Evidence summary

Population and studies description

This interventional procedures overview is based on about 7,000 people from 5 systematic review and meta-analyses (Migliorini 2022a, Kim 2020a, Migliorini 2022b, Tan 2023, da Cunha 2020), a systematic review and network meta-analysis (Migliorini 2021a), 4 RCTs (Altschuler 2023, Kim 2020b, Kon 2018, de Girolamo 2019), a 5-year follow-up analysis of an RCT (Shive 2015) and a registry study with up to 7-year follow up (Gille 2021). There was significant overlap between the studies included in the meta-analyses. The RCT of 24 people (de Girolamo 2019) was included in 4 meta-analyses, the 5-year follow up of an RCT (Shive 2015) was included in 1 meta-analysis and the registry study (Gille 2021) was included in 2 meta-analyses. Among the RCTs listed, about 328 of 535 people had the procedure. This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 12 studies as the key evidence in table 2 and table 3, and lists 69 other relevant studies in table 5.

The key evidence includes explicit comparisons between the procedure and several other procedures that can be used for this indication, or between different methods of doing the procedure. This is the reason for including several meta-analyses even if some or all studies overlap. The meta-analysis of 18 studies (Migliorini 2022a) and the meta-analysis of 29 studies (Kim 2020a) both compared the procedure with microfracture, but only 5 studies overlapped between these reviews. This may be because there were subtle differences in the inclusion criteria for these reviews. The meta-analysis by Migliorini (2022b) compared the procedure with mACI. The network meta-analysis compared using a scaffold without cultured cell implantation after microfracture with microfracture alone, ACI, mACI and OAT (Migliorini 2021a) but only included 5 studies with this procedure because of the requirement for level 1 or 2 evidence. The meta-analysis by Tan (2023) compared outcomes between the procedure being done with open surgery or with an arthroscopic approach. The meta-analysis of 10 studies by da Cunha (2020) is not comparative but includes 3 studies that were not included in any of the other meta-analyses. This is the only meta-analysis that calls the procedure 'enhanced microfracture' and not 'autologous matrix-induced chondrogenesis', but all studies do use a scaffold. This is discussed in more detail in the procedure details section.

Other inclusion criteria relating to the characteristics of the defect varied between studies. Some studies excluded multiple lesions that were touching or in different locations, lesions over a certain size, or whether the person was having concomitant surgeries such as high tibial osteotomy or other surgical management. The meta-analysis comparing arthroscopic with open surgery for this procedure (Tan 2023), the RCTs of 251 people (Altschuler 2023) and 24 people (de Girolamo 2019), and the registry study (Gille 2021) only included grade 3 or higher lesions. Two RCTs only included people if they had a certain level of pain (Altschuler 2023 and Shive 2015). The meta-analysis by da Cunha (2020) primarily focused on tibiofemoral lesions but did include some other lesions in other locations. Some studies excluded people with OA, some only excluded if they had advanced OA and some did not exclude OA.

Some meta-analyses explicitly excluded studies if the procedure was augmented with other substances. It is likely some meta-analyses excluded studies if they did not indicate that bone marrow stimulation happened. More detail is in the procedure details section.

The evidence includes research done in many countries; it is likely that only 3 studies had data from a single country. No study included evidence mostly or entirely from the UK. The network meta-analysis only included level 1 or 2 comparative evidence (Miglionini 2021a), but the other meta-analyses included studies with other research designs.

More men or males than women or females were included in most of the studies and most reported mean lesion size was between 3.0 and 4.0 cm². Kim (2020b) reported that 67% of people were female. The mean lesion size was between 4.0 and 4.7 cm². In the RCT follow-up study by Shive (2015), the mean lesion size was between 2.1 and 2.4 cm².

Follow up was 2 years in 3 of the RCTs (Altschuler 2023, Kim 2020b, Kon 2018), 100 months in the RCT of 24 people (de Girolamo 2019), 5 years in the RCT follow-up study (Shive 2015) and up to 7 years in the registry study (Gille 2021). Mean follow up was about 3 years in the meta-analyses; da Cunha (2020) reported a maximum follow up of 84 months. Table 2 presents study details.

Figure 1 Flow chart of study selection

**Table 2 Study details**
Study no.	First author, date country	Patient characteristics	Age (years)	Study design	Inclusion criteria	Intervention	Follow up
1	Migliorini, 2022a The countries where the included studies were done was not reported. The search strategy included studies written in English, German, Italian, French and Spanish.	n=548 people in 18 studies 67% male; 33% female Mean defect size 3.2 cm² (SD 1) Mean BMI 27 kg per m² (SD 1.3)	Mean 27 (SD 6)	Systematic review and meta-analysis comparing microfracture and scaffold with microfracture for focal chondral knee defects. Searches were done in January 2022.	Peer-reviewed publications of level 1 to 4 clinical trials investigating microfracture with scaffold or microfracture with scaffold compared with microfracture for focal chondral defects in the knee. Studies reporting findings from lesions in multiple locations or kissing lesions, or data on revision settings were excluded, as well as studies with missing data in the outcomes of interest.	Microfracture with scaffold compared with microfracture alone (technologies in the scaffold arm were mixed although their names were not reported). Rehabilitation protocols of the included studies were not reported.	Mean 40 months (SD 27 months)
2	Kim, 2020a The countries where the included studies were done was not reported.	n=966 knees in 29 studies Aggregate males: females was not reported Mean lesion size in the scaffold group 3.5 cm², mean lesion size in the microfracture only group 3.3 cm²	Mean in the microfracture with scaffold group 36.1 Mean in the microfracture only group 35.7	Systematic review and meta-analysis comparing microfracture with scaffold with microfracture only for cartilage repair in the knee after a minimum of 2 years of follow up. Searches were done in June 2019.	Studies that included people who had microfracture with scaffold or microfracture alone for cartilage defect in the knee and reported clinical or cartilage repair outcomes at 2 or more years of follow up were eligible. Studies were excluded if outcome reporting was incomplete, if people had concomitant high tibial osteotomy or greater than 10-year follow up.	Microfracture with scaffold (Chondro-Gide, Geistlich Pharma AG; Chondrotissue, BioTissue AG) compared with microfracture. Mixed rehabilitation protocols were reported in Table 2 of the publication. The authors did not comment on the effect of this on the findings.	Mean follow up in the scaffold group 38 months Mean follow up in the microfracture only group 53 months
3	Migliorini, 2022b The countries where the included studies were done was not reported. The search strategy included studies written in English, German, Italian, French and Spanish.	n=1,667 people in 47 studies 64% men; 36% women Mean defect size 3.9 cm² (SD 1.2) Mean BMI 25.5 kg per m² (SD 1.6)	Mean 35 (SD 7)	Systematic review and meta-analysis of studies comparing microfracture with scaffold with mACI. Searches were done in January 2022.	Level 1 to 4 studies reporting the findings of microfracture with scaffold and or mACI procedures for chondral knee defects, with a minimum of 5 people and which used a cell-free bioresorbable membrane. Studies that augmented the procedure with bone marrow concentrate, mesenchymal stem cells or growth factors were excluded. Studies including people with kissing lesions or end-stage OA were excluded. Studies also had to report the length of follow up and data for the outcomes of interest.	Microfracture with scaffold (n=15 studies, 373 people) compared with mACI (n=32 studies, 1,237 people). Rehabilitation protocols of the included studies were not described.	Mean 38 (SD 22) months
4	Migliorini, 2021a The countries where the included studies were done was not reported. The search strategy included studies written in English, German, Italian, French and Spanish.	n=2,210 people in 36 studies 64% male; 36% female Mean defect size 3.7 cm² (SD 1.2) Median BMI 25.3 kg per m²	Median 33.9 (range 30 to 37)	Systematic review and Bayesian network meta-analysis comparing surgical strategies for managing chondral knee defects. Searches were done in July 2021.	Prospective level 1 or 2 clinical evidence comparing 2 or more interventions for chondral knee defects, with at least 12 months of follow up. Studies were excluded if they included people with end-stage OA or kissing lesions, or if data were missing in the outcomes of interest. Procedures augmented with less committed cells (for example, mesenchymal stem cells) were not considered.	The following were compared with one another: microfracture with scaffold (n=5 studies with 103 people), microfracture alone, OAT, ACI, mACI alone. The study reported that a mixture of scaffold technologies were included. Rehabilitation protocols were not reported or commented on.	Median 36 months (IQR 24 to 60)
5	Tan, 2023 Included studies were done in Belgium, Singapore, Germany, Italy, Romania, Brazil, Poland, France and Norway.	n=609 people in 24 studies 62% male; 38% female Mean lesion size 3cm² in both groups Mean BMI 27 kg per m² in the open surgery group; 26 kg per m² in the arthroscopic group	Arthroscopic group mean 38 Open surgery group mean 34	Systematic review and meta-analysis of studies investigating the procedure by open or arthroscopic technique. Searches were done in October 2022.	Clinical studies (RCT, cohort, case control or case series) in adults with tibiofemoral or patellofemoral lesions grade 3 and above. All studies had to include people having the procedure with either open or arthroscopic approach. Studies with incomplete information or with people who had other surgical management, were excluded.	This study compares the open surgery approach (n=18 studies) with the arthroscopic approach (n=5 studies). Scaffolds included BioTissue, Chondrotissue, Chondro-Gide, Hyalofast and CartiFill. Rehabilitation protocols were not reported or commented on.	Arthroscopic group mean 38 months; open surgery group mean 52 months
6	da Cunha, 2020 Countries of the included studies were not reported.	n=331 people in 10 studies 56% male; 44% female Mean defect size=3.2 cm² Weighted mean BMI=25.2 kg per m²	Mean 37	Systematic review and meta-analysis of studies of enhanced microfracture with acellular scaffolds.	Peer-reviewed publications with at least 5 people. Studies had to assess the outcomes of cell-free matrices to primarily treat tibiofemoral full or partial thickness focal defects in skeletally mature people at a minimum of 12 months. Studies including people with degenerative, musculoskeletal disorders or inflammatory disease including OA, or having concomitant cartilage surgery, or surgery on multiple lesions, or reoperations were excluded.	Enhanced microfracture with acellular scaffolds (including BST-CarGel, Chondro-Gide, Hyalofast, ChonDux, CartiFill and Chondrotissue) Rehabilitation protocols were not reported but the authors commented that this was heterogeneous.	Range 12 to 84 months
7	Altschuler, 2023 26 centres across the US, Belgium, Hungary, Israel, Italy, Poland, Romania and Serbia	n=251 (n=167 in scaffold arm; n=84 surgical standard of care arm) 64% and 61% male; 36% and 39% female in the scaffold and surgical standard of care arms, respectively. 59% and 49% had lesions bigger than 3 cm² in the scaffold and surgical standard of care arms, respectively. Mean BMI 26.4 and 27.9 kg per m² in the scaffold and surgical standard of care arms, respectively	Scaffold arm: Mean 42 (SD 11) Surgical standard of care arm: mean 46 (SD 11)	2-arm multicentre RCT with 2:1 randomisation ratio. Recruitment was between September 2017 and November 2019.	People aged 21 to 75 with up to 3 joint surface lesions (grade 3a or above), or on the femoral chondyle or trochlea with total area 1 to 7 cm². People were excluded if: their KOOS pain subscale rating was less than 20 (low) or more than 65 (high), their defect was more than 8 mm deep into the bone, their lesions were in the tibia or patella and grade 4a or higher, they had severe OA or significant instability or lack of remaining meniscus in the index knee, or if the lesion was uncontained, or if the implant could not be positioned with a 2 mm recess of articular cartilage.	Scaffold (Agili-C, Cartiheal Ltd; press-fit into a hole drilled into the subchondral bone) compared with surgical standard of care (arthroscopic debridement, microfracture). Rehabilitation protocol involved partial weightbearing for 4 weeks, building to full weightbearing at 6 weeks. Isometric exercises with electrostimulation immediately after surgery. Cryotherapy with passive motion device for up to 3 weeks. Stationary cycling when knee flexion reached 100 degrees. At about 2 months, most people were advised to use full range of motion. Strengthening training at 3 months.	24 months
8	Kim, 2020b 10 hospitals in South Korea	n=100 (n=52 scaffold group: n=48 microfracture alone) 33% male; 67% female (out of 99) Mean lesion size 4.0 cm² and 4.7 cm² in the scaffold and microfracture groups, respectively. Mean BMI 25 kg per m² in both arms	Mean 49 and 52 in the scaffold and microfracture groups, respectively	2-arm multicentre RCT with 1:1 allocation. Enrolment began in 2013 and the last follow up was in September 2018.	People aged 15 to 65 with knee cartilage defects, misalignment of the tibia and femur or treatment for the misalignment. People were excluded if they had contraindications for the scaffold or glue (history of an autoimmune disease or anaphylactic reaction, sensitivity to transplant or porcine protein, were pregnant or lactating) or previous ligament surgery.	Atelocollagen gel scaffold applied after microfracture, with thrombin and fibrinogen (authors called this collagen-augmented chondrogenesis technique using CartiFill, Sewon Cellontech, Seoul, Korea) compared with microfracture alone. Rehabilitation programme included range of motion daily exercises from day 1. Toe touch ambulation only for up to 4 weeks. Full weightbearing from 6 weeks.	24 months
9	Kon, 2018 Italy, Sweden, Belgium, Switzerland, Austria, Germany, Norway, Poland and South Africa	n=100 completed the study (n=51 scaffold; n=49 bone marrow stimulation) 71% and 63% male: 29% and 37% female in the scaffold and bone marrow stimulation groups, respectively. Mean lesion size 3.4 cm² and 3.5 cm² in the scaffold and bone marrow stimulation groups, respectively. Mean BMI 26 and 25 kg per m² in the scaffold and bone marrow stimulation groups, respectively	Mean 34 and 35 in the scaffold and bone marrow stimulation groups, respectively.	2-arm multicentre RCT with 1:1 allocation. Recruitment was between 2011 and 2013.	People with chondral or osteochondral lesions in the knee.	Bioceramic composite scaffold (MaioRegen, Fin-Ceramica Faenza S.p.A., Italy; press-fit into a hole drilled into the subchondral) compared with bone marrow stimulation. Isometric and isotonic exercises from discharge with electrical neuromuscular stimulation. Weightbearing with crutches at week 4 working toward full weightbearing. Swimming and cycling from week 4 and low active functional training from 4 to 6 months. Joint impact activities from 1 year.	2 years
10	Shive, 2015 26 clinical sites across Canada, Spain and South Korea	n=60 (n=34 scaffold group; n=26 microfracture) 65% and 54% male: 35% and 46% femalein the scaffold and microfracture groups, respectively. Mean lesion size 2.4 cm² and 2.1 cm² in the scaffold and microfracture groups, respectively. Mean BMI 27.6 kg per m² and 25.7 kg per m² in the scaffold and microfracture groups, respectively	Mean 34 and 40 in the scaffold and microfracture groups, respectively	Extended follow-up phase from a 2-arm multicentre RCT with 1:1 allocation. Enrolment to the original RCT began in 2006 and last follow up of the extended study was in February 2014.	People were recruited from the original pool of RCT participants. People were aged 18 to 55 with a single, focal cartilage lesion on the femoral chondyles and had moderate pain (greater than 4 points on the VAS) on entry to the RCT.	Microfracture plus gel scaffold containing chitosan (BST-CarGel, Piramal Life Sciences, Bio-Orthopaedic Division) compared with microfracture alone. Rehabilitation included 6 weeks of no weightbearing and full weight bearing at 8 weeks. Up to 32 physiotherapy sessions over 8 weeks with assisted passive motion. Full impact activity after 12 months.	5 years
11	Gille, 2021 This was a multicentre study in Germany	n=131 80 males; 48 females Mean lesion size 3.4 cm² in males and 3.2 cm² in females Mean BMI=26 kg per m²	Mean 36 in males and 37 in females	Follow up of a previously published multicentre registry study (people enrolled in the 'AMIC registry' between 2003 and 2013). The earlier publications of short and mid-term data were included in the overview when this topic was first assessed by the committee.	People with symptomatic, circumscribed grade 3 or 4 lesions. People were excluded if they had concomitant surgery, advanced OA, significant narrowing of the joint lines, underlying rheumatic disease, total meniscectomy, BMI more than 30, or deviation of the mechanical axis of the affected compartment.	Microfracture and collagen scaffold (Chondro-Gide, Geistlich Pharma) The rehabilitation protocol was not described.	Mean 4.6 years (up to 7 years)
12	de Girolamo, 2019 Italy	n=24 (n=12 scaffold with bone marrow aspirate concentrate, n=12 scaffold only) 58% and 67% male: 42% and 33% female in the scaffold and scaffold with bone marrow aspirate concentrate groups, respectively. Mean lesion size 3.8 and 3.4 cm² in the scaffold and scaffold with bone marrow aspirate concentrate groups, respectively	Mean 30 in both groups.	2-arm single centre RCT with 1:1 allocation. Recruitment was between December 2007 and February 2010.	People aged between 18 and 55 with 1 or 2 grade 3 or 4 tibiofemoral or patellofemoral lesions between 2 and 8 cm²and with normal surrounding cartilage. People with immunomediated knee pathologies, serious cardiac pathologies or other general conditions were excluded.	Microfracture and collagen scaffold group (Chondro-Gide, Geistlich Pharma AG) compared with a microfracture, collagen scaffold (Chondro-Gide, Geistlich Pharma AG) and bone marrow aspirate concentrate group. Rehabilitation protocol was the same for both groups: for condylar chondral defect, immediate full range of motion without any weightbearing for 3 weeks, then full bearing after 6 weeks; for patellar defects, progressively restore full range of motion and bearing within a few days. All were advised to return to sports 4 to 6 months after surgery.	100 months

**Table 3 Study outcomes**
First author, date	Efficacy outcomes	Safety outcomes
Migliorini, 2022a	IKDC (subjective) The authors cite a MCID (the smallest difference on the scale that is considered to represent clinically meaningful change) of 15 out of 100 points for this scale. Compared with baseline (mean follow up 40 months), people who had the scaffold procedure had a statistically significant mean increase of 34 points (out of 100, 95% CI 33 to 35, p<0.001) on the IKDC score. Compared with microfracture (n=3 studies, mean follow up 40 months), people who had the scaffold procedure had a statistically significantly greater IKDC score than people who had microfracture. The weighted mean difference between groups was 11.8 points (95% CI 6.7 to 17.0, p<0.001). VAS (pain) The authors cite a MCID of 2.7 out of 10 points for this scale. Compared with baseline (mean follow up 40 months), people who had the scaffold procedure had a statistically significant mean decrease of 3.9 points (out of 10, 95% CI -3.7 to -4.10, p<0.001) on the VAS scale. Compared with microfracture (n=3 studies, mean follow up 40 months), people who had the scaffold procedure had a statistically significantly lower VAS score than people who had microfracture. The weighted mean difference between groups was -1.0 points (95% CI -0.05 to -2.0, p=0.04). Lysholm score The authors cite a MCID of 10 out of 100 points for this scale. Compared with baseline (mean follow up 40 months), people who had the scaffold procedure had a statistically significant mean increase of 28 points (out of 100, 95% CI 26.9 to 29.1, p<0.001) on the Lysholm score. Tegner score The authors cite a MCID of 0.5 out of 10 points for this scale. Compared with baseline (mean follow up 40 months), people who had the scaffold procedure had a statistically significant mean increase of 0.8 points (out of 10, 95% CI 0.7 to 0.9, p=0.03) on the Tegner scale.	Surgical failure rate The failure rate for people who had the scaffold procedure was 3.8% (9 out of 236 people). Revision rate The revision rate for people who had the scaffold procedure was 4.5% (9 out of 210 people) at a mean of 43.6 months. Meta-analysis showed the OR for revision surgery favoured AMIC, 0.16 (95% CI 0.06 to 0.44, p<0.001, n=6 studies). Hypertrophy At last follow up, no people who had the scaffold procedure had signs of hypertrophy.
Kim, 2020a	IKDC (subjective) After a minimum of 2 years, improvements in IKDC scores were statistically significantly larger in the scaffold group than the microfracture group (p<0.001): Scaffold group mean improvement 45.9 (out of 100, 95% CI 36.2 to 55.5, 4 studies) Microfracture mean 27.2 (out of 100, 95% CI 23.3 to 31.1, 5 studies) VAS (pain) After a minimum of 2 years, improvements in VAS scores were not statistically significantly larger in the scaffold group than the microfracture group (p=0.06): Scaffold group mean improvement 4.8 (out of 10, 95% CI 4.2 to 5.5, 7 studies) Microfracture mean 3.2 (out of 10, 95% CI 1.6 to 4.8, 5 studies) Lysholm score After a minimum of 2 years, improvements in Lysholm scores were not statistically significantly larger in the scaffold group than the microfracture group (p=0.38): Scaffold group mean improvement 33.3 (out of 100, 95% CI 28.3 to 38.2, 7 studies) Microfracture mean 30.1 (out of 100, 95% CI 25.3 to 35.0, 9 studies) Tegner score After a minimum of 2 years, improvements in Tegner scores were not statistically significantly larger in the scaffold group than the microfracture group (p=0.37): Scaffold group mean improvement 1.0 (out of 10, 95% CI 0.8 to 1.3, 4 studies) Microfracture mean 1.4 (out of 10, 95% CI 0.6 to 2.1, 5 studies) MOCART After a minimum of 2 years, overall MOCART scores were statistically significantly better in the scaffold group than the microfracture group (p=0.005): Scaffold group mean 69.3 (out of 100, 95% CI 55.1 to 83.5, 5 studies) Microfracture mean 41.0 (out of 100, 95% CI 27.3 to 54.7, 4 studies) Defect filling rate After a minimum of 2 years, defect filling rate was statistically significantly better in the AMIC group than the microfracture group (OR 1.58, 95% CI, 1.07 to 2.33, p=0.008): AMIC mean 77.3% (95% CI 66.7 to 87.9, 9 studies) Microfracture mean 47.9% (95% CI 29.2 to 66.7, 9 studies)	Safety outcomes were not reported in this systematic review and meta-analysis.
Migliorini, 2022b	Results were summarised from 47 studies including 1,667 people with collective mean follow up of 38 months (SD 22). IKDC (subjective) People who had the microfracture with scaffold procedure had a statistically significantly higher mean IKDC score than people who had mACI (MD 7.7, p=0.03): microfracture with scaffold mean 79.2 (SD 10.4) mACI mean 71.5 (SD 6.3) VAS (pain) There was no statistically significant difference in VAS scores between people who had the microfracture with scaffold procedure and mACI (MD 0.07, p=0.5, not significant): microfracture with scaffold mean 2.8 (SD 2.2) mACI mean 2.9 (SD 1.3) Lysholm score People who had the microfracture with scaffold procedure had a statistically significantly higher mean Lysholm score than people who had mACI (MD 16.1, p=0.02): microfracture with scaffold mean 81.9 (SD 7.1) mACI mean 65.7 (SD 28.2) Tegner score There was no statistically significant difference in Tegner scores between people who had the microfracture with scaffold procedure and mACI (MD 0.3, p=0.2, not significant): microfracture with scaffold mean 4.4 (SD 0.6) mACI mean 4.7 (SD 0.8)	Surgical failure rate There was a statistically significant difference in failure rate between people who had the microfracture with scaffold procedure and people who had mACI (OR 0.2, 95% CI 0.0 to 0.9, p=0.04): microfracture with scaffold rate 1.8 (2 of 114 observations) mACI rate 7.3 (41 of 562 people) Revision rate The OR for revision rate between people who had the microfracture with scaffold procedure and people who had mACI was 0.5 (95% CI 0.2 to 1.0, p=0.07): microfracture with scaffold rate 6 (7 of 117 observations) mACI rate 11.9 (39 of 328 observations) Hypertrophy The OR for hypertrophy rate between people who had the microfracture with scaffold procedure and people who had mACI was 0.1 (95% CI 0.0 to 1.0, p=0.05): microfracture with scaffold rate 0 (0 of 96 observations) mACI rate 7.6 (29 of 381 observations) Knee arthroplasty There was no statistically significant difference in the knee arthroplasty rate between people who had the microfracture with scaffold procedure and people who had mACI (OR 0.5, 95% CI 0.0 to 3.6, p=0.4): microfracture with scaffold rate 1.6 (2 of 126 observations) mACI rate 3.1 (2 of 64 observations)
Migliorini, 2021a	Lysholm score (median follow up 3 years) Compared with microfracture, ACI, mACI and OAT, the network meta-analysis found the procedure had a higher Lysholm score (SMD 4.0, 95% CI -10 to 18). Tegner score (median follow up 3 years) Compared with microfracture, ACI, mACI and OAT, the network meta-analysis found the procedure had a higher Tegner score (SMD-2.1, 95% CI -3.2 to -1.0). Tests of heterogeneity precluded network meta-analysis of the IKDC scores.	Surgical failure rate The procedure had the lowest failure rate compared with microfracture, ACI, mACI and OAT (log OR 0.2, 95% CI -2.0 to 1.7). Revision surgery The procedure had the lowest revision surgery rate compared with microfracture, ACI, mACI and OAT (log OR 0.9, 95% CI -0.8 to 2.6). Hypertrophy Microfracture had the lowest rate of hypertrophy (log OR -0.2, 95% CI -3.0 to 2.7). The procedure had the second lowest rate of hypertrophy (log OR 0.2, 95% CI -1.4 to 1.8).
Tan, 2023	Mean follow up was 51 months across the 24 studies included in this meta-analysis. KOOS There was no statistically significant difference in KOOS score at the last follow up between the open and the arthroscopic groups (mean difference 8.1, 95% CI -4.0 to 20.1, p=0.19). Both groups had statistically significant improvements from baseline: Open surgery mean improvement 27.9 (95% CI 22.2 to 33.7, p<0.001, 8 studies) Arthroscopic mean improvement 36.1 (95% CI 27.9 to 44.3, p<0.001, 3 studies) IKDC (subjective) There was no statistically significant difference in IKDC score at the last follow up between the open surgery group and arthroscopic group (mean difference 3.2, 95% CI -2.7 to 9.1, p=0.29). Both groups had statistically significant improvements from baseline: Open surgery mean improvement 39.6 (95% CI 30.8 to 48.5, p<0.001, n=6 studies) Arthroscopic mean improvement 34.0 (95% CI 22.5 to 45.5, p<0.001, n=4 studies) VAS (pain) There was a statistically significant difference in VAS score at the last follow up, favouring the arthroscopic group over the open surgery group (mean difference-6.6, 95% CI -1.8 to -11.4, p=0.007). Both groups had statistically significant improvements from baseline: Open surgery mean improvement -3.8 (95% CI -3.0 to -4.5, p<0.001, n=12 studies) Arthroscopic mean improvement -4.1 (95% CI -3.1 to -5.1, p<0.001, n=3 studies) MOCART Open surgery mean MOCART score 64.59 (95% CI 57.4 to 71.8, n=6 studies) Arthroscopic mean score 58.3 (95% CI 50.5 to 66.1, n=1 study)	Failure 3 open surgery studies reported that treatment failed in 11 people. Revision surgery 1 arthroscopic study reported whether there was any revision surgery. The revision rate was zero in this study. 10 open surgery studies reported whether there was any revision surgery. A total of 32 people had revision surgery (denominator not reported). Not all of these were related to the procedure. Infection 2 arthroscopic and 4 open surgery studies reported whether there were any infections. None of these studies reported infections. Deep vein thrombosis 1 arthroscopic study reported that 3 people had deep vein thrombosis. In 2 open surgery studies that reported it, there were no deep vein thrombosis events. Knee stiffness 1 arthroscopic study reported no knee stiffness events. 1 open surgery study reported 1 person had knee stiffness. Arthroplasty 4 studies reported that 5 people had arthroplasty.
da Cunha, 2020	IKDC (subjective) At a median follow up of 24 months (range 12 to 84), weighted mean improvement in IKDC score 33.2 (SD 10.2, n=116). VAS (pain) At a median follow up of 24.4 months (range 12 to 30 months), weighted mean decrease in VAS score 4.2 (SD 0.8, n=164). Imaging outcomes Findings varied by scaffold used and when more than 1 study reported findings for the same technology, the results also tended to vary. Overall, defect filling ranged from 19% to 'complete'.	Overall adverse event rates Seven of 10 studies reported whether there were treatment-related adverse events, including 3 studies that reported there were none. In 1 study, 13 people in the scaffold arm (19%) reported an adverse event, compared with 18 people (27%) in the microfracture arm; more than 90% were mild or moderate in both arms. In 1 study of 18 people, 78% reported mild or moderate adverse events (n=39 events). Knee pain In 1 study, the most common event was knee pain (11%). In 1 study, 1 person had persistent pain and early degenerative changes of the knee joint. In 1 study, 44% of adverse events were pain and swelling and 50% joint pain. Two events were likely or definitely device-related and classified as mild. Infection In 1 study, cellulitis was reported in 1 person. Haematoma In 1 study, 1 person developed haematoma. Knee stiffness In 1 study, 45% (9 people) needed mobilisation under anaesthesia for knee stiffness.
Altschuler, 2023	KOOS (n=164 scaffold, n=83 surgical standard of care) The scaffold group had statistically significant greater mean improvements in KOOS score compared with the surgical standard of care group at all timepoints: Mean difference in improvement between groups at 6 months 8.2 (95% CI 3.3 to 13.0, p=0.001) Mean difference in improvement between groups at 12 months 12.5 (95% CI 7.3 to 17.8, p<0.001) Mean difference in improvement between groups at 18 months 18.3 (95% CI 13.0 to 23.5, p<0.001) Mean difference in improvement between groups at 24 months (primary outcome) 22.5 (95% CI 17.0 to 28.0, p<0.001) All secondary endpoints (subscales of KOOS including pain, quality of life, ADL and responder rate [change of 30 points or more] at 24 months) were considered statistically superior in the scaffold group compared with the surgical standard of care group (posterior probability of superiority 1). This was robust to worst-case sensitivity analysis. IKDC (subjective) At 12 months, the authors cite an MCID of 16.7 points. Mean change in IKDC scores was greater than the MCID at 6, 12, 18 and 24 months, and the difference between the scaffold and surgical standard of care groups was statistically significant at all timepoints. At 6 months: Scaffold group mean IKDC score 24.0 (SD 18.8) Difference between groups was not reported. At 12 months: Scaffold group mean IKDC score 32.5 (SD 20.6) Difference between groups 12.0 (95% CI, 6.5 to 17.5, p<0.001) At 18 months: Scaffold group mean IKDC score 38.1 (SD 20.8) Difference between groups 16.3 (95% CI 10.7 to 21.9, p<0.001) At 24 months: Scaffold group mean IKDC score 43.0 (SD 21.2) Difference between groups 22.7 (95% CI 16.8 to 28.6, p<0.001) Defect filling (n=156 scaffold, n=68 surgical standard of care) At 24 months, 88.5% of the scaffold group had 75.0% or more defect fill compared with 30.9% in the surgical standard of care group (p<0.001). At 24 months, 1.3% of the scaffold group had less than 50% defect fill compared with 50% in the surgical standard of care group. Covariate analyses The effects of OA, age and lesion size were explored as covariates in this study. The difference between treatment groups in KOOS improvement at 24 months was not statistically different by OA (none compared with mild to moderate OA, p=0.48) or age (aged less than 50 compared with 50 or older, p=0.54). The difference between treatment groups in KOOS improvement at 24 months showed statistically significant variance by lesion size. People with lesions greater than 3 cm² had more improvement than people with smaller lesions (p not reported).	Revision surgery because of OA progression No people (of 167) in the scaffold group had revision surgery because of OA progression; 4.8% (4 out of 84) people in the surgical standard of care group had revision surgery because of OA progression. Surgical failure rate There were more treatment failures in the surgical standard of care group than the scaffold group (p=0.002): 7.2% (n=12 people) in the scaffold group 21.4% (n=18 people) in the surgical standard of care group Higher failure rates were seen in the surgical standard of care group in people who had larger lesions or OA. This pattern was not seen in the scaffold group. Serious adverse events Wound complications 1.2% (2 out of 167) of people in the scaffold group and 1.2% (1 out of 84) in the standard of care group had wound complications requiring antibiotics and prolonged dressing. Septic arthritis 1 person in the scaffold group had septic arthritis. The implant was removed followed by surgical debridement and antibiotics. Decreased range of motion 1.2% (2 out of 167 people) in the scaffold group had decreased range of motion in the index knee compared with baseline. Muscle atrophy 1.2% (2 out of 167 people) in the scaffold group had muscle atrophy that persisted at last follow up. Deep vein thrombosis 1 person in each group had deep vein thrombosis, which was managed pharmacologically. Other adverse events Transient knee pain Transient knee pain was the most common adverse event, seen in 15.0% of the scaffold group compared with 39.3% of the surgical standard of care group. Swelling and effusion 5.4% in the scaffold group compared with 4.8% in the surgical standard of care group. Overall adverse event rate There were fewer adverse events in the scaffold group (58.7%, 98 out of 167 people had 1 or more adverse events) compared with the surgical standard of care group (77.4%, 65 out of 84 people had 1 or more adverse events). The authors note that these rates included unrelated events and the trial was done during the COVID-19 pandemic.
Kim, 2020b	KOOS (n=45 scaffold, n=44 microfracture only) Overall KOOS was statistically significantly improved compared with baseline within the scaffold and microfracture groups at 12 and 24 months, but not statistically significantly different between the groups at either timepoint: At 12 months, the scaffold group mean KOOS 69.7 (SD 16.4) and the microfracture group mean KOOS 70.3 (SD 17.6, p=0.95) At 24 months, the scaffold group mean KOOS 77.1 (SD 14.1) and the microfracture group mean KOOS 75.2 (SD 15.5, p=0.69) At 24 months, the rate of scores equal to or more than the MCID of 16.7 points was not statistically different between groups (p=0.94) All subscales showed statistically significant improvements within both groups for the improvement in scores between baseline and 12 months and baseline and 24 months except for the sport and recreation subscale for the microfracture-only group at 12 months (p=0.06). IKDC (subjective) Overall IKDC was statistically significantly improved compared with baseline within the scaffold and microfracture groups at 12 and 24 months, but not statistically different between the groups at either timepoint: At 12 months, the scaffold group mean IKDC 65.8 (SD 19.3) and the microfracture group mean IKDC 65.8 (SD 21.2, p=0.998) At 24 months, the scaffold group mean IKDC 70.3 (SD 18.5) and the microfracture group mean IKDC 71.2 (SD 19.9, p=0.63) There were no statistically significant differences in IKDC score between groups at 12 or 24 months. All subscales showed statistically significant improvements within both groups for the improvement in scores between baseline and 12 months and baseline and 24 months. VAS (pain) Note this study used a 0- to 100-point VAS scale in which 0 is worst pain and 100 is no pain. There was no statistically significant difference in VAS scores at any timepoint between the groups. At 12 months, the scaffold group mean VAS 22.2 (SD 24.1) and the microfracture-only group 21.0 (SD 20.7, p=0.94) At 24 months, the scaffold group mean VAS 15.5 (SD 21.6) and the microfracture-only group 21.5 (SD 25.9, p=0.43) At 24 months, there were more people in the scaffold group (42.7%) than the microfracture-only group (32.6%) with a MCID compared with baseline on the VAS scale (OR 2.81, 95% CI 1.01 to 7.78, p=0.047). MOCART (n=42 scaffold, n=40 microfracture only) Total MOCART score at 12 months was not statistically different between the scaffold group (mean 50.9, SD 19.8) and microfracture group (mean 45.7, SD 19.9, p=0.23). Three subscales of MOCART at 12 months favoured the scaffold group: degree of defect repair and filling, integration with the border zone and effusion (p=0.02, p=0.006 and p=0.008, respectively). Defect filling At 12 months, 50% or higher defect filling was seen in 41.6% of the scaffold group and 29.2% of the microfracture group (OR 4.0, 95% CI 1.3 to 12.4, p=0.01).	Overall adverse event rates No adverse events were categorised as related to the scaffold or microfracture surgery. 4 serious adverse events were recorded (2 in each arm). None were classed as related to the procedure. In the scaffold arm, 1 person had a urethral caruncle removed 3 months postoperatively and 1 person had acute hepatoma 2 months postoperatively. In the microfracture only arm, 1 person had metal removed from the left distal tibia 9 months after surgery and 1 person had unexpected hospitalisation because of left knee pain and swelling 2 months postoperatively.
Kon, 2018	KOOS Exact values for KOOS outcomes were not reported. Both the scaffold and bone marrow stimulation-only groups had statistically significant improvements from baseline to 2 years postoperatively. There were no statistically significant differences between groups (p value not reported). IKDC (subjective) Both the scaffold and bone marrow stimulation-only groups had statistically significant improvements from baseline to 2 years postoperatively (p value not reported). There were no statistically significant differences between groups (p value not reported): In the scaffold group, mean IKDC subjective 43.2 (SD 16.6) at baseline, 60.7 (SD 17.3) at 1 year and 66.7 (SD 21.0) at 2 years. In the bone marrow stimulation group, mean IKDC subjective 41.1 (SD 15.9) at baseline, 61.8 (SD 18.0) at 1 year and 63.6 (SD 18.2) at 2 years. Adjusted mean difference between groups -0.48 (not significant). A subgroup analysis found the difference was statistically significantly different between treatment groups in people with deep osteochondral lesions (p=0.04) and sports active people (p=0.03), favouring the scaffold group. VAS (pain) Both the scaffold and bone marrow stimulation-only groups had statistically significant improvements from baseline to 2 years postoperatively (p value not reported). There were no statistically significant differences between groups (p value not reported): In the scaffold group, mean VAS 50.1 (SD 26.7) at baseline, 23.8 (SD 20.8) at 1 year and 26.5 (SD 27.5) at 2 years. In the bone marrow stimulation group, mean VAS 53.1 (SD 22.7) at baseline, 29.2 (SD 23.2) at 1 year and 23.2 (SD 20.9) at 2 years. Adjusted mean difference between groups=6.6 (not significant). Tegner score Both the scaffold and bone marrow stimulation-only groups had statistically significant improvements from baseline to 2 years postoperatively (p value not reported). There were no statistically significant differences between groups (p value not reported): In the scaffold group, median Tegner 3 (range 0 to 7) at baseline, 4 (range 2 to 7) at 1 year and 4 (range 1 to 9) at 2 years. In the bone marrow stimulation group, median Tegner 3 (range 0 to 9) at baseline, 4 (range 1 to 9) at 1 year and 4 (range 2 to 8) at 2 years. Adjusted mean difference between groups 0.14 (not significant). IKDC (objective) The percentage of people assessed as having 'normal' or 'nearly normal' knees increased from baseline to 2 years of follow up in the scaffold group. They did not report if this was statistically significant. The scores also increased in the bone marrow stimulation group but the authors reported this was not statistically significant (p value not reported). There was no statistically significant difference between groups (p value not reported). MOCART There was no statistically significant difference between groups. Covariate analyses In the scaffold group, people with grade 4 lesions and who did not have concomitant anterior cruciate ligament surgery had better IKDC outcomes (p<0.05). Outcomes did not statistically significantly vary by age, sex or lesion size in this group. A subgroup of people with deep lesions involving the subchondral bone who did not have anterior cruciate ligament surgery were analysed for between group differences. From baseline to 2 years, people who fit this criterion and had the scaffold procedure (n=27) had more improvement on the IKDC subjective score at 2 years than people in the bone marrow stimulation group (n=30, mean difference=12.4 points, p=0.04). Another subgroup analysis of people who were sport active found that people who had the scaffold procedure (n=16) had greater IKDC improvements than people who had bone marrow stimulation at 2 years (n=11, mean difference 16 points, p=0.03). A clinically meaningful but not statistically significant difference in improvements in IKDC scores was seen between people who had osteochondral dissecans who had the scaffold procedure (n=15) and people who had the bone marrow stimulation procedure (n=12, mean difference 12 points, p=0.14).	Overall adverse event rate There were 13 adverse events and 3 serious adverse events related to the procedure in the scaffold group compared with 4 adverse events and 1 serious adverse event in the bone marrow stimulation group. Failures There were 2 surgical failures in the scaffold group and none in the bone marrow stimulation group. Minor early postoperative symptoms There were 8 events in the scaffold group and 3 in the bone marrow stimulation group. Inflammation There were 3 inflammation events in the scaffold group and none in the bone marrow stimulation group. Joint adhesions There were 2 serious and 1 non-serious joint adhesion events in the scaffold group and none in the bone marrow stimulation group. Persistent pain There was 1 serious and 1 non-serious persistent pain event in the scaffold group and none in the bone marrow stimulation group. Loose body There was 1 loose body recorded in the bone marrow stimulation arm and none in the scaffold arm.
Shive, 2015	SF-36 (mental and physical subscales) There were no statistically significant differences between the scaffold and microfracture groups in the change from year 1 to 5 on either the mental (p=0.13) or physical (p=0.48) subscales of the SF-36. Both groups maintained the improvements seen at year 1 at year 5. While not statistically significant, the mental subscale dropped below baseline at the 5-year follow up in the microfracture group. WOMAC Both the scaffold and microfracture groups had a statistically significant improvement from baseline to 5 years in all 3 WOMAC subscales (p<0.001). There were no between group differences in the mean change from year 1 scores, adjusted for baseline, for the pain (p=0.47), stiffness (p=0.24) or function (p=0.33) subscales. Defect filling At 5 years, the scaffold group had a statistically significantly greater increase in percent defect fill than the microfracture group (p=0.02) after adjusting for lesion volume: At 5 years, mean percent fill in the scaffold group was 93.8% (SE 1.2) At 5 years, mean percent fill in the microfracture group was 87.0% (SE 2.9)	Overall adverse event rates There were 54 adverse events in 31 people in the 5-year follow up and more than 90% were mild to moderate: 19% (13 people) in the scaffold group had an adverse event including 2 unexpected and procedure-related adverse events in 1 person, 2 unexpected device-related events in 1 person, and 1 expected and procedure-related adverse event in 1 person. All were mild to moderate and ongoing at 5 years. 27% (18 people) in the microfracture group had an adverse event including 2 expected procedure-related events that were mild and ongoing at 5 years. Knee pain Knee pain was the most common adverse event: 11% of people in the scaffold group 17% of people in the microfracture group
Gille, 2021	The number of people with data available at each year's follow up was only reported for Lysholm data. Of 131 people whose data was included in any analysis, 106 had Lysholm data at year 1, 61 at year 2, 44 at year 3, 35 at year 4, 27 at year 5, 22 at year 6 and 9 at year 7. KOOS Mean KOOS statistically significantly increased from baseline (mean 45) to 1 year (mean 77, p<0.001). This improvement was maintained every year up to 7 years (p<0.001). VAS Median VAS statistically significantly decreased from baseline (median 5.5) to 1 year (median 2.3, p<0.001). The authors report that this was maintained up to 7 years (p<0.001), but there was a slight, but not statistically significant increase, by year 7. Lysholm score Mean Lysholm score statistically significantly increased from baseline (mean 46.9) to 1 year (mean 83.8, p<0.001, n=106 people). This improvement was maintained every year up to 7 years (p<0.001, n=9), with no significant difference in score at any follow-up timepoint. Covariate analyses Covariate analyses for age, sex, previous surgery, defect location and size were done. There was no statistically significant effect of any of the covariates on any of the outcomes assessed.	Safety outcomes were not reported in this study.
de Girolamo, 2019	At 60 months, 10 out of 12 people were followed up in each arm. At 100 months, 7 out of 12 people were followed up in the scaffold-only group and 9 out of 12 people in the scaffold plus bone marrow aspirate concentrate group. KOOS This was only assessed at 60 and 100 months. Exact values were not reported for this outcome. There was no statistically significant difference between groups at either timepoint (p not reported). The authors report that KOOS was satisfactory for pain and daily activities subscores up to 100 months. There was a slight progressive decrease in sport and quality of life subscales between 60 and 100 months. VAS (pain) At all postoperative timepoints (6, 12, 24, 60 and 100 months), the VAS score was statistically significantly better compared with baseline for both the scaffold and scaffold plus bone marrow aspirate concentrate groups. All timepoints showed highly statistically significant decreases in pain in the scaffold plus bone marrow aspirate concentrate group. The only timepoint with a statistically significant difference between groups was 12 months, favouring the scaffold plus bone marrow aspirate concentrate group (mean difference 1.9, 95% CI 0.5 to 3.3, n=22 people). IKDC (objective) This was only assessed at preprocedure, 6, 12 and 24 months. Objective IKDC scores showed a statistically significantly higher proportion of people whose knee was assessed as 'normal' at 24 months (p<0.05) in the scaffold plus bone marrow aspirate concentrate group. The scaffold-only group had a statistically significant improvement at 6 months but no further statistically significant improvement was seen at any other timepoint. Lysholm score The scaffold plus bone marrow aspirate concentrate group had statistically significant improvements in Lysholm score compared with baseline at all timepoints (p<0.001 at 6, 12, 24, 60, 100 months; n=11 at 6 months, n=9 at 100 months). The scaffold-only group only had statistically significant improvements at 24 and 60 months. The gains at 24 (p<0.001) and 60 months (p<0.05) were lost at the 100-month timepoint. There was a statistically significant difference between groups at 12 months (mean difference 9.9, 95% CI 2.1 to 17.6, p<0.05, n=22). Tegner score Both groups showed return to pre-injury level of activity from 12 months, with further improvements at 24 months, which then declined at 60 and 100 months. The authors justified this as a physiological drop because of the effects of age on sports activity. Scores at last follow up were not significantly lower than pre-injury. Imaging outcomes including defect filling Few people in the scaffold-only group contributed MRI data (n=5 and n=2 at 12 and 24 months). At 6 months, more people in the scaffold plus bone marrow aspirate concentrate group had evidence of graft integration but it was comparable at 12 months. The authors report that defect filling was similar between groups at 6, 12 and 24 months.	Arthrosynovitis 1 person in the scaffold-only group had arthrosynovitis. No other adverse event or complications were recorded in this study.

Procedure technique

Three of 6 meta-analyses did not mention specific technologies used but 1 did report that a mixture of scaffolds were included (Migliorini 2021a). The meta-analyses that did report what scaffolds were used also reported that multiple technologies were included in their review (Kim 2020a, Tan 2023, da Cunha 2020).

Most often, studies in the meta-analyses used Chondro-Gide (Geistlich Pharma AG) with microfracture. This is a collagen scaffold that is sutured or glued over the microfracture site. This technique with this technology has been trademarked with the term 'Autologous Matrix-Induced Chondrogenesis'. This technique was also used in the registry study (Gille 2021). Other technologies referred to in the meta-analyses were Hyalofast, ChonDux and Chondrotissue (BioTissue AG).

The RCT of 251 people used Agili-C (Cartiheal Ltd), which is an aragonite-based biphasic implant (Altschuler 2023). This is press-fit into a purpose-drilled hole that penetrates the subchondral bone. There was no explicit mention of using microfracture or other bone marrow stimulation procedure in this study.

The RCT by Kim (2020b) used CartiFill (Sewon Cellontech, Seoul, Korea), which is an atelocollagen gel scaffold. This was mixed with thrombin and fibrinogen and applied to the microfractured site. The authors described this as a collagen-augmented chondrogenesis technique.

The RCT by Kon (2018) used MaioRegen (Fin-Ceramica Faenza S.p.A., Italy), which is a bioceramic composite scaffold that is press-fit into a hole drilled into the subchondral bone. There was no explicit mention of using microfracture or other bone marrow stimulation procedure in this study.

In the RCT 5-year follow up (Shive 2015) BST-CarGel (Piramal Life Sciences, Bio-Orthopaedics Division) was used. This is a gel scaffold containing chitosan and was applied after microfracture.

Some studies augmented the procedure with other materials too. The network meta-analysis excluded augmented procedures. Meta-analyses by the same group comparing the procedure with microfracture included studies that immersed the scaffold in bone marrow concentrate before applying it to the lesion (Migliorini 2022a and 2022b). Similarly, many studies in the meta-analyses by Kim (2020), Tan (2023) and da Cunha (2020) included augmentations to the procedure such as the addition of platelet-rich plasma gel, bone marrow aspirate, or bone marrow aspirate concentrate. The RCT of 24 people (de Girolamo 2019) compared microfracture and Chondro-Gide (Geistlich Pharma AG) with microfracture, Chondro-Gide and bone marrow aspirate concentrate.

Some studies included people who had concomitant procedures, such as high tibial osteotomy, meniscal treatments such as partial meniscectomy or concomitant anterior cruciate ligament surgery. The meta-analysis including 29 studies that compared the scaffold procedure with microfracture alone (Kim 2020a) excluded studies that included people who had concomitant high tibial osteotomy.

Efficacy

KOOS

KOOS outcomes were reported in 6 studies. In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure (Tan 2023) both groups had statistically significant improvements from baseline (p<0.001). There was no statistically significant difference in KOOS score at the last follow up between the open and the arthroscopic groups (mean difference 8.1, p=0.19). The RCT of 251 people comparing the procedure with surgical standard of care (Altschuler 2023) found statistically significant differences favouring the scaffold group at all timepoints (6, 12, 18 and 24 months). This contrasted with the RCT of 100 people that compared the procedure with microfracture alone (Kim 2020b), which reported no statistically significant difference in improvement between groups at 12 or 24 months. In this study, both groups did have statistically significant improvements compared with baseline overall and on subscales, except for the sport and recreation subscale for the microfracture only group at 12 months (p=0.06). This was similar in the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018). Both the scaffold and bone marrow stimulation only groups had statistically significant improvements from baseline to 2 years postoperatively but no statistically significant difference between groups was found (p value not reported). In the registry study (Gille 2021), mean KOOS statistically significantly increased from baseline (mean 45) to 1 year (mean 77, p<0.001). This improvement was maintained every year up to 7 years (p<0.001), although it is likely that about 9 people contributed data at the 7-year follow up. The RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019) also examined this at 60 and 100 months. Exact values were not reported for this outcome but the authors reported no statistically significant differences between groups at either timepoint (p value not reported). The authors report that KOOS was satisfactory for pain and daily activities subscores up to 100 months. There was a slight progressive decline in sport and quality of life subscales.

IKDC (subjective)

Subjective IKDC scores were reported in 7 studies. Meta-analysis level evidence showed consistently better outcomes in the procedure group than comparators. In the meta-analysis including 18 studies that compared the procedure with microfracture alone (Migliorini 2022a), people who had the procedure had a statistically significant greater IKDC score than people who had microfracture alone (weighted mean difference between groups was 11.8 points, p<0.001). The increase in the procedure group was statistically significant and greater than the MCID of 15 points (mean 34 points, p<0.001). This was similar in the meta-analysis including 29 studies that compared the procedure with microfracture alone (Kim 2020a). After a minimum of 2 years, improvements in IKDC scores were statistically significantly larger in the AMIC group than the microfracture group (p<0.001) and the mean improvement was 45.9 points. Endpoint mean IKDC scores were also higher for people that had the procedure than people who had mACI in the meta-analysis including 47 studies (Migliorini 2022b). When comparing open with arthroscopic approaches to the procedure, the meta-analysis of 24 studies (Tan 2023) found no statistically significant difference between groups (p=0.29). In the meta-analysis of 10 studies (da Cunha 2020), weighted mean improvement in IKDC score was 33.2 points at a median of 24 months (range 12 to 84).

Individual RCT evidence had mixed findings. In the RCT of 251 people comparing the procedure with surgical standard of care (Altschuler 2023), mean change in IKDC scores was greater than the MCID at 6, 12, 18 and 24 months. Also, the difference between the scaffold and surgical standard of care group was statistically significant at all timepoints (p<0.001 reported at 12, 18 and 24 months). But both the RCT of 100 people that compared the procedure with microfracture alone (Kim 2020b) and the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018) found statistically significant improvements in IKDC score compared with baseline up to 2 years but did not find a difference between groups.

VAS (pain)

VAS was reported in 8 studies. Meta-analysis findings were mixed. In the meta-analysis including 18 studies that compared the procedure with microfracture alone (Migliorini 2022a), people who had the procedure had a statistically significant mean decrease of 3.9 points at an average of 40 months (p<0.001). This was statistically significantly lower than in people who had microfracture alone (weighted MD between groups was -1.0 points, p=0.04). Mean improvement was not statistically significantly lower in the meta-analysis including 29 studies that compared the procedure with microfracture alone (Kim 2020a). The mean improvement was 4.8 points in the procedure group compared with 3.2 points in the microfracture group. In the meta-analysis including 47 studies that compared the procedure with mACI (Migliorini 2022b), there was no statistically significant difference in VAS scores between people who had the procedure and people who had mACI (MD 0.07, p=not significant). In the meta-analysis including 24 studies that compared open with arthroscopic approaches (Tan 2023), both groups had statistically significant improvements from baseline (p<0.001). But there was a statistically significant difference in VAS score at the last follow up, favouring the arthroscopic group over the open surgery group (mean difference 6.6 points out of 100, p=0.007). In the meta-analysis of 10 studies, weighted mean decrease in VAS score was 4.2 points at a median of 24 months (range 12 to 30).

Both the RCT of 100 people that compared the procedure with microfracture alone (Kim 2018) and the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018) found no statistically significant differences between groups up to 2 years. But the RCT by Kim (2018) found there were more people in the scaffold group (43%) than the microfracture only group (33%) with a MCID compared with baseline on the VAS scale at 24 months (OR 2.81, p=0.047). In the registry study (Gille 2021), median VAS statistically significantly decreased from baseline (median 5.5) to 1 year (median 2.3, p<0.001). The authors report that this was maintained up to 7 years (p<0.001), but there was a slight but not statistically significant increase, by year 7. It is likely that about 9 people contributed data at the 7-year follow up in this study. In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019), VAS score was statistically significantly better compared with baseline in both groups at 6, 12, 24, 60 and 100 months. While all timepoints showed highly statistically significant decreases in pain in the scaffold plus bone marrow aspirate concentrate group, the only timepoint with a statistically significant difference between groups was 12 months (mean difference 1.9).

Lysholm score

Lysholm score was reported in 6 studies. The meta-analysis including 18 studies that compared the procedure with microfracture alone (Migliorini 2022a) did not report comparative outcomes for Lysholm. But it found that people who had the procedure had a statistically significant mean increase of 28 points at a mean of 40 months (95% CI 26.9 to 29.1, p<0.001). The authors reported the MCID was 10 points. When compared against microfracture in the meta-analysis of 29 studies (Kim 2020), improvements in Lysholm scores were not statistically significantly greater in the procedure group than the microfracture group (p=0.38). In the meta-analysis of 47 studies (Migliorini 2022b), people who had the procedure had a statistically significant higher mean Lysholm score than people who had mACI. The network meta-analysis including 103 people who had the procedure (Migliorini 2021a) found that people who had this procedure had higher Lysholm scores compared with people who had microfracture alone, ACI, mACI or OAT (SMD 4, 95% CI -10 to 18). In the registry study (Gille 2021) mean Lysholm score statistically significantly increased from baseline (mean 46.9) to 1 year (mean 83.8, p<0.001, n=106 people). This improvement was maintained every year up to 7 years (p<0.001, n=9), with no significant difference in score at any follow-up timepoint. It is likely that about 9 people contributed data at the 7-year follow up in this study. In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019), the scaffold plus bone marrow aspirate concentrate group had statistically significant improvements in Lysholm score compared with baseline at all timepoints up to 100 months (p<0.001). The scaffold-only group only had statistically significant improvements at 24 and 60 months. The gains at 24 (p<0.001) and 60 months (p<0.05) were lost at the 100-month timepoint in this group. There was a statistically significant difference between groups at 12 months only (mean difference 9.9, p<0.05, n=22).

Tegner score

Tegner scores were reported in 6 studies. In the meta-analysis including 18 studies that compared the procedure with microfracture alone (Migliorini 2022a), people who had the procedure had a statistically significant mean increase of 0.8 points (p=0.03) at a mean of 40 months. This was greater than the cited MCID of 0.5 points. The authors did not report comparative outcomes with microfracture in this study. When compared against microfracture in the meta-analysis of 29 studies (Kim 2020a), improvements in Tegner scores were not statistically significantly larger in the procedure group than the microfracture group (p=0.37) at a minimum of 2 years of follow up. Similarly, there was no statistically significant difference in Tegner scores between people who had the procedure and people who had mACI in the meta-analysis of 47 studies (Migliorini 2022b, MD 0.3, p=not significant). In the network meta-analysis including 103 people who had the procedure (Migliorini 2021a), people who had this procedure had the highest Tegner score (SMD -2.1, 95% CI -3.2 to -1.0). In the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018) both the scaffold and bone marrow stimulation only groups had statistically significant improvements from baseline to 2 years postoperatively (p value not reported). Also, there were no statistically significant differences between groups (p value not reported). In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019), both groups showed return to pre-injury level of activity from 12 months. There were further improvements at 24 months, which then declined at 60 and 100 months. The authors justified this as a physiological drop because of the effects of age on sports activity. Scores at last follow up were not significantly worse than pre-injury.

WOMAC

One study reported WOMAC scores. In the 5-year follow up of an RCT including 60 people (Shive 2015), both the scaffold and microfracture groups had a statistically significant improvement from baseline to 5 years in all 3 WOMAC subscales (p<0.001). There were no between group differences in the mean change from year 1 scores, adjusted for baseline, for the pain (p=0.47), stiffness (p=0.24) or function (p=0.33) subscales.

SF-36

One study reported SF-36 scores. In the 5-year follow up of an RCT including 60 people (Shive 2015), there were no statistically significant differences between the scaffold and microfracture groups in the change from year 1 to 5 on either the mental (p=0.13) or physical (p=0.48) subscales of the SF-36. While not statistically significant, the mental subscale dropped below baseline at the 5-year follow up in the microfracture group.

MOCART

Four studies reported MOCART outcomes. In the meta-analysis including 29 studies that compared the procedure with microfracture alone (Kim 2020a), after a minimum of 2 years, overall MOCART scores were statistically significantly better in the procedure group than the microfracture group (p=0.005). The mean score in the procedure group was 69.3, compared with 41.0 in the microfracture group. In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure (Tan 2023), the open surgery mean was 64.59 (95% CI 57.4 to 71.8) and the arthroscopic mean was 58.3 (95% CI 50.5 to 66.1). In the RCT of 100 people that compared the procedure with microfracture alone (Kim 2020b) total MOCART score at 12 months was not statistically different between the scaffold group (mean 50.9, SD 19.8) and microfracture group (mean 45.7, SD 19.9, p=0.23). But 3 subscales of MOCART at 12 months favoured the scaffold group: degree of defect repair and filling, integration with the border zone and effusion (p=0.02, p=0.006 and p=0.008, respectively). Similarly, there was no statistically significant difference between groups in the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018).

Defect fill

Defect fill was reported in 5 studies. In the meta-analysis including 29 studies that compared the procedure with microfracture alone at 2 years (Kim 2020a), defect filling rate was statistically significantly better in the procedure group than the microfracture group (77% compared with 48%, OR 1.58, p=0.008). In the meta-analysis of 10 studies (da Cunha 2020), findings varied by scaffold used and when more than one study reported findings for the same technology, the results also tended to vary. Overall, defect filling ranged from 19% to 'complete'. In the RCT of 251 people comparing the procedure with surgical standard of care (Altschuler 2023), 89% of the scaffold group had 75% or more defect fill compared with 31% in the surgical standard of care group at 24 months (p<0.001). Also, a less than 50% defect fill was reported for 1% of the scaffold group compared with 50% of the surgical standard of care group at 24 months. Lower overall fill rates were seen at 12 months in the RCT of 100 people that compared the procedure with microfracture alone (Kim 2020b) but this still favoured the procedure group; 50% or higher defect filling was seen in 42% of the scaffold group and 29% of the microfracture group (OR 4.0, p=0.01). In the 5-year follow up of an RCT including 60 people (Shive 2015), the scaffold group had a statistically significant greater increase in percent defect fill than the microfracture group (p=0.02) after adjusting for lesion volume (94% and 87% fill was seen in the procedure and microfracture groups, respectively). In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019), the authors report that defect filling was similar between groups at 6, 12 and 24 months although only 2 people completed follow up in the scaffold-only group.

IKDC objective score

Two studies reported IKDC objective outcomes. In the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018), the percentage of people assessed as having 'normal' or 'nearly normal' knees increased from baseline to 2-years of follow up in the scaffold group. They did not report if this was statistically significant. The scores also increased in the bone marrow stimulation group but the authors reported this was not statistically significant (p value not reported). There was no statistically significant difference between groups (p value not reported). In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate (de Girolamo 2019), IKDC objective score was assessed at baseline, 6, 12 and 24 months. They found a statistically significantly higher proportion of people whose knee was assessed as 'normal' at 24 months (p<0.05) in the scaffold plus bone marrow aspirate concentrate group. The scaffold-only group had a statistically significant improvement at 6 months but no further statistically significant difference after this timepoint.

Covariate analyses

Three studies reported covariate analyses (Altschuler 2023, Kon 2018, Gille 2021).

Lesion size was assessed in all 3 studies. In the RCT of 251 people (Altschuler 2023) the difference between treatment groups in KOOS improvement at 24 months showed statistically significant variance by lesion size. People with lesions greater than 3 cm² had more improvement than people with smaller lesions (p not reported). There was no effect of lesion size on improvement from baseline to 2-year follow up on the IKDC subjective in the RCT of 100 people (Kon 2018) or any outcome assessed in the registry study (Gille 2021).

In the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018), an analysis of the scaffold procedure group showed that people with grade 4 lesions and who did not have concomitant anterior cruciate ligament surgery had better IKDC outcomes (p<0.05). A subgroup of people with deep lesions involving the subchondral bone who did not have anterior cruciate ligament surgery were analysed for between group differences. From baseline to 2 years, people in this subgroup who had the scaffold procedure (n=27) had more improvement on the IKDC subjective score at 2 years than people in the bone marrow stimulation group (n=30, p=0.04). Another subgroup analysis of people who were sport active found that people who had the scaffold procedure (n=16) had greater IKDC improvements than people who had bone marrow stimulation at 2 years (n=11, p=0.03). A clinically meaningful but not statistically significant difference in improvements in IKDC scores was seen between people who had osteochondral dissecans who had the scaffold procedure (n=15) and people who had the bone marrow stimulation procedure (n=12, p=0.14).

Other covariates were assessed and found to have no effect on outcomes. The RCT of 251 people comparing the procedure with surgical standard of care (Altschuler 2023) found no effect of OA or age. In the RCT of 100 people (Kon 2018) outcomes on the IKDC subjective did not statistically significantly vary by age, sex or lesion size. The registry study (Gille 2021) found age, sex, previous surgery and defect location had no significant effect on any of the outcomes assessed.

Safety

Ten of 11 studies reported on adverse effects of the procedure. When reported, overall adverse event rates are presented in Table 3. Specific events are reported below.

Surgical failure

Failure rate was reported in 6 studies. Not all studies defined how this was measured. Details are reported alongside study findings. The meta-analysis including 18 studies that compared the procedure with microfracture alone with a mean of 40 months of follow up (Migliorini 2022a) reported a failure rate of 4% for people who had the procedure (9 out of 236 people). Failure was not defined in this study. A lower rate of 2% was reported in the meta-analysis including 47 studies that compared the procedure with mACI with a mean of 38 months of follow up (Migliorini 2022b). This was statistically lower than the rate reported in the mACI group, which was 7% (OR 0.2, 95% CI 0.0 to 0.9, p=0.04). Failure was also not defined in this study. In the network meta-analysis including 103 people who had the procedure with a mean of 36 months of follow up (Migliorini 2021a), failure was defined as pain or catching symptoms recurrence, partial or complete displaced delamination at MRI or arthroscopy. The procedure group had the lowest failure rate compared with microfracture, ACI, mACI and OAT (log OR 0.2, 95% CI -2.0 to 1.7). In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure with a mean follow up of 38 months in the procedure group (Tan 2023), 3 open surgery studies reported that treatment failed in 11 people (not defined). The RCT of 251 people comparing the procedure with surgical standard of care (Altschuler 2023) defined surgical failure as any secondary invasive intervention in the treated joint (for example, open, mini-open surgical or arthroscopic procedures, as well as any intraarticular injection), regardless if related or unrelated to the original treatment. There were more treatment failures in the surgical standard of care group (21%) than the scaffold group (7%) over a 2-year follow up (p=0.002). In the RCT of 100 people that compared the procedure with bone marrow stimulation with 2-year follow up (Kon 2018), failure was defined as the need for reintervention on the same defect based on the persistence or recurrence of symptoms. There were 2 surgical failures in the scaffold group and none in the bone marrow stimulation group (denominator not reported).

Revision surgery rate

Revision surgery rate was reported in 3 studies. In the meta-analysis including 18 studies that compared the procedure with microfracture alone (Migliorini 2022a) the revision rate for people who had the procedure was 5% over a mean of 44 months of follow up. The OR favoured the procedure compared with microfracture, OR 0.16 (95% CI 0.06 to 0.44). In the meta-analysis including 47 studies that compared the procedure with mACI (Migliorini 2022b), there was no statistically significant difference in the revision rate between people who had the procedure and people who had mACI over a mean of 38 months of follow up (OR 0.5, 95% CI 0.2 to 1.0, p=0.07); the revision rate was 7 of 117 observations in the procedure arm and 39 of 328 observations in the mACI arm. The network meta-analysis including 103 people who had the procedure with a mean of 36 months of follow up (Migliorini 2021a) found that people who had the procedure had the lowest revision surgery rate compared with microfracture, ACI, mACI and OAT (log OR 0.9, 95% CI −0.8 to 2.6). Overall revision surgery rate was not reported in the RCT of 251 people comparing the procedure with surgical standard of care with 24 months of follow up (Altschuler 2023). But, they reported that no people in the scaffold group had revision surgery because of OA progression and 5% of people (4 out of 84) in the surgical standard of care group had revision surgery because of OA progression.

Hypertrophy

Rate of hypertrophy was reported in 3 studies. The meta-analysis including 18 studies that compared the scaffold procedure with microfracture alone (Migliorini 2022a) reported that at last follow up (mean 40 months, SD 27 months), no people who had the scaffold procedure had signs of hypertrophy. The meta-analysis including 47 studies that compared the scaffold procedure with mACI (Migliorini 2022b) reported there was no statistically significant difference in the hypertrophy rate between people who had the scaffold procedure and people who had mACI (OR 0.1, p=0.05). Average follow up was 38 months in this study (SD 22). The network meta-analysis including 103 people who had the procedure (Migliorini 2021a) had an average follow up of 36 months (range 24 to 60). Among the included interventions (microfracture, OAT, ACI and mACI), microfracture had the lowest rate of hypertrophy and the scaffold procedure had the second lowest rate of hypertrophy (log OR 0.2, 95% CI -1.4 to 1.8).

Muscle atrophy

In the RCT of 251 people comparing the procedure with surgical standard of care with 24 months of follow up (Altschuler 2023) 1% of people (2 out of 167) in the scaffold group had muscle atrophy that persisted at last follow up.

Arthroplasty

In the meta-analysis including 47 studies that compared the procedure with mACI with a mean of 38 months of follow up (Migliorini 2022b), there was no statistically significant difference in the knee arthroplasty rate between people who had AMIC and people who had mACI (OR 0.5, p=0.4); 2% in the procedure group (2 out of 126) and 3% in the mACI group (2 out of 64). In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure with a mean follow up of 38 months in the procedure group (Tan 2023) 4 studies reported that 5 people had arthroplasty.

Infection and septic arthritis

The meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure with a mean follow up of 38 months in the procedure group (Tan 2023) noted that 2 arthroscopic and 4 open surgery studies reported whether there were any infections. None of these studies reported infections. The meta-analysis of 10 studies with a range of follow up from 12 to 84 months reported that in 1 study (da Cunha 2020), cellulitis was reported in 1 person. In the RCT of 251 people comparing the procedure with surgical standard of care with 24 months of follow up (Altschuler 2023), 1 person in the scaffold group had septic arthritis. The implant was removed followed by surgical debridement and antibiotics. This study also reported wound complications; 1% (2 out of 167) of people in the scaffold group and 1% (1 out of 84) in the standard of care group had wound complications requiring antibiotics and prolonged dressing.

Arthrosynovitis

In the RCT of 24 people comparing the procedure with and without bone marrow aspirate concentrate with up to 100 months of follow up (de Girolamo 2019), 1 person in the scaffold-only group had arthrosynovitis.

Deep vein thrombosis

Two studies reported whether there were any deep vein thrombosis events. In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure (Tan 2023), 1 arthroscopic study reported that 3 people had deep vein thrombosis and 2 open surgery studies reported that there were no deep vein thrombosis (mean follow up in the procedure group was 38 months in this meta-analysis). In the RCT of 251 people comparing the procedure with surgical standard of care over 24 months of follow up (Altschuler 2023), 1 person in each group had deep vein thrombosis, which was managed pharmacologically.

Haematoma

In the meta-analysis of 10 studies, 1 study reported that 1 person developed haematoma (da Cunha 2020; range of follow up was 12 to 84 months).

Swelling, effusion and other postoperative symptoms

In the RCT of 251 people comparing the procedure with surgical standard of care with 2-year follow up (Altschuler 2023), 5% of people in both groups had swelling and effusion. These were not considered serious adverse events. The RCT of 100 people that compared the procedure with bone marrow stimulation with 2-year follow up (Kon 2018) reported 8 minor early postoperative events in the scaffold group and 3 in the bone marrow stimulation group.

Stiffness and decreased range of motion

Stiffness and decreased range of motion was reported in 3 studies. In the meta-analysis including 24 studies that compared open with arthroscopic approaches to the procedure (Tan 2023), 1 arthroscopic study reported no knee stiffness events and 1 open surgery study reported 1 person had knee stiffness (mean follow up in the procedure group was 38 months). In the meta-analysis of 10 studies (da Cunha 2020) 1 study reported that 45% (9 people) needed mobilisation under anaesthesia for knee stiffness (range of follow up was 12 to 84 months). In the RCT of 251 people comparing the procedure with surgical standard of care with 24 months of follow up (Altschuler 2023), 1% (2 out of 167 people) in the scaffold group had decreased range of motion in the index knee compared with baseline.

Joint adhesion

Joint adhesion was reported in the RCT of 100 people that compared the procedure with bone marrow stimulation (Kon 2018). In this study with a 2-year follow up, there were 2 serious and 1 non-serious joint adhesion events in the scaffold group and none in the bone marrow stimulation group.

Knee pain

Three studies reported knee pain as an adverse event. In the meta-analysis of 10 studies with a range of follow up between 12 and 84 months (da Cunha 2020), 1 study reported that the most common event was knee pain (11%). Another study in this review reported that 1 person had persistent pain and early degenerative changes of the knee joint. In another study in this review, 44% of adverse events were pain and swelling and 50% were joint pain. Two events in this study were likely or definitely device-related and classified as mild. In the RCT of 251 people comparing the procedure with surgical standard of care with 24 months of follow up (Altschuler 2023), transient knee pain was the most common adverse event, seen in 15% of the scaffold group compared with 39% of the surgical standard of care group. In the RCT of 100 people that compared the procedure with bone marrow stimulation with 2-year follow up (Kon 2018), there was 1 serious and 1 non-serious persistent pain event in the scaffold group and none in the bone marrow stimulation group. Similarly in the 5-year follow up of an RCT including 60 people (Shive 2015), knee pain was the most common adverse event, in 11% in the scaffold group and 17% in the microfracture group.

Anecdotal and theoretical adverse events

Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).

They listed the following adverse events that were not categorised as anecdotal or theoretical:

patch displacement
displacement of fixation pins.

Six professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.

Validity and generalisability

Most of the evidence is from outside of the UK.
There were several meta-analyses, RCTs and a registry study included in the key evidence that explored differences in outcomes on a range of patient-reported and imaging outcomes, between scaffolds without cultured cell implantation and a range of comparator interventions.
The key evidence explored outcomes at a range of follow ups (from 6 to 100 months).
Generally, studies found the procedure to reliably show improvements compared with baseline across outcomes, have superior outcomes to comparator interventions for chondral knee defects on the IKDC subjective score and imaging findings, but there were mixed findings across other outcomes when in comparison with other interventions. The non-comparative registry study (Gille 2021) showed statistically significant improvements in KOOS, VAS and Lysholm scores that were maintained up to 7 years.
A key claimed benefit of the procedure is articular cartilage repair. Data on defect fill and MOCART scores pertain to this. Findings generally indicated that people who had the scaffold procedure had better outcomes on these measures if measured at 2 or more years. Some studies found no difference between groups. One meta-analysis found outcomes varied between different scaffolds and variations on the procedure (da Cunha 2020).
Each of the 5 RCTs and the registry study in the key evidence used different scaffolds and all of the meta-analyses included a mixture of scaffolds. Some techniques augmented scaffolds with other substances. At least 1 study in the key evidence may not have used bone marrow stimulation; both the RCT by Kon (2018) and the RCT by Altschuler (2023) did not report using microfracture, but drilled a hole into the subchondral bone and press-fit the scaffold they used.
There are many other factors that may have influenced variation in safety and efficacy outcomes: many studies included people who had concomitant surgery, the membrane fixation technique varied, rehabilitation protocols were not always defined or varied between studies, whether people were having primary or rehabilitation surgery was not always clear, location and aetiology of the lesion was often mixed. Also, surgical approaches varied although this difference was explicitly researched by Tan (2023) and concluded there was little advantage of one approach over the other. Similar limitations were acknowledged across the discussions in the included meta-analyses. Some authors acknowledged that while these factors may confound the findings, these factors reflect variations in the population of people who would have this procedure in the real world.
More men or males than women or females were included in the studies in the overview. Cartilage damage progressing to significant OA may be more common in women. Mean age for most studies was between 27 and 39 but the mean in the RCT by Altschuler (2023) and RCT by Kim (2020b) were both older. Cartilage damage as a result of disease, trauma or sport injuries can occur more commonly in adolescents and young adults.
The meta-analysis by Migliorini (2022a) included a high proportion of retrospective and non-comparative evidence, and it included some studies that augmented with bone marrow concentrate. Two authors of this review were main authors on 2 papers included in the analysis. Similarly, the meta-analysis by Kim (2020a) acknowledges that much of the evidence is retrospective and single arm. Both of these studies had the same research question but they included different studies to each other. They had different efficacy conclusions on the VAS, but both had positive findings for the procedure on the IKDC subjective score. Some more recent evidence was included in the Migliorini (2022a) study. This study references the Kim (2020a) study but does not acknowledge reasons for differences in their findings. One explanation for the differences in findings is that the microfracture arm in the meta-analysis by Kim (2020a) had longer average follow up than the scaffold arm. Neither study reported conflicts of interest.
The meta-analysis comparing the procedure with mACI (Migliorini 2022b) acknowledged that there were more people and procedures in the mACI arm that may generate biased results in detection of complications. No conflicts of interest were reported in this study.
The network meta-analysis by Migliorini (2021a) only included prospective, level 1 and 2 evidence. This was at the expense of only including 106 people in the AMIC group and only being able to aggregate findings on 2 outcomes that relate to activity level. Most studies used the Chondro-Gide scaffold after microfracture. One author is the editor in chief of the journal this was published in. No other competing interests were reported. This study did not include studies that used scaffolds augmented with other substances.
The meta-analysis by Tan (2023) included both RCT and non-RCT level evidence. The authors noted that there was no direct comparative evidence and much more evidence for the open approach than arthroscopic. No conflicts of interest were reported in this study.
The meta-analysis by da Cunha (2020) reported some conflicts of interest with a company developing enhanced microfracture techniques.
The RCT by Altschuler (2023) had some imbalances at baseline: there were more mild to moderate instances of OA in the surgical standard of care group and the scaffold arm had more deep osteochondral defects and larger lesions on average. The range of concomitant procedures was limited in this study to reduce bias. This trial was funded by the company that manufactured the scaffold and several authors had conflicts of interest because of financial involvement in the company.
The RCT by Kim (2020b) was funded by the company that manufactured the scaffold but no other conflicts were reported.
The RCT by Kon (2018) did not reach its target sample size and the authors acknowledge this may have affected the ability to show statistically significant differences. The study was partly funded by the company that manufactured the scaffold and several conflicts of interest were reported.
The 5-year follow up of an RCT by Shive (2015) had 25% loss to follow up. The group of people analysed was sampled from the RCT group and they had comparatively higher BMI and lesion size than the original RCT group, although they entered these as covariates in their analysis. The follow-up study was funded by the company that manufactured the scaffold and some conflicts of interest were reported.
The registry study (Gille 2021) had significant loss to follow up; of 131 people that were included at baseline, only 9 had Lysholm data at 7 years. This is likely reflective of the number of people with data for other outcomes in this study. No conflicts of interest were reported.
The RCT by de Girolamo (2019) was included in 3 meta-analyses in the key evidence. It was also included in the key evidence because it compared using a scaffold with and without augmentation with bone marrow aspirate concentrate. This is a useful comparison given that the mixture of the evidence from techniques with and without augmentation, but this was a small RCT and so the conclusions are limited in generalisability. The first author of this study received speaker's honoraria from the company that manufactured the scaffold. No other conflicts of interest were reported.
Professional experts indicate that this procedure is being used to fill a gap between microfracture, which is suitable for small lesions, and more complex or technical procedures with cultured cells or resurfacing, which is suitable for large lesions.
Any ongoing trials:
- A Randomised Controlled Trial of Scaffold InSertion and Microfracture Compared to Microfracture Alone for the Treatment of Chondral or Osteochondral Defects of the Knee: The SISMIC Study; ISRCTN 90992837; n=176; UK; the chief investigator of this NIHR-funded trial said that it was stopped early because the funding was withdrawn. Final enrolment was 10.
- A ProSpective, MulticEnter, Concurrently Controlled Clinical Study of Chondro-Gide® ArticUlar Cartilage CoveR for the Treatment of Large Chondral Lesions in the KnEe (SECURE); NCT04537013; n=234; international (not UK); estimated completion date November 2026.
- A Randomized, Controlled, Comparative, Single-blinded, Multi-center Study Evaluating JointRep® and Microfracture in Repair of Focal Articular Cartilage Lesions on the Femoral Condyle or Trochlea, The JMAC Trial; NCT04840147; n=185; Australia and Canada; estimated study completion date Dec 2025.
- A Prospective, Multicenter, Randomized, Parallel Controlled Study Evaluating the Safety and Efficacy of Chondro-Gide® Bilayer Collagen Membrane in Knee Cartilage Defect Repair; RCT, n=140; China; NCT05785949; estimated study completion February 2027.
- Randomized Study Comparing Two Methods for the Treatment of Large Chondral and Osteochondral Defects of the Knee: Augmented Microfracture Technique versus 3rd Generation of ACI; n=80; Switzerland; NCT05651997; estimated study completion June 2032.

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