4.1801EOR0010.1302/2058-5241.4.180103 research-article2019 EOR | volume 4 | June 2019 Instructional Lecture: Sports & Arthroscopy DOI: 10.1302/2058-5241.4.180103 www.efortopenreviews.org Meniscal allograft transplants and new scaffolding techniques Hélder Pereira1,2,3,4,5 Ibrahim Fatih Cengiz4,5 Sérgio Gomes3 João Espregueira-Mendes4,5,6,7 Pedro L. Ripoll2 Joan C. Monllau8 Rui L. Reis4,5,9 J. Miguel Oliveira4,5,8,9 „„ Clinical management of meniscal injuries has changed patient-specific implants of correct size and shape, as well radically in recent years. We have moved from the model as advanced strategies combining cells, bioactive agents, of systematic tissue removal (meniscectomy) to under- hydrogels or gene therapy. standing the need to preserve the tissue. „„ Herein, the clinical evidence and tips concerning MAT, „„ Based on the increased knowledge of the basic science currently available meniscus scaffolds and future perspec- of meniscal functions and their role in joint homeostasis, tives are discussed. meniscus preservation and/or repair, whenever indicated Keywords: meniscal repair; meniscectomy; meniscus allo- and possible, are currently the guidelines for manage- graft transplantation (MAT); partial meniscus replacement; ment. scaffold; tissue engineering and regenerative medicine „„ However, when repair is no longer possible or when fac- ing the fact of the previous partial, subtotal or total loss of Cite this article: EFORT Open Rev 2019;4 the meniscus, meniscus replacement has proved its clini- DOI: 10.1302/2058-5241.4.180103 cal value. Nevertheless, meniscectomy remains amongst the most frequent orthopaedic procedures. „„ Meniscus replacement is currently possible by means of meniscal allograft transplantation (MAT) which provides Introduction replacement of the whole meniscus with or without bone Injuries of the meniscus are probably the most frequent plugs/slots. Partial replacement has been achieved by injuries occuring in the knee.1 According to the statement means of meniscal scaffolds (mainly collagen or polyure- from Prof. René Verdonk, ‘Nothing has changed so much thane-based). Despite the favourable clinical outcomes, in recent years of orthopedics as the treatment algorithm it is still debatable whether MAT is capable of preventing of meniscus lesions’.2 A radical change occurred since the progression to osteoarthritis. Moreover, current scaffolds ‘recommendation’ during the 1970s to remove as much have shown some fundamental limitations, such as the as possible of what was formerly considered as a useless fact that the newly formed tissue may be different from structure,3 to the present-day movement supporting the the native fibrocartilage of the meniscus. preservation, repair or replacement of the meniscus.2 „„ Regenerative tissue engineering strategies have been used Recent basic science research reinforced the claim that the in an attempt to provide a new generation of meniscal menisci are fundamental components of a healthy knee implants, either for partial or total replacement. The goal joint.4–6 Menisci are C-shaped fibro-cartilage structures is to provide biomaterials (acellular or cell-seeded con- with a wedge-like cross-section (Fig. 1), present between structs) which provide the biomechanical properties but each tibial plateau and the corresponding femoral con- also the biological features to replace the loss of native tis- dyle.5,7 They have a specific extracellular matrix,8,9 multi- sue. Moreover, these approaches include possibilities for ple cell types10,11 and particular cell distribution.5,12 They a) b) c) e) d) Fig. 1 (a) Lateral meniscus of a right knee; in blue is demonstrated a radial cut; (b) light optical amplification of a radial cut for ultra- structure evaluation; (c) and (d) the density of collagen network is visible; (e) schematic drawing of meniscus vascularization on the sagital view. have unique biomechanical features13 and are known to procedures worldwide.20–24 Meniscus repair commonly have segmental and regional variations concerning ultras- provides superior clinical outcomes when compared with tructure, vascularity, biology, and function.7,12,13 There meniscectomy.25,26 As a general rule, the meniscus tissue are differences between the medial and the lateral menisci should be preserved whenever possible. However, menis- in knee kinematics. The lateral meniscus is accountable for cus repair has specific indications and limitations.26–28 most of the load transfer within the lateral compartment It is widely recognized that there is an urgent need for (around 70%),14 while the transmission of loading is more an improved description of meniscal tear patterns,29 equally dispersed through the cartilage surfaces and the standardized reporting of outcome measures, and better- medial meniscus (50%) in the medial compartment.15,16 quality study methodologies in order to help in making Concerning kinematics, the lateral meniscus is more the best decision for the treatment option and/or tech- mobile, while the medial one is more static to resist ante- nique, as well as establishing prognosis.26 A very impor- rior tibial translation, acting as a secondary agonist of the tant distinction, which often is not easy to make, is anterior cruciate ligament (ACL).6,14 between traumatic and degenerative lesions.30–33 The It has been recently shown by 2-dimensional (2-D) and physiopathology of meniscal lesions is not always easy to 3-dimensional (3-D) analysis of the menisci segments that understand and frequently is part of the whole of the knee cellular density is relatively higher on the anterior seg- joint loss of balance.6 A traumatic meniscus tear is typi- ment when compared to other parts, and that the poste- cally related to an acute trauma which produces sufficient rior segments tend to be stiffer.12,13 It was hypothesized energy to split the tissue. The tear patterns more com- that the higher damping properties of the anterior seg- monly linked to traumatic tears are: longitudinal, bucket- ments could be related to the higher cellular density, handle and radial tears.34 Nevertheless, most flap tears are meaning that biology and biomechanical features are also classified as traumatic. High-energy traumatic events combined.12,13 which might cause fractures around the knee can also be One should bear in mind the basic science knowledge involved in meniscus tears.35 Some of these lesions require related to each meniscus since it surely has implications combined osteochondral and meniscal transplanta- for tissue loss, repair, healing and outcomes of replace- tion.36,37 Contrarywise, degenerative meniscus lesions are ment.12,17 Moreover, vascularization of the menisci is criti- characteristically caused by chronic degenerative changes cal for treatment decisions. The peripheral vessels infiltrate including cavitation, fibrillation, softened/brittle tissue, or around 10% to 25% of the width of the lateral meniscus more complex tear patterns, among others.29 Horizontal and 10% to 30% of the width of the medial meniscus in lesions represent the typical type of such lesions.38–40 Such adults (Fig. 1).18 Children and adolescents are known to cases often have a degenerative nature even in younger have increased vascular supply. Thus, they have more patients.37–39 possibilities for repair when a meniscal injury occurs, Considering posterior root tears, lateral tears are more despite sometimes suffering from more complex menis- frequently traumatic (often combined with anterior cruci- cus lesions.19 ate ligament rupture), while medial meniscus root tears Meniscectomy has significant consequences for the have more often a degenerative nature.41,42 There has joint and causes a higher risk of early joint degeneration, been a recent technical development linked to meniscal despite remaining one of the most frequent orthopaedic repair, and some lesions classically classified as irreparable 280 Meniscal allograft transplants and new scaffolding techniques (e.g. radial or horizontal tears) are having encouraging by using 3-D printing based on patient imaging.60,61 Tis- results with repair.26 Globally, a failure rate for meniscus sue engineering technologies raise the possibilities, in repair of approximately 15% is widely accepted, despite future, of providing a limitless source of effective tissue for the fact that in the literature it ranges from 5% to 43.5%.43 meniscus replacement (partial or total), avoiding the pre- Furthermore, it has been demonstrated that the failure of viously described limitations and concerns of allografts a meniscal repair does not worsen the outcome, nor dic- related to donors, with the associated complicated pro- tate a need for a bigger loss of tissue volume, if a re-­ cessing and size-matching issues.27,62 operation 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. Meniscus allograft transplantation (MAT) However, if repair is not possible, partial or total menis- Fundamentals, indications and techniques of MAT cal replacement seems to be the most adequate method, whenever possible.44 This choice is not purely based on The ‘ideal candidate’ for MAT is a young patient with a the meniscus injury but also on the global condition and history of symptomatic femorotibial compartment symp- function of the joint, considering the cartilage condition toms having undergone a previous meniscectomy, with a and ligament status and function.45 The first description of stable knee, neutral alignment and no severe chondral meniscus allograft transplantation (MAT) was in the damage or arthritis. Presence of cartilage degeneration, 1970s, in patients with post-traumatic osteoarthritis sec- obesity and smoking habit are considered risk factors.49,63 ondary to fractures of the tibial plateau treated by an oste- A summary of indications and contraindications for MAT ochondral allograft resurfacing procedure combining are summarized in Table 1. bone, cartilage, and meniscus in a single step.46,47 The first free MAT was performed in 1984.48 Since then the tech- Preservation and sterilization methods nique has been intensely developed and proposed for the Preservation and sterilization methods of the meniscal treatment of patients with a symptomatic painful knee as allografts appear to play a role in outcome.49,50 Currently, consequence of meniscectomy, under specific indications there are four types of meniscal allograft: fresh, cryopre- and contraindications.49 MAT has been demonstrated to served, deep-frozen49 and lyophilized, although lyophili- be a reliable therapeutic option.50,51 It has received and zation is not currently used anymore (Table 2).37,63–65 keeps receiving relevant improvements and increasing Deep-frozen (fresh-frozen) and cryopreserved meniscal interest from surgeons and researchers based on favoura- allografts are the most frequently used.65 There is a grow- ble outcomes, already with long-term follow-up.37,50–55 ing trend for the use of fresh allografts.37,57,65 The concept of meniscal replacement by means of Cryopreservation proved to be a significantly better using a scaffold was introduced in the 1990s.56 Total method of preservation, when compared with fresh-­ meniscus allograft transplantation and partial meniscal frozen. Fresh meniscal transplantation is logistically replacement by means of scaffolds (with or without bio- demanding and expensive given the short period of time logical enhancement) have, by definition, different indica- between the donor’s death and transplantation. The use tions and possibilities. The implantation of a scaffold for of fresh tissue transplantation has inherently a higher risk partial meniscus replacement necessitates that the menis- for disease transmission.65 This risk has been estimated to cal roots and peripheral rim remain conserved. These be 1:8,000,000 for HIV67 and 1:2600 for Clostridium67 (as requirements are not needed for MAT, which enables examples). However, most likely this method shall be the complete replacement of the meniscus by means of creat- one which preserves the most native biological and bio- ing new ‘root-like’ attachments.49 mechanical features of the meniscus for MAT.37,57,65 In the Access to and acceptance of allografts are not equal in case of fresh meniscal allografts transplantation, there is all countries, because of some legal, economical, disease also a risk of transmission of pathogens, so specific care transmission concerns, as well as ethical, or even religious and procedures are required to minimize risks, including objections.57 For all these reasons, considerable restric- special tests aiming to exclude infection.65 Moreover, con- tions of access to proper meniscal allografts remain in sev- cerning cells, the advantage of preserving donor cells is eral countries.44,57,58 debatable once host cells are capable of repopulating the There are high expectations of tissue engineering and graft within a few weeks following MAT.65 regenerative medicine. Future perspectives include new, more effective, biomaterials, combined with augmenta- Technical choices for MAT fixation tion by means of effective use of cells, bioactive agents As technical choices for MAT fixation, several techniques (e.g. growth factors or medication molecules), nanotech- have been proposed including bone blocks, or soft tissue nology or gene therapy in advanced strategies.27,59 More- only (Fig. 2).49,68 There is still no clinical evidence favour- over, it is also possible to produce patient-specific implants ing any technique over another.49,68 Concerning fixation, 281 Table 1. Meniscus replacement options: indications and contraindications Meniscus allograft transplantation Meniscus partial replacement by acellular scaffold INDICATIONS INDICATIONS • Prior total or subtotal meniscectomy, with pain in the involved tibiofemoral • Age between 16 and 50 years old. compartment. • Skeletally mature patient. • Age of 50 years or younger (relative). • Irreparable medial or lateral meniscal tear or partial • Cartilage degenerative changes in young patients after meniscectomy. • meniscal loss (> 25%). • Absence of radiographic evidence of advanced joint arthritis. • Partial meniscus defect with preservation of meniscal roots and • 2 mm or more of tibiofemoral joint space on 45° weight-bearing peripheral rim. posteroanterior radiographs. • Aligned knee joint (favourable axis of less than 5°). CONTRAINDICATIONS CONTRAINDICATIONS • Advanced joint arthritis with flattening of the femoral condyle, concavity of • Full-thickness loss of articular cartilage with exposed bone –International the tibial plateau, and osteophytes that impairs anatomic placement of the Cartilage Repair Society classification > 3. meniscus allograft. • Meniscal root lesions. • Less than 2 mm of tibiofemoral joint space remaining on 45° weight-bearing • Uncorrected ligamentous instability. posteroanterior radiographs. • Axial malalignment (deformity greater than 5°). • Axial malalignment. • Osteonecrosis of the involved knee. • Uncorrected ligamentous instability. • Uncorrected ligamentous instability. • Arthrofibrosis. • Systemic or local infection. • Muscular atrophy. • Autoimmune diseases or inflammatory arthritis. • Systemic or local infection. • Presence of cartilage degeneration, smokers and obese (Body Mass Index • Autoimmune diseases or inflammatory arthritis. > 35) patients have higher risk of failure. • Presence of cartilage degeneration, smokers and obese (Body Mass Index > 35) patients have higher risk of failure. Table 2. Preservation and sterilization methods of the meniscal allografts •  reeze drying or lyophilization – this preservation technique includes dehydration. It has been shown that it increases the risk of meniscal shrinkage, so it F 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.37,57 a) b) c) Fig. 2 (a) Cryopreserved lateral meniscus graft prepared with bone slot and a suture in the junction of the posterior segment to the mid-body to assist in introducing the graft in the joint; (b) Preparation of a fresh meniscus graft (anterior and posterior horns as well as top side are marked); (c) soft tissue only allograft with all the marks and the suture to assist introduction within the joint. multiple studies have shown comparable graft survival outcome was noticed for either, and more studies are still and outcomes between different fixation options.49,50 required on the topic.69 Some authors have reported that a meniscus allograft Two relevant topics for research on MAT are the fixa- fixed with the suture-only technique had a higher degree tion and integration of the meniscus tissue itself and its of extrusion of the meniscal body and a trend for higher anchorage to the bone. There are different anatomic char- rate of MAT tears (Fig. 3) when compared to the bony fixa- acteristics for the lateral and medial meniscus which influ- tion method.69 However, no influence on the functional ence the technical approach considering the previous 282 Meniscal allograft transplants and new scaffolding techniques a) b) c) d) Fig. 3 (a) Arthroscopic view of a posterior longitudinal peripheral tear of a lateral meniscus transplant 3 years after implantations; (b) all-inside suture; (c) knot tying; (d) stable suture. topics. The anterior and posterior root attachments of the spine; type 2 has an insertion medial to the spine; and lateral meniscus are closer when compared to the medial type 3 (less frequent) has an insertion anterior to the ante- meniscus in which they are more separated.5,26,70 Consid- rior edge of the tibial plateau.71 Gelber et al hypothesized ering the previous, when performing a medial MAT, two that placing a MAT posterior to the tibial edge in a knee bone tunnels in the tibia will often be required. For lateral with previous type 3 meniscus might result in overstuffing MAT, the vicinity of root attachments makes it more diffi- of the anterior compartment.63 These details are examples cult to create such tunnels (risk of coalescence) and a of technical tips based on anatomic and biomechanical bone slot/block technique can be considered as it pre- knowledge which play a major role in outcome. serves the native tibial root attachments of the graft.49 The most frequently used sizing method was described by Pollard et al, and is based on calibrated anteroposterior Measurement techniques for sizing (AP) and lateral radiographs.72 However, its major limita- One determinant pre-operative requirement is evaluation tion mainly affects lateral allograft sizing given the signifi- of the size of the knee receptor compartment and finding cant interindividual variability between the medial and the a matching meniscus allograft. Several measurement lateral compartment dimensions measured on plain techniques for sizing the recipient compartment have X-rays (mainly in the AP view).72 Some attempts have been studied based on plain X-ray, CT, MRI and anthropo- been made to increase its effectiveness by means of math- metric data.63 A graft which is too small will be exposed to ematical models.63 CT and MRI-based imaging are consid- an increased biomechanical load, which will most likely ered to be more precise but increase the cost, and CT has lead to an early failure. Conversely, a graft that is too big inherent radiation. However, to assess the anterior horn of will have an extruded position within the joint, lowering the medial meniscus, an MRI of the opposite knee is its biomechanical function and resulting in a continuous required. overload of the articular cartilage.63 The choice of surgical technique (with or without bony Three types of medial anterior horn anatomy have been fixation) is also linked with the reliability of sizing and described: the most common is type 1, with an insertion matching the graft. Bone block fixation requires anatomi- posterior to the anterior tibial edge and lateral to the cal reconstruction of the anterior and posterior horns. 283 Table 3. Technical tips for meniscus allograft transplantation • Have a good communication with your tissue bank. • In tight knees (varus), if required for visualization and access, do not hesitate to release the medial collateral ligament (pie-crust technique). • 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 Thus, this technique is more demanding in terms of with premature loss of meniscus leading to early progres- matching the receptor and the graft, and requires an sive degenerative joint disease. Discoid meniscus tears rep- experienced allograft bank. Bone-free MAT technique is resent another possible cause of meniscus-deficient knees less demanding concerning size mismatching. in youngsters, with further candidates for MAT.77 To date, no method of sizing has proven to be more Gelber et al advise that patients with open physis, reliable or user-friendly than any other. might require an expectative attitude with clinical and MRI assessment every year, in order to follow the evolu- MAT’s extrusion tion of the articular cartilage’s status.63 If progressive carti- MAT’s extrusion (radial displacement of the allograft) has lage deterioration is identified, a MAT may be suggested, been a matter of debate for several years. Its relation with even in the absence of clinical signs, beside considering clinical outcome is not completely clear and an extrusion that the clinical evidence in this population is low.63 up to 3 mm has been considered as ‘normal’.63,73,74 How- ever, one can understand that, if significant displacement Rehabilitation of a graft occurs, its biomechanical role in resisting com- Concerning rehabilitation, once more there is no consen- pressive, radial, cutting or hoop stresses could be com- sus. Some surgeons permit immediate weight-bearing promised.6 Extrusion following MAT seems to be a while others recommend a variable period of non-weight- frequent finding, which usually appears shortly after sur- bearing (3 to 6 weeks). Similarly, some promote a period gery, and does not always progress through time. It seems of immobilization, however, most surgeons permit early that bony fixation is less prone to extrusion than soft tissue motion (in the first 2–3 weeks) from 0º to 60º. The ration- technique.69 Lateral MAT seems to be more prone to ale is that the movement of the menisci is minimal within extrusion than the medial.75 Some attempts have been this range. Therapy focuses on gradually restoring full made to diminish extrusion such as aiming for the most knee extension, decreasing swelling and pain control. anatomical graft placement, reducing the size of the graft Another goal is recovery of quadriceps strength with iso- by 5%,76 the excision of peripheral osteophytes of the tib- metric exercises, passive and active motion. After the first ial plateau, the fixation of the meniscus allograft on the 3–4 weeks, gradual increase in knee flexion up to 90°, tibial surface or the reduction and fixation of the lateral combined with progressive weight-bearing, and closed- capsule to the tibia.63 However, as previously stated, chain kinetic exercises are advised. At 6–8 weeks after sur- based on the literature, no major adverse consequences gery, the patient should be capable to fully weight-bear, have been linked to extrusion, so one cannot favour any and at 4–6 months running on flat ground is usually technique over another.63,73 encouraged.63,73 Forced flexion and pivoting maneuvers Currently, most MAT procedures are performed by are avoided for the first 6–12 months. arthroscopy. Fixation of the meniscal horns may be achieved either by sutures passed through bone tunnels Clinical outcome of MAT or bony fixation (press-fit, anchors, interference screws). The main goal of MAT is to prevent or delay the arthritic Peripheral fixation is usually performed by combining all- degeneration of the joint. However, it has not yet been inside with outside-in meniscus sutures.26 Some technical confirmed whether this target is systematically accom- tips are described in Table 3. plished.63,74,74 For many years, and to this day in some places, MAT was seen as an experimental procedure.50 MAT in the pediatric population However, over time, MAT has provided reliable and There is a paucity of data concerning the application of reproducible favourable results if proper indications are MAT in the pediatric population.77 The increasing partici- followed.50,63,73 MAT has proven its effectiveness in reduc- pation of children in sports, including elite sports, has led ing pain and improving function and quality of life.63,73 to a rising number of sports-related injuries in children and However, there are still some questions to address regard- adolescents. This results in a higher number of children ing the integration and longevity of the graft, the efficacy 284 Meniscal allograft transplants and new scaffolding techniques of MAT in prevention of osteoarthritis and the possibility study, MAT is more cost-effective for young patients (20– of returning to high-demand activities.49 29 years old) and less cost-effective in obese patients A recent meta-analysis reported the published out- (Body Mass Index of 30–35).84 However, further research come of 2977 patients (3157 allografts).73 Thirty-eight per is required. cent of cases received an isolated MAT while the remain- ing underwent at least one concomitant procedure. In dif- ferent studies, clinical assessment included Lysholm, Knee Meniscus scaffold replacement (MSR) Injury and Osteoarthritis Outcome (KOOS), International Knee Documentation Committee (IKDC) and Visual Ana- Fundamentals, current options and clinical outcome of MSR logue Scale (VAS) scores. A significant improvement in all The concept of meniscal scaffolds was initiated in the scores and a good patient satisfaction at long-term follow- 1990s.56 Currently, two acellular meniscal scaffolds have up was demonstrated. The mean overall survival rate been used in Europe for clinical application:85 the colla- reported was 80.9%. There was a negative evolution in gen meniscus implant or ‘CMI’ (Ivy Sports Medicine, radiological osteoarthritis with at least one grade lowering Lochhamer, Germany) which is based on type I bovine in 1760 of the studied patients. Concomitant procedures collagen matrix;56,85 and the polyurethane-based also had no significant effect on outcome, although age at known as ‘ACTIFIT’ (Orteq Bioengineering, London, transplantation was determined as a negative prognostic UK).86,87 Partial meniscus substitution with scaffolds and factor and body mass index had a slight negative correla- MAT have different indications as scaffold implantation tion with the outcome of MAT. The identified rate of com- requires that the meniscal roots and peripheral rim plications was equivalent to standard meniscal repair remains preserved.74 However, they were developed to surgery.73 overcome the consequences of symptomatic knees after It has been recently stated, on a short-term follow-up, partial meniscectomies. that is possible to return to high-demand sports (e.g. soc- A summary of indications and contraindications on the cer, basketball, rugby and volleyball) after MAT. Zaffag- use of acellular meniscal scaffolds for partial meniscal nini et al reported 74% of patients returning to sports, replacement is presented in Table 1. 50% of these at the previous level of participation, after 8 Partial meniscus replacement by using scaffolds has months of rehabilitation.51,78–80 Similar results have been been used with promising short-term clinical results for reported from other small series at short term follow- chronic partial meniscus defects.85,88–90 Clinical studies are up51,79,80. Given these facts, such data must be considered based on acellular scaffolds while basic science research- with care before more definitive and brad conclusions can ers promote some biological enhancement.85 Its applica- be drawn. tion in acute cases remains somewhat limited and Concerning the pediatric population, there are few controversial.91 Technically, these procedures are also per- reports in the literature on the outcome of MAT.77 MAT is formed arthroscopically (Fig. 4). A measurement of the an effective method for treating meniscal deficiency fol- defect is performed during surgery and the scaffold is cut lowing irreparable tears in discoid meniscus based on a in order to match the defect. A slight oversizing of the scaf- series that compared MAT in discoid versus nondiscoid fold is recommended. A suture can be used in the middle knees at a minimum 2-year follow-up.81 Despite the fact of the scaffold to assist in bringing the scaffold into place that the discoid group had a significantly lower range of (similarly to the technique described for MAT), and fixa- motion, functional scores improved similarly in both tion is performed to the meniscus remnant by means of groups. A recent paper reported on 37 MAT procedures vertical and horizontal sutures by all-inside and/or out- performed in 36 children, with mean age of 15 years, 84% side-in/inside-out techniques. lateral and 16% medial at 2-years follow-up, with at least Both scaffolds achieved positive clinical results in the similar improvements in functional outcomes as reported treatment of partial medial and lateral meniscal loss with for adults.82 Moreover, another study reported 3 cases of self-reported pain reduction, improved knee function and MAT at 2-year follow-up (two after discoid meniscus and quality of life. These results have been described for both one after medial bucket-handle tear combined with ante- the polyurethane-based and the collagen-based implants. rior cruciate ligament rupture), with the authors conclud- (745,88–90,92–103) Moreover, meniscal replacement by ing that MAT in skeletally immature patients leads to both implants has proven to be safe for medial and lateral acceptable clinical outcomes without growth deviation.83 menisci.85,97 However, the final tissue obtained has been There is limited analysis of the cost-effectiveness of documented as different from the native meniscus MAT; however, a recent analysis concluded that MAT (Fig. 5).85 Resorption of the implants98 and extrusion needs to be approximately one-third more effective in (Fig. 6) of the scaffold has been a matter of growing delaying osteoarthritis in post-meniscectomized knees to debate and concern.101 Nevertheless, the clinical outcome be considered as cost-effective.84 According to the same does not completely correlate with the imaging findings, 285 a) b) c) d) Fig. 4 (a) Debridement and trephination of the peripheral meniscus rim to enhance healing prior to scaffold implantation; (b) measurement of the defect; (c) cutting of the scaffold with slight oversizing; (d) suturing the scaffold with all-inside technique. a) b) Fig. 5 (a) Frontal and (b) lateral MRI view of lateral ACTIFIT (yellow circle; red arrows) with morphologic Genovese Grade 3 and signal intensity grade 2 after 5 years’ implantation. with patients’ satisfaction and clinical scores being 5-year period and it aimed to provide a template for tissue reported has higher than for imaging assessment and ingrowth (Fig. 7).104 However, MRI assessment, including outcome.98 Genovese score (assessment of size/morphology and signal The ACTIFIT scaffold consists of porous polycaprolac- intensity; each in 3 degrees),105 often shows extrusion, tone and urethane segments which degrade slowly over a reduced volume with time or even complete resorption 286 Meniscal allograft transplants and new scaffolding techniques a) b) Fig. 6 (a) MRI of a medial ACTIFIT extrusion (red arrows between thin blue lines) with morphologic Genovese Grade 3 and signal intensity grade 2 after 5 years’ implantation. (b) 3-D reconstruction of the morphology of the implanted ACTIFIT. a) b) Fig. 7 (a) Arthroscopic view of an ACTIFIT 2 years after implantation (the colour and texture are very different than the native meniscus); (b) haematoxylin and eosin stain (H&E) histology of ACTIFIT biopsy showing increased neovascularization and paucity of fibrochondrocites when compared to native meniscus. Source: Courtesy of Dr. Pedro Pessoa and Dr. Manuel Virgolino. without reaching normal signal.98 The CMI theoretically concomitant surgeries such as anterior cruciate ligament has a more biocompatible profile (collagen type I from reconstruction (ACLR) and high tibial osteotomy (HTO) bovine Achilles tendons) and was ‘designed as a regenera- could have an influence on these results. Clinical outcome tion template into which the body’s own tissue may evaluation using VAS for pain, Lysholm Knee Scores, and grow’.56 According to a recent systematic review, higher Tegner Activity Scores improved from pre-operatively to rates of scaffolds with reduced size were found at longer latest follow-up for both scaffolds. The KOOS and IKDC follow-up when compared with initial evaluations.89 How- scores improved from pre-operatively to latest follow-up ever, MRI signal intensity was reported as more similar to only for ACTIFIT patients. Overall, patients receiving CMI normal meniscus.89 scaffolds had higher grades for Genovese morphology A recent systematic review comparing both scaffolds and signal intensity (Fig. 4) when compared to ACTIFIT has reported on 658 patients (347 ACTIFIT, 311 CMI) at scaffold patients. In conclusion, the authors stated that mean 45 months’ follow-up.97 Treatment failure occurred patients might expect improved clinical outcome with in 9.9% of patients receiving the ACTIFIT scaffold and either or both scaffolds, particularly when combined with 6.7% of patients receiving CMI. However, failure rate ACLR or HTO.97 ranged from 0% to 31.8% amongst the evaluated stud- There is one single case report describing return to ies.97 Such discrepancy might be due to a variable defi- sports activity at pre-injury level on a professional foot- nition of ‘failure’ or publication bias (authors are less baller after partial lateral meniscus replacement, 10 prone to publish failures).106 Moreover, the presence of months after the operation, with lasting results.107 287 a) b) Patient Tissue harvest from Patient’s Knee MRI the patient Implantation Cell isolation and 3D model of the culture patient’s meniscus In vitro maturation Patient-specific scaffold Cell seeding manufacture Patient-specific cell-scaffold construct Fig. 8 A silk fibroin scaffold for meniscus tissue engineering applications. Therefore there is insufficient evidence in the literature as a spacer, trying to redistribute loads transmitted across supporting the use of these strategies when aiming for the knee joint, even if it does not replace normal anatomy. return to high-level sports. It is made of polycarbonate-urethane, and is under clinical Concerning rehabilitation protocol as described for trial and development.74,108 Despite early favorable clini- MAT, there is a lack of consensus. However, despite the cal outcome reported from developers, some complica- fact that this surgery of scaffold implantation is usually tions have been described (e.g. dislocation).109 less invasive as it does not require bone tunnels for root Tissue Engineering and Regenerative Medicine (TERM) fixation, the basics of rehabilitation are quite similar to approaches aim to develop new implants, biomaterials those for MAT. However, a lower inflammatory post-oper- (Fig. 8), biological enhancement of surgical approaches ative response is expected. (cells, growth factors, proteins, nanotechnology, hydrogels), amongst many other advanced approaches aiming to fix, replace or improve any biological Road for future in meniscus replacement system.44,45,62,110,111 Since the implications of meniscectomy have been recog- Gene therapy is another promising research field dedi- nized (loss or diminished meniscus function), the future cated to improving meniscal repair or replacement.112,113 developments of meniscus replacement are strongly Growth factor technology is under intense development motivated by a clinical need. aiming to permit the selective control of cell activity to Synthetic, non-anatomical approaches are being accelerate tissue healing, in future.44,114 Nevertheless, the tested. NUsurface Meniscus Implant ®, intends to function understanding of the complex mechanisms of cell 288 Meniscal allograft transplants and new scaffolding techniques a) b) c) R 6 6 d) Fig. 9 (a) and (b) MRI axial views showing meniscus tear dislocated to the meniscotibial recess (white arrows); (c) frontal MRI view of the same lesion with the meniscus fragment contoured in green (yellow arrow); (d) 3-D MRI-based image showing the tear and enabling use for rapid prototype scaffold printing. function, activation and differentiation, together with to its function.27,59,60,120,121 With the developments in comprehension of their interaction, is far from being medical imaging (Fig. 9), the scaffold is manufactured in a achieved. Mesenchymal stem cell (MSC) research is patient-specific way. Additional developments could be another field under powerful expansion.44,111,113,115–117 A obtainable through new technologies such as rapid proto- clinical study using human adult MSCs injected into the typing (RP).60,61,121 Besides permitting patient-specific knee for treatment of symptomatic consequences from scaffolds with the accurate architecture, it could ease the partial medial meniscectomy has shown a significant correct distribution of different cells within the meniscus increase in the volume of the menisci as assessed by MRI implant.60,61. Cengiz et al60 have described how to pro- at 2-years follow-up.118 The more advanced strategy of duce patient-specific meniscal implants from medical using cell-laden scaffolds (constructs) for meniscus repair images. has been described in several pre-clinical studies.44,85 Once the cells and the bioactive molecules are intro- However, a fibrocartilage with similar biological and bio- duced into the scaffold, and the implant is cultured and mechanical characteristics to the native meniscus has not matured within a bioreactor, the extracellular matrix will been consistently obtained so far. Maturation of such con- start to be synthesized inside the scaffold leading to final structs in dedicated bioreactors might be required in the formation of the tissue, hopefully similar to the native. process (simulating the biomechanical environment of Once this is achieved we could have an implant for ade- the meniscus, thus assisting cells in their activity to pro- quate and effective replacement. This is the future road we duce a similar tissue).95,119 hope for, creating an endless source of meniscal implants When considering acellular strategies, the most critical without further clinical complications or limitations.44,85,111 component of meniscus TERM is the scaffold. The scaffold Many materials are under study as possibilities for menis- is used as a replacement for the missing tissue, and cal scaffolds: collagen,122–125 poly(lactic acid) based,126–128 receives and interrelates with the cells that are either pre- poly(glycolic acid),128,129 poly(lactic-co-glycolic acid),130,131 viously seeded in vitro, and/or migrate after surgical polycaprolactone,116,132 hyaluronic acid/polycaprolac- placement. The size and shape of the scaffold are critical tone,133–135 hyaluronic acid/gelatin,115,136,137 poly(glycolic 289 acid)/hyaluronic acid,138 silk-based,139–141, gelatin/ of meniscus lesions. This option has provided satisfac- chitosan,142, bacterial cellulose, 143,144 and vicryl.145 tory outcome for the treatment of irreparable meniscal Nanobiomaterials have been considered for TERM lesions in some patients, but it might also lead to subse- applications.146,147 These can be produced with different quent joint degeneration due to the loss of meniscal methods into various structures including nanofibres,148,149 function. nanoparticles,150 nanotubes151 and nanofilms.152 Nano- With the growing knowledge of the menisci functions technology also permits modification of the surfaces of in the knee joint homeostasis, there is a growing trend biomaterials.153 Biologics are biologically active natural towards meniscal preservation. There has been a gradual components that can activate cells and enhance tissue increase in indications for meniscal repair rather than healing, including specific growth factors154,155 and plate- meniscectomy. let rich plasma (PRP).114 PRP is an autologous source of a When preservation is no longer possible, replacement ‘cocktail’ of several autologous growth factors (including is the next step for symptomatic patients or those with platelet-derived growth factor, endothelial growth factor, evidence of systematic progression towards arthritis at a and transforming growth factor) as well as anti- and pro- young age. inflammatory cytokines (including interleukin-4, -8, -13, Meniscal allograft transplantation (MAT) is no longer -17, tumor necrosis factor-α, and interferon-α) which an experimental treatment and enables favourable out- might influence the process of tissue healing.156–160 There come in the long term. Concerning preservation and steri- are methodological limitations in current studies includ- lization methods, cryopreservation is the most frequently ing the preparation of PRP, and inclusion/type of cells and used, with a growing trend towards fresh allograft. As for scaffolds as well as the lack of standardization on evaluat- technical choices for MAT fixation, bone block seems to be ing the outcomes PRP clinical studies, which limits further technically more demanding but has lower incidence of conclusions regarding this therapy.59 Hydrogels can serve extrusion and re-rupture. Sizing methods are required in as scaffolds, carriers of cells, or biologics, or can even con- order to obtain matching between graft and patient which trol the neovascularization process.161–163 influences outcome. TERM research is engaged in the search for effective par- There is no straight correlation between extrusion and tial but also total meniscal replacement, which has proven clinical outcome. to be an even more demanding task. However, the first Application of MAT in skeletally immature patients and steps have been made. Lee et al, using a sheep model,164 high-demand athletes is in its early stages and under produced polycaprolactone scaffolds which were 3-D research. printed into anatomically correct scaffolds. These were There are two clinically available meniscus scaffolds for loaded with microspheres for the controlled release (in partial meniscus replacement when indicated (collagen- time and space) of connective tissue growth factor and based and polyurethane-based). Despite promising clini- transforming growth factor-β. The release of growth fac- cal results, imaging assessment has shown that the tors induced autologous cells to differentiate and generate achieved tissue is different than the native meniscus. Both zone-specific collagen type I and II in order to obtain a enable similar clinical outcome but diminished volume neotissue biologically and biomechanically closer to the with time has been described for both. native tissue.164 This study summarizes the application of Despite the favourable clinical outcome, it is still debat- advanced TERM strategies for meniscus replacement. able whether meniscus replacement enables prevention Considering scaffolds for complete meniscal replace- of osteoarthritis. ment, a recent study on a sheep model suggests total While most basic-science researchers are enhancing medial meniscal replacement could successfully be per- scaffolds for this propose, most clinical studies report only formed (one year follow-up) by using a cross-linked to acellular scaffold replacement. collagen-hyaluronan sponge reinforced with synthetic, ­ Current TERM strategies have not yet met the clinical resorbable poly(DTD DD) fibres.165 The anchorage of the needs. The problems are related to the lack of simulta- scaffold to the tibial plateau was carried out using tita- neous success in biology (tissue infiltration, neovascu- nium interference screws at the anterior and posterior larization, matrix maturation) and biomechanics (capable roots and was peripherally sutured to the medial capsule to withstand suture and early mechanical function) of achieving promising results.165 the scaffolds. The achieved tissue, so far, does not com- pletely achieves the biologic and mechanical require- ments of the native meniscus. However, we have found Conclusions and take-home messages a road: a combination of agents, methods and technolo- Arthroscopic meniscectomy is still one of the most fre- gies. The pathway is promising but the walk will cer- quent orthopedic procedures given the high incidence tainly be long. 290 Meniscal allograft transplants and new scaffolding techniques 5. Pereira H, Cengiz IF, Silva-Correia J, et al. 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Osteoarthritis Cartilage 2005;13:548–560. at University of Minho, Avepark, Barco, Guimarães, Portugal. 12. Cengiz IF, Pereira H, Pêgo JM, et al. Segmental and regional quantification of Correspondence should be sent to: Hélder Pereira, Orthopedic Department of 3D cellular density of human meniscus from osteoarthritic knee. J Tissue Eng Regen Med Póvoa de Varzim-Vila do Conde, Porto, Portugal. 2017;11:1844–1852. Email: helderduartepereira@gmail.com 13. Pereira H, Caridade SG, Frias AM, Silva-Correia J, Pereira DR, Cengiz IF, et al. Biomechanical and cellular segmental characterization of human meniscus: building Acknowledgements the basis for tissue engineering therapies. Osteoarthritis Cartilage 2014;22:1271–1281. I. F. Cengiz thanks the Portuguese Foundation for Science and Technology (FCT) for 14. McDermott ID, Masouros SD, Amis AA. Biomechanics of the menisci of the knee. the Ph.D. scholarship (SFRH/BD/99555/2014). Curr Orthop 2008;22:193–201. J. M. 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