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Revision cartilage cell transplantation for failed autologous chondrocyte transplantation in chronic osteochondral defects of the knee S. Vijayan, G. Bentley, J. Rahman, T. W. R. Briggs, J. A. Skinner, R. W. J. Carrington From Royal National Orthopaedic Hospital, Stanmore, United Kingdom

The management of failed autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI) for the treatment of symptomatic osteochondral defects in the knee represents a major challenge. Patients are young, active and usually unsuitable for prosthetic replacement. This study reports the results in patients who underwent revision cartilage transplantation of their original ACI/MACI graft for clinical or graft-related failure. We assessed 22 patients (12 men and 10 women) with a mean age of 37.4 years (18 to 48) at a mean of 5.4 years (1.3 to 10.9). The mean period between primary and revision grafting was 46.1 months (7 to 89). The mean defect size was 446.6 mm2 (150 to 875) and they were located on 11 medial and two lateral femoral condyles, eight patellae and one trochlea. The mean modified Cincinnati knee score improved from 40.5 (16 to 77) pre-operatively to 64.9 (8 to 94) at their most recent review (p < 0.001). The visual analogue pain score improved from 6.1 (3 to 9) to 4.7 (0 to 10) (p = 0.042). A total of 14 patients (63%) reported an ‘excellent’ (n = 6) or ‘good’ (n = 8) clinical outcome, 5 ‘fair’ and one ‘poor’ outcome. Two patients underwent patellofemoral joint replacement. This study demonstrates that revision cartilage transplantation after primary ACI and MACI can yield acceptable functional results and continue to preserve the joint. Cite this article: Bone Joint J 2014;96-B:54–8.

 S. Vijayan, BSc(Hons), MBBS, Clinical Research Associate  G. Bentley, ChM, FRCS, FMedSci, Emeritus Professor of Orthopaedic Surgery  J. Rahman, MRCS, Clinical Research Fellow  T. W. R. Briggs, MD(Res), MCh(Orth), FRCS, Professor of Orthopaedic Surgery  J. A. Skinner, FRCS(Orth), Consultant Orthopaedic Surgeon  R. W. J. Carrington, FRCS(Orth), Consultant Orthopaedic Surgeon Royal National Orthopaedic Hospital, Joint Reconstruction and Cartilage Transplantation Unit, Brockley Hill, Stanmore HA7 4LP, UK. Correspondence should be sent to Dr S. Vijayan; e-mail: [email protected] ©2014 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.96B1. 31979 $2.00 Bone Joint J 2014;96-B:54–8. Received 12 March 2013; Accepted after revision 4 September 2013

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Autologous chondrocyte implantation (ACI) was the first cell-based technique employed to treat symptomatic isolated articular cartilage lesions of the knee.1 Matrix-assisted autologous chondrocyte implantation (MACI) is a third-generation variation of ACI, in which chondrocyte cells are pre-loaded onto a porcine collagen membrane, which is cut to fit the defect and held in place with fibrin glue.2 MACI resulted in shorter operating times and a more even distribution of cells, which led to its increased popularity among surgeons.2,3 ACI or MACI can be offered as an option to patients who have failed conventional methods of cartilage repair including drilling, microfracture and mosaicplasty.3-5 The institutional costs and prolonged post-operative patient rehabilitation associated with primary cartilage transplantation make the management of failed ACI or MACI grafts particularly difficult. We report our experience of revision cartilage transplantation, performed in patients with chronically symptomatic articular cartilage lesions after failed ACI or MACI.

Patients and Methods Between April 2002 and September 2008, 22 patients were identified as a subset of a larger

multi-surgeon prospective trial involving ACI and MACI (Table I). Patients deemed suitable for this study had a symptomatic isolated chondral or osteochondral lesion > 1 cm2 in the knee, and were considered likely to be able to complete the rehabilitation programme. All patients had been treated with primary ACI or MACI, which had failed to heal, experiencing intolerable pain and knee swelling. There were 12 men and ten women with a mean age of 37.4 years (18 to 48). The mean pre-operative duration of symptoms prior to revision surgery was 3.8 years (0.6 to 7.4). The mean period between primary and revision grafting was 46.1 months (7 to 89). Patients with severe clinical symptoms, assessed by a poor pre-operative functional score using the modified Cincinnati knee scoring system6 and the Stanmore Bentley functional score,7 and a poor visual analogue pain score (VAS) (0, no pain to 10, maximum pain), whether or not obvious radiological failure or arthroscopic evidence of graft delamination was present, were defined as failures. All 22 patients in this study complained of severe pain and as well as swelling, locking and giving-way. All knees were stable, in that the patients had both THE BONE & JOINT JOURNAL

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Table I. Baseline patient characteristics Patient/Gender/Age (yrs)

Knee

Site*

Diagnosis†

Lesion size (mm2)

Symptom duration (mths)

Follow-up after revision (mths)

1 / M / 45 2 / M / 32 3 / F / 46 4 / M / 18 5 / F / 39 6 / F / 46 7 / M / 35 8 / F / 30 9 / F / 38 10 / M / 40 11 / F / 25 12 / M / 45 13 / F / 47 14 / M / 36 15 / M / 27 16 / F / 36 17 / M / 48 18 / M / 37 19 / M / 46 20 / F / 30 21 / M / 40 22 / F / 36

Left Right Left Left Left Right Left Left Left Right Left Left Left Left Left Right Right Left Right Right Left Right

MFC MFC MFC MFC Patella Patella Trochlea MFC MFC LFC MFC MFC Patella Patella Patella LFC MFC MFC MFC Patella Patella Patella

OCD Trauma OCD Trauma CP CP Trauma Trauma OCD Trauma Trauma Trauma CP CP CP Trauma Trauma OCD Trauma CP CP CP

600 400 600 400 150 875 250 400 500 400 600 400 560 400 300 225 200 400 625 400 740 400

73 17 89 42 74 11 56 51 32 19 38 7 85 36 60 65 48 72 47 36 19 38

37 36 16 114 65 131 48 68 39 88 69 45 41 72 72 96 92 48 39 72 132 116

* MFC, medial femoral condyle; LFC, lateral femoral condyle † OCD, osteochondritis dissecans; CP, chondromalacia patellae

stable ligaments and showed no symptoms of instability. Given their relatively young age, none were deemed suitable for joint replacement and all were keen for further surgical reintervention because of their symptoms. Pre-operative medical and lifestyle management advice was given to all patients including those who smoked and had a high body mass index (BMI). All underwent diagnostic arthroscopy immediately prior to the revision procedure. The mean size of the lesions was 446.6 mm2 (150 to 875). The original surgery was ACI in 17 and MACI in five. At revision 13 patients underwent MACI and nine ACI. Shorter operating times and suture-free application of the membrane allowing a smaller surgical exposure have been reported with MACI when compared with ACI2, leading to its increased popularity amongst surgeons in cases of revision cartilage transplantation. Operative technique. All patients had anteroposterior (AP) full weight-bearing radiographs of the knee prior to surgery and arthroscopic confirmation of graft failure. The size, depth and containment of the graft site were noted at arthroscopy. A small portion of full thickness articular cartilage (approximately 2 cm by 1 cm) was immediately harvested from non-weight-bearing medial or lateral margin of the trochlea groove using a small gouge. The sample was sent in a transport medium to the laboratory (Verigen/Genzyme, Copenhagen, Denmark) along with 30 ml of the patient’s blood in an individual vial. Laboratory enzymatic breakdown and culture of chondrocytes in a monolayer system using the patient’s serum from their blood sample was undertaken for ACI. For MACI, a chondrocyte-seeded VOL. 96-B, No. 1, JANUARY 2014

porcine type I/III collagen membrane (Genzyme, Narden, The Netherlands) was produced. Second stage revision surgery was performed three to five weeks after the harvesting stage. Under tourniquet control, through the previous mid-line incision, a medial or lateral parapatellar arthrotomy was used to access the joint. The failed graft was identified and debrided to a healthy stable rim of articular cartilage using a scalpel. A curette was used to remove any residual cartilage and occasionally sclerotic bone from the base of the lesion. Care was taken not to breach the subchondral bone plate but if bleeding occurred it was controlled with a mini-swab soaked in noradrenalin (4 mg in 4 ml solution ampoule). ACI involved covering the defect with an appropriately sized ‘chondrogide’ type I/III collagen membrane (Geistlich Biomaterials, Wolhusen, Switzerland) or periosteum in a few early cases. The membrane was secured at the periphery of the defect with 6/0 or 5/0 Vicryl sutures (Ethicon, Livingstone, United Kingdom) spaced 3 mm to 4 mm apart. The junction between the patch and healthy cartilage was sealed with fibrin glue (Tisseel; Baxter, Vienna, Austria), except for a small gap superiorly to allow the insertion of a fine plastic catheter to apply the cells. The cells were gently agitated in their glass vial to ensure uniform distribution and drawn into a micro-syringe and the cultured chondrocyte suspension (5 to 10 million cells) injected. The membrane was inflated by the suspension to ensure there was no spillage of the cells and to avoid placing excess tension on the sutures by overfilling and leakage. Filling of the

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S. VIJAYAN, G. BENTLEY, J. RAHMAN, T. W. R. BRIGGS, J. A. SKINNER, R. W. J. CARRINGTON

Fig. 1 Sagittal T2-weighted MRI of the medial femoral condyle (MFC) in a symptomatic right knee (symptoms including pain and locking) in a 32-year-old male patient at one year after primary matrix-assisted autologous chondrocyte implantation, showing poor graft coverage of the previously treated MFC osteochondral defect.

defect with cells in suspension was observed as a rising tidemark on the dry chondrogide membrane. A suture was used to close the injection site and sealed with fibrin glue. In the MACI procedure, the membrane was templated and cut to fit the size of the prepared defect. The roughened cell-containing side of the membrane (approximately 1 million cells per cm2) was positioned face down onto the defect and secured in place by fibrin glue at its periphery. Gentle finger pressure was applied to the centre of the graft for approximately three minutes until the glue set. The joint was then put through a full range of movement. If necessary, interrupted 6/0 or 5/0 Vicryl sutures were inserted to further stabilise the graft. In both procedures, the wound was closed in layers and no drains were used to avoid damage to the graft. The leg was initially placed in a Robert Jones bandage with a plaster-of-Paris backslab and elevated for 12 hours post-operatively and isometric quadriceps exercises commenced as soon as possible. Full weight-bearing commenced at 24 hours to encourage fluid exchange in the articular cartilage. At 48 hours, a lightweight plaster cylinder was applied for ten days with the knee in full extension and the patient was discharged from hospital with crutches. At ten days post-operatively, the cast was removed, the wound inspected and the patient commenced a standard rehabilitation programme,8 which was identical for both operative techniques. All patients were reviewed at six weeks, six months, at one year post-operatively and annually thereafter. Patientreported outcomes were assessed by clinicians who had no direct involvement in any of the surgery and were blinded to the procedure. Results were graded as excellent (> 80), good (55 to 79), fair (30 to 45) or poor (< 30) based on the

Cincinnati knee scoring system. A lower Stanmore Bentley functional score (range 0 to 4) represented better function. Failure was defined as persistent pain with a VAS equal to or higher than pre-operatively documented, with associated ‘poor’ functional scores, and arthroscopic or radiological (magnetic resonance imaging (MRI)) confirmation of graft failure (Fig. 1). The patients were invited for arthroscopic assessment of the revised graft at one year but given the nature of their surgery, all but one declined, fearing any risk to graft stability. In the single patient who consented, a full thickness biopsy was taken from the centre of the graft including subchondral bone using a 2.5 mm Jamshidi needle (Allegiance Healthcare, Swindon, UK). Statistical analysis. Mean pre- and post-operative scores were compared using the paired t-test (Microsoft Excel 2013). The level of statistical significance was set at a p-value < 0.05.

Results Patients were followed for a mean of 5.4 years (1.3 to 10.9). There was a significant improvement of all three clinical outcome scores following revision cartilage transplantation surgery (Table II). Of the 22 patients, 14 had an ‘excellent’ (six) or ‘good’ (eight) modified Cincinnati knee score, five ‘fair’, one ‘poor’ and two ‘failures’ at review. One patient required manipulation under anaesthesia for knee stiffness at three months post-operatively. In the five patients who underwent arthroscopic evaluation approximately one year post-operatively (Fig. 2), four had arthroscopic trimming for graft hypertrophy (three MACI and one ACI) and one had a graft biopsy. All grafts were found to be stable. Histological assessment showed a well-integrated fibrous tissue (Fig. 3). This patient had a modified Cincinnati knee score of 40, a Stanmore Bentley score of three and a VAS of six at latest follow-up (6 years). One patient reported ‘good’ scores during the initial postoperative three years but later complained of knee pain, with arthroscopic confirmation of graft delamination. She underwent a third revision MACI procedure for a lesion of her patella and at latest follow-up of six years has an ‘excellent’ modified Cincinnati knee score, VAS of zero and a Stanmore Bentley score of zero. Two patients developed pain and intermittent locking of their knees. At arthroscopy graft delamination of their patella lesions was confirmed, with osteophyte formation in keeping with osteoarthritis of their tibio-femoral joints. Both underwent patellofemoral joint replacement at 14 and 25 months subsequent to the revision surgery. Both patients regained full activities of daily living and remain pain free following joint replacement at a mean follow-up of 5.3 years (4.4 to 6). No wound infections, haematomas or deep vein thromboses were encountered. Discussion When compared with previous reports from this unit,2-4,8-11 the patients in this study were older, with a longer overall mean duration of symptoms, a poorer level of pre-operative function and had undergone multiple (≥ two) previously THE BONE & JOINT JOURNAL

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Table II. Modified Cincinnati knee score, Stanmore/Bentley score and visual analogue scale (VAS) for pain pre-operatively and at most recent mean follow-up of 5.4 years (1.3 to 10.9) (CI, confidence interval) Mean (SD) result Score

Pre-operative (n = 22) Post-operative (n = 22)

Mean difference (95% CI)

Paired t-test p-value

Modified Cincinnati knee score Stanmore/Bentley score VAS for pain

40.5 (17.4) 3.1 (0.7) 6.1 (1.9)

24.4 (10.7 to 35.9) 1.2 (0.7 to 1.3) 1.4 (0.05 to 2.9)

< 0.001 < 0.001 0.042

64.9 (21.3) 1.9 (1.3) 4.7 (2.9)

Fig. 2

Fig. 3

Arthroscopic image of the patient in Figure 1 at one year after revision matrix-assisted autologous chondrocyte implantation, with a firm and stable graft to probing, showing complete coverage of the defect on the medial femoral condyle.

Histological photomicrograph showing a revision autologous chondrocyte implantation (ACI) graft after failed primary ACI composed of fibrous tissue (haematoxylin and eosin staining at 200 × magnification).

failed surgical procedures. Such factors have been shown to negatively influence outcome and make this sub-group of patients the most complex to treat.4 In our study, revision ACI and MACI was performed because patients were significantly disabled and not considered to be candidates for joint replacement. Despite this, functional scores following revision were excellent or good in 14 patients, fair in five, poor in one case and failed in two (9%). Further analysis of patients who had a fair, poor or failed outcomes, showed that in four the location of the defect was on the patella and four patients smoked. Of the two patients who had ‘failed’, both had lesions of their patella and a positive smoking habit. This was in keeping with previous reports of primary ACI showing inferior outcomes following treatment of osteochondral lesions on the patella compared to the femoral condyles12 and the negative impact smoking has on long-term outcomes.13 Two patients diagnosed with chondromalacia patellae failed at 2.3 and 2.1 years after revision of their original graft. Both patients had advanced patella-femoral joint osteoarthritis on arthroscopy and were revised directly to a patellofemoral joint replacement. But primary and revision

cartilage transplantation had afforded symptomatic relief in both the failed patients and preserved the natural joint for 3.9 and 5.3 years respectively, following the revision surgery. We recognise the measured improvements shown by patients in this study are not as great as those we have previously reported,2-4,8-11 but we suspect that this is a reflection of a poorer pre-operative functional condition secondary to multiple failed previous knee procedures. Although satisfactory clinical outcomes were achieved with revision cartilage transplantation, it is vital that the patient’s pre-operative expectations are managed carefully. Careful consideration of revision surgery should be undertaken in patients with known pre-operative risk factors, including being smokers and defects on the patella;4,13 however, the overall reported improvement in functional outcome and pain in this group of patients justifies undertaking revision cartilage transplantation in certain circumstances.

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The authors wish to thank Professor A. Flanagan, Professor and Consultant Histopathologist, University College London / Royal National Orthopaedic Hospital (UK), for her preparation of and advice on the histological material. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by D. Rowley and first-proof edited by G. Scott.

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References 1. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994; 331:889–895.

8. Bentley G, Biant LC, Carrington RW, et al. A prospective, randomized comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg [Br] 2003;85-B:223–230.

2. Bartlett W, Skinner JA, Gooding CR, et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J Bone Joint Surg [Br] 2005;87B:353–373.

9. Gooding CR, Bartlett W, Bentley G, et al. A prospective, randomised study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: Periosteum covered versus type I/III collagen covered. Knee 2006;13:203–210.

3. Vijayan S, Bentley G, Briggs T, et al. Cartilage repair: a review of Stanmore experience in the treatment of osteochondral defects in the knee with various surgical techniques. Ind J Orthop 2010;44:238–245.

10. Bentley G, Biant LC, Vijayan S, et al. Minimum ten-year results of a prospective randomised study of autologous chondrocyte implantation versus mosaicplasty for symptomatic articular cartilage lesions of the knee. J Bone Joint Surg [Br] 2012;94B:504–509.

4. Krishnan SP, Skinner JA, Bartlett W, et al. Who is the ideal candidate for autologous chondrocyte implantation? J Bone Joint Surg [Br] 2006;88-B:61–64. 5. No authors listed. National Institute of Clinical Excellence. Guidance on the use of autologous chondrocyte transplantation for full thickness cartilage defects in knee joints: technology appraisal guidance No. 16. 2000. http://www.nice.org.uk/nicemedia/pdf/guidanceactknee.pdf (date last accessed 9 September 2013). 6. Noyes FR, Barber SD, Mooar LA. A rationale for assessing sports activity levels and limitations in knee disorders. Clin Orthop Relat Res 1989;246:238–249. 7. Meister K, Cobb AG, Bentley G. Treatment of painful articular cartilage defects of the patella by carbon-fibre implants. J Bone Joint Surg [Br] 1998;80-B:965–970.

11. Vijayan S, Bartlett W, Bentley G, et al. Autologous chondrocyte implantation for osteochondral lesions in the knee using a bilayer collagen membrane and bone graft: a two- to eight-year follow-up study. J Bone Joint Surg [Br] 2012;94-B:488–492. 12. Micheli LJ, Browne JE, Erggelet C, et al. Autologous chondrocyte implantation of the knee: multicenter experience and minimum 3-year follow-up. Clin J Sport Med 2001;11:223–228. 13. Jaiswal PK, Macmull S, Bentley G, et al. Does smoking influence outcome after autologous chondrocyte implantation?: a case-controlled study. J Bone Joint Surg [Br] 2009;91-B:1575–1578.

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Revision cartilage cell transplantation for failed autologous chondrocyte transplantation in chronic osteochondral defects of the knee.

The management of failed autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI) for the treatment of...
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