work: satisfactory clinical outcome was presented together with a high MOCART score, revealing a good integrity of neoformed tissue.
Short- and mid-term results found by us and other authors for patients with unilateral chondral defects treated with different ACI modalities- ACI in liquid medium under periosteal flap, MACI or HD-ACI
Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial.
were comparable. All these publications support autologous chondrocyte implantation effectiveness. Decision about whether to treat bilateral chondral defects in one or two surgical acts must be always taken on the basis of patient's quality of life (QOL). For this reason, in this work QOL was monitored along the study. As other authors have found in patients with unilateral defects,
patients with bilateral cartilage defects treated with autologous chondrocyte implantation had a significant QOL improvement two years after surgery.
Another secondary finding in our work was that improvement in VAS and IKDC was not cartilage defect location- or size-dependent. We also found the lack of influence of both factors in HD-ACI treatment in patients with unilateral cartilage defects.
Although patients in the aforementioned work were treated with chondrocytes cultured with a different method to the one described in the present work, authors did not find patient's clinical outcome to be influenced by either injury location or size.
Limitations
The main weakness of the present study is the limited sample size, which is due to the low bilateral chondral defect prevalence. However, results are consistent enough to make them valid. On the light of these results, patients with bilateral chondral defects are currently offered to undergo one or two surgeries and they decide according their preferences.
Conclusion
Both chondral defects of patients with bilateral cartilage defects in the knee can be treated simultaneously at the same surgical act with HD-ACI, with good clinical outcome and without having a significant impact on their quality of life.
Informed consent
All patients signed an informed consent
Declaration of competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work has been financed by Fundación Pedro Guillén. We would like to thank Mario Wensell for carefully revising the linguistics for this article.
REFERENCES
Xiang Y.
Bunpetch V.
Zhou W.
Ouyanga H.
Optimization strategies for ACI: a step-chronicle review.
Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: determination of interobserver variability and correlation to clinical outcome after 2 years.
All-arthroscopic hydrogel-based autologous chondrocyte transplantation in the knee joint: good clinical and magnetic resonance imaging outcome after 24 months.
Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial.
IGV: patient selection, surgery and follow-up, paper writing; JML: data analysis, paper writing; ERI: data collection, paper reviewing; MGV: surgery and follow-up of patients, data analysis; TFFJ: patient selection and follow-up, paper writing; JMC: patients follow-up, data collection; SA: surgery, paper writing; PG: patient selection and surgery, paper reviewing
Institutional Review Board (IRB) approval:
This work was approved by the Clínica CEMTRO Education and Research Committee. All patients included signed an informed consent.
Box-plot representation of pain (A) and subjective perception of knee function (B) evolution, measured by the Visual Analogic Scale (VAS) and International Knee Documentation Committee (IKDC), respectively. Statistical significant differences were found in the evolution of both parameters (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test ). Pairwise comparisons : *P < .05 level; **P < .001 level.
Box-plot graph representing differences at 12 and 24 months with respect to baseline, of pain (A) measured by the Visual Analogic Scale (VAS) and subjective perception of knee function (B) assessed by International Knee Documentation Committee (IKDC). Blue horizontal line represents the Minimal Clinically Important Difference (MCID) value established for VAS and IKDC. VAS and IKDC improvements at 12 and 24 months were statistically higher than MCID (P = .001 in all one-sample comparisons, one-sample Wilcoxon signed rank test).
Evolution of EQ-5D-5 L score (A) and visual analogic scale for health (B) from basal visit to 24 months post-op in the 8 patients included in the study. Statistically significant differences of score evolution were found (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test). Pairwise comparisons: *P < .05 level; **P < .001 level.
MRI corresponding to the right (A) and left (B) knees from the same patient in the basal visit (A1, B1) and 24 months after HD-ACI (A2, B2). Chondral lesions are indicated with arrows.
Bilateral knee chondral defects can be treated in one or two surgical acts.
Objectives
To study clinical outcome of patients with bilateral knee chondral defects treated with High-Density Autologous Chondrocyte Implantation (HD-ACI) during the same surgery.
Methods
Study on eight patients (4 women and 4 men) with chondral defects in both knees treated with HD-ACI during the same surgical act. Patients were evaluated 2, 6, 12 and 24 months post-op for treatment safety and efficacy: visual analogic scale (VAS) for pain, International Knee Documentation Committee (IKDC) for subjective patient's perception of both knees and EuroQol five-dimensional five-level questionnaire (EQ-5D-5 L) for quality of life. Integrity of neoformed tissue at 12 and 24-month follow-up was assessed by the magnetic resonance observation of cartilage repair tissue (MOCART) score.
Results
VAS decreased from baseline to 24 months from a median of 8 (6 – 9) to a median of 0 (0 – 5) (P < .001). IKDC increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a median of 83.7 (24.0 – 98.0) in the 24-month visit (P < .001). EQ-5D-5 L decreased at 2 months post-op and increased throughout the follow-up visits thereafter, needing 24 months after surgery to reach a value higher than the basal one. Median MOCART at 12 months was 80.3 (58.0 – 89.7) and 81.3 (54.0 – 89.9) at 24 months.
Conclusions
Treatment of both knees with HD-ACI during the same surgical act in patients with bilateral chondral lesions is a safe procedure, providing good clinical results.
Synovial joints are covered with hyaline cartilage, a special type of dense connective tissue responsible for their special properties.1x1Xiang, Y., Bunpetch, V., Zhou, W., and Ouyanga, H. Optimization strategies for ACI: a step-chronicle review. J Orthop Translat. 2019;
17: 3–14 Crossref | PubMed | Scopus (10) | Google ScholarSee all References Articular cartilage lesions are relatively common since this tissue has to withstand the high compressive forces exerted in everyday life. In the knee, trauma and osteochondritis dissecans are responsible for most cartilage lesions.2x2Andriolo, L., Candrian, C., Papio, T., Cavicchioli, A., Perdisa, F., and Filardo, G. Osteochondritis dissecans of the knee - conservative treatment strategies: a systematic review. Cartilage. 2019;
10: 267–277 Crossref | PubMed | Scopus (25) | Google ScholarSee all References,3x3Schenck Jr, R.C. and Goodnight, J.M. Osteochondritis dissecans. J Bone Joint Surg Am. 1996;
78: 439–456 Crossref | PubMed | Scopus (352) | Google ScholarSee all References Additionally, cartilage lesions of unknown etiology or idiopathic cartilage lesions may also occur.4x4Fischer, W. Perspective on idiopathic subchondral, osteochondral, and chondral lesions with emphasis on the knee. Semin Musculoskelet Radiol. 2019;
23: 534–546 Crossref | PubMed | Scopus (2) | Google ScholarSee all References Although knee cartilage lesions are mainly located in one limb, some patients have bilateral injuries. There is little information published about bilateral knee cartilage. In this sense, prevalence of bilateral juvenile knee osteochondritis dissecans and associated risk factors was published in 2015 by Cooper et al.5x5Cooper, T., Boyles, A., Samora, W.P., and Klingele, K.E. Prevalence of bilateral JOCD of the knee and associated risk factors. J Pediatr Orthop. 2015;
35: 507–510 Crossref | PubMed | Scopus (23) | Google ScholarSee all References They demonstrated a 29% prevalence of bilateral osteochondritis dissecans of the knee, with up to 40% of the cases being asymptomatic.5x5Cooper, T., Boyles, A., Samora, W.P., and Klingele, K.E. Prevalence of bilateral JOCD of the knee and associated risk factors. J Pediatr Orthop. 2015;
35: 507–510 Crossref | PubMed | Scopus (23) | Google ScholarSee all References
Limited healing capacity of articular hyaline cartilage, related to the lack of cell progenitors and growth factors due to the lack of blood and lymphatic vessels, has been extensively demonstrated.6x6Huey, D.J., Hu, J.C., and Athanasiou, K.A. Unlike bone, cartilage regeneration remains elusive. Science. 2012;
338: 917–921 Crossref | PubMed | Scopus (762) | Google ScholarSee all References If left untreated, cartilage injuries may progress to osteoarthritis, a clinical entity that limits people's life. Cell therapy and regenerative medicine techniques, especially autologous chondrocyte implantation (ACI) are nowadays considered the best option to treat chondral lesions, providing good clinical outcome by regeneration of hyaline cartilage tissue in the defect area.7x7Chimutengwende-Gordon, M., Donaldson, J., and Bentley, G. Current solutions for the treatment of chronic articular cartilage defects in the knee. EFORT Open Rev. 2020;
5: 156–163 Crossref | PubMed | Scopus (23) | Google ScholarSee all References,8x8Nimkingratana, P. and Brittberg, M. Returning to work after articular cartilage repair intervention: a systematic review. Orthop J Sports Med. 2020;
8: 2325967120905526 Crossref | Scopus (7) | Google ScholarSee all References This technique is indicated to treat unstable symptomatic knee chondral lesions of more than 1–2 cm2 in size. The technique has been developed from the first publication of ACI, in which cells were implanted in liquid medium under a periosteal flap,9x9Pelissier, A., Boyer, P., Boussetta, Y. et al. Satisfactory long-term MRI after autologous chondrocyte implantation at the knee. Knee Surg Sports Traumatol Arthrosc. 2014;
22: 2007–2012 Crossref | PubMed | Scopus (19) | Google ScholarSee all References to the current use of biomaterials such as porcine type I/III collagen membranes in MACI10x10Gillogly, S.D. and Wheeler, K.S. Autologous chondrocyte implantation with collagen membrane. Sports Med Arthrosc Rev. 2015;
23: 118–124 Crossref | PubMed | Scopus (24) | Google ScholarSee all References and high-density autologous chondrocyte implantation (HD-ACI) .11x11Guillén-García, P., Rodríguez-Iñigo, E., Guillén-Vicente, I. et al. Increasing the dose of autologous chondrocytes improves articular cartilage repair: histological and molecular study in the sheep animal model. Cartilage.2014;
5: 114–122 Crossref | PubMed | Scopus (23) | Google ScholarSee all References Although this last alternative, as well as the other ACI variants, is a two-step technique implying two surgeries (a first surgery to take a biopsy of healthy cartilage as a cell source and a second one to implant cultured chondrocytes), it has been successfully used to treat knee or talus chondral defects.12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References,13x13López-Alcorocho, J.M., Guillén-Vicente, I., Rodríguez-Iñigo, E. et al. High-density autologous chondrocyte implantation as treatment for ankle osteochondral defects. Cartilage. 2019;
https://doi.org/10.1177/1947603519835898 Crossref | Scopus (11) | Google ScholarSee all References
Treatment of bilateral lesions in the knee represents a challenge and no publications concerning this topic can be found in scientific literature. Whether to operate one limb after the other in separate procedures under different anesthesia or both limbs during the same surgical act using the same anesthesia is a decision that surgeons have to take depending on the patient's situation. In the present work, we describe the clinical outcome of 8 patients with bilateral knee lesions of different etiology treated with HD-ACI on the same surgical act.
Patients and methods
Eight patients (4 women and 4 men) with a median age of 25.5 years (16 – 48 years) and chondral defects in both knees (16 damaged knees) evidenced by MRI, were included in this retrospective study. Inclusion criteria were: Outerbridge grade III-IV cartilage lesion in both knees diagnosed by an imaging test (X-ray, magnetic resonance or arthro-resonance), 1 – 4 lesions of a minimum of 1 cm2 in size and an age ranged from 16 to 55 years. The exclusion criteria of the study were: arthrosis, specular lesions (femoral condyle and tibial plateau from the same side), misalignment of the limb (more than 10° varus or valgus), meniscal lesions, allergy to penicillin and/or streptomycin, hypersensitivity to bovine-derived products, active infection, tumoral pathology, and systemic disease as rheumatoid arthritis or other autoimmune diseases with articular affectation. MRI revealed grade III (1 patient) and grade IV chondral defects in both knees according to the Outerbridge classification. All patients agreed to participate in the study and signed the provided informed consent form. In all cases, clinical diagnosis was the same in both knees: osteochondritis dissecans (OD) in four cases, osteonecrosis in one case, and in 3 cases the origin of chondral lesions was unclear and which is why they were diagnosed with idiopathic chondropathy. Three patients with OD had previously undergone arthroscopic surgeries in order to extract loose bodies and to clean one knee in one case and both knees in the remaining two. Regarding other previous treatments for cartilage damage, two of the patients diagnosed as having idiopathic chondropathy underwent platelet-rich plasma (PRP) infiltrations in both knees.
Chondral lesions were treated with high-density autologous chondrocyte implantation (HD-ACI). HD-ACI is a two-step technique: during the first arthroscopic surgery in one of the knees, a sample of healthy cartilage, similar to 3 or 4 rice grains in size, was taken from the upper-medial area of the femoral trochlea. Each sample was placed in a tube with 25 ml of Dulbecco's Modified Eagle's Medium (DMEM) (Lonza Group Ltd., Basel, Switzerland) and immediately processed in a Good Manufacturing Practices (GMP) certified laboratory, authorized by the Spanish Health Authority for the culture of autologous chondrocytes for the treatment of articular cartilage lesions. The culture process was performed as previously described.12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References In the case of one knee, it has been estimated that the time to reach necessary cell number of 5 million cells per cm2 is 4 – 6 weeks.12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References
In a second surgery, both legs were operated, one after the other, under the same anesthesia. Chondral lesions were debrided and HD-ACI was carried-out following the previously published procedure.12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References Cells resuspended in culture medium were seeded onto a porcine type I/III collagen membrane (Chondro-Gide, Geistlich Biomaterials, Wolhusen, Switzerland) at a rate of 5 million cells per cm2 of lesion. After waiting for 10 min, the cells were adsorbed onto the membrane, and the membrane was then sutured to the adjacent bone and sealed to the injury using Tissucol (Baxter, Madrid, Spain).
Patients were kept under non weight-bearing conditions, performing flexion-extension exercises for 8 weeks. After the 8th week, patients started active physical therapy, with progressive hold up of both limbs with the aim of regaining any lost range of motion. From the 24th to the 36th week, patients were instructed to perform exercises to gain quadriceps strength: walking in swimming-pool, elliptical treadmill, bicycle (sitting-down). Five out the eight patients practiced recreational sports and were allowed to practice low-intensity sports one year after surgery.
Patients were evaluated 2, 6, 12 and 24 months after surgery to check for treatment safety and efficacy. Pain was assessed with the visual analogic scale (VAS) and International Knee Documentation Committee (IKDC) scale was used to evaluate patient's subjective perception of both knees. Established minimal clinically important difference (MCID) of VAS and IKDC were considered according to Jones et al.14x14Jones, K.J., Kelley, B.V., Arshi, A., McAllister, D.R., and Fabricant, P.D. Comparative effectiveness of cartilage repair with respect to the minimal clinically important difference. Am J Sports Med. 2019;
47: 3284–3293 Crossref | PubMed | Scopus (40) | Google ScholarSee all References Overall health of patients was evaluated with the EuroQol five-dimensional five-level questionnaire (EQ-5D-5 L) and Visual Analogic Scale for health included in the questionnaire.15x15van Hout, B., Janssen, M.F., Feng, Y.S. et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5 L to EQ-5D-3 L value sets. Value Health. 2012;
15: 708–715 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1075) | Google ScholarSee all References At baseline and at each time point of follow-up, biomechanical evaluation of knees was checked by testing mobility (flexion and extension). Adverse events and possible relationship with surgery were also recorded. Magnetic resonance images were performed at baseline, 12 and 24 months, Neo-formed tissue integration at 12 and 24-month follow-up was assessed by the magnetic resonance observation of cartilage repair tissue (MOCART) score.16x16Marlovits, S., Singer, P., Zeller, P., Mandl, I., Haller, J., and Trattnig, S. Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: determination of interobserver variability and correlation to clinical outcome after 2 years. Eur J Radiol. 2006;
57: 16–23 Abstract | Full Text | Full Text PDF | PubMed | Scopus (457) | Google ScholarSee all References
Statistical analysis was performed using IBM® SPSS® Statistics Version 22.0.0.0 software. Continuous variables were expressed as the median as central tendency measure, and minimum and maximum as dispersion measure. Distribution of continuous variables at different time points of evaluation (basal, 2, 6, 12 and 24 months) was contrasted using Friedman's one-way repeated measures analysis of variance by ranks test. Median difference values of pain and IKDC at 12 and 24 months with respect to baseline was compared with established MCID using one-sample Wilcoxon signed rank test. Kruskall-Wallis test was used to study distribution of pain and IKDC improvement at 12 and 24 months in the different categories of a factor. Non-parametric Spearman correlation was used to study the existence of any relationship between variables. All comparisons were two-sided and a P value < .05 was considered statistically significant.
Results
Location of bilateral chondral lesions of patients included in this work is depicted in Table 1Table 1. In 6 patients injuries were located in the patellas of both knees: in 3 of them diagnosis was OD while in the remaining 3 diagnosis was idiopathic chondropathy. As shown in Table 1Table 1, in 1 patient, injuries were located in both medial femoral condyles and diagnosis was OD. In the remaining patient, the medial femoral condyle of one knee and the lateral femoral condyle of the other knee were affected and diagnosis was osteonecrosis. Median of chondral defect surface area was 302 mm2 (minimum – maximum: 150 mm2 – 756 mm2). Median elapsed time between sampling and implantation surgery was 6 weeks (4 – 7 weeks).
Pain, evaluated with VAS, significantly decreased from a median value of 8 (6 – 9) in the basal evaluation to a median score of 0 (0 – 5) at 24 months post-op (P < .001) (Fig. 1Fig. 1A). Subjective perception of knee function measured by the IKDC score, significantly increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a median score of 83.7 (24.0 – 98.0) at the 24-month visit (P < .001) (Fig. 1Fig. 1B). In Figure 2Figure 2, median differences between baseline and 12 and 24 months after surgery in VAS (Fig. 2Fig. 2A) and IKDC (Fig. 2Fig. 2B), are depicted. In both cases, improvement showed a statistically significant higher value than published MCID = 2.7 for VAS (P = .001 at 12 and 24 months) and MCID=16.7 for IKDC (P = .001 at 12 and 24 months). Median IKDC improvement at 12 and 24 months did not reach MCID in the two knees diagnosed as having osteonecrosis (11.8 at 12 months and 7.8 at 24 months). No statistical differences were found in VAS and IKDC improvement with respect to location or lesion size. Statistically significant negative correlations between age and IKDC improvement at 12 months (Spearman's Rho = −0.721; P =.002) and 24 months (Spearman's Rho = −0.655; P = .006) were found.
Fig. 1
Box-plot representation of pain (A) and subjective perception of knee function (B) evolution, measured by the Visual Analogic Scale (VAS) and International Knee Documentation Committee (IKDC), respectively. Statistical significant differences were found in the evolution of both parameters (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test ). Pairwise comparisons : *P < .05 level; **P < .001 level.
Box-plot graph representing differences at 12 and 24 months with respect to baseline, of pain (A) measured by the Visual Analogic Scale (VAS) and subjective perception of knee function (B) assessed by International Knee Documentation Committee (IKDC). Blue horizontal line represents the Minimal Clinically Important Difference (MCID) value established for VAS and IKDC. VAS and IKDC improvements at 12 and 24 months were statistically higher than MCID (P = .001 in all one-sample comparisons, one-sample Wilcoxon signed rank test).
Figure 3Figure 3A shows EQ-5D-5 L score evolution throughout the study period in the 8 patients included. In all patients, EQ-5D-5 L decreased at 2 months post-op compared with basal value and score increased throughout the follow-up visits thereafter, reaching a higher value at 24 months after surgery than at the basal point. In pairwise comparisons, statistical significant differences were found when basal EQ-5D-5 L score was compared with 12-month (P = .027) and 24-month (P < .001) scores (Fig. 3Fig. 3A). A similar behavior was observed in Visual Analogic Scale for health included in EQ-5D-5 L questionnaire (Fig. 3Fig. 3B), and statistically significant differences with basal value at 12-month (P = .001) and 24-month (P < .001) follow-ups were found. No correlations with defect size or location and previous surgeries were observed. With respect to graft integration, median MOCART at 12 months was 80.3 (58.0 – 89.7) and 81.3 (54.0 – 89.9) at 24 months (Fig. 4Fig. 4). No statistical differences in MOCART value between 12 and 24 months were observed. No correlations with diagnostic, previous surgeries and defect size or location were observed. Osteophytes or bone edema were no observed in any case.
Fig. 3
Evolution of EQ-5D-5 L score (A) and visual analogic scale for health (B) from basal visit to 24 months post-op in the 8 patients included in the study. Statistically significant differences of score evolution were found (P < .001, one-way repeated measures analysis of variance by ranks Friedman's test). Pairwise comparisons: *P < .05 level; **P < .001 level.
MRI corresponding to the right (A) and left (B) knees from the same patient in the basal visit (A1, B1) and 24 months after HD-ACI (A2, B2). Chondral lesions are indicated with arrows.
Figure 5Figure 5 shows biomechanical evaluation, consisting in checking extension (Fig. 5Fig. 5A) and flexion (Fig. 5Fig. 5B) values of operated knees. Although percentage of knees with complete extension increased from basal visit to 24 months after surgery, differences were not statistically significant.
Fig. 5
Extension (A) and flexion (B) degrees of operated knees.
No swelling was observed in any knee after surgery and no adverse events occurred in any patient.
Discussion
The main finding in this work is that patients with bilateral cartilage defects in whom both knees have been treated with HD-ACI in the same surgical act under the same anesthesia have a satisfactory clinical outcome, with a quality of life improvement with respect to their situation before surgery. Deciding whether to operate both legs during the same surgical act or to operate them in different surgical acts is mainly based on the time that patients need to be able to return to previous activities after recovery from either option. Both decisions have pros and cons. If considering to operate each knee in turn, after recovering from the first surgery, patients will probably spend more time to return to previous activities, because they have to recover from two surgeries, but in contrast, one leg is immobilized after each surgery, so patients may have less mobility limitations during their recovery time. If both legs are simultaneously operated, patients only have to recover from one surgery but they have the inconvenience of having both legs immobilized. Bilateral chondral lesions are relatively infrequent and, to the best of our knowledge, there are no publications mentioning the treatment of bilateral chondral lesions with ACI during the same surgical act.
In this work, clinical outcome for 8 patients with bilateral chondral defects treated with HD-ACI is reported. In our patients, the patella was the most frequent location of chondral injuries. In some patient series, medial femoral condyle is the main chondral lesion location,5x5Cooper, T., Boyles, A., Samora, W.P., and Klingele, K.E. Prevalence of bilateral JOCD of the knee and associated risk factors. J Pediatr Orthop. 2015;
35: 507–510 Crossref | PubMed | Scopus (23) | Google ScholarSee all References,17x17Fodor, P., Sólyom, Á., Ivănescu, A., Fodor, R., and Bățagă, T. Prevalence of chondral lesions in knee arthroscopy. J of Interdisciplinary Med. 2018;
3: 21–24 Crossref | Google ScholarSee all References in contrast to patella which is the most frequent location in other series.18x18Widuchowski, W., Widuchowski, J., and Trzaska, T. Articular cartilage defects: study of 25,124 knee arthroscopies. Knee. 2007;
14: 177–182 Abstract | Full Text | Full Text PDF | PubMed | Scopus (503) | Google ScholarSee all References In our experience, the medial femoral condyle is the most frequent location observed in unilateral knee cartilage lesions12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References but we do not have a clear explanation for their prevalence in the patella in bilateral defects. Patellar cartilage injuries may also show a high prevalence while they may be better tolerated than medial femoral condyle lesions or could be asymptomatic and would not be detected if an image test is finally not performed.
Clinical outcome of operated patients at 12 and 24 months was satisfactory in terms of pain (measured with VAS and subjective perception of knee function assessed by IKDC). Both parameters significantly improved from basal to 12 and 24 months follow-up, reaching a value that was significantly higher than published MCID.14x14Jones, K.J., Kelley, B.V., Arshi, A., McAllister, D.R., and Fabricant, P.D. Comparative effectiveness of cartilage repair with respect to the minimal clinically important difference. Am J Sports Med. 2019;
47: 3284–3293 Crossref | PubMed | Scopus (40) | Google ScholarSee all References These results indicate that improvement in pain and knee function is perceived by patients as a real improvement, indicating a satisfactory clinical outcome in these patients. In the case of unilateral lesions, improvement in clinical parameters is accompanied by good integration of the implant in the surrounding cartilage measured by MOCART score, as demonstrated by several authors.19x19Zak, L., Kleiner, A., Albrecht, C., Tichy, B., and Aldrian, S. Third-generation autologous chondrocyte implantation at the knee joint using the igor scaffold: a case series with 2-year follow-up. Orthop J Sports Med. 2021;
9: 2325967120969237https://doi.org/10.1177/2325967120969237 (doi:) Crossref | Scopus (5) | Google ScholarSee all References,20x20Blanke, F., Oehler, N., Haenle, M., Lenz, R., Vogt, S., and Tischer, T. All-arthroscopic hydrogel-based autologous chondrocyte transplantation in the knee joint: good clinical and magnetic resonance imaging outcome after 24 months. Arthroscopy. 2021;
https://doi.org/10.1016/j.arthro.2021.01.038 (S0749-8063(21)00055-4) Abstract | Full Text | Full Text PDF | PubMed | Scopus (6) | Google ScholarSee all References Similar events took place for patients with bilateral lesions studied in the present work: satisfactory clinical outcome was presented together with a high MOCART score, revealing a good integrity of neoformed tissue.
Short- and mid-term results found by us and other authors for patients with unilateral chondral defects treated with different ACI modalities- ACI in liquid medium under periosteal flap, MACI or HD-ACI12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References,14x14Jones, K.J., Kelley, B.V., Arshi, A., McAllister, D.R., and Fabricant, P.D. Comparative effectiveness of cartilage repair with respect to the minimal clinically important difference. Am J Sports Med. 2019;
47: 3284–3293 Crossref | PubMed | Scopus (40) | Google ScholarSee all References,21x21Niemeyer, P., Porichis, S., Steinwachs, M. et al. Long-term outcomes after first-generation autologous chondrocyte implantation for cartilage defects of the knee. Am J Sports Med. 2014;
42: 150–157 Crossref | PubMed | Scopus (118) | Google ScholarSee all References,22x22Zeifang, F., Oberle, D., Nierhoff, C., Richter, W., Moradi, B., and Schmitt, H. Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial. Am J Sports Med. 2010;
38: 924–933 Crossref | PubMed | Scopus (190) | Google ScholarSee all References were comparable. All these publications support autologous chondrocyte implantation effectiveness. Decision about whether to treat bilateral chondral defects in one or two surgical acts must be always taken on the basis of patient's quality of life (QOL). For this reason, in this work QOL was monitored along the study. As other authors have found in patients with unilateral defects,23x23Cvetanovich, G.L., Riboh, J.C., Tilton, A.K., and Cole, B.J. Autologous chondrocyte implantation improves knee-specific functional outcomes and health-related quality of life in adolescent patients. Am J Sports Med. 2017;
45: 70–76 Crossref | PubMed | Scopus (32) | Google ScholarSee all References,24x24Gou, G.H., Tseng, F.J., Wang, S.H. et al. Autologous chondrocyte implantation versus microfracture in the knee: a meta-analysis and systematic review. Arthroscopy. 2020;
36: 289–303 Abstract | Full Text | Full Text PDF | PubMed | Scopus (25) | Google ScholarSee all References,25x25Everhart, J.S., Campbell, A.B., Abouljoud, M.M., Kirven, J.C., and Flanigan, D.C. Cost-efficacy of knee cartilage defect treatments in the United States. Am J Sports Med. 2020;
48: 242–251 Crossref | PubMed | Scopus (29) | Google ScholarSee all References patients with bilateral cartilage defects treated with autologous chondrocyte implantation had a significant QOL improvement two years after surgery.
Another secondary finding in our work was that improvement in VAS and IKDC was not cartilage defect location- or size-dependent. We also found the lack of influence of both factors in HD-ACI treatment in patients with unilateral cartilage defects.12x12Lopez-Alcorocho, J.M., Aboli, L., Guillen-Vicente, I. et al. Cartilage defect treatment using high-density autologous chondrocyte implantation: two-year follow-up. Cartilage. 2018;
9: 363–369 Crossref | PubMed | Scopus (17) | Google ScholarSee all References,13x13López-Alcorocho, J.M., Guillén-Vicente, I., Rodríguez-Iñigo, E. et al. High-density autologous chondrocyte implantation as treatment for ankle osteochondral defects. Cartilage. 2019;
https://doi.org/10.1177/1947603519835898 Crossref | Scopus (11) | Google ScholarSee all References Cartilage defect location and size influence on 3D-cultured autologous chondrocytes implantation has been recently studied by Niethammer et al. .26x26Niethammer, T.R., Gallik, D., Chevalier, Y. et al. Effect of the defect localization and size on the success of third-generation autologous chondrocyte implantation in the knee joint. Int Orthop. 2020;
https://doi.org/10.1007/s00264-020-04884-4 Crossref | PubMed | Scopus (6) | Google ScholarSee all References Although patients in the aforementioned work were treated with chondrocytes cultured with a different method to the one described in the present work, authors did not find patient's clinical outcome to be influenced by either injury location or size.
Limitations
The main weakness of the present study is the limited sample size, which is due to the low bilateral chondral defect prevalence. However, results are consistent enough to make them valid. On the light of these results, patients with bilateral chondral defects are currently offered to undergo one or two surgeries and they decide according their preferences.
Conclusion
Both chondral defects of patients with bilateral cartilage defects in the knee can be treated simultaneously at the same surgical act with HD-ACI, with good clinical outcome and without having a significant impact on their quality of life.
Informed consent
All patients signed an informed consent
Declaration of competing interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work has been financed by Fundación Pedro Guillén. We would like to thank Mario Wensell for carefully revising the linguistics for this article.
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3: 21–24
19Zak, L., Kleiner, A., Albrecht, C., Tichy, B., and Aldrian, S. Third-generation autologous chondrocyte implantation at the knee joint using the igor scaffold: a case series with 2-year follow-up. (doi:)Orthop J Sports Med. 2021;
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38: 924–933
24Gou, G.H., Tseng, F.J., Wang, S.H. et al. Autologous chondrocyte implantation versus microfracture in the knee: a meta-analysis and systematic review. Arthroscopy. 2020;
36: 289–303
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48: 242–251
26Niethammer, T.R., Gallik, D., Chevalier, Y. et al. Effect of the defect localization and size on the success of third-generation autologous chondrocyte implantation in the knee joint. Int Orthop. 2020;
https://doi.org/10.1007/s00264-020-04884-4
IGV: patient selection, surgery and follow-up, paper writing; JML: data analysis, paper writing; ERI: data collection, paper reviewing; MGV: surgery and follow-up of patients, data analysis; TFFJ: patient selection and follow-up, paper writing; JMC: patients follow-up, data collection; SA: surgery, paper writing; PG: patient selection and surgery, paper reviewing
Institutional Review Board (IRB) approval:
This work was approved by the Clínica CEMTRO Education and Research Committee. All patients included signed an informed consent.
Article Info
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