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Meniscal allograft transplants and new scaffolding techniques

Clinical management of meniscal injuries has changed radically in recent years. We have moved from the model of systematic tissue removal (meniscectomy) to understanding the need to preserve the tissue. Based on the increased knowledge of the basic science of meniscal functions and their role in joint homeostasis, meniscus preservation and/or repair, whenever indicated and possible, are currently the guidelines for management. However, when repair is no longer possible or when facing the fact of the previous partial, subtotal or total loss of the meniscus, meniscus replacement has proved its clinical value. Nevertheless, meniscectomy remains amongst the most frequent orthopaedic procedures. Meniscus replacement is currently possible by means of meniscal allograft transplantation (MAT) which provides replacement of the whole meniscus with or without bone plugs/slots. Partial replacement has been achieved by means of meniscal scaffolds (mainly collagen or polyurethane-based). Despite the favourable clinical outcomes, it is still debatable whether MAT is capable of preventing progression to osteoarthritis. Moreover, current scaffolds have shown some fundamental limitations, such as the fact that the newly formed tissue may be different from the native fibrocartilage of the meniscus. Regenerative tissue engineering strategies have been used in an attempt to provide a new generation of meniscal implants, either for partial or total replacement. The goal is to provide biomaterials (acellular or cell-seeded constructs) which provide the biomechanical properties but also the biological features to replace the loss of native tissue. Moreover, these approaches include possibilities for patient-specific implants of correct size and shape, as well as advanced strategies combining cells, bioactive agents, hydrogels or gene therapy. Herein, the clinical evidence and tips concerning MAT, currently available meniscus scaffolds and future perspectives are discussed. Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180103


Introduction
Injuries of the meniscus are probably the most frequent injuries occuring in the knee. 1 According to the statement from Prof. René Verdonk, 'Nothing has changed so much in recent years of orthopedics as the treatment algorithm of meniscus lesions'. 2 A radical change occurred since the 'recommendation' during the 1970s to remove as much as possible of what was formerly considered as a useless structure, 3 to the present-day movement supporting the preservation, repair or replacement of the meniscus. 2 Recent basic science research reinforced the claim that the menisci are fundamental components of a healthy knee joint. [4][5][6] Menisci are C-shaped fibro-cartilage structures with a wedge-like cross-section ( Fig. 1), present between each tibial plateau and the corresponding femoral condyle. 5,7 They have a specific extracellular matrix, 8,9 multiple cell types 10, 11 and particular cell distribution. 5,12 They Meniscal allograft transplants and new scaffolding techniques have unique biomechanical features 13 and are known to have segmental and regional variations concerning ultrastructure, vascularity, biology, and function. 7,12,13 There are differences between the medial and the lateral menisci in knee kinematics. The lateral meniscus is accountable for most of the load transfer within the lateral compartment (around 70%), 14 while the transmission of loading is more equally dispersed through the cartilage surfaces and the medial meniscus (50%) in the medial compartment. 15,16 Concerning kinematics, the lateral meniscus is more mobile, while the medial one is more static to resist anterior tibial translation, acting as a secondary agonist of the anterior cruciate ligament (ACL). 6,14 It has been recently shown by 2-dimensional (2-D) and 3-dimensional (3-D) analysis of the menisci segments that cellular density is relatively higher on the anterior segment when compared to other parts, and that the posterior segments tend to be stiffer. 12,13 It was hypothesized that the higher damping properties of the anterior segments could be related to the higher cellular density, meaning that biology and biomechanical features are combined. 12,13 One should bear in mind the basic science knowledge related to each meniscus since it surely has implications for tissue loss, repair, healing and outcomes of replacement. 12,17 Moreover, vascularization of the menisci is critical for treatment decisions. The peripheral vessels infiltrate around 10% to 25% of the width of the lateral meniscus and 10% to 30% of the width of the medial meniscus in adults (Fig. 1). 18 Children and adolescents are known to have increased vascular supply. Thus, they have more possibilities for repair when a meniscal injury occurs, despite sometimes suffering from more complex meniscus lesions. 19 Meniscectomy has significant consequences for the joint and causes a higher risk of early joint degeneration, despite remaining one of the most frequent orthopaedic procedures worldwide. [20][21][22][23][24] Meniscus repair commonly provides superior clinical outcomes when compared with meniscectomy. 25,26 As a general rule, the meniscus tissue should be preserved whenever possible. However, meniscus repair has specific indications and limitations. [26][27][28] It is widely recognized that there is an urgent need for an improved description of meniscal tear patterns, 29 standardized reporting of outcome measures, and betterquality study methodologies in order to help in making the best decision for the treatment option and/or technique, as well as establishing prognosis. 26 A very important distinction, which often is not easy to make, is between traumatic and degenerative lesions. [30][31][32][33] The physiopathology of meniscal lesions is not always easy to understand and frequently is part of the whole of the knee joint loss of balance. 6 A traumatic meniscus tear is typically related to an acute trauma which produces sufficient energy to split the tissue. The tear patterns more commonly linked to traumatic tears are: longitudinal, buckethandle and radial tears. 34 Nevertheless, most flap tears are also classified as traumatic. High-energy traumatic events which might cause fractures around the knee can also be involved in meniscus tears. 35 Some of these lesions require combined osteochondral and meniscal transplantation. 36,37 Contrarywise, degenerative meniscus lesions are characteristically caused by chronic degenerative changes including cavitation, fibrillation, softened/brittle tissue, or more complex tear patterns, among others. 29 Horizontal lesions represent the typical type of such lesions. [38][39][40] Such cases often have a degenerative nature even in younger patients. [37][38][39] Considering posterior root tears, lateral tears are more frequently traumatic (often combined with anterior cruciate ligament rupture), while medial meniscus root tears have more often a degenerative nature. 41,42 There has been a recent technical development linked to meniscal repair, and some lesions classically classified as irreparable (e.g. radial or horizontal tears) are having encouraging results with repair. 26 Globally, a failure rate for meniscus repair of approximately 15% is widely accepted, despite the fact that in the literature it ranges from 5% to 43.5%. 43 Furthermore, it has been demonstrated that the failure of a meniscal repair does not worsen the outcome, nor dictate a need for a bigger loss of tissue volume, if a reoperation and menisectomy is needed. 43 This fact reinforces the point that it is fair and advisable to 'save the meniscus and preserve the future of the joint' whenever possible. However, if repair is not possible, partial or total meniscal replacement seems to be the most adequate method, whenever possible. 44 This choice is not purely based on the meniscus injury but also on the global condition and function of the joint, considering the cartilage condition and ligament status and function. 45 The first description of meniscus allograft transplantation (MAT) was in the 1970s, in patients with post-traumatic osteoarthritis secondary to fractures of the tibial plateau treated by an osteochondral allograft resurfacing procedure combining bone, cartilage, and meniscus in a single step. 46,47 The first free MAT was performed in 1984. 48 Since then the technique has been intensely developed and proposed for the treatment of patients with a symptomatic painful knee as consequence of meniscectomy, under specific indications and contraindications. 49 MAT has been demonstrated to be a reliable therapeutic option. 50,51 It has received and keeps receiving relevant improvements and increasing interest from surgeons and researchers based on favourable outcomes, already with long-term follow-up. 37,[50][51][52][53][54][55] The concept of meniscal replacement by means of using a scaffold was introduced in the 1990s. 56 Total meniscus allograft transplantation and partial meniscal replacement by means of scaffolds (with or without biological enhancement) have, by definition, different indications and possibilities. The implantation of a scaffold for partial meniscus replacement necessitates that the meniscal roots and peripheral rim remain conserved. These requirements are not needed for MAT, which enables complete replacement of the meniscus by means of creating new 'root-like' attachments. 49 Access to and acceptance of allografts are not equal in all countries, because of some legal, economical, disease transmission concerns, as well as ethical, or even religious objections. 57 For all these reasons, considerable restrictions of access to proper meniscal allografts remain in several countries. 44,57,58 There are high expectations of tissue engineering and regenerative medicine. Future perspectives include new, more effective, biomaterials, combined with augmentation by means of effective use of cells, bioactive agents (e.g. growth factors or medication molecules), nanotechnology or gene therapy in advanced strategies. 27,59 Moreover, it is also possible to produce patient-specific implants by using 3-D printing based on patient imaging. 60,61 Tissue engineering technologies raise the possibilities, in future, of providing a limitless source of effective tissue for meniscus replacement (partial or total), avoiding the previously described limitations and concerns of allografts related to donors, with the associated complicated processing and size-matching issues. 27,62 Meniscus allograft transplantation (MAT)

Fundamentals, indications and techniques of MAT
The 'ideal candidate' for MAT is a young patient with a history of symptomatic femorotibial compartment symptoms having undergone a previous meniscectomy, with a stable knee, neutral alignment and no severe chondral damage or arthritis. Presence of cartilage degeneration, obesity and smoking habit are considered risk factors. 49,63 A summary of indications and contraindications for MAT are summarized in Table 1.

Preservation and sterilization methods
Preservation and sterilization methods of the meniscal allografts appear to play a role in outcome. 49,50 Currently, there are four types of meniscal allograft: fresh, cryopreserved, deep-frozen 49 and lyophilized, although lyophilization is not currently used anymore (Table 2). 37,[63][64][65] Deep-frozen (fresh-frozen) and cryopreserved meniscal allografts are the most frequently used. 65 There is a growing trend for the use of fresh allografts. 37,57,65 Cryopreservation proved to be a significantly better method of preservation, when compared with freshfrozen. Fresh meniscal transplantation is logistically demanding and expensive given the short period of time between the donor's death and transplantation. The use of fresh tissue transplantation has inherently a higher risk for disease transmission. 65 This risk has been estimated to be 1:8,000,000 for HIV 67 and 1:2600 for Clostridium 67 (as examples). However, most likely this method shall be the one which preserves the most native biological and biomechanical features of the meniscus for MAT. 37,57,65 In the case of fresh meniscal allografts transplantation, there is also a risk of transmission of pathogens, so specific care and procedures are required to minimize risks, including special tests aiming to exclude infection. 65 Moreover, concerning cells, the advantage of preserving donor cells is debatable once host cells are capable of repopulating the graft within a few weeks following MAT. 65 Technical choices for MAT fixation As technical choices for MAT fixation, several techniques have been proposed including bone blocks, or soft tissue only (Fig. 2). 49,68 There is still no clinical evidence favouring any technique over another. 49,68 Concerning fixation, multiple studies have shown comparable graft survival and outcomes between different fixation options. 49,50 Some authors have reported that a meniscus allograft fixed with the suture-only technique had a higher degree of extrusion of the meniscal body and a trend for higher rate of MAT tears (Fig. 3) when compared to the bony fixation method. 69 However, no influence on the functional outcome was noticed for either, and more studies are still required on the topic. 69 Two relevant topics for research on MAT are the fixation and integration of the meniscus tissue itself and its anchorage to the bone. There are different anatomic characteristics for the lateral and medial meniscus which influence the technical approach considering the previous

Table 2. Preservation and sterilization methods of the meniscal allografts
• Freeze drying or lyophilization -this preservation technique includes dehydration. It has been shown that it increases the risk of meniscal shrinkage, so it is no longer used. 49,65 • Deep or fresh frozen -the tissues are frozen without further processing, at -80 ºC, which makes it simple and relatively cheap. It annihilates the cells from the graft; however, it reasonably preserves the collagen architecture, despite some changes in collagen structure having been reported. 64 • Cryopreservation -Cryopreservation freezes the graft at -180 ºC with the addition of glycerol or dimethyl sulfoxide as antifreezing agents. This method is believed to preserve some donor cells' integrity and viability. It has been demonstrated to preserve the most relevant meniscal ultrastructure despite the preservation of cellular viability being less reliable. 166 • Fresh and viable -Fresh menisci can be obtained from multiorganic donors. This maintains cellular viability but concerns exist in relation to risk of infectious disease transmission. Incubation of the fresh meniscus in serum for 15 days is required, to preserve viability as well as diminishing risks by performing specific tests. Although expensive and logistically complex, this is an attractive option. 37 topics. The anterior and posterior root attachments of the lateral meniscus are closer when compared to the medial meniscus in which they are more separated. 5,26,70 Considering the previous, when performing a medial MAT, two bone tunnels in the tibia will often be required. For lateral MAT, the vicinity of root attachments makes it more difficult to create such tunnels (risk of coalescence) and a bone slot/block technique can be considered as it preserves the native tibial root attachments of the graft. 49

Measurement techniques for sizing
One determinant pre-operative requirement is evaluation of the size of the knee receptor compartment and finding a matching meniscus allograft. Several measurement techniques for sizing the recipient compartment have been studied based on plain X-ray, CT, MRI and anthropometric data. 63 A graft which is too small will be exposed to an increased biomechanical load, which will most likely lead to an early failure. Conversely, a graft that is too big will have an extruded position within the joint, lowering its biomechanical function and resulting in a continuous overload of the articular cartilage. 63 Three types of medial anterior horn anatomy have been described: the most common is type 1, with an insertion posterior to the anterior tibial edge and lateral to the spine; type 2 has an insertion medial to the spine; and type 3 (less frequent) has an insertion anterior to the anterior edge of the tibial plateau. 71 Gelber et al hypothesized that placing a MAT posterior to the tibial edge in a knee with previous type 3 meniscus might result in overstuffing of the anterior compartment. 63 These details are examples of technical tips based on anatomic and biomechanical knowledge which play a major role in outcome.
The most frequently used sizing method was described by Pollard et al, and is based on calibrated anteroposterior (AP) and lateral radiographs. 72 However, its major limitation mainly affects lateral allograft sizing given the significant interindividual variability between the medial and the lateral compartment dimensions measured on plain X-rays (mainly in the AP view). 72 Some attempts have been made to increase its effectiveness by means of mathematical models. 63 CT and MRI-based imaging are considered to be more precise but increase the cost, and CT has inherent radiation. However, to assess the anterior horn of the medial meniscus, an MRI of the opposite knee is required.
The choice of surgical technique (with or without bony fixation) is also linked with the reliability of sizing and matching the graft. Bone block fixation requires anatomical reconstruction of the anterior and posterior horns. Thus, this technique is more demanding in terms of matching the receptor and the graft, and requires an experienced allograft bank. Bone-free MAT technique is less demanding concerning size mismatching.
To date, no method of sizing has proven to be more reliable or user-friendly than any other.

MAT's extrusion
MAT's extrusion (radial displacement of the allograft) has been a matter of debate for several years. Its relation with clinical outcome is not completely clear and an extrusion up to 3 mm has been considered as 'normal'. 63,73,74 However, one can understand that, if significant displacement of a graft occurs, its biomechanical role in resisting compressive, radial, cutting or hoop stresses could be compromised. 6 Extrusion following MAT seems to be a frequent finding, which usually appears shortly after surgery, and does not always progress through time. It seems that bony fixation is less prone to extrusion than soft tissue technique. 69 Lateral MAT seems to be more prone to extrusion than the medial. 75 Some attempts have been made to diminish extrusion such as aiming for the most anatomical graft placement, reducing the size of the graft by 5%, 76 the excision of peripheral osteophytes of the tibial plateau, the fixation of the meniscus allograft on the tibial surface or the reduction and fixation of the lateral capsule to the tibia. 63 However, as previously stated, based on the literature, no major adverse consequences have been linked to extrusion, so one cannot favour any technique over another. 63,73 Currently, most MAT procedures are performed by arthroscopy. Fixation of the meniscal horns may be achieved either by sutures passed through bone tunnels or bony fixation (press-fit, anchors, interference screws). Peripheral fixation is usually performed by combining allinside with outside-in meniscus sutures. 26 Some technical tips are described in Table 3.

MAT in the pediatric population
There is a paucity of data concerning the application of MAT in the pediatric population. 77 The increasing participation of children in sports, including elite sports, has led to a rising number of sports-related injuries in children and adolescents. This results in a higher number of children with premature loss of meniscus leading to early progressive degenerative joint disease. Discoid meniscus tears represent another possible cause of meniscus-deficient knees in youngsters, with further candidates for MAT. 77 Gelber et al advise that patients with open physis, might require an expectative attitude with clinical and MRI assessment every year, in order to follow the evolution of the articular cartilage's status. 63 If progressive cartilage deterioration is identified, a MAT may be suggested, even in the absence of clinical signs, beside considering that the clinical evidence in this population is low. 63

Rehabilitation
Concerning rehabilitation, once more there is no consensus. Some surgeons permit immediate weight-bearing while others recommend a variable period of non-weightbearing (3 to 6 weeks). Similarly, some promote a period of immobilization, however, most surgeons permit early motion (in the first 2-3 weeks) from 0º to 60º. The rationale is that the movement of the menisci is minimal within this range. Therapy focuses on gradually restoring full knee extension, decreasing swelling and pain control. Another goal is recovery of quadriceps strength with isometric exercises, passive and active motion. After the first 3-4 weeks, gradual increase in knee flexion up to 90°, combined with progressive weight-bearing, and closedchain kinetic exercises are advised. At 6-8 weeks after surgery, the patient should be capable to fully weight-bear, and at 4-6 months running on flat ground is usually encouraged. 63,73 Forced flexion and pivoting maneuvers are avoided for the first 6-12 months.

Clinical outcome of MAT
The main goal of MAT is to prevent or delay the arthritic degeneration of the joint. However, it has not yet been confirmed whether this target is systematically accomplished. 63,74,74 For many years, and to this day in some places, MAT was seen as an experimental procedure. 50 However, over time, MAT has provided reliable and reproducible favourable results if proper indications are followed. 50,63,73 MAT has proven its effectiveness in reducing pain and improving function and quality of life. 63,73 However, there are still some questions to address regarding the integration and longevity of the graft, the efficacy • The suture-only fixation technique is usually less demanding than bony fixation. • A larger graft can be implanted anatomically by pulling it more to the inside of the osseous tunnel. • A smaller graft can be positioned short of the anterior horn in the tibial plateau to avoid overtension and achieve fair coverage of the joint surface. • A suture passed at the junction between the posterior one third and mid-body of the allograft, is very useful to bring the graft in place. This suture shall be retrieved out of the join from an outside-in pulling loop, and tension is applied while bringing the graft in place. • Enlarge the arthroscopic portal of the involved compartment generously to facilitate introducing the graft in the join.
Source: Based on Gelber PE, et al. JISAKOS 2017;2:339-349. 63 of MAT in prevention of osteoarthritis and the possibility of returning to high-demand activities. 49 A recent meta-analysis reported the published outcome of 2977 patients (3157 allografts). 73 Thirty-eight per cent of cases received an isolated MAT while the remaining underwent at least one concomitant procedure. In different studies, clinical assessment included Lysholm, Knee Injury and Osteoarthritis Outcome (KOOS), International Knee Documentation Committee (IKDC) and Visual Analogue Scale (VAS) scores. A significant improvement in all scores and a good patient satisfaction at long-term followup was demonstrated. The mean overall survival rate reported was 80.9%. There was a negative evolution in radiological osteoarthritis with at least one grade lowering in 1760 of the studied patients. Concomitant procedures had no significant effect on outcome, although age at transplantation was determined as a negative prognostic factor and body mass index had a slight negative correlation with the outcome of MAT. The identified rate of complications was equivalent to standard meniscal repair surgery. 73 It has been recently stated, on a short-term follow-up, that is possible to return to high-demand sports (e.g. soccer, basketball, rugby and volleyball) after MAT. Zaffagnini et al reported 74% of patients returning to sports, 50% of these at the previous level of participation, after 8 months of rehabilitation. 51,78-80 Similar results have been reported from other small series at short term followup 51,79,80 . Given these facts, such data must be considered with care before more definitive and brad conclusions can be drawn.
Concerning the pediatric population, there are few reports in the literature on the outcome of MAT. 77 MAT is an effective method for treating meniscal deficiency following irreparable tears in discoid meniscus based on a series that compared MAT in discoid versus nondiscoid knees at a minimum 2-year follow-up. 81 Despite the fact that the discoid group had a significantly lower range of motion, functional scores improved similarly in both groups. A recent paper reported on 37 MAT procedures performed in 36 children, with mean age of 15 years, 84% lateral and 16% medial at 2-years follow-up, with at least similar improvements in functional outcomes as reported for adults. 82 Moreover, another study reported 3 cases of MAT at 2-year follow-up (two after discoid meniscus and one after medial bucket-handle tear combined with anterior cruciate ligament rupture), with the authors concluding that MAT in skeletally immature patients leads to acceptable clinical outcomes without growth deviation. 83 There is limited analysis of the cost-effectiveness of MAT; however, a recent analysis concluded that MAT needs to be approximately one-third more effective in delaying osteoarthritis in post-meniscectomized knees to be considered as cost-effective. 84 According to the same study, MAT is more cost-effective for young patients (20-29 years old) and less cost-effective in obese patients (Body Mass Index of [30][31][32][33][34][35]. 84 However, further research is required.

Fundamentals, current options and clinical outcome of MSR
The concept of meniscal scaffolds was initiated in the 1990s. 56 Currently, two acellular meniscal scaffolds have been used in Europe for clinical application: 85 the collagen meniscus implant or 'CMI' (Ivy Sports Medicine, Lochhamer, Germany) which is based on type I bovine collagen matrix; 56,85 and the polyurethane-based also known as 'ACTIFIT' (Orteq Bioengineering, London, uK). 86,87 Partial meniscus substitution with scaffolds and MAT have different indications as scaffold implantation requires that the meniscal roots and peripheral rim remains preserved. 74 However, they were developed to overcome the consequences of symptomatic knees after partial meniscectomies.
A summary of indications and contraindications on the use of acellular meniscal scaffolds for partial meniscal replacement is presented in Table 1.
Partial meniscus replacement by using scaffolds has been used with promising short-term clinical results for chronic partial meniscus defects. 85,[88][89][90] Clinical studies are based on acellular scaffolds while basic science researchers promote some biological enhancement. 85 Its application in acute cases remains somewhat limited and controversial. 91 Technically, these procedures are also performed arthroscopically (Fig. 4). A measurement of the defect is performed during surgery and the scaffold is cut in order to match the defect. A slight oversizing of the scaffold is recommended. A suture can be used in the middle of the scaffold to assist in bringing the scaffold into place (similarly to the technique described for MAT), and fixation is performed to the meniscus remnant by means of vertical and horizontal sutures by all-inside and/or outside-in/inside-out techniques.
Both scaffolds achieved positive clinical results in the treatment of partial medial and lateral meniscal loss with self-reported pain reduction, improved knee function and quality of life. These results have been described for both the polyurethane-based and the collagen-based implants. (745,88-90,92-103) Moreover, meniscal replacement by both implants has proven to be safe for medial and lateral menisci. 85,97 However, the final tissue obtained has been documented as different from the native meniscus (Fig. 5). 85 Resorption of the implants 98 and extrusion (Fig. 6) of the scaffold has been a matter of growing debate and concern. 101 Nevertheless, the clinical outcome does not completely correlate with the imaging findings, with patients' satisfaction and clinical scores being reported has higher than for imaging assessment and outcome. 98 The ACTIFIT scaffold consists of porous polycaprolactone and urethane segments which degrade slowly over a 5-year period and it aimed to provide a template for tissue ingrowth (Fig. 7). 104 However, MRI assessment, including Genovese score (assessment of size/morphology and signal intensity; each in 3 degrees), 105  without reaching normal signal. 98 The CMI theoretically has a more biocompatible profile (collagen type I from bovine Achilles tendons) and was 'designed as a regeneration template into which the body's own tissue may grow'. 56 According to a recent systematic review, higher rates of scaffolds with reduced size were found at longer follow-up when compared with initial evaluations. 89 However, MRI signal intensity was reported as more similar to normal meniscus. 89 A recent systematic review comparing both scaffolds has reported on 658 patients (347 ACTIFIT, 311 CMI) at mean 45 months' follow-up. 97 Treatment failure occurred in 9.9% of patients receiving the ACTIFIT scaffold and 6.7% of patients receiving CMI. However, failure rate ranged from 0% to 31.8% amongst the evaluated studies. 97 Such discrepancy might be due to a variable definition of 'failure' or publication bias (authors are less prone to publish failures). 106 Moreover, the presence of concomitant surgeries such as anterior cruciate ligament reconstruction (ACLR) and high tibial osteotomy (HTO) could have an influence on these results. Clinical outcome evaluation using VAS for pain, Lysholm Knee Scores, and Tegner Activity Scores improved from pre-operatively to latest follow-up for both scaffolds. The KOOS and IKDC scores improved from pre-operatively to latest follow-up only for ACTIFIT patients. Overall, patients receiving CMI scaffolds had higher grades for Genovese morphology and signal intensity (Fig. 4) when compared to ACTIFIT scaffold patients. In conclusion, the authors stated that patients might expect improved clinical outcome with either or both scaffolds, particularly when combined with ACLR or HTO. 97 There is one single case report describing return to sports activity at pre-injury level on a professional footballer after partial lateral meniscus replacement, 10 months after the operation, with lasting results. Therefore there is insufficient evidence in the literature supporting the use of these strategies when aiming for return to high-level sports. Concerning rehabilitation protocol as described for MAT, there is a lack of consensus. However, despite the fact that this surgery of scaffold implantation is usually less invasive as it does not require bone tunnels for root fixation, the basics of rehabilitation are quite similar to those for MAT. However, a lower inflammatory post-operative response is expected.

Road for future in meniscus replacement
Since the implications of meniscectomy have been recognized (loss or diminished meniscus function), the future developments of meniscus replacement are strongly motivated by a clinical need.
Synthetic, non-anatomical approaches are being tested. Nusurface Meniscus Implant ®, intends to function as a spacer, trying to redistribute loads transmitted across the knee joint, even if it does not replace normal anatomy. It is made of polycarbonate-urethane, and is under clinical trial and development. 74,108 Despite early favorable clinical outcome reported from developers, some complications have been described (e.g. dislocation). 109 Tissue Engineering and Regenerative Medicine (TERM) approaches aim to develop new implants, biomaterials (Fig. 8), biological enhancement of surgical approaches (cells, growth factors, proteins, nanotechnology, hydrogels), amongst many other advanced approaches aiming to fix, replace or improve any biological system. 44,45,62,110,111 Gene therapy is another promising research field dedicated to improving meniscal repair or replacement. 112,113 Growth factor technology is under intense development aiming to permit the selective control of cell activity to accelerate tissue healing, in future. 44,114 Nevertheless, the understanding of the complex mechanisms of cell  function, activation and differentiation, together with comprehension of their interaction, is far from being achieved. Mesenchymal stem cell (MSC) research is another field under powerful expansion. 44,111,113,[115][116][117] A clinical study using human adult MSCs injected into the knee for treatment of symptomatic consequences from partial medial meniscectomy has shown a significant increase in the volume of the menisci as assessed by MRI at 2-years follow-up. 118 The more advanced strategy of using cell-laden scaffolds (constructs) for meniscus repair has been described in several pre-clinical studies. 44,85 However, a fibrocartilage with similar biological and biomechanical characteristics to the native meniscus has not been consistently obtained so far. Maturation of such constructs in dedicated bioreactors might be required in the process (simulating the biomechanical environment of the meniscus, thus assisting cells in their activity to produce a similar tissue). 95, 119 When considering acellular strategies, the most critical component of meniscus TERM is the scaffold. The scaffold is used as a replacement for the missing tissue, and receives and interrelates with the cells that are either previously seeded in vitro, and/or migrate after surgical placement. The size and shape of the scaffold are critical to its function. 27,59,60,120,121 With the developments in medical imaging (Fig. 9), the scaffold is manufactured in a patient-specific way. Additional developments could be obtainable through new technologies such as rapid prototyping (RP). 60,61,121 Besides permitting patient-specific scaffolds with the accurate architecture, it could ease the correct distribution of different cells within the meniscus implant. 60,61 . Cengiz et al 60 have described how to produce patient-specific meniscal implants from medical images.
Once the cells and the bioactive molecules are introduced into the scaffold, and the implant is cultured and matured within a bioreactor, the extracellular matrix will start to be synthesized inside the scaffold leading to final formation of the tissue, hopefully similar to the native. Once this is achieved we could have an implant for adequate and effective replacement. This is the future road we hope for, creating an endless source of meniscal implants without further clinical complications or limitations. 44,85,111 Many materials are under study as possibilities for meniscal scaffolds: collagen, 122-125 poly(lactic acid) based, 126-128 poly(glycolic acid), 128,129 poly(lactic-co-glycolic acid), 130,131 polycaprolactone, 116,132 hyaluronic acid/polycaprolactone, 133-135 hyaluronic acid/gelatin, 115 acid)/hyaluronic acid, 138 silk-based, [139][140][141] , gelatin/ chitosan, 142 , bacterial cellulose, 143,144 and vicryl. 145 Nanobiomaterials have been considered for TERM applications. 146,147 These can be produced with different methods into various structures including nanofibres, 148,149 nanoparticles, 150 nanotubes 151 and nanofilms. 152 Nanotechnology also permits modification of the surfaces of biomaterials. 153 Biologics are biologically active natural components that can activate cells and enhance tissue healing, including specific growth factors 154,155 and platelet rich plasma (PRP). 114 PRP is an autologous source of a 'cocktail' of several autologous growth factors (including platelet-derived growth factor, endothelial growth factor, and transforming growth factor) as well as anti-and proinflammatory cytokines (including interleukin-4, -8, -13, -17, tumor necrosis factor-α, and interferon-α) which might influence the process of tissue healing. [156][157][158][159][160] There are methodological limitations in current studies including the preparation of PRP, and inclusion/type of cells and scaffolds as well as the lack of standardization on evaluating the outcomes PRP clinical studies, which limits further conclusions regarding this therapy. 59 Hydrogels can serve as scaffolds, carriers of cells, or biologics, or can even control the neovascularization process. [161][162][163] TERM research is engaged in the search for effective partial but also total meniscal replacement, which has proven to be an even more demanding task. However, the first steps have been made. Lee et al, using a sheep model, 164 produced polycaprolactone scaffolds which were 3-D printed into anatomically correct scaffolds. These were loaded with microspheres for the controlled release (in time and space) of connective tissue growth factor and transforming growth factor-β. The release of growth factors induced autologous cells to differentiate and generate zone-specific collagen type I and II in order to obtain a neotissue biologically and biomechanically closer to the native tissue. 164 This study summarizes the application of advanced TERM strategies for meniscus replacement.
Considering scaffolds for complete meniscal replacement, a recent study on a sheep model suggests total medial meniscal replacement could successfully be performed (one year follow-up) by using a cross-linked collagen-hyaluronan sponge reinforced with synthetic, resorbable poly(DTD DD) fibres. 165 The anchorage of the scaffold to the tibial plateau was carried out using titanium interference screws at the anterior and posterior roots and was peripherally sutured to the medial capsule achieving promising results. 165

Conclusions and take-home messages
Arthroscopic meniscectomy is still one of the most frequent orthopedic procedures given the high incidence of meniscus lesions. This option has provided satisfactory outcome for the treatment of irreparable meniscal lesions in some patients, but it might also lead to subsequent joint degeneration due to the loss of meniscal function.
With the growing knowledge of the menisci functions in the knee joint homeostasis, there is a growing trend towards meniscal preservation. There has been a gradual increase in indications for meniscal repair rather than meniscectomy.
When preservation is no longer possible, replacement is the next step for symptomatic patients or those with evidence of systematic progression towards arthritis at a young age.
Meniscal allograft transplantation (MAT) is no longer an experimental treatment and enables favourable outcome in the long term. Concerning preservation and sterilization methods, cryopreservation is the most frequently used, with a growing trend towards fresh allograft. As for technical choices for MAT fixation, bone block seems to be technically more demanding but has lower incidence of extrusion and re-rupture. Sizing methods are required in order to obtain matching between graft and patient which influences outcome.
There is no straight correlation between extrusion and clinical outcome.
Application of MAT in skeletally immature patients and high-demand athletes is in its early stages and under research.
There are two clinically available meniscus scaffolds for partial meniscus replacement when indicated (collagenbased and polyurethane-based). Despite promising clinical results, imaging assessment has shown that the achieved tissue is different than the native meniscus. Both enable similar clinical outcome but diminished volume with time has been described for both.
Despite the favourable clinical outcome, it is still debatable whether meniscus replacement enables prevention of osteoarthritis.
While most basic-science researchers are enhancing scaffolds for this propose, most clinical studies report only to acellular scaffold replacement.
Current TERM strategies have not yet met the clinical needs. The problems are related to the lack of simultaneous success in biology (tissue infiltration, neovascularization, matrix maturation) and biomechanics (capable to withstand suture and early mechanical function) of the scaffolds. The achieved tissue, so far, does not completely achieves the biologic and mechanical requirements of the native meniscus. However, we have found a road: a combination of agents, methods and technologies. The pathway is promising but the walk will certainly be long.