Surgical techniques for the articular cartilage repair: literature review and meta-analysis

Objective. To evaluate the clinical efficacy and safety of implement - ing the extracellular matrix (ECM), Autologous Matrix Induced Chondrogenesis (AMIC), adipose tissue derived mesenchymal stem cell (AD-MSCs), as well as bone marrow mesenchymal stem cells (BM-MSCs) for treating the osteochondral defects of knee joint and the talocrural one. Methods. Investigating by the facilities of PubMed, Embase and the manual searches, implemented from 2018 till January, 2022. There have been included articles with the І‒ІV level of evidence, studying the osteochondral defects over 0.5 сm 2 , with at least one-year duration of monitoring more than 10 patients, defining the scores on VAS (Visual Analogue Scale), Tegner Activity Scale, FAOS (Foot and Ankle Outcome Score). The results were evaluated after 1–2, 3–5 and over 5 years-period of monitoring. Meta-analysis was applied by the facilities of RStu - dio. Results. 14 investigations with 720 patients were incorporated. ECM, AMIC, AD-MSCs and BM-MSCs represented significantly better functional outcomes in comparison with the bone marrow stimulation procedures (MSP) on the VAS, Tegner Activity Scale, and FAOS scales. Patients treated according to the AMIC+BMAC (bone marrow aspirate concentrate) method showed better


Introduction
Articular cartilage is a connective tissue with a unique structure that has shock-absorbing properties, considerable durability, and the smoothness of the articular surfaces minimizes friction during movements [1]. It also has an alymphatic and hypocellular structure, which, in combination with weak metabolic activity, limits regeneration [2].
Cartilage regeneration occurs with the formation of fibrous tissue, which contains type I collagen [3,4], significantly affecting its biomechanics [5]. Bone marrow stimulation procedure (MSP) is indicated for patients with small area (less than 150 mm 2 ) or diameter (less than 15 mm) defects with a depth of less than 7 mm [6,7]. One of the cartilage repair techniques is microfracture (MFx). The main problems of this technique are the quality of the obtained reparative tissue (fibrous cartilage), the unpredictable volume of the regenerate. An alternative technique is tunneling or micro-drilling (MD). In the case of creating microfractures of the bone with the help of an awl, unlike microdrilling, the bone is compacted. Besides, more type II collagen is formed and the defect is more evenly filled [8].
«BioCartilage» is an extracellular auto-or allocartilage matrix (ECM), which contains growth factors, proteoglycans, and type II collagen [6]. The principle of its application involves creating a matrix over the defect after microfractures or microdrilling, which ensures the interaction of autologous articular cartilage cells in the regenerate. ECM requires hydration with platelet-rich plasma (PRP) or bone marrow aspirate concentrate (BMAC).
The results of the use of autologous matrix for induction of chondrogenesis (Autologous Matrix-Induced Chondrogenesis, AMIC) were published in 2005 [9]. As a result of the microfracture manipulation, a «super clot» is formed, which contains stem cells and growth factors. Consequently, it is fixed with a membrane based on porcine collagen type I/ III, thereby providing stability and favorable conditions for the formation of new cartilage tissue [10]. Matrix-associated stem cell transplantation (MAST) is a technique in which bone marrow aspirate is additionally used during AMIC [11].
Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, as they can differentiate into osteocytes and chondrocytes in vitro [12], for cartilage regeneration most often -mesenchymal stem cells of adipose tissue (AD-MSCs) and bone marrow (BM-MSCs) [13].
The purpose of the study: to conduct a meta-analysis and evaluate the clinical effectiveness and safety of the use of ECM, AMIC, AD-MSCs and BM-MSCs for the treatment of osteochondral defects of the knee and talocrural joints.

Literature search strategy
The review was prepared in accordance with the recommendations of the «Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines». PubMed and Embase were searched from 2018 to January 2022 using the following terms: «Osteochondral», «BioCartilage», «Allograft cartilage extracellular matrix», «Autologous Matrix Induced Chondrogenesis» or «AMIC», «MSC» or «Mesenchymal stem cells», «AD-MSCs», «BM-MSCs». References of reviews and studies were also manually searched.
Inclusion criteria Studies were selected by two reviewers independently. Relevant articles were included after reading the full text and determining the necessary parameters. Inclusion criteria: 1) osteochondral defects over 0.5 cm2; 2) articles with evidence level I-IV; 3) duration of observation not less than one year; 4) more than 10 patients included in the study; 5) articles in foreign languages.
Data extraction According to the specified criteria, two independent researchers checked the search results by title, abstract and full text. Extracted data included: first author, year of publication, level of evidence, study design, location of lesion, number and age of patients, bone marrow stimulation technique, defect size, treatment groups, primary outcomes, and follow-up. VAS (Visual Analogue Scale), Tegner Activity Scale, FAOS (Foot and Ankle Outcome Score) scores were determined. The results were evaluated after 1-2; 3-5 and more than 5 years.
Statistical analysis Meta-analysis was performed using RStudio software (https://www.rstudio.com/), a meta package to generate hazard ratios for categorical outcomes, mean differences for continuous outcomes, and 95 % confidence intervals (CIs).

Literature search results
In total, 1,563 articles were found by searching the literature in electronic databases, of which 724 were from the PubMed database, 834 from Embase, and 5 were selected by manual search.  Thirty-seven potentially eligible articles were assessed by reading. Ultimately, 14 articles were included (Fig. 1).

Demographic indicators
In total, based on the materials of the selected articles, 720 patients aged 26 to 59 years were included in the study. There were 370 men among them, although it should be noted that in one study the gender distribution of patients was not reported. The duration of observation was from 12 months to 9 years. 57.14 % of cases involved the knee joint and 42.86 % the talocrural one (Tables 1, 2).

Clinical research results
Since the treatment of patients implied the use of various techniques, the surgical treatment strategies and postoperative results differed ( Table 3).
Results of statistical analysis according to VAS In 1-2 years, the mean difference for the ECM group between preoperative and postoperative re-  (Table 4).
Complications No intraoperative complications were reported. Among 14 studies (with the participation of 720 patients), postoperative complications were not recorded in 3, and revision operations were reported in 6. They were performed due to constant pain syndrome, progression of degenerative changes in the joint, unsuccessful surgical intervention.
Discussion ECM showed significantly better VAS outcomes at 3-5 years of follow-up compared to MFx, and MFx revealed significantly worse outcomes compared to AD-MSCs, BM-MSCs, and AMICs. According to the Tegner scale, in the case of using AMIC + BMAC under observation conditions of more than 5 years, better results were established compared to AMIC without stem cells. Regarding the FAOS score, the results of the ECM group were better at 5-year follow-up compared to MFx.
ECM is a modern, simple surgical procedure that complements the well-known MFx technique. Histological and immunohistochemical studies showed that the formed regenerate contained type II collagen. In 2021, J. Commins et al. [28] published the findings that BioCartilage acts as a scaffold and also has a characteristic composition to support cell adhesion and migration.
Better functional results were determined in patients who received treatment using the AMIC + BMAC method compared to the standard AMIC method. MRI analysis in 12 months confirmed this observation.
Comparison of the results of both groups revealed that the majority of mesenchymal progenitor cells were important in the initial stages of cartilage repair, as they accelerated the repair process. It has been demonstrated in vitro that bone marrow mesenchymal cells can differentiate into different cell types under the influence of appropriate stimuli, such as 3D culture media [29]. Significant differences between the standard AMIC procedure and AMIC + BMAC were found after one year, which may indicate that MSCs have a temporary effect on the repair processes, reducing the local inflammatory process and, in turn, alleviating pain. In 2017, a group of authors published the results of a fiveyear study comparing the use of AMIC and MFx. Significantly better results (according to the Cincinnati, ICRS and VAS scales) were obtained after using the AMIC technology, and MRI showed more complete filling of the chondral defect [30].