Characteristics
Indications
Side
Approval
Type of studies
Outcomes
Actifit®
Polyurethane aliphatic, synthetic, biodegradable, acellular
Partial meniscal replacement
Lateral and medial
Europe, Chile, South Africa
Phase I and II
Clinically and statiscally improvements
In process: USA (FDA), Brazil (ANVISA)
Collagen meniscal implant (CMI®)
Achilles bovine tendon, bioresorbable
Partial meniscal replacement
Lateral and medial
Europe, South Africa, USA
Phase I and II
Pain relief and functional improvements 10-year follow-up; MRI and histologic results are controversial
NUsurface®
Synthetic, nonabsorbable
Total meniscal replacement
Medial
Europe
Phase I
No long-term results
28.2.2.1 Collagen Matrix Scaffolds
The first studies that used collagen matrix scaffolds date from the late 1980s and early 1990s [20–22]. Although these studies were preliminary and mostly experimental, they helped to define the parameters of the scaffolds that are used more recently. At that time, studies both in dogs [20] and rabbits [21] revealed significant histologic findings in the cartilage of the femoral condyles of the animals that were treated with unseeded small intestinal submucosa (SIS) during a period of 6–12 months following a partial medial meniscectomy compared with the animals that underwent a simple meniscectomy. However, a more recent study has contradicted these results [23]. With the development of tissue engineering techniques, the first collagen meniscus implant (CMI®) for clinical use was developed in the United States. This biocompatible and degradable implant was designated Menaflex, and to date, this implant is only marketed in some European countries and trying new FDA approval again by the name CMI®. This implant comprises type I collagen fibers purified from bovine Achilles tendon [10, 22]. In the late 1990s, Stone et al. [24] initially reported the use of this technology, but with limited results due to the small number of cases and the short follow-up time. In addition, the procedure was only partially effective and had a reoperation rate of 22%. However, these studies demonstrated the safety of the technique [23]. Zaffagnini et al. [25] published a study with eight patients with a follow-up of 6–8 years and good clinical and radiological results. However, a second-look arthroscopic assessment and magnetic resonance imaging (MRI) revealed the deterioration of the implant over time, with a considerable reduction in size or the complete degradation of the implant. The same authors published a comparative, nonrandomized study [26] with a 10-year follow-up that indicated good results using a CMI® with various clinical outcomes. However, the faster degradation rate of this scaffold (6 months to 2 years) may limit its clinical benefits.
In a multicenter, randomized, controlled clinical study, 311 patients were divided into an experimental group comprising patients with scaffolds implanted after a partial meniscectomy and a control group that comprised patients submitted to a simple partial meniscectomy, and these groups were monitored for an average period of 59 months [27]. In addition, the patients were divided into acute and chronic cases prior to the randomization, and the results of these two groups were analyzed separately. The authors concluded that the clinical results of the chronic cases were more relevant than those of the acute cases. Indeed, for the acute cases, none of the measured parameters improved significantly compared with the controls. In contrast, among the parameters measured in the chronic patients, the Tegner score was significantly different and favored the CMI® (P = 0.04). Consequently, it may be inferred that this implant is an alternative to the partial meniscectomy. However, some important limitations are still unsolved, including the possibility of a reduction in the size or complete degradation of the implant. In addition, tissue growth inside the implant must be further studied in vivo because some authors argue that the implant tissue should exhibit the same biomechanical characteristics as those of native meniscal tissue [28].
28.2.2.2 Noncollagen Matrix Scaffolds
Another promising alternative for the treatment of irreparable injuries is Actifit®. Actifit® consists of a synthetic and bioabsorbable polyurethane scaffold that attaches to the vascular zone of the meniscus and enables the growth of similar meniscal tissue within the scaffold’s porous [17, 18]. The synthetic nature of this material may favor the implant customization; Actifit is manufactured differently for the medial and lateral menisci. Moreover, this implant exhibits a porous surface that occupies up to 80% of its structure, which facilitates the penetration of neomeniscal tissue; tissue integration occurs in 97.7% of the patients. An experimental study confirmed that this type of polyurethane scaffold allows the penetration of tissue composed of extracellular matrix and blood vessels [29, 30]. In 12 cases involving surgery who were submitted to MRI and a second-look arthroscopic assessment, Verdonk et al. found only one case in which meniscal tissue had not replaced the polyurethane scaffold [29].
The implant itself does not assume the function of the meniscus, but the polyurethane scaffold is engulfed by macrophages and giant cells and allows the replacement of the meniscal tissue [31] in a process that takes approximately 5 years. Moreover, a prospective, multicenter clinical study by the same authors [17] evaluated 52 patients (50 chronic and 2 acute cases) who underwent the implantation of an Actifit with a follow-up of 2 years. At the end of the study, a significant improvement was observed in all the clinical parameters evaluated [the Knee Injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee (IKDC) score, the Lysholm score and the visual analogue scale (VAS) for pain assessment] in addition to the stabilization or improvement of the ICRS score for cartilage in 92.5% of the patients. Despite these good results, the adverse events and treatment failure rates were high (17.3%), particularly in the lateral meniscus, where failure rates reached 33.3%. Given that the study was a multiple case study, it had methodological limitations, including the lack of randomization and the lack of a control group; these limitations must overcome for this technique to be compared with a traditional partial meniscectomy [17].
28.2.3 Total Meniscal Substitutes
Despite the recent concept of preserving as much meniscal tissue as possible, orthopedic surgeons still perform surgical interventions on serious injuries for which total meniscectomy is required. A few years following the meniscectomy procedure, nearly 50% of the patients are symptomatic and consequently require meniscal replacement to reduce both pain and the progression to more advanced stages of osteoarthritis [10]. In cases where the peripheral meniscal rim is absent, a total meniscal replacement should be prioritized. For many decades, the only option for symptomatic patients who had undergone a total meniscectomy was meniscal transplantation. However, despite encouraging results in the first 5 years, an assessment performed 20 years after the initiation of surgical interventions indicates a decrease in favorable clinical results [32]. In addition, meniscal transplantation would ideally protect the knee joint from articular wear; however, there is insufficient evidence to support the chondroprotective ability of meniscal transplantations.
At present, meniscal transplantation is the best alternative therapy for symptomatic patients who have undergone a meniscectomy. However, problems related to graft availability, size differences between the donor and recipient grafts, the high cost, and the risk of disease transmission limit the use of this technique. Due to the difficulty of transplantation, a complete meniscal replacement with synthetic materials has been studied for decades. Recently, a synthetic and floating implant that lacks an anatomic shape and is used for the medial meniscus (NUsurface®, Israel) is being tested in patients in a Phase I clinical trial [10]. Despite being considered a total replacement, the meniscal periphery together with the meniscal horns must be intact to accommodate the implant, which does not require fixation.
28.2.3.1 Allograft Meniscus Transplantation
Since the first meniscal transplantation in 1989, satisfactory results of meniscal transplantation have been reported in more than 30 clinical trials, and these results are primarily related to the improvement of pain and function. Even considering the different processing, sterilization, storage, surgical, and assessment procedures, the positive results in 85% of the patients justify and encourage the performance of this type of transplantation in select cases [32, 33]. The preoperative planning must be meticulous, starting with the indication, the graft size compatibility, and the surgical procedures to be used. In general, those patients who are relatively young, aged between 20 and 50 years, with a history of total or partial meniscectomy and persistent pain restricted to the operated region are considered the ideal candidates. The knee joint should be stable, with a normal alignment of the lower limbs, and the chondral injury should not exceed grade 2 (ICRS); however, if the injury grade exceeds 2, it should be a focal injury and would require concomitant treatment. Likewise, osteotomy and ligament reconstruction procedures must be performed during the same intervention with the goal of optimizing the longevity of the surgical results [34–37]. Several factors influence the clinical outcome following transplantation and are categorized into knee-specific factors (i.e., chondral damage, ligamentous stability, axial alignment, prior surgery), graft-specific factors (i.e., medial vs. lateral side, the method of preservation, sterilization, the sizing method), surgeon-specific factors (i.e., surgeon experience, the insertion method, graft fixation, concomitant procedures) and rehabilitation-specific factors (i.e., the range of passive motion, weight bearing, continuous passive motion, return to activities) [36]. Undoubtedly, one of the most critical factors for the success of meniscal surgery is the preoperative measurement of the meniscus. In addition, the measurements of allografts must be made accurately and analyzed during processing, and only a 10% measurement error is acceptable. However, no previous studies have compared the clinical outcomes with regard to graft size tolerance.
The most reliable method to determine the width and length of the meniscus, and which professional is responsible for the measurement—the surgeon or nurse working in the tissue bank—have not yet been determined [36]. In our opinion, both professional categories should know which methods are available, and which methods would provide increased reliability, including radiographic, MRI or a regression equation using anthropometric data, as proposed by Van Thiel et al. [38]. MRI of the contralateral knee, when healthy, seems to be the best option for meniscus measurement [39], and if not available, an alternative technique that uses different calculations for the medial and lateral menisci can be employed. The method proposed by Pollard et al. [40] in 1995 is a good option for determining the length and width of the medial meniscus. For the lateral meniscus, the radiographic method proposed by Yoon et al. [41] is a good option to determine length, whereas the anthropometric method [38] should be used to determine width.
The meniscal allograft may be cool (4 °C), fresh-frozen (−80 °C), cryopreserved or lyophilized (freeze-dried), and most surgeons use the prolonged fresh- or deep-frozen grafts because previous studies have indicated that donor cells are repopulated with recipient DNA [36], even without complete cell viability. Regarding surgery, various techniques have been reported, and it has been established that the fixation of the anterior and posterior horns is one of the essential steps in the technique. In addition, the proximity of the horns of the lateral meniscus is of special importance, which is why the most used method for the lateral meniscus is the construction of the bridge bone. In general, studies in the literature have a limited scope because of the absence of control groups. Nonetheless, the success of transplantation varies depending on the compartment involved. According to Verdonk et al. [42] success rates reached 72% for the medial meniscus and 63% for the lateral meniscus. In contrast, Cole et al. [43] reported that patient satisfaction varied from 93% for a lateral meniscal transplant to 68% for a medial meniscal transplant. Despite these encouraging results, some difficulties and risks of meniscal transplantation exist. The main concerns involve the low availability of grafts in tissue banks, high cost of the tissue graft, and precision of the surgical technique and the risk of bacterial contamination.
28.3 Research Potential
In recent decades, regenerative medicine has made significant advancements, and many experimental studies have addressed the issue of meniscal regeneration. In particular, researchers are working on the development of regenerative solutions for different clinical scenarios that require distinct surgical interventions. These solutions involve the following: (1) improving biological adherence and the repair of injuries, (2) the partial regeneration of meniscal tissues to restore the tissue removed after a meniscectomy, and (3) total meniscal regeneration when total or partial meniscectomy is performed. The following sections describe the foundations of tissue engineering (cells, growth factors, and scaffolds) with respect to meniscal regeneration and experimental strategies that combine distinct techniques.
In a recent revision paper, three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. The reports show increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types with promising future for meniscus replacement. Neither does the literature provide clarity on the optimal meniscus scaffold type nor biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process; however, it is hoped that this may lead to improvements in this strategy [44].
28.3.1 Cells
Mesenchymal stem cells are pluripotent cells found in various tissues, such as adipose tissue and bone marrow. The use of mesenchymal cells remains limited to scientific research for the treatment of meniscal injuries. Even in this context, the use of mesenchymal cells has had limited results and is not entirely reproducible. Another alternative to mesenchymal cells is bone marrow stromal cells (BMSCs), which experienced the same limitations. In a clinical study, Vangsness et al. [45] compared the infiltration of mesenchymal cells using two cellular concentrations to a control group containing hyaluronic acid. According to the authors, MRI examination indicated an increase in the meniscal volume in 24% of the patients who received 50 × 106 allogeneic mesenchymal stem cells. This increase was higher than those found in the other experimental groups. Zellner et al. [46] created injuries in the avascular zone of the meniscus in rabbits and treated these injuries with a noncellular matrix of hyaluronan collagen in one group. The second group was supplemented with platelet-rich plasma (PRP); the third group was supplemented with autologous bone marrow; the fourth group comprised mesenchymal cells cultured for 14 days; in addition, there was an untreated control group. The mesenchymal cells group differed from the other groups with the appearance of a repair tissue resembling fibrocartilage although this tissue was not yet fully integrated into the native meniscal tissue. The authors believe that, experimentally, mesenchymal cells exhibit the biological potential to repair injuries in the avascular zones [46, 47]. However, according to some authors, cells from the resected meniscal fragment are considered ideal because these cells exhibit less morbidity and can be seeded into biological scaffolds. In addition to meniscal and mesenchymal cells and BMSCs, other cell types can be used for meniscal regeneration, including synoviocytes, articular chondrocytes, ear chondrocytes, nose chondrocytes, and rib chondrocytes.
Among the most promising strategies to improve the final outcome, cell augmentation deserves particular attention. The available preclinical evidence, despite being not conclusive, suggests that cells may enhance tissue regeneration with respect to the use of biomaterials alone, which warrants further research in this direction. Exploring the best cell sources, manipulation and application modalities could contribute to a possible translation of bioengineered tissues in the clinical practice, being aware, however, that the beneficial effects of cellular augmentation reported in animal trials might be not confirmed when used in the human model [48].
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