Meniscus Repair and Regeneration





Meniscus injuries are among the most common athletic injuries and result in functional impairment in the knee. Repair is crucial for pain relief and prevention of degenerative joint diseases like osteoarthritis. Current treatments, however, do not produce long-term improvements. Thus, recent research has been investigating new therapeutic options for regenerating injured meniscal tissue. This review comprehensively details the current methodologies being explored in the basic sciences to stimulate better meniscus injury repair. Furthermore, it describes how these preclinical strategies may improve current paradigms of how meniscal injuries are clinically treated through a unique and alternative perspective to traditional clinical methodology.


Key points








  • Meniscus injury is one of the most common athletic injuries.



  • Current reparative techniques fail to produce long-term improvements, and thus, alternative regenerative medicine applications are being investigated in the meniscus field.



  • Acellular and cellular therapies as well as their delivery methods are being investigated for repair and regeneration of meniscus tissue.



  • Various progenitor/stem cell types are being investigated as optimal cell sources to help stimulate native tissue regeneration of the meniscus.




Introduction


The meniscal injury is a major cause of functional impairment in the knee joint. This fibrocartilaginous tissue was once considered to be an unnecessary, vestigial appendage that could be sacrificed with minimal consideration. This total meniscectomy technique, although common in the past, has largely been abandoned because long-term results after major meniscectomy reported disappointing and adverse effects, such as the degradation of underlying articular cartilage and subsequent development of early osteoarthritis. As clinical medicine and basic science have evolved, the meniscus is now properly recognized as a necessary structure in the knee joint that is vital for biomechanical and anatomic purposes. Namely, the menisci are key for knee stability, distributing axial load, shock absorption between the articular cartilage of the tibia and femur, and nutrient distribution for protection of the underlying articular cartilage.


Biochemical Composition


The meniscus is composed of a dense extracellular matrix (ECM) that consists of 72% water, 22% collagen, and 0.8% glycosaminoglycans (GAGs). The remaining dry weight is made up of proteins, glycoproteins, and interspersed cells within the meniscus. These cells are referred to as fibrochondrocytes , because they have a marked resemblance to both fibroblasts and chondrocytes and synthesize the ECM and meniscal tissue. Type I collagen is expressed abundantly throughout the meniscus, whereas type II collagen is detected in the inner region. The interactions of these collagens, GAGs, and proteins likely account for the compressive load resistance, lubrication, and semielastic deformation properties of the meniscus.


Biomechanics and Gross Anatomy


The knee joint capsule houses the menisci, which are smooth, lubricated, crescent-shaped discs composed of fibrocartilaginous tissue with a medial and lateral component. These menisci sit on the natural contours of the tibial plateau between the femoral condyle and tibia of the knee. Joint motion and the biomechanical stressors associated with physical activity are important factors in determining the orientation of the collagen fibers that provide meniscal structure. There are 2 types of structural fibers that make up the meniscus: type I and type II collagen. These fibers are typically oriented based on the layers of the meniscus from surface to core: superficial (random orientation), lamellar (more organized radially at anterior and posterior horns), and deep (oriented circumferentially with some radial fibers) and allow the meniscus to expand under compressive forces to increase contact area of the joint.


A capillary network that originates in the synovium provides a direct blood supply to the meniscus, but only in certain “zones” of the meniscus. These zones are named based on the extent of vascularization of each respective region. The peripheral, outer third of the meniscus is known as the “red-red” zone, which has an excellent prognosis for repair because the blood supply is directly provided here. The intermediate “red-white” zone receives a limited blood supply and usually has a fair prognosis, as long as it is at the border of the vascular zone. The inner “white-white” zone of the meniscus, however, is completely avascular and presents a poor prognosis for recovery, regeneration, and healing. The lack of blood supply in this region confers difficulties for lesion/injury repair and regeneration of injured meniscus tissue. Current clinical reparative capacity seems to be restricted mainly to the peripheral, “red-red” vascular region of the meniscus, where there is a sufficient blood supply to promote healing. Biological tissue engineering and cell-based therapies constitute preclinical meniscus repair/regeneration strategies that offer much promise for the future.


Injury Prevalence and Call for Repair


With a combination of axial loading and rotational forces that generate a shear force, the meniscus is subject to both acute and degenerative injury, making it arguably the most commonly injured tissue in the knee. The epidemiologic data for the incidence and prevalence of meniscus injuries and clinical repair are limited, but seem to be rising every year. Logerstedt and colleagues, Hede and colleagues, and Jones and colleagues reported that the incidence rate of meniscus injury was 0.33 and 0.61 per 1000 person-years, with a prevalence of 12% to 14%. In the United States, of the estimated 850,000 to 1,000,000 cases per year in 2010, 10% to 20% of orthopedic surgeries involved surgical repair of the meniscus.


Clinicians and scientists alike agree that meniscal injury is considered an essential predictor of the subsequent development of degenerative joint disease and specifically strongly correlated with the development of early osteoarthritis. Therefore, considering the high incidence rate and increased risk of osteoarthritis development, it is critical to develop an ideal method for the prevention, repair, and treatment of injured meniscus tissue. Recent efforts have been directed toward regeneration of native meniscus tissue rather than meniscal resection. Although surgical techniques for mending damaged meniscus tissue have been extensively explored in the clinical setting, these repair attempts continue to fail for various reasons (ie, lack of longevity, tissue avascularity). Thus, it seems ideal to reframe this problem through an alternative perspective from the lens of basic science and regenerative medicine. This avenue, rather than meniscectomy or resection, has become an intriguing idea for addressing meniscal injuries in preclinical models. This review comprehensively details the current methodologies that are being explored in the basic sciences to stimulate better meniscus injury repair. Furthermore, it describes how these preclinical strategies may stand to improve current paradigms of how meniscal injuries are clinically treated through a unique and alternative perspective to traditional clinical methodology.


Current clinical paradigm


When clinicians come across an irreparable tear in the meniscus or with patients who have undergone a total or subtotal meniscectomy, meniscal allograft transplantation (MAT) may be considered a preferred modality for knee joint restoration. However, the indications for MAT remain controversial, because meniscal transplantation has been demonstrated to produce unsatisfactory results in the knee, including issues with graft size mismatching, donor incompatibility and sterilization, transplant remodeling and stability, and long-term chondroprotection.


With an increasing incidence rate of meniscal injury, the urgent need for an innovative and efficacious repair strategy has become evident. Because of the aforementioned limitations, MAT cannot serve as a “fix-all” model. Because of this, the development of acellular biological scaffolds emerged as an interesting alternative to MAT. The primary goal of using these scaffolds is to use a minimally immunogenic 3-dimensional (3D) tissue-replacement that stimulates migration, proliferation, and integration of endogenous/native cells into the scaffold for the purpose of restoring meniscus function with a secondary goal of chondroprotection with respect to joint-loading function.


Collagen Meniscus Implant


Currently in the United States, there is only 1 Food and Drug Administration–approved cell-free scaffold for meniscus replacement: the collagen meniscus implant (CMI). This scaffold was the first regenerative technique specifically invented and used for meniscus replacement in the clinical setting. The CMI is composed primarily of type I collagen fibers and GAGs isolated from bovine Achilles tendon that are sterilized via gamma-irradiation. This scaffold is perforated and porous to allow for ideal cell infiltration for better tissue integration purposes; clinical studies have indeed reported this native cell integration into the CMI. In theory, this scaffold appears to be a better replacement than MAT; because it is less destructive to the joint, its shape can be custom fit, and it is composed of biological tissue, thus virtually eliminating the risk of an immunologic response from donor mismatch. However, there has been debated controversy in terms of efficacy of the CMI. In 1999, Rodkey and colleagues reported that 8 patients who underwent arthroscopic replacement with the CMI at short-term follow-up demonstrated tissue regeneration, no degenerative progression, and chondroprotection of the joint surface. These results were confirmed by radiographs, and the histologic grading was confirmed new fibrocartilage formation. Furthermore, a medium-term follow-up study was done by Bulgheroni and colleagues in 2010, with 34 patients who underwent CMI implantation. These patients were evaluated 2 to 5 years later and showed good to excellent results with chondroprotection, no further degradation of the joint surface, and some newly synthesized tissue that appeared healthy. However, the CMI had rescinded in size and was presenting some clinical challenges. Long-term follow-up studies have demonstrated similar adverse results, because the implant significantly shrank in size after 5 to 6 years, possibly because of degradation, and led to decreased biomechanical function. The dangers of a potential size mismatch in the joint after implantation of the CMI would change the mechanical environment of the knee and decrease the chondroprotection of the underlying cartilage, resulting in further joint damage and likely further the progression of osteoarthritis.


Platelet-Rich Plasma/Fibrin


Within the field of orthopedics, the use of platelet-rich plasma (PRP) as a clinical therapeutic technique has seen a rapid increase in popularity. In the United States alone, it is estimated that 86,000 athletes are treated with PRP annually. PRP is an autologous blood product containing numerous growth factors and cytokines that is being implemented as a clinical intervention for musculoskeletal defects, including meniscus injuries. The increased concentration of platelets and growth factors is purported to aid in the native wound-healing process through the stimulation of meniscus cell proliferation and migration, angiogenesis, and matrix synthesis. Despite its growing popularity both in medicine and in the mainstream media, the efficacy and usage of this biological treatment remain controversial.


Pujol and colleagues attempted to augment repair and promote meniscal healing through the use of PRP treatment of horizontal meniscal tears. At a minimum of 24 months postoperatively, they reported a slight improvement in functional outcome and MRI-documented healing during midterm follow-up in young patients. Furthermore, Blanke and colleagues treated 10 patients with grade II meniscal lesions with percutaneous injections of PRP in 7-day intervals. Four of 10 patients showed a decrease of the meniscal lesion and relief of pain in a follow-up MRI and pain score after 6 months. In addition to slight pain relief and improved functional outcomes, certain groups have demonstrated the growth factor and immunologic response associated with PRP treatment. Wasterlain and colleagues found that serum growth factors were significantly elevated after PRP injection, which may contribute to a better repair response. It is thought that PRP may augment healing by increasing the levels of growth factors and cytokines localized to the injury site.


Although these groups have demonstrated positive results, there are also many others that report either (1) no significant improvements using PRP treatment or (2) adverse outcomes associated with PRP treatment. For example, 1 study conducted at the University of Virginia performed 35 isolated arthroscopic meniscal repairs with and without PRP augmentation and reported no clinical advantage of using PRP over non-PRP after a minimum follow-up of 2 years. Furthermore, Zellner and colleagues reported that implantation of a composite matrix loaded with PRP failed to improve meniscal healing in the avascular zone. The PRP-loaded matrix treatment outcome was characterized by poor tear filling without meniscal regeneration after a 3-month period. Available in vitro data reporting on the efficacy of PRP treatment of meniscal tears appear to be mixed as well, with groups finding contrasting results. It should be noted that recent studies have found some success by using various mesenchymal stem cell (MSC) sources supplemented with PRP for meniscus repair ; however, this field is still being investigated and needs more published data.


Although some studies have demonstrated the benefits of PRP as a therapeutic for meniscal regeneration and healing, the clinical efficacy and results seem to be mixed and unclear. More clinical studies with larger sample sizes and medium- to long-term follow-ups with measurable outcomes, such as histologic analysis and functional grading of meniscus repair, are needed to determine the true efficacy of PRP.


Acellular meniscus regeneration and repair techniques in basic/translational science


Decellularized Scaffold and Growth Factors


As an alternative method for a biomimetic cell-free scaffold, some have suggested using the process of decellularization of intact, native meniscus tissue in order to preserve the native structure and fiber-level organization. This decellularized scaffold technique is a significant advantage compared with other scaffolds because these retain the naturally occurring collagen networks present in the healthy meniscus. Furthermore, this type of scaffold would have a much lower risk of an adverse immunogenic reaction. However, 1 major challenge associated with using decellularized tissue is the low infiltration of cells into these scaffolds, because of their dense ECM structure as well as improper fitting and mismatch sizing issues in the joint.


In response to this, some groups have suggested using biomimetic, biosynthetic scaffolds coupled with chemotactic agents, such as growth factors, to stimulate native cell migration and infiltration to enhance integration into the scaffold. These growth factors that are used usually play a significant role in limb development. Local delivery or supplementation of growth factors may create a beneficial microenvironment to promote endogenic repair and integration for engineered tissue scaffolds. Growth factors act on target cells to stimulate cellular growth, proliferation, healing, and cellular differentiation. This effect is achieved usually through a receptor-mediated mechanism, whereby a growth factor will bind to its respective receptor and trigger a secondary system of signals or messengers to activate nuclear genes that control different cellular processes.


Certain growth factors have been demonstrated to play a key role in the metabolic activity of meniscal fibrochondrocytes (MFCs): regulating development, homeostasis, cell rejuvenation, and regeneration. With this idea in mind, there have been a myriad of different growth factor delivery methods to treat native fibrochondrocytes in both in vivo and in vitro experimental studies with the ultimate goal of optimizing meniscus tissue engineering and repair. Specifically, this review focuses on the supplementation of growth factors to MFCs (the native cell of the meniscus) or direct addition of growth factors to meniscal tissue. The most commonly used growth factors for treating meniscal tissue or MFCs seem to be basic fibroblast growth factor (bFGF), transforming growth factor beta-1 and -3 (TGFB1, TGFB3), and insulin-like growth factor-1 (IGF-1), with others being used less frequently ( Table 1 ).



Table 1

Effect of different growth factor supplementation on meniscal fibrochondrocytes
































































































































































Citation Source Growth Factor Used Cell Source Results/Effects In Vitro/In Vivo
Ionescu et al, 2012 bFGF None (tissue scaffold) Short-term delivery-enhanced integration strength of native tissue with scaffold In vitro explant–scaffold (bovine)
Hiraide et al, 2005 bFGF MFCs Enhanced cell proliferation In vitro–monolayer
Kasemkijwattana et al, 2000 bFGF MFCs Enhanced cell proliferation In vitro–monolayer
Stewart et al, 2007 bFGF MFCs Enhanced cell proliferation In vitro–PGA scaffold culture
Ionescu et al, 2012 bFGF + TGFB3 None (scaffold) Improved scaffold/tissue integration and enhanced meniscus repair In vitro–electrospun PCL scaffold
Ionescu et al, 2012 TGFB3 None (tissue scaffold) Sustained delivery-enhanced integration strength of native tissue with scaffold and increased proteoglycan content In vitro explant–scaffold (bovine)
Bochyńska et al, 2017 TGFB3 None (scaffold) Regeneration of articular cartilage underlying meniscus by homing of endogenous cells In vivo–PCL-HA scaffold (rabbit)
Tarafder et al, 2018 CTGF + TGFB3 None (tissue scaffold) Remodeling of fibrous matrix into fibrocartilaginous matrix by TGFB3 mechanism, induced recruitment of synovial mesenchymal cells/progenitor cells and meniscal tissue integration through CTGF application In vitro–loaded fibrin glue scaffold (bovine)
Tanaka et al, 1999 TGFB1 MFCs Increased collagen and GAG synthesis In vitro–monolayer
Pangborn & Athanasiou, 2005 TGFB1 MFCs Increased collagen and GAG synthesis In vitro–PGA scaffold
Imler et al, 2004 TGFB1 MFCs Increased collagen and GAG synthesis In vitro–meniscus explant culture
Marsano et al, 2007 TGFB1 MFCs Enhanced cell proliferation In vitro–monolayer
De Mulder et al, 2013 TGFB1 MFCs Enhanced cell proliferation In vitro–PU scaffold
Forriol et al, 2014 BMP-7 None Filled meniscal defect with cellular fibrous tissue In vivo–intraarticular injection (sheep)
Bhargava et al, 1999 BMP-7 (OP-1) MFCs Enhanced cell migration/proliferation In vitro
Tumia & Johnstone, 2004 IGF-1 MFCs Enhanced cell proliferation, synthesis of proteoglycans and ECM while inhibiting destruction of matrix In vitro–monolayer culture
Puetzer et al, 2013 IGF-1 MFCs Increased levels of collagen and GAG synthesis In vitro–scaffold culture
Bhargava et al, 1999 IGF-1 MFCs Enhanced cell migration/homing of cells In vitro–explant culture
Acosta et al, 2008 IGF-1 + TGFB1 None (tissue scaffold) Enhanced repair of avascular (white-white) zone of meniscus In vitro–explant culture
Petersen et al, 2007 VEGF None (suture coating) Failure to enhance repair or cell migration In vivo–VEGF-coated sutures (sheep)
Hidaka et al, 2002 HGF MFCs Increased angiogenesis to promote healing response In vivo–PGA scaffold (mice)
Nishida et al, 2004 CTGF None (scaffold) Enhanced articular cartilage regeneration In vivo–hydrogel collagen scaffold (rat)
Tumia & Johnstone, 2009 PDGF-AB MFCs Increased cell proliferation rate and matrix synthesis/formation In vitro–monolayer culture
Marsano et al, 2007 FGF-2 MFCs/tissue Enhanced cell proliferation In vitro–monolayer culture
Pangborn & Athanasiou, 2005 FGF-2 MFCs/tissue Enhanced collagen synthesis In vitro–scaffold culture

Abbreviation : PGA, polyglycolic acid.


Basic fibroblast growth factor


bFGF is a bioactive protein that acts as both a growth factor and a signaling protein that possesses broad mitogenic and cell survival activities, which play a primary role in angiogenesis, mitogenesis of fibroblasts, tyrosine activation, and inhibition of bone morphogenetic proteins (BMPs). When culturing MFCs in monolayer, Hiraide and colleagues and Kasemkijwattana and colleagues found that addition of bFGF resulted in enhanced cell proliferation. Further in vitro studies have demonstrated that bFGF addition resulted in enhanced native tissue integration into various scaffold models and improved meniscus repair.


Transforming growth factor-beta


The multifunctional cytokine superfamily, that is, TGFB, is involved in a receptor kinase mechanism that initiates a signaling cascade, which activates many downstream substrates and proteins. The role of TGFB isoforms TGFB1 and TGFB3 in the regulation of differentiation, chemotaxis, cell proliferation, and the immune response has been studied extensively in orthopedic research. In vitro supplementation of TGFB1 and TGFB3 to MFCs in monolayer, synthetic scaffolds, and explant tissue culture models have generally yielded positive results. These positive results include increased GAG and proteoglycan synthesis by native cells, enhanced native cell proliferation, regeneration of articular cartilage, and targeted homing of endogenous cells.


Insulin Growth Factor-1


IGF-1 is a member of the insulin-related peptide family that plays an important role in childhood growth with continued anabolic effects in adults. IGF-1 is a primary mediator of the effects of growth hormone, which stimulates systemic body growth and is of key interest in the orthopedic research field for musculoskeletal purposes. Addition of IGF-1 to MFCs in monolayer, scaffold culture, and explant culture in vitro resulted in enhanced cell proliferation, increased GAG and proteoglycan production, and better homing of cells.


Cell-based meniscal regeneration and augmentation techniques in basic/translational science


The cell-based therapeutic potential of human multipotent MSC has long been investigated in the field of meniscal tissue healing and regenerative medicine. This tissue engineering strategy is closer to translation than some might think, and there are even some clinical trials currently underway ( ClinicalTrials.gov Identifier: NCT02033525 ). Currently, groups are investigating several promising cell types and isolation methods to identify ideal MSC sources for meniscus repair. This exploration has produced encouraging but mixed results that are likely due to varying experimental conditions used in each individual investigation. This wide variation has made it difficult to directly compare efficacious outcomes in the field of tissue engineering and regeneration. With an aim to alleviate these difficulties, in 2006, the International Society for Cellular Therapy (ISCT) published a minimal criterion to define human MSCs. First, the MSCs must adhere to tissue culture plastic when maintained in standard culture conditions. Second, the phenotypic profile and epitope expression of MSCs must be at the very minimum: CD105 + , CD73 + , CD90 + while being CD45 , CD34 , CD14 , CD11b , CD79a , or CD19 . Third, MSCs must demonstrate trilineage potential, meaning that they can be differentiated into osteoblasts, adipocytes, and chondroblasts in vitro. In addition, it is thought that these stem cells must be self-renewing and have a high proliferation capacity in the sense that they can perpetually divide/replicate while maintaining an undifferentiated state.


Therefore, this review focuses exclusively on what the authors, in accordance with the ISCT minimal criterion, consider the MSC sources most widely used and most promising in the basic and translational science research setting for cell-based meniscus regeneration: bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose-derived stem cells (ADSCs), synovium-derived stem cells (SDSCs), native MFCs, and progenitor cells, articular cartilage-derived progenitor cells (CPCs).


In the following paragraphs, the authors report on preclinical, in vivo studies with data on meniscal tear augmentation using various cell-based therapies. These data are the focus of Table 2 , which provides the cell type and quantity used, the animal model that was used, the length of time of the study, the measurements of successful treatment outcomes (histology, MRI, macroscopic, formation of neomeniscal tissue, presence of fibrochondrocytes, and so forth), and finally, the limitations for each cell type.



Table 2

Various mesenchymal stem cell sources used for meniscus repair/regeneration and their preclinical application
















































































































































































































































































































































































































Cell Source Number of Cells Used Animal Model Meniscus Injury Model Experimental Treatment Control Outcome/Results Reference
SPIO-labeled ADSCs 2 × 10 6 Rabbit ½ anterior meniscectomy of medial meniscus SPIO-labeled ADSCs Saline OR unlabeled ADSCs


  • 12 wk:




    • Targeted ADSC delivery promoted meniscal regeneration + protective effects from OA damage


Qi et al, 2015
Allogeneic rabbit ADSCs 0.1 × 10 6 Rabbit Longitudinal lesion in avascular zone Suture + ADSCs suspended in Matrigel Suture + Matrigel only


  • 12 wk:




    • Improved healing rate in avascular zone for acute lesions that received suture + ADSCs


Ruiz-Ibán et al, 2011
Autologous sheep ADSCs 20 × 10 6 Sheep Medial meniscectomy (and ACL resection) Autologous chondrogenically induced ADSCs Culture medium


  • 6 wk:




    • Regenerated de novo cartilage underlying meniscus


Ude et al, 2014
Autologous Human ADSCs 16 × 10 6 Human Grade II meniscal tear Autologous hADSCs + PRP and hyaluronic acid injections PRP + Hyaluronic acid injections


  • 3 mo:




    • Reduced pain and minimal regeneration of meniscus tissue


Pak et al, 2014
Autologous equine ADSCs Equine Medial meniscus defect Autologous ADSCs Autologous BM-MSCs


  • 12 mo:




    • Some defects appeared to fill in with fibrocartilaginous tissue, others did not heal or fill in


González-Fernández et al, 2016
Human ADSCs Bovine (explant in vitro) Radial tear on cylindrical explant punch biopsy from inner avascular region of meniscus Photo-crosslinked hydrogel loaded with ADSCs + TGFB3 TGFB3 only


  • 4 wk and 8 wk:




    • Increased matrix-sulfated proteoglycan deposition and some healing of meniscus


Sasaki et al, 2018
Allogeneic rabbit ADSCs Rabbit Complete meniscectomy of medial meniscus PVA/Ch scaffold seeded with ADSCs Scaffold seeded with articular chondrocytes OR cell-free scaffold


  • 7 mo:




    • Minor meniscus regeneration for articular chondrocyte group (ADSCs had no significant contribution in healing process and lower Col II, Aggrecan, and Col 1)


Moradi et al, 2017
Allogeneic rabbit ADSCs 5 × 10 4 cells/spheroid
(400–500 spheroids)
Rabbit Partial meniscectomy of the medial meniscus High-density ADSC spheroid construct (3D culture) No cells


  • 2, 4, 8, and 12 wk:




    • Mixed results; some rabbits showed beneficial healing effect in the avascular zone of the meniscus


Toratani et al, 2017
Autologous SDSCs 0.25 × 10 6 Primate Partial meniscectomy of medial meniscus + insertional ligament of medial meniscus transection Autologous SDSC aggregate Intraarticular SDSC injection


  • 8 and 16 wk:




    • Apparent meniscus regeneration in aggregate and control group; SDSC aggregate group had better articular cartilage histology scores



    • *No statistical analysis


Kondo et al, 2017
Allogeneic SDSCs 20 × 10 6 Microminipig Longitudinal tear lesion in medial menisci Injection of SDSC suspension + suture Suture only


  • 12 wk:




    • Meniscal healing in SDSC group reported to be significantly better than control group with collagen fibrils present in SDSC group only


Nakagawa et al, 2015
Allogeneic SDSCs 50 × 10 6 Pig Partial meniscectomy of medial menisci Intraarticular injection of SDSCs at 0.2 and 4 wk Intraarticular injection of PBS


  • 2, 4, 8, 12, and 16 wk:




    • Resected meniscus regeneration enhanced in SDSC group based on histology and MRI + better articular cartilage protection


Hatsushika et al, 2014
Syngeneic and allogeneic SDSC 5 × 10 6 Rat Partial meniscectomy of medial meniscus Intraarticular injection of syngeneic SDCSs, minor immune mismatch model cell transplantation, major immune mismatch model cell transplantation
(for histocompatibility)
Intraarticular injection of PBS


  • 4 wk:




    • Regenerated area of meniscus was larger in minor mismatch and syngeneic SDSC groups than major mismatch group with more cells present (indicated by immunofluorescence)


Okuno et al, 2014
Autologous SDSCs 10 × 10 6 Rabbit Partial meniscectomy of medial meniscus Intraarticular injection of autologous SDSCs in PBS No cells


  • 1, 3, 4, and 6 mo:




    • Meniscus size was larger in SDSC-treated group initially, but at months 4 and 6 there was no difference; SDSCs adhered to local area of defect; and articular cartilage appeared thicker in SDSC group than control (better histologic scoring)


Hatsushika et al, 2013
SDSCs 0.25 × 10 6 Rat Partial meniscectomy SDSC aggregate Intraarticular injection of 5 × 10 6 cell suspension in PBS AND 0.25 × 10 5 cell suspension in PBS


  • 12 wk:




    • Larger meniscal area and better histologic scores for aggregate groups


Katagiri et al, 2013
Allogeneic SDSCs 0.2 × 10 6 cells cultured for 3 wk to make 3D construct Pig 4-mm cylindrical defect in medial meniscus Cultured SDSC 3D cell/matrix tissue construct (scaffold-free) No treatment


  • 6 mo:




    • SDSC 3D construct group filled meniscal defect and showed improved tissue integration compared with control


Moriguchi et al, 2013
Allogeneic SDSCs 2 × 10 6 Rabbit 1.5-mm cylindrical defect in avascular zone of medial meniscus Allogeneic SDSCs suspended in PBS PBS only


  • 4, 12, and 24 wk:




    • Mixed results:




      • Quantity of regenerated tissue significant ONLY at 4 and 12 wk. Quality of repair scores significant at 12 and 24 wk. Cells expressed type I and type II collagen at 24 wk



Horie et al, 2012
Allogeneic SDSCs 5 × 10 6 Rat Partial meniscectomy of medial meniscus Intraarticular injection of Luc/LacZ + SDSCs
AND BM-MSCs
PBS only


  • 12 wk:




    • Some meniscal regeneration in SDSC group that were LacZ + ; SDSCs reportedly differentiated into meniscal cells and promoted regeneration of tissue


Horie et al, 2009
Allogeneic/exogenous SDSCs Rat Cylindrical defect created in meniscus Intraarticular injection of GFP-positive SDSCs PBS only


  • 1 d, 2, 4, 8, and 12 wk:




    • SDSC group expressed type II collagen, attached to the defect site and seemed to have improved histologic scores at week 12, BUT there was NO statistically significant difference between groups


Mizuno et al, 2008
Allogeneic SDSCs Rabbits Full-thickness longitudinal incision on medial meniscus Fibrin gel loaded with SDSCs + CTGF and TBGFB3 Fibrin alone OR Fibrin + CTGF


  • 6 wk:




    • Fibrocartilaginous tissue integration demonstrated by hematoxylin and eosin and Saf-O fast green stain; tensile testing revealed enhanced biomechanical properties


Tarafder et al, 2018
Autologous BM-MSCs 6 × 10 6 Sheep Unilateral medial meniscectomy Autologous BM-MSCs from iliac crest in HA construct BMC in HA construct


  • 12 wk:




    • BMC in HA construct allowed for better tissue regeneration than BM-MSCs and this group seemed to inhibit OA progression with a reduction in cartilage and meniscus inflammation. BUT subchondral bone thickness was decreased in both BM-MSC and MSC groups


Desando et al, 2016
Autologous BM-MSCs 15–20 × 10 6 Horse Meniscal tear Intraarticular injection of autologous, expanded BM-MSCs into the joint Surgery only, NO treatment


  • 24 mo:




    • 75% of horses returned to some level of work posttreatment of meniscal injury with BM-MSCs


Ferris et al, 2014
Autologous BM-MSCs 0.1 × 10 6 Rabbit 4-mm longitudinal tear in avascular zone of medial meniscus Implantation of autologous BM-MSCs cultured and embedded in hyaluronan/collagen matrix Suture only, cell-free matrix construct, or PRP


  • 6 and 12 wk:




    • BM-MSC matrix constructs initiated fibrocartilage-like repair tissue and demonstrated better integration and biomechanical properties than any control group


Zellner et al, 2013
Human BM-MSCs and rat BM-MSCs 2 × 10 6 Rats Partial meniscectomy Intraarticular injection of human BM-MSCs or rat BM-MSCs PBS only


  • 2, 4, and 8 wk:




    • Human BM-MSCs rapidly decreased in number over time, but enhanced meniscal regeneration similar to rat BM-MSCs. Human BM-MSCs increased local expression of Col II and Indian hedgehog (Ihh), with a subset that activated local expression of PTHLH and BMP2


Horie et al, 2012
Human BM-MSCs 2 × 10 6 Rabbit Complete radial tear of medial meniscus at the anterior tibial attachment site Pull-out surgical repair + human BM-MSCs embedded in a matrix gel scaffold Pull-out surgical repair (NO cells)


  • 2, 4, and 8 wk:




    • n = 20/25 rabbits survived postoperation. Of these, there was no significant difference in regenerative healing or fibrocartilage-like tissue formation between BM-MSC treatment and no cell control group


Hong et al, 2011
Autologous BM-MSCs 1.5 × 10 6 Rabbit 2-mm meniscal tissue punch defect in avascular zone Hyaluronan-collagen composite matrices loaded with autologous BM-MSCs PRP loaded in matrices OR autologous bone marrow loaded in matrices OR cell-free matrices


  • 12 wk:




    • Neither bone marrow nor PRP loaded in matrices produced improvements in healing compared with cell-free implants; BM-MSCs loaded in collagen matrix resulted in fibrocartilage-like tissue repair that only partially integrated with the native meniscus


Zellner et al, 2010
Autologous BM-MSCs 1–2 × 10 6 Pig Radial tear in the avascular zone of the meniscus Autologous BM-MSCs + sutures and fibrin glue No treatment OR sutures and fibrin glue alone


  • 8 wk:




    • No complete healing in the no treatment group or with sutures and fibrin glue alone; complete healing was seen in 3 animals and incomplete healing was seen in 5 of the animals in the BM-MSC treated group


Dutton et al, 2010
Autologous BM-MSCs 30 × 10 6 cells/mL Goat Full-thickness meniscal defect in white-white area of meniscus BM-MSCs transfected with hIGF-1 + calcium alginate gel Nontransfected BM-MSCs OR calcium alginate gel alone OR no treatment


  • 4, 8, and 16 wk:




    • Defects were filled with fibrocartilage-like tissue composed of cells embedded in matrix spaces of meniscal fibers with enhanced proteoglycan levels in hIGF-1 overexpressed BM-MSCs


Zhang et al, 2009
Autologous BM-MSCs 2.5 × 10 6 , then 14 d in culture Rabbit Partial meniscectomy of middle ⅓ of meniscus Autologous BM-MSCs (cultured for 14 d in chondrogenic conditions) loaded into a hyaluronan/gelatin scaffold Cell-free scaffold OR no treatment


  • 12 wk:




    • Untreated defects showed no healing; cell-free scaffolds showed some repair of fibrocartilaginous tissue; BM-MSC-loaded scaffold had significantly enhanced fibrocartilage repair compared with either control


Angele et al, 2008
BM-MSCs 0.5 × 10 6 /mL Rabbit Partial meniscectomy of medial meniscus Type I collagen sponge loaded with autologous BM-MSCs Cell-free collagen sponge OR periosteal autograft OR no treatment


  • 24 wk:




    • Periosteal autograft differentiated into a bonelike composite that is harmful for meniscus repair; collagen sponge alone supported a fibrous repair response; collagen sponge loaded with BM-MSCs produced fibrocartilaginous tissue similar to native tissue, but the biomechanical function of the meniscus was NOT restored


Walsh et al, 1999
BM-MSCs ∼1 × 10 6 cells (from bone marrow aspirant) Rabbit 1.5-mm full-thickness defect in avascular zone of meniscus BM-MSCs suspended in fibrin glue Fibrin glue alone OR no treatment


  • 1, 3, 6, and 12 wk:




    • Defects were smaller in the fibrin glue alone group and the fibrin glue + BM-MSC group; healing response was faster in the fibrin glue + BM-MSC group


Ishimura et al, 1997
Allogeneic BM-MSCs 0.3 × 10 6 Rabbit and rat Explant culture Allogeneic rabbit BM-MSCs or rabbit MDSC housed in Matrigel


  • 3 wk:




    • BM-MSCs had a high propensity for cartilage hypertrophy and bone formation. MDSCs exhibited greater chondrogenic potential than BM-MSCs


Ding & Huang, 2015
Allogenic horse BM-MSCs 0.2 × 10 6 Nude mice Equine meniscal sections Allogeneic horse BM-MSCs + fibrin glue subcutaneously implanted into rat PBS OR fibrin glue alone BM-MSC group showed increased vascularization with increased total bonding of repair and native tissue Ferris et al, 2012
Autologous BM-MSCs 11–12 × 10 6 Sheep Meniscal tear of medial meniscus Intraarticular injection of BM-MSC suspension Intraarticular injection of suspension medium (NO cells)


  • 6–12 mo:




    • BM-MSC injection group showed no adverse immunologic effects, and meniscus regeneration was demonstrated through histology and macroscopic parameters, BUT these instances were limited and case dependent


Caminal et al, 2014
Autologous BM-MSCs 10 × 10 6 Sheep Complete meniscectomy of the medial meniscus + ACL excision Intraarticular injection of chondrogenically induced BM-MSCs OR intraarticular injection of basal-culture medium BM-MSCs Intraarticular injection of basal medium (NO cells)


  • 6 wk:




    • Control group had severe OA and meniscus damage; no significant ICRS scoring was detected between the 2 BM-MSC groups; chondrogenically induced BM-MSC group displayed better meniscus regeneration than basal BM-MSCs and significantly better than the control group


Al Faqeh et al, 2012
Allogeneic BM-MSCs 1 × 10 6 vs 10 × 10 6 Rats Meniscal tear + ACL tear + articular cartilage defect Intraarticular injection of allogeneic GFP-positive BM-MSCs Sham operation OR saline


  • 4 wk:




    • GFP-positive BM-MSCs mobilized to the injury site and contributed to tissue regeneration compared with control groups


Agung et al, 2006
Autologous BM-MSCs 10 × 10 6 Goat Osteoarthritis (OA) induction through complete meniscectomy of the medial meniscus Intraarticular injection of autologous BM-MSCs expressing eGFP (retrovirus) suspended in sodium hyaluronan Sodium hyaluronan alone (NO cells)


  • 26 wk:




    • BM-MSC treatment group displayed meniscus regeneration, with eGFP fluorescent cells located in the newly formed tissue; degeneration of cartilage and the OA phenotype was reduced in the BM-MSC group compared with the control group


Murphy et al, 2003
Human BM-MSCs 30 × 10 cells/mL Rat Radial cut of the medial meniscus (2 mm × 2 mm excision) Human BM-MSCs encapsulated in decellularized ECM hydrogel PBS


  • 8 wk:




    • Significant tissue regeneration in BM-MSC group with higher GAG, type I and type II collagen than control group; some tissue regeneration in control animals


Yuan et al, 2017
Autologous BM-MSCs Rabbit Total meniscectomy BM-MSC seeded PCL scaffold meniscus replacement Cell-free scaffold, sham operation, and total meniscectomy alone


  • 12 and 24 wk:




    • BM-MSC seeded PCL scaffold group had a better gross meniscus appearance with higher expression of type I, II, and III collagen and proteoglycan production found in native fibrochondrocytes + less cartilage degradation than any control group + better tensile and compressive properties in cell-seeded implant


Zhang et al, 2017
Allogeneic BM-MSCs ∼4.8 × 10 6 Rat Partial meniscectomy (1/2 resection) of the medial meniscus Allogeneic BM-MSCs cultured in a cell “sheet” from monolayer culture No treatment


  • 4 and 8 wk:




    • Histologic evaluation revealed regenerated tissue “similar” to native tissue with some collagen bridging as a measure of tissue integration with some alleviation of degenerative cartilage damage compared with the control group


Qi et al, 2016
Allogeneic BM-MSCs Rat Meniscal defect Allogeneic rat-derived BM-MSCs were seeded into a scaffold and cultured for 4 wk and then implanted Cell-free scaffold OR meniscectomy


  • 4 and 8 wk:




    • Expression of extracellular matrices was observed in transplanted tissue 4 wk postsurgery. Articular cartilage was better protected/less damaged in MSC scaffold group than either control group


Yamasaki et al, 2008
Allogeneic human BM-MSCs Rat Meniscal defect Allogeneic human GFP-positive BM-MSCs cultured in monolayer and then embedded in fibrin glue and transplanted to injury defect No treatment OR fibrin glue only (NO cells)


  • 8 wk:




    • GFP-positive BM-MSCs survived and proliferated in the meniscal defects while producing ECM


Izuta et al, 2005
Autologous BM-MSCs Rabbit Partial meniscectomy of white-red zone Autologous BM-MSCs loaded in a polyurethane scaffold (Actifit) and sutured into the defect Polyurethane scaffold alone (Actifit) (NO cells)


  • 6 and 12 wk:




    • Both cell-free and BM-MSC loaded scaffolds led to well-integrated and stable meniscus-like repair tissue with dense vascularization; accelerated healing was achieved by the BM-MSC loaded scaffold


Koch et al, 2018
CPCs 0.1 × 10 6 Rat (ex vivo) Radial tear in inner anterior horn C-PC line 3 + SDF-1 pretreatment OR primary C-PCs + SDF-1 pretreatment BM-MSCs OR no cell treatment


  • 3, 5, 10, 17, and 20 d:




    • Chondroprogenitors (CPCs) promoted meniscal fibrochondrocyte proliferation and native tissue integration of torn meniscal tissue through progressive; SDF-1/CXCR4 axis is required to successfully fill meniscus tissue tears


Jayasuriya et al, 2018

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Aug 15, 2020 | Posted by in SPORT MEDICINE | Comments Off on Meniscus Repair and Regeneration
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