Interventional procedure overview of single-step scaffold insertion for repairing symptomatic chondral knee defects

Akmese R, Özbek EA, Kocaoğlu H, et al (2021). Comparison of All Arthroscopic Implantation of Chitosan-Based Liquid Scaffold and Hyaluronan-Based Soft Scaffold in the Treatment of Condylar Osteochondral Lesions in the Knee. J Knee Surg 35: 222-230

Retrospective comparative study

n=69 (n=37 hyaluronan-based scaffold; n=32 chitosan-based scaffold)

Follow-up 24 months

Statistically significant improvements in patient reported and objective functional and radiological assessments were seen at 3 and 12 months postprocedure (p<0.05). No further improvements were seen at 24 months. There were no statistically significant differences between the different scaffold groups showing clinical and radiological equivalence.

Prospective and larger studies with longer follow-up were included in the key evidence.

Andrade R, Nunes J, Hinckel BB et al (2021). Cartilage Restoration of Patellofemoral Lesions: A Systematic Review. Cartilage 13: 57-73.

Systematic review

n=47 knees had AMIC (of a total 1314 knees in the review).

Mean follow-up (overall) 59 months

Weighted mean improvement in IKDC scores after the procedure was 32.5 points, 39.8 points on the KOOS and 27 points on the Lysholm score. Compared with other procedures evaluated in the review these were larger improvements, but inferior results were seen on the Kujala score. Radiological scoring of cartilage repair showed incomplete filling in 40 to 60% of people and 70 to 100% had irregular surface; 60 to 100% had heterogenous cartilage structure. The authors conclude there is no evidence to show that one procedure is superior to another, but all have significant functional improvement with low failure rates.

Only 4 small case series were included in the AMIC subgroup review. The focus was patellofemoral articular cartilage defects only.

Andriolo L, Reale D, Di Martino A, Boffa A, Zaffagnini S, Filardo G (2021). Cell-free scaffolds in cartilage knee surgery: a systematic review and meta-analysis of clinical evidence. Cartilage 12(3): 277-

292.

Systematic review and meta-analysis

n=23 studies (n=521 people)

3 or more years of follow-up was the last end-point summarised

This systematic review qualitatively and quantitatively summarised clinical scores at 1, 2 and 3 or more years. The meta-analysis of 16 studies showed improvement in clinical scores at 1,2 and 3 or more years compared with baseline. The authors conclude that in the short and mid-term, cell-free scaffolds provide good results but more evidence is needed to see how it compares with cell-based strategies.

Other systematic review and meta-analyses covering similar evidence were included in the key evidence.

D'Ambrosi R, Giacco F, Ragone V & Ursino N (2018). Arthroscopic treatment of osteochondral knee defects with resorbable biphasic synthetic scaffold: clinical and radiological results and long-term survival analysis. International Orthopaedics 43: 2183-2189.

Case series

n=21

Follow-up 102 months

Two of 21 people with osteochondral knee defects had knee replacement surgery at 24 and 65 months after the procedure. Overall, statistically significant improvements in clinical outcomes on the KOOS and HSS were seen at an average of 36 and 101 months compared with before the procedure. At an average of 101 months, mean MOCART score was 46 (SD 5). No correlation was seen between clinical and radiographic outcomes.

Larger, more recent studies were included in the key evidence.

D'Antimo C, Biggi F, Borean A et al (2017). Combining a novel leucocyte-platelet-concentrated membrane and an injectable collagen scaffold in a single-step AMIC procedure to treat chondral lesions of the knee: a preliminary retrospective study. European journal of orthopaedic surgery & traumatology 27: 673-681.

Retrospective case series

n=25

Follow-up 12 months

A leucocyte-platelet-concentrated membrane in combination with an injectable collagen scaffold (Cartifill) was used in this study. The authors concluded that given no adverse events were observed and the ikdc and VAS scores improved during follow-up, the combined AMIC procedure with membrane was a promising approach for chondral knee defects.

This was included in the meta-analysis by Tan (2023) and da Cunha (2020) in the key evidence. Larger, prospective studies with longer follow-up and more standard procedures were included in the key evidence.

Arshi A, Fabricant PD, Go DE, Williams RJ, McAllister DR, Jones KJ. (2018). Can Biologic Augmentation Improve Clinical Outcomes Following microfracture for Symptomatic cartilage Defects of the Knee? A Systematic Review. Cartilage 9: 146-155.

Systematic review

n=18 (n=10 studies used scaffolding as adjuvants to microfracture)

Follow-up ranged from 2 to 5 years

The authors narratively compared outcomes between injectable adjuvants or scaffold adjuvants to microfracture with microfracture alone. They conclude evidence is mixed within the scaffold subgroup, but tends to report equivalent or superior clinical outcomes with no additional safety concerns.

A more recent systematic review with meta-analysis was included.

Astur DC, Lopes JC, Santos MA et al (2018). Surgical treatment of chondral knee defects using a collagen membrane- autologus matrix-induced chondrogenesis. Rev Bras Ortop 53: 733-739.

Retrospective case series

n=7

Follow-up 12 months

Mean MOCART score was 66 points at 12 months. Lysholm, Kujala and VAS scores all indicated significant improvements compared with baseline at 12 months. The authors conclude these were favourable outcomes.

This study was included in the meta-analysis by Migliorini (2022a, 2022b) and Tan (2023) in the key evidence. Larger, prospective studies with longer follow up were included in the key evidence.

Bakowski P, Grzywacz K, Prusinska A, et al (2022). Autologous Matrix-Induced Chondrogenesis (AMIC) for Focal Chondral Lesions of the Knee: A 2-Year Follow-Up of Clinical, Proprioceptive, and Isokinetic Evaluation. Journal of Functional Biomaterials 13: 277.

Retrospective case control study (single centre)

n=69 (n=48 people had AMIC; n=21 healthy controls)

Follow-up 2 years

Compared with baseline, a statistically significant improvement was seen in Lysholm and IKDC outcome scores and almost all objective functional scores analysed up to the 2-year follow up. Compared with healthy controls, postural strategy was significantly worse at 2 years. The authors conclude that evidence of durable effectiveness was seen in their study.

Larger, prospective studies with longer follow-up were included in the key evidence.

Bardas CA, Zsolt GJ, Apostu D, Dan DO, Tomoaia G, Benea HRC, (2018). Functional results of different repair techniques for knee articular cartilage lesions. Rev Chem 69:3288–91.

Retrospective case series

n=106 (n=7 had a scaffold)

Follow-up 6 months

This study evaluated IKDC outcomes pre and postoperatively. All techniques (debridement, microfracture, osteochondral autologous transfer mosaicplasty and autologous matrix induced chondrogenesis) showed significant improvements. The largest improvement was in the autologous matrix induced chondrogenesis group.

This study was included in the meta-analysis by Tan (2023) in the key evidence. Studies with a larger scaffold group and longer follow-up were included in the key evidence.

Bertho P, Pauvert A, Pouderoux T, et al (2018). Treatment of large deep osteochondritis lesions of the knee by autologous matrix-induced chondrogenesis (AMIC): Preliminary results in 13 patients. Orthopaedics & traumatology, surgery & research 104: 695-700.

Prospective case series (single centre)

n=13

Median follow-up 24 months

At a median of 2 years, 11 of 13 people with osteochondral lesions had significant improvements on the IKDC and KOOS scores. Of the people who did not have significant improvements, one had a history of multiple surgeries and the other had the largest lesion of the sample. The authors conclude that good outcomes were seen in these osteochondral lesions.

This study was included in the meta-analysis by Tan (2023) and da Cunha (2020) in the key evidence. Larger studies with longer follow-up were included in the key evidence.

Bong GSP & Lee YHD, (2022). Injectable Scaffold with microfracture using the Autologous Matrix-Induced Chondrogenesis (AMIC) Technique: A Prospective Cohort Study. Malaysian Orthopaedic Journal 16: 86-93.

Prospective case series (single centre)

n=21 knees (31 defects)

Average follow-up 43 months

In this single-centre study of injectable scaffolds, on average, statistically significant increases were seen in the Lysholm and the KOOS score (26 points, 23 points respectively) within 1 year and maintained during follow-up. No complications or reinterventions were required in the duration of follow-up. The authors conclude that safe and effective outcomes were seen in the short to medium term.

Larger studies with randomised evidence were included in the key evidence.

Chen Chou AC & Tjoen Lie DT (2020). Clinical Outcomes of an All-Arthroscopic Technique for Single-Stage Autologous Matrix-Induced Chondrogenesis in the Treatment of Articular Cartilage Lesions of the Knee. Arthroscopy 2:353-359.

Retrospective case series (single centre)

n=22

Follow-up 24 months

All procedures were performed arthroscopically in this study. Statistically significant improvements in IKDC scores at 6 and 24 months were seen. The authors conclude that an all-arthroscopic method of doing this procedure shows early clinical improvements for people with osteochondral lesions.

This study was included in the meta-analysis by Tan (2023). Larger, prospective studies with longer follow-ups and more clinical outcomes were included in the key evidence.

Dávila Castrodad IM, Kraeutler MJ, Fasulo SM et al (2022). Improved Outcomes with Arthroscopic Bone Marrow Aspirate Concentrate and Cartilage-Derived Matrix Implantation versus Chondroplasty for the Treatment of Focal Chondral Defects of the Knee Joint: A Retrospective Case Series. Arthroscopy, Sports Medicine, and Rehabilitation 4: e411-e416.

Retrospective comparative study

n=39 in the sub-analysis that controlled for differences between bone marrow aspirate with cartilage scaffold and chondroplasty groups (total sample 98)

Mean follow-up 24 months in the scaffold group, mean follow-up 41 months in the chondroplasty group

The bone marrow aspirate concentrate plus cartilage scaffold groups had superior outcomes (VAS, activity score, KOS ADL and KOS Sport subscores), compared with chondroplasty. There were no statistically significant differences in postoperative injections, subsequent surgeries, or conversion to total knee arthroplasty between groups.

Larger and prospective studies and studies with standardised follow-ups were included in the key evidence.

Enea D, Cecconi S, Calcagno S, Busilacchi A, Manzotti S, Gigante A. (2015). One-step cartilage repair in the knee: collagen-covered microfracture and autologous bone marrow concentrate. A pilot study. Knee 22: 30-35.

Case series

n=9

Mean follow-up 29 months.

Consecutive patients had microfracture plus collagen membrane immersed in bone marrow concentrate in this single stage procedure. Significant clinical improvements were seen at last follow up.

This study was included in the meta-analyses by Migliorini (2022a, 2022b). Larger studies with longer follow-up were included in the key evidence.

Fossum V, Hansen AK, Wilsgaard T, et al (2019). Collagen-Covered Autologous Chondrocyte Implantation Versus Autologous Matrix-Induced Chondrogenesis. The Orthopaedic Journal of Sports Medicine, 7: 2325967119868212.

RCT

n=41 (n=21 in the ACI-C group and n=20 in the AMIC group)

Mean follow-up 2 years

In this RCT comparison of AMIC and collagen covered-ACI, there were no statistically significant differences in patient reported outcomes at 2 years after the procedure (KOOS, Lysholm, VAS). At 2 years, 2 of 20 people in the AMIC group had a total knee replacement compared with none in the ACI-C group. The authors report no significant differences in the procedures but indicate long term outcomes will be important.

This RCT was included in the meta-analyses by Migliorini (2021a) and Tan (2023) in the key evidence.

Gao L, Orth P, Cicchiarini M & Madry H (2019). Autologous Matrix-Induced Chondrogenesis: A Systematic Review of the Clinical Evidence. The American Journal of Sports Medicine 47: 222-231.

Systematic review

n=245 people in 12 studies focusing on the knee (n=28 studies in total; other joints were included)

Follow-ups were summarised including a 5 year or greater timepoint.

In most studies, people reported less pain (VAS), and mostly reported improved knee functional scores within 2 years of the procedure. The range of Lysholm scores improved within the first 2 years and at 5 years but worsened overall in years 2 to 5. Overall, the MOCART score was similar at the first and second post operative years. Reoperation rate was 5 out of 245 for AMIC in the knee. They conclude it is a safe procedure but indications are unclear with the current evidence.

More recent systematic reviews that largely cover the evidence in this systematic review were included in the key evidence.

Ginesin E, Chari NS, Barnhart J et al (2023). Cartilage Restoration for Isolated Patellar Chondral Defects: An updated systematic review. Orthopaedic journal of sports medicine 11: 23259671231153422

Systematic review

n=3 AMIC studies (n=24 studies in total in the review)

Follow up not reported

The authors reviewed a series of cartilage restoration techniques. They conclude that advanced microfracture techniques showed promise, but indications (including size of lesion) and variability in techniques need to be elucidated in higher-level studies.

There was no meta-analysis in this study. Systematic review and meta-analyses with more, relevant literature were included in the key evidence.

Glasbrenner J, Peterson W, Raschke MJ et al (2020). Matrix-Augmented Bone Marrow Stimulation With a Polyglycolic Acid Membrane With Hyaluronan vs microfracture in Local Cartilage Defects of the Femoral Condyles: A Multicenter Randomized Controlled Trial. The Orthopaedic Journal of Sports Medicine, 8: 2325967120922938.

Multicentre RCT

n=24 (n=12 microfracture only; n=12 microfracture with scaffold)

Follow-up 108 weeks

Mean lesion size was 1.2cm² in this study. There was no statistically significant difference between groups in the percent of defect filling at 12, 54 and 108 weeks. No statistically significant different was found in patient reported outcomes at any time point (KOOS, IKDC, VAS, SF-36). An infected haematoma (serious adverse event) was treated and the person recovered in the microfracture plus scaffold group.

Larger RCTs with longer follow-up were included in the key evidence.

Gobbi A, Chaurasia S, Karnatzikos G et al (2015). Matrix-Induced Autologous Chondrocyte Implantation versus Multipotent Stem Cells for the Treatment of Large Patellofemoral Chondral Lesions: A Nonrandomized Prospective Trial. Cartilage 6: 82-97.

Prospective non-randomised trial

n=37 (n=18 bone marrow aspirate concentrate with scaffold, n=19= Maci).

Mean follow-up 60 months

All people in this trial had lesions 4cm² or larger. Both groups showed significant improvements in all scores from baseline to last follow-up (IKDC, KOOS, VAS, Tegner). The only score that favoured the bone marrow aspirate concentrate group was IKDC at last follow up. MRI showed complete filling of the defects in 76% of patients in Maci and 81% of patients in the bone marrow aspirate concentrate group. The authors conclude both techniques are effective for lesions at least 4cm² for at least 3 years.

Larger prospective and randomised studies were included.

Gobbi A, Scotti C, Karnatzikos G, Mudhigere A, Castro M, Peretti GM (2017). One step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years. Knee Surg Sports Traumatol Arthrosc 25:2494–

501.

Prospective non-randomised comparison study

n=40 (n=20 had a scaffold augmented with bone marrow aspirate concentrate)

Follow-up 4 years

All people had a hyaluronan-based scaffold and half had treatment augmented with bone marrow aspirate concentrate in this study. Neither group had microfracture. At 2 years, the augmented treatment group showed superior Tegner and KOOS subscores than control. At final follow-up, all outcomes (KOOS, IKDC, VAS Tegner score and MRI evaluation) had significantly improved. Improvements varied by lesion size and number of lesions.

Larger, randomised studies were included in the key evidence.

Gobbi A, Whyte GP, (2016). One-Stage Cartilage Repair Using a Hyaluronic Acid–Based Scaffold With Activated Bone Marrow–Derived Mesenchymal Stem Cells Compared With microfracture: Five-Year Follow-up. American Journal of Sports Medicine 44: 2846-2854.

Prospective non-randomised comparison study

n=50 (hyaluronic acid–based scaffold with activated bone marrow aspirate concentrate compared with microfracture alone)

Follow-up 5 years

Both groups had significant improvements at 2 years on the IKDC. Tegner, IKDC objective, and Knee injury and Osteoarthritis Outcome Score (KOOS) assessments demonstrated higher scores in the HA-bone marrow aspirate concentrate treatment group compared with microfracture at 5 years. Lysholm and IKDC subjective scores were similar between treatment groups at 5 years. The authors conclude that more durable effects can be observed with the hyaluronic acid based scaffold than microfracture alone.

Larger prospective case series have been included, with similar follow up.

Gobbi A, Whyte GP (2019). Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid–Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate. The American Journal of Sports Medicine, 47: 1621-1628.

Prospective case series

n=23

Mean follow-up 8 years

All clinical outcome scores were significantly improved at last follow-up (IKDC, KOOS, Tegner). The authors conclude that good to excellent long term outcomes can be achieved in full thickness lesions with the hyaluronic acid based scaffold with bone marrow aspirate concentrate. Outcomes may be more successful in younger people.

Larger and randomised prospective studies are included in the key evidence.

Gudas R, Maciulaitis J, Staskunas M et al (2019). Clinical outcome after treatment of single and multiple cartilage defects by autologous matrix-induced chondrogenesis. Journal of Orthopaedic Surgery 27: 1-8.

Retrospective case series (single centre)

n=15

Median 5 years

A statistically significant increase in mean IKDC score was seen at follow up and 73% of people reported a return to their previous level of sporting activities.

Larger, prospective studies were included. This study was included in the Migliorini 2022a and 2022b meta-analyses in the key evidence.

Guérin G, Pujol N (2020). Repair of large condylar osteochondral defects of the knee by collagen scaffold. Minimum two-year outcomes. Orthopaedics & Traumatology 106: 475-479.

Retrospective case series (single centre)

n=17

Mean follow-up 46 months

At follow-up, incomplete scaffold healing was seen on MOCART (MRI assessment of cartilage healing) in 21% of people. This did not correlate with subjective clinical assessment (KOOS, IKDC) scores. The authors suggest that MOCART is difficult to interpret in the medium term and long-term studies are needed to see if the functional subjective scores are stable over time.

Larger, prospective studies were included in the key evidence.

Hoburg A, Leitsch JM, Diedrichs G, et al (2018). Treatment of osteochondral defects with a combination of bone grafting and AMIC technique. Archives of Orthopaedic and Trauma Surgery 138: 1117-1126.

Case series

n=15

Mean follow-up 49 months

Osteochondral defects of the knee were treated with a combined bone-grafting and AMIC procedure in this study. All functional scores (IKDC, KOOS, Lysholm) and pain significantly improved during follow-up. The physical subscale of the sf-36 showed improvement and the mental health subscale remained stable. Imaging showed mean MOCART was 77 at final follow-up; 21% of lesions had incomplete integration and 36% had incomplete filling.

This study was included in the meta-analysis by Tan (2023) in the key evidence. Larger studies were included in the key evidence.

Jaramillo Quiceno GA, Sarmiento Riveros PA, Ochoa Perea GA, et al (2023). Satisfactory clinical outcomes with autologous matrix-induced chondrogenesis in the treatment of grade IV chondral injuries of the knee. Journal of ISAKOS 8: 86-93.

Retrospective case series

n=50

Follow-up 32 months

Average patient-reported level of satisfaction after the procedure was 8 out of 10 (SD 1.5). The overall score and symptoms and sports activities subscales of the IKDC score statistically significantly improved from baseline at 12, 24 and 32 months. Function and activity of daily living was not statistically significantly improved at 12 months, but was at 24 and 32 months.

Larger, prospective studies with more clinical outcomes were included in the key evidence.

Kaiser N, Jakob RP, Pagenstert G, et al (2021). Stable clinical long term results after AMIC in the aligned knee. Archives of Orthopaedic and Trauma Surgery 141: 1845- 1854.

Retrospective case series

n=33

Mean follow-up 9.3 years

Compared with baseline, there was statistically significant improvement in VAS and Lysholm scores at 2 years, which were maintained at last follow-up (mean 9 years). This was consistent across subgroups of lesions in different sites. Two of 33 people had total knee prosthesis. The authors conclude that durable results were seen.

This study was included in the Tan (2023) meta-analysis in the key evidence.

Karpinski K, Häner M, Bierke S, Peterson W, (2021). Matrix‑induced chondrogenesis is a valid and safe cartilage repair option for small‑ to medium‑sized cartilage defects of the knee: a systematic review. Knee Surgery, Sports Traumatology, Arthroscopy 29:4213-4222.

Systematic review of RCTs

n=136 (n=5 publications about 4 RCTs)

Up to 5 years

RCTs showed good comparative effectiveness and safety with other treatment options for small to medium-sized cartilage defects in the knee. The authors conclude the procedure is a good alternative to offer.

Larger, more recent systematic reviews with meta-analyses were included in the key evidence. Three of 4 RCTs in this review were included in other meta-analyses in Table 2.

Kim MS, Koh IJ, Choi YJ, Pak KH, In Y. (2017). Collagen augmentation improves the quality of cartilage repair after microfracture in patients undergoing high tibial osteotomy: A randomized controlled trial. Am J Sports Med 45: 1845-1855.

RCT

n=28 (n=14 microfracture only, n=14 microfracture plus scaffold).

Follow-up 1 year

All people in this study were also having high tibial osteotomy. Statistically significant clinical improvements (VAS, KOOS, IKDC, Tegner) were seen in both groups, and there were no between group differences (p> 0.1). The scaffold group had superior imaging outcomes compared with microfracture alone. The authors report longer follow up is needed to see if the difference in tissue repair affects clinical outcomes in the longer term.

Larger RCTs with longer follow-up were included.

Kim SJ, Shetty AA, Kurian NM, et al (2020). Articular cartilage repair using autologous collagen‑induced chondrogenesis (ACIC): a pragmatic and cost‑effective enhancement of a traditional technique. Knee Surgery, Sports Traumatology, Arthroscopy 28: 2598-2603.

Prospective case series (single centre)

n=30

Follow-up up to 6 years

An atelocollagen (gel) scaffold was injected after microfracture. Statistically and clinically significant improvement was seen in 2 years and sustained at 6 years, on Lysholm, KOOS and IKDC scores. Average MOCART score was 79 (SD 10). The authors conclude this can be used for moderate to severe chondral lesions.

Larger studies with comparative data were included in the key evidence.

Kon E, Di Matteo B, Verdonk P, et al (2021). Aragonite-based scaffold for the treatment of joint surface lesions in mild to moderate osteoarthritic knees: results of a 2-year multicenter prospective study. Am J Sports Med, 49: 588-598.

Prospective case series

n=86

Follow-up24 months

All clinical outcome scores improved significantly from baseline, at 12 and 24 months (KOOS, IKDC). The MRI imaging showed increasing defect filling over time. Revision surgery was needed in 9% of people. The authors conclude using the aragonite scaffold in mild to moderate lesions in OA knees was promising.

Randomised evidence with larger sample of this procedure is included in the key evidence.

Krych AJ, Nawabi DH, Farshad-Amacker NA, et al (2015). Bone Marrow Concentrate Improves Early Cartilage Phase Maturation of a Scaffold Plug in the Knee.

Single centre comparative cohort

n=46 (n=11 in the scaffold only arm)

Follow-up 12 months

Compared with a cell-free scaffold with no supplement, those supplemented with platelet rich plasma or bone marrow aspirate concentrate had statistically superior cartilage fill at 12 months. There was no statistically significant difference in quantitative assessment that graded cartilage morphology between the platelet rich plasma and scaffold only group, but the bone marrow aspirate concentrate group had statistically superior scores at 12 months.

Larger prospective studies with patient reported outcomes and longer follow-up were included in the key evidence.

Lahner M, Ull C, Hagen M et al (2018). Cartilage Surgery in Overweight Patients: Clinical and MRI Results after the Autologous Matrix-Induced Chondrogenesis Procedure. BioMed Research International 2018: 6363245.

Prospective case series (single centre)

n=9

Mean follow-up 15 months

This study focused on outcomes for the procedure in people with overweight. VAS and Lysholm scores both statistically significantly improved after the procedure. Two lesions had to be reoperated on because of persisting knee pain. The authors indicated that success rate is reduced in this procedure when used in people with high BMI.

This stidy was included in the meta-analyses by Migliorini (2022a, 2022b) and Kim (2023). Larger studies with longer follow-ups in less specific patient groups were included in the key evidence.

di Martino A, Kon E, Perdisa F et al (2015). Surgical treatment of early knee osteoarthritis with a cell-free osteochondral scaffold: results at 24 months of follow-up. Injury 46: s33-38.

Prospective case series

n=23

Follow-up 24 months

Statistically significant improvements were seen at 12 months and maintained at 24 months on IKDC, and Tegner scores. Activity level was significantly lower than pre-injury. The authors conclude it is a promising option for early osteoarthritic lesions which have failed conservative management, especially for younger people.

Larger studies with longer follow-up were included in the key evidence.

McDermott I (2019). Patellar chondral defect treatment with a cell-free polyglycolic acid–hyaluronan-based implant and platelet-rich fibrin glue after previously failed microfracture. SAGE Open Medical Case Reports 7: 1-4.

Case study

n=1

Follow up 9 months

A person with patellofemoral full-thickness defect had previously failed multiple surgeries including microfracture. After microfracture with biocompatible resorbable polyglycolic acid–hyaluronan scaffold implant, MRI showed complete cartilage filling at 6 months. This was confirmed with arthroscopy at 9 months.

Larger studies were included in the key evidence.

Methot S, Changoor A, Tran-Khanh N, Hoemann CD, Stanish WD, Restrepo A, Shive MS, Buschmann MD (2016). Osteochondral biopsy analysis demonstrates that BST-CarGel treatment improves structural and cellular characteristics of cartilage repair tissue compared with microfracture. Cartilage 7:16–28.

Secondary analysis of additional RCT data

n=38 (n=21 scaffold group; n=17 microfracture only)

Average follow-up 13 months

This study analysed additional data from an RCT published in 2013. The focus was histological assessment of the repair tissue. The authors conclude that use of the scaffold alongside microfracture resulted in better repair tissue (structural and cellular characteristics).

Studies with patient reported outcomes at longer follow-up points were included in the key evidence.

Migliorini F, Eschweiler J, Maffulli N, et al (2021b). Autologous Matrix-Induced Chondrogenesis (AMIC) and microfractures for Focal Chondral Defects of the Knee: A Medium-Term Comparative Study. Life 11: 183.

Non-randomised comparative study (single institution)

n=91

Mean follow-up 42 months

On average, people who had AMIC had a statistically significant greater IKDC, Lysholm, Tegner and VAS score at follow-up, and a lower rate of failure and revision surgery. There was no statistically significant difference in the magnetic resonance observation of cartilage repair tissue score, or the rate of arthroplasty. No delamination or hypertrophy were detected.

Larger, prospective studies were included in the key evidence. This study was also included in the meta-analysis by Migliorini et al (2022b) in the key evidence.

Migliorini F, Eschweiler J, Maffulli N, et al (2021c). Management of Patellar Chondral Defects with Autologous Matrix Induced Chondrogenesis (AMIC) Compared to microfractures: A Four Years Follow-Up Clinical Trial. Life 11: 141.

Non-randomised comparative study (single institution)

n=38 (n=28 AMIC, n=11 microfracture)

Mean follow-up 45 months

This sub-study of Migliorini et al (2021a) focused on outcomes in patellar facet joints. At the last follow-up, people who had AMIC had a statistically significant greater IKDC, Tegner and Lysholm score, and lower VAS than people who had microfracture alone. No statistically significant difference was found in the radiographic findings, or rates of complication (revision, arthroplasty, delamination, hypertrophy). Failure rate was lower in people who had AMIC.

This is a likely a sub-group of the sample reported in Migliorini et al (2021a). This study was also included in the meta-analysis by Migliorini et al (2022b) in the key evidence.

Mitrousias V, Chalatsis G, Mylonas T et al (2023). Satisfactory patient-reported outcomes in patients treated with impaction bone grafting and autologous matrix-induced chondrogenesis for osteochondral knee defects. Knee surgery, sports traumatology, arthroscopy 31: 5698-5706.

Retrospective case series

n=25

Mean follow-up 3.8 years

AMIC was combined with impaction bone grafting in this procedure. At follow-up, quality of life (EQ-5D) all functional scores (IKDC, KOOS, Lysholm) had significantly improved with all patient reported outcomes at least a minimally clinically important difference, except for the sports subscale of KOS. Mean Tegner scores reached pre-injury scores and the patient-assessed acceptable symptom state was 100% positive. Mean MOCART was 53.

Larger, prospective studies of more standard procedures were included in the key evidence.

Miyahira MKC, Novaretti JV, Astur DC, et al (2020). Larger Chondral Lesions Treated with Collagen Membrane – Matrix-Induced Autologous Chondrogenesis – Show Larger Increase in Clinical Scores. Rev Bras Ortop 56: 333-339.

Single-centre case series

n=15

Follow-up 12 months

There was statistically significant improvement in Lysholm and IKDC scores after 12 months. Average MOCART score was 65 points. The greatest benefit was observed in larger lesions.

This study was included in the meta-analyses by Miyahara (2022a) and Kim 2023). Larger, prospective studies with longer follow-up were included in the key evidence.

Perdisa F, Filardo G, Sessa A et al (2017). One-Step Treatment for Patellar Cartilage Defects With a Cell-Free Osteochondral Scaffold: A Prospective Clinical and MRI Evaluation. Am J Sports Med 45: 1581-1588.

Prospective case series (single centre)

n=34

Follow-up 24 months

This study focused on patellar cartilage lesions. Post-operative scores on the IKDC and Tegner outcomes were statistically significantly improved compared with baseline at 12 and 24 months. MOCART assessment found that 87% of lesions showed complete cartilage filling at 24 months; 96% showed complete integration of the scaffold and 70% showed intact repair tissue surface at final follow-up.

Larger studies with more patient reported outcomes and longer follow-up were included in the key evidence.

Pipino G, Risitano S, Alviano F, Wu EJ, Bonsi L, Vaccarisi DC, Indelli PF (2019) microfractures and hydrogel scaffolds in the treatment of osteochondral knee defects: a clinical and histological evaluation. J Clin Orthop Trauma 10:67–75.

Non-randomised comparative study

n=69 (n=46 had microfracture plus injectable hydrogel scaffold; n=23 had microfracture alone).

Follow-up 24 months

Microfracture plus hydrogel was assessed at 6, 12 and 24 months and compared with matched control group who had microfractures alone. Significant short-term improvements in pain, stiffness and function were seen when compared with patients having microfractures alone.

Randomised studies and studies with longer follow-up were included in the key evidence.

Roessler PP, Pfister B, Gesslein M, et al (2015). Short-term follow up after implantation of a cell-free collagen type I matrix for the treatment of large cartilage defects of the knee. International Orthopaedics (SICOT) 39: 2473-2479.

Prospective case series (single centre)

n=28

Follow-up 24 months

Within 6 weeks, there was a statistically significant reduction in VAS (pain) compared with preprocedure. Significant improvements in all other outcomes (IKDC, Tegner, KOOS) except the symptoms subscale of the KOOS were seen at 12 months and maintained at 24 months. At 24 months, radiographic imaging showed that 24 of 28 people had complete defect filling.

Larger, comparative studies with longer follow-up were included in the key evidence.

Rosa F, Fernander JC, Delisle J et al (2022). Clinical and quality-of-life outcomes of a combined synthetic scaffold and autogenous tissue graft procedure for articular cartilage repair in the knee. Journal of orthopaedic surgery and research 17: 112.

Case series

n=60 people

Follow-up 24 months

In this single step procedure, autologous cartilage was grafted into the lesion site with a synthetic scaffold after microfracture. Significant improvements in IKDC, quality of life (physical and mental domains), and VAS were seen.

Larger, comparative studies with longer follow-up were included in the key evidence.

Sadlik B, Puszkarz M, Kosmalska L & Wiewiorski M (2017). All-Arthroscopic Autologous Matrix-Induced Chondrogenesis-Aided Repair of a Patellar Cartilage Defect Using Dry Arthroscopy and a Retraction System. J Knee Surg 30: 925-929.

Case series (single centre)

n=12

Mean follow-up 38 months

This study described arthroscopic method of doing the AMIC procedure. A statistically significant increase in mean KOOS and IKDC scores and decreased in VAS scores was seen postprocedure. Mean MOCART at follow-up was 58.3 points. The authors state that the arthroscopic method of doing the procedure is promising but requires confirmation with comparative evidence.

This study was included in the study by Lim (2020a) and Tan (2023). Larger, prospective studies with longer follow-up were included in the key evidence.

Schagemann J, Behrens P, Paech A, et al (2018). Mid-term outcome of arthroscopic AMIC for the treatment of articular cartilage defects in the knee joint is equivalent to mini-open procedures. Archives of orthopaedic and trauma surgery 138: 819- 825.

Retrospective case series

n=50

Follow-up 2 years

This study compared outcomes between people who had arthroscopic and open surgery for the AMIC procedure. The findings show statistically significant improvement in VAS, KOOS and Lysholm scores 2 years after surgery compared with baseline. There were no statistically significant differences in outcomes between the surgical approaches.

This study was included in the meta-analyses by Kim (2020a), Tan (2023) and Migliorini (2022a, 2022b). Larger, prospective studies with longer follow-up were included in the key evidence.

Schiavone Panni A, Del Regno C, Mazzitelli G et al (2018). Good clinical results with autologous matrix-induced chondrogenesis (Amic) technique in large knee chondral defects. Knee surgery, sports traumatology, arthroscopy 26: 1130-1136.

Retrospective case series

n=21

Median follow-up 7 years

A statistically significant improvement in IKDC and Lysholm scores was seen at last follow up. 76% of people rated they were satisfied or extremely satisfied with their outcomes. 67% showed good quality tissue on MRI imaging. The authors conclude that AMIC is effective for full thickness defects greater than 2cm².

This study was included in the meta-analysis by Kim (2020a), Tan (2023), da Cunha (2020) and Migliorini (2022a, 2022b). Larger, prospective studies were included in the key evidence.

Schneider U. (2016). Controlled, randomized multicenter study to compare compatibility and safety of ChondroFiller liquid (cell free 2-component collagen gel) with microfracturing of patients with focal cartilage defects of the knee joint. J Ortop Surg 1: 1-8.

RCT

n=23 (n=13 scaffold, n=10 microfracture)

Follow-up 1 year

6 of 10 people in the microfracture group refused the allocated treatment so were not analysed. Statistically significant improvements in IKDC were seen by month 3 and 6 and maintained at 1 year. The authors report good filling of the lesion.

Higher quality RCTs with longer follow up and more people were included.

Schüttler KF, Götschenberg A, Klasan A et al (2019). Cell-free cartilage repair in large defects of the knee: increased failure rate 5 years after implantation of a collagen type I scaffold. Archives of Orthopaedic and Trauma Surgery 139: 99-106.

Prospective case series

n=28

Follow up 5 years

Good to excellent clinical results were seen in 82% of people, according to KOOSM, IKDC, VAS and Tegner outcomes. Revision surgery was needed in 18%. Repair tissue showed cartilage-like appearance but medium tissue quality, which reduced in MOCART score between 2 and 5 years.

Larger studies were included in the key evidence.

Sciaretta FV, Ascani C, Sodano L et al (2023). One-stage cartilage repair using the autologous matrix-induced chondrogenesis combined with simultaneous use of autologous adipose tissue graft and adipose tissue mesenchymal cells technique: clinical results and magnetic resonance imaging evaluation at five-year follow-up. International Orthopaedics 48@ 267-277.

Prospective case series

n=18

Follow-up 60 months

AMIC was combined with autologous adipose tissue graft and adipose mesenchymal cells in this procedure. In grade 3 to 4 lesions, statistically significant increases were seen in IKDC, Lysholm score between baseline and 2 years, which was maintained at last follow up. The authors conclude these outcomes are superior to those seen in AMIC alone.

Larger, comparative studies with more standard procedures were included in the key evidence.

Sessa A, Andriolo L, Di Martino A, et al. (2019). Cell-free osteochondral scaffold for the treatment of focal articular cartilage defects in early knee OA: 5 years' follow-up results. J Clin Med 14: e1978.

Prospective case series

n=22

Follow-up 60 months

All outcomes (IKDC subjective and objective, Tegner) improved at 2 years compared with baseline and remained stable at final follow-up. There were no major adverse events. Minor adverse events included joint stiffness. There was a 16.6% failure rate.

Larger prospective studies with similar follow-up were included in the key evidence.

Shaikh N, Seak MKT, & Khan WS (2017). Systematic review on the use of autologous matrix-induced chondrogenesis for the repair of articular cartilage defects in patients. World J Orthop 8: 588-601.

Systematic review

n=16 studies

Mean follow-up 30 months

The authors conclude that despite improvements on patient reported outcomes in the short term, they required more evidence to understand the long-term effects. They also noted that conclusions could not be drawn about whether the size of the defect, the location and other patient factors affected the outcome.

More recent systematic reviews with meta-analyses were included in the key evidence.

Shanmugaraj A, Coughlin RP, Kuper GN et al (2019). Changing trends in the use of cartilage restoration techniques for the patellofemoral joint: a systematic review. Knee Surgery, Sports Traumatology, Arthroscopy 27: 854-867.

Systematic review

n=71 people in 6 studies (n=28 studies in the review in total)

Follow up was between 24 and 38 months in 4 studies and not reported in 2.

This systematic review included studies focused on the patellofemoral joint. Three of 4 studies that reported VAS outcomes showed statistically significant improvements, 2 of 2 studies reporting IKDC outcomes showed a statistically significant improvement and 2 of 3 studies reporting KOOS outcomes showed a significant improvement.

More recent systematic reviews with meta-analyses and less restrictive populations were included in the key evidence.

Shetty AA, Kim SJ, Shetty V, et al (2016). Autologous collagen induced chondrogenesis (ACIC: Shetty–Kim technique) – A matrix based acellular single stage arthroscopic cartilage repair technique. Journal of Clinical Orthopaedics and Trauma 7: 164-169.

Case series (single centre)

n=30

Follow-up 4 years

A gel scaffold was applied to defects in this study. At 4 years, the Lysholm score, KOOS and IKDC had significantly improved. Average MOCART score was 72.

Larger studies with more methodological detail on data collection and analysis were included in the key evidence.

Shivji FS, Mumith A, Yasen S et al (2020). Treatment of focal chondral lesions in the knee using a synthetic scaffold plug: Long-term clinical and radiological results. Journal of Orthopaedics 20: 12-16

Retrospective case series (single centre)

n=11

Mean follow-up for n=6 people 121 months

This study did not recommend using the TruFit plug in full-thickness lesions because of high conversion rate to arthroplasty and failure of plug incorporation and limited evidence of chondral surface regeneration. There was no statistically significant improvement in Oxford Knee Score, Tegner or Lysholm scores or radiological findings.

Larger, prospective studies with more complete follow-up data were included in the key evidence. This device is no longer in use in the UK.

Snow M, Middleton L, Mehta S, et al (2023). A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee. The American Journal of Sports Medicine: 1-12.

RCT

n=390 (ACI compared with alternative management, which included n=50 AMIC)

Follow-up 1 year

This RCT compared autologous cell implants with alternative cartilage management, including AMIC. A subgroup analysis of the 'alternative management' group found that patient reported functioning on the Lysholm knee scoring scale was not significantly different from matrix-induced-ACI; mean difference=1.7 (95%CI -5.5 to 9).

Only a small subgroup analysis of data on the AMIC group was reported in this RCT.

Sofu H, Camurcu Y, Ucpunar H, Ozcan S, Yurten H, Sahin V. (2019). Clinical and radiographic outcomes of chitosan-glycerol phosphate/blood implant are similar with hyaluronic acid-based cell-free scaffold in the treatment of focal osteochondral lesions of the knee joint. Knee Surg Sports Traumatol Arthrosc.27: 773-781.

Comparative case series

n=46 (n=25 people had microfracture with chitosan-glycerol phosphate/blood implant; n=21 has microfracture plus hyaluronic acid-based scaffold).

Mean follow-up 24 months

There were no significant differences between groups at any time interval during the follow-up. Only for those with small lesions was the chitosan-glycerol phosphate/blood group superior to larger lesions in the same group. The authors conclude the hyaluronic acid scaffold group was less sensitive to lesion size, but for small lesions there are some benefits for the comparator procedure.

This study was included in the meta-analysis by da Cunha (2020). Larger studies with longer follow-up were included.

Sofu H, Kockara N, Oner A, Camurcu Y, Issın A & Sahin V (2017). Results of Hyaluronic Acid-Based Cell-Free Scaffold Application in Combination with microfracture for the Treatment of Osteochondral Lesions of the Knee: 2-Year Comparative Study. Arthroscopy 33: 209-216.

Comparative case series

n=43 (n=19 hyaluronic scaffold plus microfracture, n=23 microfracture alone)

Mean follow-up 26 months

At 12 and 24 months postprocedure, the microfracture plus scaffold groups has statistically significant improvements compared with microfracture alone on the VAS and Lysholm scores. They also had better activity level (Tegner score) at 24 months and faster return to non-impact sports. Complete repair of cartilage was 37% compared with 17%. The authors conclude with uncertainty about the clinical significance of these differences.

Larger prospective studies with longer follow up were included.

Šprláková-Puková A, Štouračová A, Repko et al (2021). Prospective Multiparametric Magnetic Resonance Monitoring of Changes in Lesions of Hyaline Cartilage of the Knee Joint After Treatment by microfractures and Implantation of Biological Collagen Type I Matrix Implants. Academic Radiology 28: 1133-1141.

Prospective comparative study

n=25 (n=14 scaffold insertion; n=11 microfracture alone)

Follow-up 18 months

This study used imaging techniques to compare AMIC and microfracture outcomes. No statistically significant differences were seen in glycosaminoglycans chains at 6, 12, 18 months. The greatest decrease in this indicator of cartilage changes was in the AMIC group at 12 months. The authors conclude that there was no difference in MRI-detectable outcomes between groups but it may take longer than was observed in this study to see a difference.

Larger, prospective studies with longer follow-up and patient reported outcomes were included.

Steinwachs M, Cavalcanti N, Reddy SMV et al (2019). Arthroscopic and open treatment of cartilage lesions with BST-CARGEL scaffold and microfracture: A cohort study of consecutive patients. The Knee 26: 174-184.

Retrospective case series (single centre)

n=91

Mean follow up 6 months

This study assessed outcomes in people who had microfracture followed by a liquid bioscaffold in patellar lesions. No reinterventions were seen. Statistically significant decreases in pain, swelling and increases in radiological healing of the cartilage were seen at follow up. No statistically significant changes were seen for range of motion.

This study was included in the Migliorini et al 2022b meta-analysis. Prospective and comparative studies were included.

Steinwachs MR, Gille J, Volz M, et al (2021). Systematic Review and Meta-Analysis of the Clinical Evidence on the Use of Autologous Matrix-Induced Chondrogenesis in the Knee. Cartilage 13: 42-56.

Systematic review and meta-analysis

n=375 (n=12 studies)

137 people had greater than 4 years of follow-up data; minimum of 1 year follow-up was required for inclusion.

Meta-analysis showed clinically significant improvement in pain on the VAS from baseline to follow-up at 1 to 2 years after the procedure. This remained significant after 3 years. Lysholm and IKDC scores were also significantly improved after 1 and maintained at 3 years.

Larger and more recent systematic reviews were included.

Tradati D, de Luca P, Maione A et al (2020). AMIC—Autologous Matrix-Induced Chondrogenesis Technique in Patellar Cartilage Defects Treatment: A Retrospective Study with a Mid-Term Follow-Up. Journal of Clinical Medicine 9:1184.

Retrospective case series

n=14

Mean follow-up 69 months

In people with patellofemoral lesions at 12 months, Kujala, IKDC, and VAS scores significantly increased compared with pre-procedure. This effect was maintained at final follow-up. Patient satisfaction was good or excellent in 100% of people.

Larger, prospective studies were included. This study was included in the meta-analysis by Migliorini (2022a) and Tan (2023)

Volz M, Schaumburger J, Frick H et al (2017). A randomized controlled trial demonstrating sustained benefit of Autologous Matrix-Induced Chondrogenesis

over microfracture at five years. International Orthopaedics (SICOT) 41: 797-804.

Multicentre RCT

n=47 (n=13 microfracture only, n=17 autologous matrix induced chondrogenesis (glued), n=17 autologous matrix induced chondrogenesis sutured)

Follow-up 5 years

Whilet the microfracture only group saw an improvement in functional outcomes (modifified Cincinnati score, modified ICRS score, VAS) over the first 2 years, there was a subsequent decline up to 5 years, the autologous matrix induced chondrogenesis groups improved and sustained improvements up to 5 years. MRI examination of defect filling showed superiority in the autologous matrix induced chondrogenesis groups. No serious adverse events related to the procedure were recorded.

This RCT was included in the meta-analyses by Migliorini (2021a, 2022a, 2022b), Kim (2020a) and Tan (2023) that was included in the key evidence.

Waltenspül M, Suter C, Ackermann J et al (2021). Autologous Matrix-Induced Chondrogenesis (AMIC) for Isolated Retropatellar Cartilage Lesions: Outcome after a Follow-Up of Minimum 2 Years. Cartilage 13:1280-1290.

Retrospective case series (single centre)

n=31

Mean 4.1 years

The procedure failed in 13% of people at an average of 21 months. 77% of people reported a satisfactory result but only 35% returned to their previous level of sport. Almost all procedures were performed at the same time as corrective surgery for instability.

This was included in the meta-analysis by Migliorini (2022a) in the key evidence. Larger, prospective studies with longer follow ups were included.

Wang D, Nawabi DH, Krych AJ et al (2021). Synthetic Biphasic Scaffolds versus microfracture for Articular Cartilage Defects of the Knee: A Retrospective Comparative Study. Cartilage 13: 1002S-1013S.

Retrospective case series

n=132 (n=66 scaffold, n=66 microfracture only)

Follow-up 5 years

Both groups had clinically significant improvements in clinical outcomes over 5 years. There were no significant differences between groups at 5 years on the KOS-acitivities of daily living and IKDC scores. Marx activity level scores declined in the microfracture only group but significant improvements were seen in the scaffold group. MRI appearance was superior in the longer term for the scaffold group.

Prospective studies and randomised studies were included.

Wolf MT, Zhang H, Sharma B, Marcus NA, Pietzner U, Fickert S, et al. (2018). Two year follow-up and remodeling kinetics of ChonDux hydrogel for full thickness cartilage defect repair in the knee. Cartilage.11: 447-457.

Single arm trial

n=18

Follow-up 24 months

A hydrogel scaffold in combination with microfracture was used in people with full-thickness lesions. Durable tissue restoration over 24 months was seen, with final percent fill of 94% (SD 16%). VAS pain scores reduced between 1 and 6 weeks and IKDC scores significantly improved by approximately 30 points over 24 months. The authors conclude this is a safe adjunct to microfracture.

This study was included in the meta-analysis by da Cunha (2020) in the key evidence. Larger studies with longer follow up were included.

Wylie JD, Hartley MK, Kapron AL et al (2016). Failures and reoperations after matrix assisted cartilage repair of the knee: A systematic review. The Journal of Arthroscopic and Related Research 32: 386-392.

Systematic review

n=6 AMIC studies with 163 people (n=66 in total)

Follow-up reported at a minimum of 5 years.

Among the evidence aggregated from 163 people, there were 15 reoperations (9%) that included 4 treatment failures (2%), 9 manipulations under anaesthesia (6%), and 2 debridements for graft hypertrophy (1%).

More recent systematic reviews and long-term studies were included.

Zamborsky & Danisovic L (2020). Surgical Techniques for Knee Cartilage Repair: An Updated Large-Scale Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Arthroscopy: The Journal of Arthroscopic and Related Surgery 36: 845-858.

Systematic review and network meta-analysis

n=891 people in n=21 articles (only n=1 RCT examining AMIC with 34 people was included)

Follow-up of studies in the meta-analysis ranged from 12 months to 15 years.

Evidence for the glued AMIC arm of the Volz (2017) RCT was entered into a network meta-analysis with other surgical techniques for knee cartilage repair. Compared with microfracture alone (direct comparison) and indirect comparison with matrix induced-ACI, AMIC was better for reintervention rates.

Meta-analyses with more data and focus on AMIC were included. The RCT included in this study was also included in other meta-analyses and in the main evidence.