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Meniscus Repair and Regeneration: A Systematic Review from a Basic and Translational Science Perspective
Abstract
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.
... The function of meniscus is to distribute load, absorb shock and protect the cartilage tissue of the lower knee joint.Knee meniscus injury is receiving more and more attention from medical staff because of its inducing effect on knee osteoarthritis and rheumatoid arthritis and its widespread presence in the population [1]. Due to the different classification criteria and diagnosis methods of meniscus injury, there are certain differences in the statistical differences of the prevalence of meniscus injury. ...
... The knee meniscus is located in the knee joint capsule, between the femoral condyle and the surface of the tibia, and is a smooth crescent-shaped intervertebral disc [1]. The meniscus can be roughly divided into the medial meniscus and the lateral meniscus. ...
... The biochemical composition of meniscus is mainly dense extracellular matrix (ECM), in which 72% is water, 22% is collagen tissue, and 0.8% is glycosaminoglycans (GAGs). In collagen tissue, 80% is type I collagen, which is distributed throughout the meniscus, and 20% is type II collagen, which is basically distributed in the inner region [1,4]. The distribution and direction of type I collagen and type II collagen in different depths from the surface to the inside of the meniscus also have obvious differences, which endows the meniscus with complex mechanical properties, and the complex distribution of collagen is also the most challenging topic in the tissue reconstruction technology mentioned below [4]. ...
Knee meniscus injury has a high incidence, which can change the load-bearing structure of the knee joint, causing pain and further cartilage damage and osteoarthritis and other related diseases, and is difficult to prevent and treat effectively. Therefore, how to treat meniscus injury has become one of the hot issues concerned by patients and medical staff in recent years. Compared with simple meniscectomy, tissue engineering meniscectomy has fewer adverse effects and some techniques have achieved satisfactory results. At present, the meniscus tissue engineering treatment method is continuously developing and innovating. In this paper, the promising techniques of collagen scaffold implantation, silk fibroin scaffold implantation, hydrogel implantation and bone marrow stimulation were discussed, we hope to provide the basis for the further development of meniscus repair.
... Both the anterior and the posterior cruciate ligaments are situated in the middle of the knee joint and anchor the femur to the tibia. These cruciate ligament have a microstructure that consist of collagen bundles and a matrix made up of proteins, elastin, glycoproteins and glycosaminoglycans (GAGs) (33). Functionally, the ACL prevents anterior translation of the tibia on the femur, and posterior translation is prevented by the PCL (34). ...
... Functionally, the ACL prevents anterior translation of the tibia on the femur, and posterior translation is prevented by the PCL (34). The cruciate ligaments are vascularized by branches of the middle genicular artery that enters the joint capsule posteriorly through an aperture in the oblique popliteal ligament (33). Damage to these branches due to rupture of cruciate ligaments lead to intra-articular bleeding also known as hemarthrosis. ...
... Damage to these branches due to rupture of cruciate ligaments lead to intra-articular bleeding also known as hemarthrosis. The proximal part of the ACL is better endowed with blood vessels than the distal part which is poorly vascularized, contributing to the poor healing potential of the ACL (33). The ACL is innervated by the tibial nerve and PCL is innervated by both the tibial and the obturator nerves. ...
Knee injuries such as anterior cruciate ligament ruptures and meniscal injury are common and are most frequently sustained by young and active individuals. Knee injuries will lead to post-traumatic osteoarthritis (PTOA) in 25–50% of patients. Mechanical processes where historically believed to cause cartilage breakdown in PTOA patients. But there is increasing evidence suggesting a key role for inflammation in PTOA development. Inflammation in PTOA might be aggravated by hemarthrosis which frequently occurs in injured knees. Whereas mechanical symptoms (joint instability and locking of the knee) can be successfully treated by surgery, there still is an unmet need for anti-inflammatory therapies that prevent PTOA progression. In order to develop anti-inflammatory therapies for PTOA, more knowledge about the exact pathophysiological mechanisms and exact course of post-traumatic inflammation is needed to determine possible targets and timing of future therapies.
... The meniscus is a crescentshaped fibrocartilage located between the tibial plateau and the femoral condyle, playing essential roles in shock absorption, lubrication, and stabilization of the knee joint [7]. Given that meniscal injury often reduces meniscal function and commonly precedes OA development, repair is highly recommended whenever possible [6,8]. Accordingly, native meniscus tissue regeneration is preferred over meniscal resection, not only for treating but also for preventing and restoring injured meniscal tissues [8]. ...
... Given that meniscal injury often reduces meniscal function and commonly precedes OA development, repair is highly recommended whenever possible [6,8]. Accordingly, native meniscus tissue regeneration is preferred over meniscal resection, not only for treating but also for preventing and restoring injured meniscal tissues [8]. ...
... The fibres and fascicles in the meniscus are distributed in various arrangements, depending on the location of the tissue. 2 The inner component of the meniscus is composed of small and irregular radial collagen fibrils with a structure similar to that of hyaline cartilage. 3 Conversely, the outer region is composed of organised interweaved collagen fibrils, fibres and fascicles with a circumferential orientation. ...
... 29 Synthetic materials commonly used in meniscus tissue engineering include polyglycolic acid (PGA), polylactic acid (PLA), polylactide glycolide acid (PLGA), polycaprolactone (PCL), polyurethane (PU), polyvinyl alcohol (PVA) and new nanomaterials. 2,3 Typically, scaffolds that consist of more than two kinds of composite materials are called composite scaffolds, such as PGA/PLGA and HA/PCL. These materials are biocompatible and have good mechanical strength. ...
Introduction:
The meniscus plays an important role in maintaining homeostasis to facilitate the normal function of the knee joint. It is one of the most commonly injured areas of the knee joint. Meniscal-related injuries can lead to significantly decreased athletic ability, and their incidence has increased yearly. It has been found that most meniscal injuries are irreparable, and meniscectomy can increase the predisposition to knee osteoarthritis. Tissue engineering technology on meniscus repairing and transplantation has received widespread attention recently. This review aimed to analyse the scientific literature regarding the potential applications of tissue engineering on meniscus repairing and transplantation procedures.
Method and materials:
The electronic search was carried out using PubMed/MEDLINEⓇdatabases with the keywords "tissue engineering AND meniscus" spanning the period of publications from Jan 1980 until Dec 2022.
Results:
The literature search identified 405 references in PubMed/MEDLINE, and 179 were selected following the eligibility requirements. The research analysis showed that the existing meniscal tissue engineering studies used a wide variety of seed cells, cytokines, bioactive materials and 3D structures. Each showed distinct advantages and disadvantages in terms of biocompatibility, degradability, mechanical strength, porosity, and etc. It was noted that 3D printing technology is promising for tissue engineering meniscus research. In addition, the optimal use of compression and hydrostatic pressure to markedly improve the functional properties of tissue-engineering meniscal can serve as an useful strategy.
Conclusion:
This review analysed the different approaches employed for meniscus tissue engineering and regeneration. Meniscal tissue engineering still faces several major challenges in terms of seed cells, choice of materials and 3D printing strategies, which should be effectively overcome to harness the full potential of this technology.
... For instance, a gradient of collagen types and the spatial distribution of proteoglycans endow different areas within the same tissue with distinct mechanical characteristics [3]. This complexity is further compounded by the presence of diverse cell types, each finely tuned to their specific microenvironment [4,5]. This zonal heterogeneity is essential for the proper function of these tissues, but also complicates the development of effective treatment strategies. ...
Meniscus injuries present significant therapeutic challenges due to their limited self-healing capacity and the diverse biological and mechanical properties across the tissue. Conventional repair strategies do not replicate the complex zonal characteristics within the meniscus, resulting in suboptimal outcomes. In this study, we introduce an innovative fetal/adult and stiffness-tunable meniscus decellularized extracellular matrix (DEM)-based hydrogel system designed for precision repair of heterogeneous, zonal-dependent meniscus injuries. By synthesizing fetal and adult DEM hydrogels, we identified distinct cellular responses, including that hydrogels with adult meniscus-derived DEM promote more fibrochondrogenic phenotypes. The incorporation of methacrylated hyaluronic acid (MeHA) further refined the mechanical properties and injectability of the DEM-based hydrogels. The combination of fetal and adult DEM with MeHA allowed for precise tuning of stiffness, influencing cell differentiation and closely mimicking native tissue environments. In vivo tests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration. This study represents a significant advance in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues.
... Another important element in tissue engineering approaches is identifying the most suitable cell source. Several cell populations have been tested for meniscus repair and regeneration, such as articular chondrocytes [15] and fibrochondrocytes [16,17], and histological evidence highlighted the ability of these cell populations to generate fibrocartilaginous tissue resembling the meniscus. However, due to the difficulty of harvesting a sufficient number of cells, autologous fibrochondrocytes or chondrocytes do not represent optimal cell sources in tissue engineering approaches. ...
Strategies to repair the meniscus have achieved limited success; thus, a cell-based therapy combined with an appropriate biocompatible scaffold could be an interesting alternative to overcome this issue. The aim of this project is to analyze different cell populations and a collagen gel scaffold as a potential source for meniscus tissue engineering applications. Dermal fibroblasts (DFs) and mesenchymal stem cells (MSCs) isolated from adipose tissue (ASCs) or bone marrow (BMSCs) were analyzed. Two different fibro-chondrogenic media, M1 and M2, were tested, and qualitative and quantitative analyses were performed. Significant increases in glycosaminoglycans (GAGs) production and in fibro-cartilaginous marker expression were observed in MSCs in the presence of M1 medium. In addition, both ASCs and BMSCs cultured in M1 medium were used in association with the collagen hydrogel (MSCs-SCF) for the development of an in vitro meniscal-like tissue. Significant up-regulation in GAGs production and in the expression of aggrecan, collagen type I, and collagen type II was observed in BMSCs-SCF. This study improves knowledge of the potential of combining undifferentiated MSCs with a collagen gel as a new tissue engineering strategy for meniscus repair.
... Specifically, several potential therapies are undergoing animal trials focused on administration of growth factors implicated for soft tissue repair [11,12]. Whether utilized for recovery of cartilage [13], extracellular matrix (ECM) [8], muscle [14], tendons [15], ligaments [16], or even assistance in bone repair [17]; advances in peptide therapy show promise as a treatment mechanism to aid in joint regeneration and prevent future degeneration. ...
Background: The musculoskeletal system, due to inherent structure and function, lends itself to contributing toward joint pain, whether from inflammatory disorders such as rheumatoid arthritis, degenerative diseases such as osteoarthritis, or trauma causing soft tissue injury. Administration of peptides for treatment of joint pain or inflammation is an emerging line of therapy that seeks to offer therapeutic benefits while remaining safe and relatively non-invasive. Purpose: The purpose of this study is to review the current literature on existing oral peptide agents, intra-articular peptide agents, and new developments in human trials to assess route of administration (RoA) for drug delivery in terms of soft tissue regeneration. Study Design: Narrative Review. Methods: A comprehensive literature search was conducted using the PubMed database. The search included medical subject headings (MeSH) terms related to peptide therapy, soft tissue regeneration, and RoA. Inclusion criteria comprised articles focusing on the mechanisms of action of peptides, clinical or biochemical outcomes, and review articles. Exclusion criteria included insufficient literature or studies not meeting the set evidence level. Conclusion: The review identified various peptides demonstrating efficacy in soft tissue repair. Oral and intra-articular peptides showed distinct advantages in soft tissue regeneration, with intra-articular routes providing localized effects and oral routes offering systemic benefits. However, both routes have limitations in bioavailability and absorption. Still in their infancy, further inquiries/research into the properties and efficacy of emerging peptides will be necessary before widespread use. As a viable alternative prior to surgical intervention, peptide treatments present as promising candidates for positive outcomes in soft tissue regeneration.
... 1 The meniscus is recognized as an integral component of the knee joint, and its presence is vital for the normal function of the meniscus. 2 In recent years, meniscus regeneration has been studied using tissue engineering principles. In that regard, combining cells and scaffolds is the first step in tissue engineering. ...
Three-dimensional (3D) structures are actually the state-of-the-art technique to create porous scaffolds for tissue engineering. Since regeneration in cartilage tissue is limited due to intrinsic cellular properties this study aims to develop and characterize three-dimensional porous scaffolds of poly (L-co-D, L lactide-co-trimethylene carbonate), PLDLA-TMC, obtained by 3D fiber deposition technique. The PLDLA-TMC terpolymer scaffolds (70:30), were obtained and characterized by scanning electron microscopy, gel permeation chromatography, differential scanning calorimetry, thermal gravimetric analysis, compression mechanical testing and study on in vitro degradation, which showed its amorphous characteristics, cylindrical geometry, and interconnected pores. The in vitro degradation study showed significant loss of mechanical properties compatible with a decrease in molar mass, accompanied by changes in morphology. The histocompatibility association of mesenchymal stem cells from rabbit’s bone marrow, and PLDLA-TMC scaffolds, were evaluated in the meniscus regeneration, proving the potential of cell culture at in vivo tissue regeneration. Nine New Zealand rabbits underwent total medial meniscectomy, yielding three treatments: implantation of the seeded PLDLA-TMC scaffold, implantation of the unseeded PLDLA-TMC and negative control (defect without any implant). After 24 weeks, the results revealed the presence of fibrocartilage in the animals treated with polymer. However, the regeneration obtained with the seeded PLDLA-TMC scaffolds with mesenchymal stem cells had become intimal to mature fibrocartilaginous tissue of normal meniscus both macroscopically and histologically. This study demonstrated the effectiveness of the PLDLA-TMC scaffold in meniscus regeneration and the potential of mesenchymal stem cells in tissue engineering, without the use of growth factors. It is concluded that bioresorbable polymers represent a promising alternative for tissue regeneration.
... With meniscectomy groups showing a notably higher progression rate towards osteoarthritis compared to repair groups, the data suggest a compelling argument for the adoption of meniscal repair as a strategy to preserve knee integrity. This distinction not only reflects the inherent benefits of meniscal repair in maintaining joint health, as previously suggested [57][58][59], but also suggests potential long-term advantages, including a reduced need for subsequent surgical interventions such as total knee replacement. ...
This systematic review aims to evaluate critically and synthesize the existing literature on the outcomes of meniscectomy versus meniscal repair for posterior medial meniscus injuries, with a focus on osteoarthritis (OA) development. We sought to assess the incidence of OA following both treatment modalities, compare functional outcomes post-treatment, and identify factors influencing treatment choice, providing evidence-based recommendations for clinical decision-making. A comprehensive search strategy was employed across PubMed, Scopus, and Embase up until December 2023, adhering to PRISMA guidelines. The primary outcomes included OA development, functional knee outcomes, and quality of life measures. Six studies met the inclusion criteria, encompassing 298 patients. The systematic review revealed a significant association between meniscal repair and decreased progression of OA compared to meniscectomy. Meniscectomy patients demonstrated a 51.42% progression rate towards OA, significantly higher than the 21.28% observed in meniscal repair patients. Functional outcomes, as measured by the International Knee Documentation Committee (IKDC) and Lysholm scores, were notably better in the repair group, with average scores of 74.68 (IKDC) and 83.78 (Lysholm) compared to 67.55 (IKDC) and 74.56 (Lysholm) in the meniscectomy group. Furthermore, the rate of complete healing in the repair group was reported at 71.4%, as one study reported, indicating a favorable prognosis for meniscal preservation. However, these pooled data should be interpreted with consideration to the heterogeneity of the analyzed studies. Meniscal repair for posterior medial meniscus injuries is superior to meniscectomy in preventing OA development and achieving better functional outcomes and quality of life post-treatment. These findings strongly suggest the adoption of meniscal repair as the preferred treatment modality for such injuries, emphasizing the need for a paradigm shift in clinical practice towards preserving meniscal integrity to optimize patient outcomes.
... Furthermore, the slow degradability of the hydrogels ensures their ability to retain their position within the body and perform their function, herein the regeneration of avascular regions of the menisci. The inhibited regenerative capacity of the target region would imply the incorporation of a growth factor rich hydrogel with a fairly slow degradation rate delivery vehicle to accommodate the regeneration in the region [39,40]. Our hydrogel constructs showed clinically relevant degradation rates of <50 % in enzymatic and <10 % in saline over 12 weeks ( Fig. 2A), which is required for the stabilisation during initial healing of the avascular regions of the meniscus [41]. ...
Meniscus tears and injuries in the avascular region often lead to pain, swelling and locking of the knee joint due to the non-healing nature of fibrocartilaginous tissue. The current mandate of partial meniscectomy leads to osteoarthritis and loss of integrity of the knee joint. Stabilisation of the torn meniscal tissue must be achieved at the earliest to prevent damage to articular cartilage. We have developed a patient-specific facile approach in the form of a silk-based injectable hydrogel blend comprising of silk fibroin methacrylate, gelatin methacrylate, polyethylene glycol diacrylate and patient-derived autologous platelet-rich-plasma lysate for ameliorating meniscal tears. Our hydrogel could be crosslinked promptly within 60 s and demonstrated robust physico-chemical and mechanical resilience in vitro. The injectable hydrogel demonstrated amicable shear thinning, optimal water uptake behaviour (~1.2 times), sustained release of PRP proteins (>70 %) over 40 days and an intricate microporous architecture. We could observe sustained degradability (~40 %) over 85 days under enzymatic conditions in vitro. Photocrosslinking imparts our hydrogel composition with physiologically relevant compressive strength and ample tensile strength to retain their position and aids in their stability over 3 weeks of confined cyclic compression cycles. Hydrogel-encapsulated human-derived neonatal mesenchymal stem cells showed >3 times proliferation, in vitro migration, fibrochondrogenic differentiation and meniscus-specific extracellular matrix deposition after 3 weeks. Our hydrogel demonstrated minimal in vitro immunogenicity when presented to murine and human macrophages. A pilot-scale in vivo evaluation in rabbit meniscal tears demonstrated the healing capacity of the injectable hydrogel composition in full-thickness tears of rabbit menisci compared to untreated counterparts after 8 weeks of treatment. Our patient-specific photopolymerisable injectable hydrogel could be a potential translational treatment modality for various partial and full-thickness meniscal tears in vivo.
... ADSCs have been reported extensively for in vivo and clinical meniscus regeneration applications due to their multipotency, proliferation and ease of derivation from autologous sources [56][57][58]. Hence ADSCs derived from porcine sources were used for further biological evaluation of our constructs in vitro. ...
Fibrocartilaginous meniscal tear regeneration is a major challenge due to the large avascular regions which suffer several injuries among all age-groups. Mostly, meniscus implants are focused on the development of multi-layered meniscus constructs and scaffolds that mimic the macro-architecture, functionality and mechanical strength. The native human menisci consist of vascular and avascular regions that contain different cellular phenotypes and are hence composed of a gradient of extracellular matrix (ECM) components. The biochemical composition of the inner, middle and outer regions of the knee menisci plays a significant role in the mechanical behavior and its overall functionality. We have developed a photo-polymerizing mulberry and non-mulberry silk-based biomaterial ink which is laden with growth factor loaded gelMA microspheres for the zone-specific regeneration of full thickness meniscus tears using three-dimensional (3D) fabrication. We have fabricated growth factor loaded gelMA microspheres and encapsulated them within the biomaterial ink for controlled release of Connective Tissue Growth Factor (CTGF) and Transforming Growth Factor-beta3 (TGF-β3) from the different zones of the meniscus constructs. The growth factor releasing constructs demonstrate the requisite mechanical resilience, degradability and release behaviour for regeneration of meniscal tissue. The developed growth factor loaded constructs demonstrate zone specific phenotypic differentiation of adipose derived stem cells and extracellular matrix deposition by the differentiated stem cells in vitro. The microsphere loaded constructs were found to be immuno-compatible as well. Therefore, these bioactive microsphere-laden 3D printed meniscus constructs would potentially promote regeneration and integration of meniscal tissue in vivo.
... Moreover, growth factors and bone marrow MSCs have been reported to possess an integral role in meniscal repair. MSCs were recruited at tear site, proliferated, and differentiated into meniscal cells, whereas growth factors involving PDGF, VEGF, IGF-1, TGF-β, and FGF have an integral function in hemostasis, angiogenesis, ECM matrix synthesis, and meniscal fibrochondrocyte cells metabolism (de Albornoz and Forriol, 2012;Twomey-Kozak and Jayasuriya, 2020). ...
Repair of meniscal tears in the avascular zone represents an obstacle for orthopedic surgeons. Several therapeutic methods have been suggested to mange these tears including meniscectomy and meniscal allografts; however, their clinical application was restricted due to their disadvantages. These limitations inspired the necessity to develop products that possess the ability to initiate healing in such avascular tears. Hence, the goal of the current study is to assess and compare the regenerative capability of bone marrow aspirate (BMA) and platelet-rich plasma (PRP) to enhance repair of avascular meniscal tears. After preparation of BMA and PRP, meniscal tear was conducted in the inner avascular zones in dogs and left untreated as control or treated with either BMA or PRP. Clinical observation of weight bearing, lameness, pain on manipulation, gait, and functional disability were investigated after 3, 6, 9, and 12 weeks of surgery. In addition, gross and histological evaluations were performed at weeks 4, 8, and 12 after surgery. Both materials demonstrated a positive improvement in clinical observations compared to the control group. Furthermore, repair of meniscal tears was stimulated in tears treated with either BMA or PRP with better gross and histological outcomes in PRP-treated group than BMA-treated group. To conclude, our findings showed that BMA and PRP possess the potential to enhance the healing process of meniscal tears in the inner avascular region with the superiority of PRP.
... All-inside, inside-out, and outside-in meniscal repair are the most common techniques of meniscal repair [58,61]. The outside-in technique was first described by Warren et al. to decrease the risk of peroneal nerve injury [64]. ...
Purpose:
Meniscal injuries are common. Outside-in meniscal repair is one of the techniques advocated for the management of traumatic meniscal tears. This systematic review investigated the outcomes of the outside-in repair technique for the management of traumatic tears of the menisci. The outcomes of interest were to investigate whether PROMs improved and to evaluate the rate of complications.
Methods:
Following the 2020 PRISMA statement, in May 2023, PubMed, Web of Science, Google Scholar, and Embase were accessed with no time constraints. All the clinical investigations which reported data on meniscal repair using the outside-in technique were considered for inclusion. Only studies which reported data on acute traumatic meniscal tears in adults were considered. Only studies which reported a minimum of 24 months of follow-up were eligible.
Results:
Data from 458 patients were extracted. 34% (155 of 458) were women. 65% (297 of 458) of tears involved the medial meniscus. The mean operative time was 52.9 ± 13.6 min. Patients returned to their normal activities at 4.8 ± 0.8 months. At a mean of 67-month follow-up, all PROMs of interest improved: Tegner scale (P = 0.003), Lysholm score (P < 0.0001), International Knee Documentation Committee (P < 0.0001). 5.9% (27 of 458) of repairs were considered failures. Four of 186 (2.2%) patients experienced a re-injury, and 5 of 458 (1.1%) patients required re-operation.
Conclusion:
Meniscal repair using the outside-in technique can be effectively performed to improve the quality of life and the activity level of patients with acute meniscal tears.
Level of evidence:
Level IV.
... Small nucleolar RNA host gene (SNHG)14 is a newly discovered long non-coding RNA that could induce osteogenic differentiation of hMSCs in vitro by targeting miR-2861 [81]. Although it would be much easier to use only hMSCs (one cell source) for all three zones, the ligamentous [82] and fibrocartilaginous [83][84][85] differentiation of hMSCs is very controversially discussed. In contrast to another study, where the colonization of a decellularized scaffold was performed with a zonal application of growth factors [53], no supplements except for ascorbic acid in the growth medium to stimulate collagen synthesis were used in this study. ...
Successful anterior cruciate ligament (ACL) reconstructions strive for a firm bone-ligament integration. With the aim to establish an enthesis-like construct, embroidered functionalized scaffolds were colonized with spheroids of osteogenically differentiated human mesenchymal stem cells (hMSCs) and lapine (l) ACL fibroblasts in this study. These triphasic poly(L-lactide-co-ε-caprolactone) and polylactic acid (P(LA-CL)/PLA) scaffolds with a bone-, a fibrocartilage transition- and a ligament zone were colonized with spheroids directly after assembly (DC) or with 14-day pre-cultured lACL fibroblast and 14-day osteogenically differentiated hMSCs spheroids (=longer pre-cultivation, LC). The scaffolds with co-cultures were cultured for 14 days. Cell vitality, DNA and sulfated glycosaminoglycan (sGAG) contents were determined. The relative gene expressions of collagen types I and X, Mohawk, Tenascin C and runt-related protein (RUNX) 2 were analyzed. Compared to the lACL spheroids, those with hMSCs adhered more rapidly. Vimentin and collagen type I immunoreactivity were mainly detected in the hMSCs colonizing the bone zone. The DNA content was higher in the DC than in LC whereas the sGAG content was higher in LC. The gene expression of ECM components and transcription factors depended on cell type and pre-culturing condition. Zonal colonization of triphasic scaffolds using spheroids is possible, offering a novel approach for enthesis tissue engineering.
... While a number of studies have evaluated the literature concerning orthobiologics as an adjunct to meniscal repair 15,16 or as a treatment in pre-clinical studies 17,18 , we are not aware of any studies that have systematically reviewed the clinical literature concerning orthobiologics as a standalone treatment for degenerative meniscal lesions. The aim of the present systematic review is to summarize the available evidence concerning the use of orthobiologics to treat degenerative meniscal lesions. ...
Background
: The treatment of degenerative meniscal lesions usually consists of conservative measures such as physical therapy and/or knee injections. Recently, the use of orthobiologics, in the form of PRP and cell-based therapies, gained huge popularity in orthopedic practice.
Objectives
: The aim of the present systematic review is to summarize the available evidence concerning the use of orthobiologics in the treatment of degenerative meniscal lesions
Data sources
: A comprehensive search of PubMed, Google Scholar, Cochrane, and EMBASE was performed using various combinations of the following keywords: Meniscus AND (platelet OR BMAC OR bone marrow OR adipose OR stromal vascular fraction OR placental OR cord OR jelly).
Study eligibility criteria, participants, and interventions
: Articles were screened according to the following inclusion criteria: (i)clinical reports and/or randomized trials that included injections to treat degenerative meniscal lesions; (ii)written in the English language; (iii)published from 2012 to 2022.
Results
: 9 studies were finally included in the present systematic review: 8 for PRP and 1 for MFAT. All the studies reported clinical and functional improvements for degenerative meniscal lesions treated with orthobiologics.
Limitations
: Included studies highlight considerable heterogeneity in methodological approaches. Differences in product choice, outcome measures and follow up preclude the ability to generate definitive suggestions for application in the everyday clinical practice.
Conclusions and implications of key findings
: The literature suggests that the use of orthobiologics may offer a new effective therapeutic strategy for the treatment of degenerative meniscus lesions.
Systematic review registration number: Not applicable.
... Cell-based meniscus repair strategies are currently being investigated using several musculoskeletal tissue specific mesenchymal cell sources; including progenitors derived from meniscus tissue itself, as well as synovium, adipose, and cartilage (Muhammad et al., 2014;Seol et al., 2017;Sun et al., 2020;Twomey-Kozak and Jayasuriya, 2020;Trivedi et al., 2022). CPCs are a promising cell-type for musculoskeletal tissue engineering applications given their inherently high chondrogenicity, propensity for colony formation, and resistance to chondrocyte hypertrophy (Dowthwaite et al., 2004;Fickert et al., 2004;Williams et al., 2010;McCarthy et al., 2012;Vinod et al., 2020). ...
Meniscal tearing in the knee increases the risk of post-traumatic osteoarthritis (OA) in patients. The therapeutic application of tissue-specific mesenchymal progenitor cells is currently being investigated as an emerging biologic strategy to help improve healing of musculoskeletal tissues like meniscal fibrocartilage and articular hyaline cartilage. However, many of these approaches involve isolating cells from healthy tissues, and the low yield of rare progenitor populations (< 1% of total cells residing in tissues) can make finding a readily available cell source for therapeutic use a significant logistical challenge. In the present study, we investigated the therapeutic efficacy of using expanded cartilage-derived and bone marrow-derived progenitor cell lines, which were stabilized using retroviral SV40, for repair of meniscus injury in a rodent model. Our findings indicate that these cell lines express the same cell surface marker phenotype of primary cells (CD54+, CD90+, CD105+, CD166+), and that they exhibit improved proliferative capacity that is suitable for extensive expansion. Skeletally mature male athymic rats treated with 3.2 million cartilage-derived progenitor cell line exhibited approximately 79% greater meniscal tear reintegration/healing, compared to injured animals that left untreated, and 76% greater compared to animals treated with the same number of marrow-derived stromal cells. Histological analysis of articular surfaces also showed that cartilage-derived progenitor cell line treated animals exhibited reduced post-traumatic OA associated articular cartilage degeneration. Stable cell line treatment did not cause tumor formation or off-target engraftment in animals. Taken together, we present a proof-of-concept study demonstrating, for the first time, that intra-articular injection of a stable human cartilage-derived progenitor cell line stimulates meniscus tear healing and provide chondroprotection in an animal model. These outcomes suggest that the use of stable cell lines may help overcome cell source limitations for cell-based medicine.
... Advances in biomaterial technology have also found their way into orthopedic clinical practice: collagen meniscus implants and polyurethane polymeric implants are being used for meniscus replacement in limited indications [32]. Many different growth factors and stem cell-based therapies are also being studied on pre-clinical models [33]. Together with advancing surgical techniques, increased potential for meniscal healing can be achieved in the near future. ...
The purpose of this study was to perform a systematic review of randomized controlled trials (RCTs) that report outcomes regarding meniscal healing, and to provide a summary on the healing potential of menisci and the effect of various interventions on this potential. Seven different studies reported evidence of meniscal healing after different interventions: six were on meniscal body while one was on ramp lesions. The investigated therapeutic interventions were surgical in four studies, percutaneous injections in two studies, and a postoperative rehabilitation regimen in one study. Positive results were reported for platelet-rich plasma augmentation, bone marrow venting procedure, allogenic mesenchymal stem cell injection, and free postoperative rehabilitation regimen. The literature on meniscal injuries may be expanding at a high rate, but the amount of high-quality evidence is limited. The included RCTs are heterogeneous by means of meniscal injury classification, diagnostic methods, therapeutic interventions, and outcome assessment. Certain interventions such as augmentation with platelet-rich plasma, bone marrow venting procedure, and postoperative free rehabilitation after surgical repair have shown improved results in increasing the healing potential of the meniscal tissue. However, current evidence is not strong enough to support routine use of any of these techniques, and more high-quality evidence is necessary.
... However, the meniscus can be injured by accidents or affected by aging, and an injured meniscus causes instability, pain, and cartilage degeneration in the knee joint [1]. Interestingly, the meniscus is hard to heal naturally, as blood vessels are not distributed in the area, except in the edges [2]; therefore, in some cases, it may transmit excessive load to the knee joint and cause osteoarthritis (OA) [3]. Meniscectomy is performed to treat a severely ruptured meniscus. ...
Although allogenic meniscus grafting can be immunologically safe, it causes immune rejection due to an imbalanced tissue supply between donor and recipient. Pigs are anatomically and physiologically similar to adult humans and are, therefore, considered to be advantageous xenotransplantation models. However, immune rejection caused by genetic difference damages the donor tissue and can sometimes cause sudden death. Immune rejection is caused by genes; porcine GGTA1, CMAH, and B4GLANT2 are the most common. In this study, we evaluated immune cells infiltrating the pig meniscus transplanted subcutaneously into BALB/c mice bred for three weeks. We compared the biocompatibility of normal Jeju native black pig (JNP) meniscus with that of triple knockout (TKO) JNP meniscus (α-gal epitope, N-glycolylneuraminic acid (Neu5Gc), and Sd (a) epitope knockout using CRISPR-Cas 9). Mast cells, eosinophils, neutrophils, and macrophages were found to have infiltrated the transplant boundary in the sham (without transplantation), normal (normal JNP), and test (TKO JNP) samples after immunohistochemical analysis. When compared to normal and sham groups, TKO was lower. Cytokine levels did not differ significantly between normal and test groups . Because chronic rejection can occur after meniscus transplantation associated with immune cell infiltration, we propose studies with multiple genetic editing to prevent immune rejection.
... Given this scientific evidence, meniscal repair is recommended, especially in younger individuals. [9][10][11] The success or failure of meniscal repair is highly influenced by factors such as tear location, pattern, chronicity, size, and extent; repair technique; and patient age and habits. 12,13 A recent meta-analysis by Xu and Zhao 14 concluded that better long-term outcomes are obtained after meniscal repair than after meniscectomy, but the reoperation rate is on the higher side. ...
Meniscal tears are among the most common injuries in the knee, and partial as well as total meniscectomy has been advocated as the treatment for meniscal injury. Over the years, the role of the meniscus as a shock absorber, load transmitter, and secondary anterior stabilizer, along with its proprioceptive and lubrication role, has been well established, and meniscal repair is recommended, especially in younger individuals. Factors such as tear location, pattern, chronicity, size, and extent; repair technique; and patient age and habits can influence meniscal repair, and to enhance meniscal healing, a variety of augmentation techniques have been introduced. These include needling, trephination, synovial abrasion, and the use of adjuvants such as platelet-rich plasma, platelet clots, fibrin clots, bone marrow clots, and stem cells. A second-generation platelet derivative called “platelet-rich fibrin” (PRF) has predictable platelet, growth factor, and cell mediator concentrations without using any anticoagulants. We describe a reproducible and simple way to harvest PRF and create and use a PRF clot, along with detailed instructions on how to integrate the clot with a meniscal repair arthroscopically.
... Moreover, the restricted self-healing ability of the avascular white zone continues to be a challenge. With progression in tissue engineering and cell-based knowledge, novel therapeutic choices for irredeemable meniscal lesions currently exist [135,136]. These approaches are aimed at potentiating regeneration to reach exclusive quality repair of tissue and inhibit the joint degeneration associated with an injured meniscus. ...
Menisci play an important role in the biomechanics of knee joint function, including loading transmission, joint lubrication, prevention of soft tissue impingement during motion and joint stability. Meniscal repair presents a challenge due to a lack of vascularization that limits the healing capacity of meniscal tissue. In this review, the authors aimed to untangle the available treatment options for repairing meniscal tears. Various surgical procedures have been developed to treat meniscal tears; however, clinical outcomes are limited. Consequently, numerous researchers have focused on different treatments such as the application of exogenous and/or autologous growth factors, scaffolds including tissue-derived matrix, cell-based therapy and miRNA-210. The authors present current and prospective treatment strategies for meniscal lesions.
... While the former attempts to use scaffolds seeded with MSCs, the latter tends to implant scaffold into the joint without cells, repairing the meniscus by recruiting endogenous MSCs (Guo et al., 2018). In general, meniscus regeneration strategies using various MSC sources have been well documented in the literature, which can possibly provide a new strategy for meniscus repair (Twomey-Kozak and Jayasuriya, 2020;Dai et al., 2021). Nevertheless, a huge challenge still lies in mimicking its natural anisotropic structure. ...
Meniscus is a semilunar wedge-shaped structure with fibrocartilaginous tissue, which plays an essential role in preventing the deterioration and degeneration of articular cartilage. Lesions or degenerations of it can lead to the change of biomechanical properties in the joints, which ultimately accelerate the degeneration of articular cartilage. Even with the manual intervention, lesions in the avascular region are difficult to be healed. Recent development in regenerative medicine of multipotent stromal cells (MSCs) has been investigated for the significant therapeutic potential in the repair of meniscal injuries. In this review, we provide a summary of the sources of MSCs involved in repairing and regenerative techniques, as well as the discussion of the avenues to utilizing these cells in MSC therapies. Finally, current progress on biomaterial implants was reviewed.
... To counteract the increasing incidence rate of meniscal injury, innovative, and effective repair strategies are required 16 and among vanguard approaches, 3D printing technologies seem to be intriguing and promising. Reviewing the literature, the interest that 3D printing/bioprinting applied to tissue engineering is gaining, appears particularly evident. ...
Meniscal tears are a frequent orthopedic injury commonly managed by conservative strategies to avoid osteoarthritis development descending from altered biomechanics. Among cutting-edge approaches in tissue engineering, 3D printing technologies are extremely promising guaranteeing for complex biomimetic architectures mimicking native tissues. Considering the anisotropic characteristics of the menisci, and the ability of printing over structural control, it descends the intriguing potential of such vanguard techniques to meet individual joints’ requirements within personalized medicine. This literature review provides a state-of-the-art on 3D printing for meniscus reconstruction. Experiences in printing materials/technologies, scaffold types, augmentation strategies, cellular conditioning have been compared/discussed; outcomes of pre-clinical studies allowed for further considerations. To date, translation to clinic of 3D printed meniscal devices is still a challenge: meniscus reconstruction is once again clear expression of how the integration of different expertise (e.g., anatomy, engineering, biomaterials science, cell biology, and medicine) is required to successfully address native tissues complexities.
... Recent literature reviews about MSCs in meniscal injuries have reported that the most common source of MSCs is BM-MSCs, and they lead to good short-to medium-term outcomes with no serious adverse events [63,64]. S-MSCs and BM-MSCs are comparable in terms of their repair capacity in both small and larger animal models, although for both cases, cellular hypertrophy or OA markers either pre-or posttreatment have been measured [65]. ...
Background
The present review is focused on general aspects of the synovial membrane as well as specialized aspects of its cellular constituents, particularly the composition and location of synovial membrane mesenchymal stem cells (S-MSCs). S-MSC multipotency properties are currently at the center of translational medicine for the repair of multiple joint tissues, such as articular cartilage and meniscus lesions.
Methods and results
We reviewed the results of in vitro and in vivo research on the current clinical applications of S-MSCs, surface markers, cell culture techniques, regenerative properties, and immunomodulatory mechanisms of S-MSCs as well as the practical limitations of the last twenty-five years (1996 to 2021).
Conclusions
Despite the poor interest in the development of new clinical trials for the application of S-MSCs in joint tissue repair, we found evidence to support the clinical use of S-MSCs for cartilage repair. S-MSCs can be considered a valuable therapy for the treatment of repairing joint lesions.
... rough the two-phase theory, we can fully understand the viscous reaction caused by the liquid flowing in the porous and permeable solid matrix and the elastic reaction caused by the deformation of the solid matrix, and it is not difficult to explain the creep and stress of the meniscus. e relaxation phenomenon is that the meniscus is prone to tensile fracture when it is stretched in the horizontal and vertical axis directions, and it is not prone to tensile fracture in the long axis direction [23,24]. ...
Knee meniscus injuries are more likely to occur in young adults in clinical practice, and their lower age of onset and greater impact on joint function after injury also put forward higher requirements for the treatment and rehabilitation of meniscus injuries. With the rapid development of artificial intelligence technology and arthroscopic minimally invasive technology, arthroscopic meniscus plasty and perovskite nanobiomaterial repair have gradually replaced the previous open meniscus surgery of the knee joint and has become the main method of meniscus injury treatment, and the perovskite nanobiomaterial repair technique that incorporates artificial intelligence technology is also gradually being applied. Therefore, this article studies the role of perovskite nanobiomaterials in the repair of meniscus injuries in football sports and analyzes the biological characteristics of the inner and outer meniscus to provide help to improve the healing rate of meniscus injuries. The study selected six male meniscus-injured patients (meniscus injuries caused by football sports) and obtained six injured menisci. The same cross section of the same part of the meniscus was analyzed inside and outside the meniscus. At the same time, a meniscal injury step was performed on the patient. The biological characteristics of perovskite nano-biomaterials in the repair of meniscus injuries in football sports were compared and analyzed, and the patient's gait before and after surgery was also compared. Experiments have shown that the percentage of the postoperative support phase of the affected limb is significantly higher than that before surgery (P
... Recently, considerable efforts have been put into meniscal regeneration rather than meniscal resection. The complex array of meniscal tissue structure and avascularity presents quite a thorny problem for clinicians; thus, tissue engineering aimed at tissue remodeling and functional restoration seems to be an alternative strategy (Twomey-Kozak and Jayasuriya, 2020). From traditional allograft menisci to currently used polymer materials, tissue-engineered meniscus scaffolds have been continuously progressing. ...
Knee menisci are structurally complex components that preserve appropriate biomechanics of the knee. Meniscal tissue is susceptible to injury and cannot heal spontaneously from most pathologies, especially considering the limited regenerative capacity of the inner avascular region. Conventional clinical treatments span from conservative therapy to meniscus implantation, all with limitations. There have been advances in meniscal tissue engineering and regenerative medicine in terms of potential combinations of polymeric biomaterials, endogenous cells and stimuli, resulting in innovative strategies. Recently, polymeric scaffolds have provided researchers with a powerful instrument to rationally support the requirements for meniscal tissue regeneration, ranging from an ideal architecture to biocompatibility and bioactivity. However, multiple challenges involving the anisotropic structure, sophisticated regenerative process, and challenging healing environment of the meniscus still create barriers to clinical application. Advances in scaffold manufacturing technology, temporal regulation of molecular signaling and investigation of host immunoresponses to scaffolds in tissue engineering provide alternative strategies, and studies have shed light on this field. Accordingly, this review aims to summarize the current polymers used to fabricate meniscal scaffolds and their applications in vivo and in vitro to evaluate their potential utility in meniscal tissue engineering. Recent progress on combinations of two or more types of polymers is described, with a focus on advanced strategies associated with technologies and immune compatibility and tunability. Finally, we discuss the current challenges and future prospects for regenerating injured meniscal tissues.
Over 850,000 surgeries are performed to treat meniscal injuries each year in the United States. Even with repair, patients are likely to develop osteoarthritis (OA) within the next two decades. There is a pressing clinical need to improve meniscal repair procedures to restore tissue function and prevent joint degeneration later in life. Here we present a review of recently published articles (2020–2024) spanning basic science, translational, and clinical studies to highlight new advances in meniscus research across development, animal models, finite element models, and clinical interventions. Key progenitor cell populations and vascularity changes have been identified in human meniscus tissue development, aging, and degeneration with implications for novel tissue repair strategies. The use of animal and finite element models has expanded our understanding of meniscus tissue function and evaluated new therapies in preclinical studies. Further, advances in clinical diagnostics with machine learning models and surgical techniques have shed light on evidence‐based practices for improving patient outcomes. We discuss across multiple length scales (micro‐, meso‐, macro‐) the structure‐function relationship of the meniscus in development and disease, recent advances in models and tools to study the meniscus, knowledge gaps in the field, persisting challenges in clinical treatments and assessments, and the translation of basic science therapies into the clinic.
Meniscus injuries present significant therapeutic challenges due to their limited self-healing capacity and diverse biological and mechanical properties across meniscal tissue. Conventional repair strategies neglect to replicate the complex zonal characteristics within the meniscus, resulting in suboptimal outcomes. In this study, we introduce an innovative, age- and stiffness-tunable meniscus decellularized extracellular matrix (DEM)-based hydrogel system designed for precision repair of heterogeneous, zonal-dependent meniscus injuries. By synthesizing age-dependent DEM hydrogels, we identified distinct cellular responses: fetal bovine meniscus-derived DEM promoted chondrogenic differentiation, while adult meniscus-derived DEM supported fibrochondrogenic phenotypes. The incorporation of methacrylate hyaluronic acid (MeHA) further refined the mechanical properties and injectability of the DEM-based hydrogels. The combination of age-dependent DEM with MeHA allowed for precise stiffness tuning, influencing cell differentiation and closely mimicking native tissue environments. In vivo tests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration. This study represents a significant advancement in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues.
The knee menisci maintain stability and function of a healthy knee joint. Therefore, degenerative, or traumatic meniscus injuries may require meniscal implants to restore function. The aim of this study was to create a 3D-printable meniscus implant that emphasizes the representation of circumferential collagen fibres for biomechanical function. A novel Lugol-staining and freeze-drying technique was developed to prepare six human menisci for analysis of circumferential fibre volume proportion using μCT scans. Average volumes of 46.09% and 50.23% were observed in the medial and lateral meniscus, respectively. The resulting STL file, generated with UltiMaker Cura, had a circumferential infill structure occupying 48% of the total volume. A Python script was developed to extract coordinates from the G-code, facilitating the conversion of complex STL geometries into detailed volumetric finite element models (FEMs). These FEMs allow adjustment of volume proportions and outer layer thicknesses for finite element analysis (FEA), enabling virtual simulations to assess biomechanical properties and modify designs prior to implant manufacture. This methodology represents a promising avenue for advances in orthopaedic tissue engineering employing 3D-printing approaches.
Meniscus tears in the avascular region undergoing partial or full meniscectomy lead to knee osteoarthritis and concurrent lifestyle hindrances in the young and aged alike. Here they reported ingenious photo‐polymerizable autologous growth factor loaded 3D printed scaffolds to potentially treat meniscal defects . A shear‐thinning photo‐crosslinkable silk fibroin methacrylate–gelatin methacrylate–polyethylene glycol dimethacrylate biomaterial‐ink is formulated and loaded with freeze‐dried growth factor rich plasma (GFRP) . The biomaterial‐ink exhibits optimal rheological properties and shape fidelity for 3D printing. Initial evaluation revealed that the 3D printed scaffolds mimic mechanical characteristics of meniscus, possess favourable porosity and swelling characteristics, and demonstrate sustained GFRP release. GFRP laden 3D scaffolds are screened with human neo‐natal stem cells in vitro and biomaterial‐ink comprising of 25 mg mL⁻¹ of GFRP (GFRP25) is found to be amicable for meniscus tissue engineering. GFRP25 ink demonstrated rigorous rheological compliance, and printed constructs demonstrated long term degradability (>6 weeks), GFRP release (>5 weeks), and mechanical durability (3 weeks). GFRP25 scaffolds aided in proliferation of seeded human neo‐natal stem cellsand their meniscus‐specific fibrochondrogenic differentiation . GFRP25 constructs show amenable inflammatory response in vitro and in vivo. GFRP25 biomaterial‐ink and printed GFRP25 scaffolds could be potential patient‐specific treatment modalities for meniscal defects.
Pendahuluan: Robekan meniskus merupakan salah satu yang paling umum cedera lutut yang dirawat. Meniskus sangat penting untuk fungsi normal lutut, termasuk beban transmisi, stabilitas sendi, pelumasan, dan nutrisi dari tulang rawan artikular. Hilangnya fungsi meniskus normal menyebabkan peningkatan tekanan kontak lutut dan tulang rawan articular degenerasi dari waktu ke waktu. Perbaikan meniscus (meniscus repair) adalah salah satu jenis operasi yang dilakukan Ketika meniscus haru dilakukan operasi dengan cara menjahit meniscus yang mengalami robekan. Fisioterapi sangat berperan penting dalam perbaikan meniscus dengan latihan isometric, isokinetic yang bertujuan untuk menguatkan grub otot-otot yang lemah. Tujuan: meningkatkan ke fase seterusnya dan meningkatkan aktivitas fungsional untuk bisa Kembali kebidang olahraga. Metode: subjek diberikan latihan penguatan isometric dan isokinetic selama 4 minggu yang dilakukan 3x/minggu. Hasil: evaluasi dilakukan dengan menggunakan instrument penggukuran Visual Analog Scale (VAS), Range Of Motion (ROM), Manual Muscle Testing, dan Antropometri. Kesimpulan: terdapat peningkatan pada ROM, MMT, dan Antropometri setelah diberikan terapi Lathan selama 4 minggu.
During the construction of tissue-engineered meniscus, the low porosity of extracellular matrix restricts the flow of nutrient solution and the migration and proliferation of cells, thus affecting the tissue remodeling after transplantation. In this study, the canine allogeneic meniscus was drilled first and then decellularized. The drilled tissue-engineered menisci (Drilled Allogeneic Acellular Meniscus + Bone Marrow Mesenchymal Stem Cells, BMSCs) were transplanted into the knee joints of model dogs. On the basis of ensuring the mechanical properties, the number of the porosity and the cells implanted in allogeneic acellular meniscus was significantly increased. The expression levels of glycosaminoglycans and type II collagen in the drilled tissue-engineered meniscus were also improved. It was determined that the animals in the experimental group recovered well-compared with those in the control group. The graft surface was covered with new cartilage, the retraction degree was small, and the tissue remodeling was good. The surface wear of the femoral condyle and tibial plateau cartilage was light. The results of this study showed that increasing the porosity of allogeneic meniscus by drilling could not only maintain the mechanical properties of the meniscus and increase the number of implanted cells but also promote cell proliferation and differentiation. After transplantation, the drilled tissue-engineered meniscus provided a good remodeling effect in vivo and played a positive role in repairing meniscal injury, protecting articular cartilage and restoring knee joint function.
Objective:
To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms.
Methods:
Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery.
Results:
Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors.
Conclusion:
SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.
As the body ages, it experiences a gradual decline in the functioning of cells, tissues and systems, which eventually leads to dysfunction and increased susceptibility to disease. At the cellular level, a reduction in the activity or number of stem cells is an important feature of cell senescence, and such changes may also directly drive the aging of the organism. Thus, finding ways to prevent or even reverse stem cell senescence holds promise for the development of aging therapies in tissues and organisms. This review discusses the relationship between changes in stem cell senescence, tissues aging, and related diseases, focusing on four categories of tissue stem cells: hematopoietic stem cells (HSCs), mesenchymal stromal/stem cells (MSCs), intestinal stem cells (ISCs), and muscle stem cells (MuSCs).
Objective:
To review the research progress of meniscus repair in recent years, in order to provide help for the clinical decision-making of meniscus injury treatment.
Methods:
The domestic and foreign literature related to meniscal repair in recent years was extensively reviewed to summarize the reasons for the prevalence of meniscal repair, surgical indications, various repair methods and long-term effectiveness, the need to deal with mechanical structural abnormalities, biological enhancement repair technology, rehabilitation treatment, and so on.
Results:
In order to delay the occurrence of osteoarthritis, the best treatment of meniscus has undergone an important change from partial meniscectomy to meniscal repair, and the indications for meniscal repair have been expanding. The mid- and long-term effectiveness of different meniscal repair methods are ideal. During meniscus repair, the abnormality of lower limb force line and meniscus protrusion should be corrected at the same time. There are controversies about the biological enhancement technology to promote meniscus healing and rehabilitation programs, which need further study.
Conclusion:
Meniscal repair can restore the normal mechanical conduction of lower limbs and reduce the incidence of traumatic osteoarthritis, but the poor blood supply and healing ability of meniscal tissue bring difficulties to meniscal repair. Further development of new biological enhanced repair technology and individualized rehabilitation program and verification of its effectiveness will be an important research direction.
Introduction: Xerosis is a term for dry skin that often occurs on the lower limbs, heels, elbows, and fingers. Xerosis is caused by reduced moisture due to loss of lipids and natural moisturizing factors in the Stratum Corneum. The purpose of this study is to determine the implementation of physiotherapy in reducing xerosis in both lower limbs and maintaining skin elasticity with. Methods: patients are given oiling treatment, ankle pumping, bridging exercise, balance exercise and sensory stimulus exercises on the feet for 4 weeks which are carried out 3x/week. Results: evaluation was carried out using Range Of Motion (ROM), Manual Muscle Testing, Anthropometry, ODSS (Overall Dry Skin Score). Conclusion: there is an increase in ROM, MMT, ODSS (Overall Dry Skin Score) and a decrease in Anthropometry after being given Exercise therapy for 4 weeks.
Purpose:
To evaluate the cost-effectiveness of three isolated meniscal repair (IMR) treatment strategies: platelet-rich plasma (PRP)-augmented IMR, IMR with a marrow venting procedure (MVP), and IMR without biologic augmentation.
Methods:
A Markov model was developed to evaluate the baseline case: a young adult patient meeting the indications for IMR. Health utility values, failure rates, and transition probabilities were derived from the published literature. Costs were determined based on the typical patient undergoing IMR at an outpatient surgery center. Outcome measures included costs, quality-adjusted life years (QALYs), and the incremental cost effect ratio (ICER).
Results:
Total costs from IMR with MVP were 12,031, and total costs from IMR without PRP or MVP were 161,742/QALY, which is well above the 50,000 willingness-to-pay threshold, IMR with MVP was determined the overall cost-effective treatment strategy in the setting of young adult patients with isolated meniscal tears.
Level of evidence:
Level 3: economic and decision analysis.
The knee is the largest joint in the human body that permits flexion/extension movements and partial internal/external rotation. The knee contains four major structural tissues that maintain the integrity of the joint: bone, ligament, cartilage, and meniscus. The meniscus is the least studied of these tissues. The word meniscus is derived from the Greek term, mēniskos, which means “crescent” that alludes to the half-moon shape of this tissue. This tissue is fibrocartilaginous and it exists between the femoral condyle and the tibial plateau of the knee. The meniscus not only provides shock absorption and mechanical stability to the knee, but increasing evidence indicates that it also has indispensable biological functions that are essential for maintaining a healthy knee joint. The many mechanical functions of the meniscus tissue are accomplished by its unique composition, shape, and anatomy. Unlike articular cartilage and bone, which have fixed positions relative to other tissues, the menisci is relatively mobile during knee flexion/extension. Evolutionarily, evidence of the meniscus can be traced back more than 1.3 million years when the hominid lineage (that led to homo sapiens) developed complete bipedal locomotion and the patellofemoral joint came into existence. In homo sapiens, the structural variation in the meniscus indicates the evolutionary consequences of full knee extension movements during bipedal locomotion. Menisci were once described as vestigial organs or functionless remnants of embryonic development and they were often removed surgically, when injured, as a strategy to subside acute inflammation and to prevent resulting knee degeneration. However, the meniscus is now recognized as a vital component of the healthy joint, and its injury or removal is shown to correlate with the onset of osteoarthritis.
The meniscus is a semilunar fibrocartilage structure that plays important roles in maintaining normal knee biomechanics and function. The roles of the meniscus, including load distribution, force transmission, shock absorption, joint stability, lubrication, and proprioception, have been well established. Injury to the meniscus can disrupt overall joint stability and cause various symptoms including pain, swelling, giving-way, and locking. Unless treated properly, it can lead to early degeneration of the knee joint. Because meniscal injuries remain a significant challenge due to its low intrinsic healing potential, most notably in avascular and aneural inner two-thirds of the area, more efficient repair methods are needed. Mesenchymal stem cells (MSCs) have been investigated for their therapeutic potential in vitro and in vivo. Thus far, the application of MSCs, including bone marrow-derived, synovium-derived, and adipose-derived MSCs, has shown promising results in preclinical studies in different animal models. These preclinical studies could be categorized into intra-articular injection and tissue-engineered construct application according to delivery method. Despite promising results in preclinical studies, there is still a lack of clinical evidence. This review describes the basic knowledge, current treatment, and recent studies regarding the application of MSCs in treating meniscal injuries. Future directions for MSC-based approaches to enhance meniscal healing are suggested.
Objective:
To investigate the clinical effect of a modified arthroscopic outside-in suture technique in the treatment of meniscus tear using a spinal needle.
Methods:
From January 2015 to October 2017, 95 patients treated with this method were followed-up. Among these cases, there were 36 males and 59 females. The age of the patients ranged from 16 to 77 years, (46.79±18.07) years in average. Among them, there were 28 patieats aged 16-35, 53 patients aged 36-65, and 14 patients aged over 65 years old. 28 cases were diagnosed with medial meniscus tear, 43 cases with lateral meniscus tear and 24 cases with both medial and lateral meniscus tear. Causes of the injury included sports, sprain, etc. According to Barrett standard, the clinical healing of meniscus tear was judged. Lysholm score, knee range of motion, visual simulation score (VAS) and magnetic resonance imaging (MRI) were used to evaluate the postoperative knee function and recovery of the patients.
Results:
The 95 patients were followed up for 22 to 36 months, with an average of (28.32±3.98) months. According to Barrett standard, 90 patients (94.7%) obtained meniscus clinical healing. Meniscal healing rates were 96.43%, 96.23% and 85.71% in the three age groups, respectively. The meniscal healing rate was lower in the elderly group, but there was no significant difference in statistical results (P=0.262). Five patients had deep tenderness in the joint space of the injured side, and the overstretch test was positive. The preoperative and postoperative VAS scores, Lysholm scores and knee motion were compared in each group, and the differences were statistically significant (P < 0.01). At the end of the last follow-up, there were no cases of knee joint effusion, swelling and interlocking, and the joint function was effectively improved in most patients. No surgical site infection, periarticular vascular/nerve injury or knotting reaction was found during the follow-up.
Conclusion:
This modified arthroscopic outside-in suture technique using a spinal needle has the characteristics of simple operation, small trauma and rapid recovery, and the mid-term follow-up results were satisfactory. Therefore, we consider this method to be a safe and efficient method for the treatment of meniscus anterior horn and body tear.
Meniscus injuries are among the most common orthopaedic injuries. Tears in the inner one‐third of the meniscus heal poorly and present a significant clinical challenge. In this study, we hypothesized that progenitor cells from healthy human articular cartilage (C‐PCs) may be more suitable than bone‐marrow mesenchymal stem cells (BM‐MSCs) to mediate bridging and reintegration of fibrocartilage tissue tears in meniscus. C‐PCs were isolated from healthy human articular cartilage based on their expression of mesenchymal stem/progenitor marker ALCAM (CD166). Our findings revealed that healthy human C‐PCs are CD166+, CD90+, CD54+, CD106‐ cells with multi‐lineage differentiation potential and elevated basal expression of chondrogenesis marker SOX‐9. We show that, similar to BM‐MSCs, C‐PCs are responsive to the chemokine stromal cell derived factor‐1 (SDF‐1) and they can successfully migrate to the area of meniscal tissue damage promoting collagen bridging across inner meniscal tears. In contrast to BM‐MSCs, C‐PCs maintaining reduced expression of cellular hypertrophy marker collagen X in monolayer culture and in an ex‐plant organ culture model of meniscus repair. Treatment of C‐PCs with SDF‐1/CXCR4 pathway inhibitor AMD3100 disrupted cell localization to area of injury and prevented meniscus tissue bridging thereby indicating that the SDF‐1/CXCR4 axis is an important mediator of this repair process. This study suggests that C‐PCs from healthy human cartilage may potentially be a useful tool for fibrocartilage tissue repair/regeneration because they resist cellular hypertrophy and mobilize in response to chemokine signaling. © AlphaMed Press 2018 Using an explant model of meniscus repair, we demonstrate that progenitor cells from healthy human articular cartilage resist cellular hypertrophy and mediate meniscal fibrocartilage healing in a manner that is dependent of SDF‐1/CXCR4 chemokine signaling.
The meniscus plays a vital role in protecting the articular cartilage of the knee joint. The inner two-thirds of the meniscus are avascular, and injuries to this region often fail to heal without intervention. The use of tissue engineering and regenerative medicine techniques may offer novel and effective approaches to repairing meniscal injuries. Meniscal tissue engineering and regenerative medicine typically use one of two techniques, cell-based or cell-free. While numerous cell-based strategies have been applied to repair and regenerate meniscal defects, these techniques possess certain limitations including cellular contamination and an increased risk of disease transmission. Cell-free strategies attempt to repair and regenerate the injured tissues by recruiting endogenous stem/progenitor cells. Cell-free strategies avoid several of the disadvantages of cell-based techniques and, therefore, may have a wider clinical application. This review first compares cell-based to cell-free techniques. Next, it summarizes potential sources for endogenous stem/progenitor cells. Finally, it discusses important recruitment factors for meniscal repair and regeneration. In conclusion, cell-free techniques, which focus on the recruitment of endogenous stem and progenitor cells, are growing in efficacy and may play a critical role in the future of meniscal repair and regeneration.
Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone. Upon injury, the outer zone of the meniscus can be repaired and expected to functionally heal but tears in the inner avascular region are unlikely to heal. To date, no regenerative therapy has been proven successful for consistently promoting healing in inner-zone meniscus tears. Here, we show that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) can induce seamless healing of avascular meniscus tears by inducing recruitment and step-wise differentiation of synovial mesenchymal stem/progenitor cells (syMSCs). A short-term release of CTGF, a selected chemotactic and profibrogenic cue, successfully recruited syMSCs into the incision site and formed an integrated fibrous matrix. Sustain-released TGFβ3 then led to a remodeling of the intermediate fibrous matrix into fibrocartilaginous matrix, fully integrating incised meniscal tissues with improved functional properties. Our data may represent a novel clinically relevant strategy to improve healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells.
A meniscus tear often happens during active sports. It needs to be repaired or replaced surgically to avoid further damage to the articular cartilage. To address the shortage of autologous meniscal cells, we designed a co-culture system of synovial stem cells (SMSCs) and meniscal cells (MCs) to produce a large cell number and to maintain characteristics of MCs. Different ratios of SMSCs and MCs at 3:1, 1:1, and 1:3 were tested. Mono-culture of SMSCs or MCs served as control groups. Proliferation and differentiation abilities were compared. The expression of extracellular matrix (ECM) genes in MCs was assessed using an ECM array to reveal the mechanism at the gene level. The co-culture system of SMSCs/MCs at the ratio of 1:3 showed better results than the control groups or those at other ratios. This co-culture system may be a promising strategy for meniscus repair with tissue engineering.
The endogenous healing potential of avascular meniscal lesions is poor. Up to now, partial meniscectomy is still the treatment of choice for meniscal lesions within the avascular area. However, the large loss of meniscus substance predisposes the knee for osteoarthritic changes. Tissue engineering techniques for the replacement of such lesions could be a promising alternative treatment option. Thus, a polyurethane scaffold, which is already in clinical use, loaded with mesenchymal stromal cells, was analyzed for the repair of critical meniscus defects in the avascular zone. Large, approximately 7 mm broad meniscus lesions affecting both the avascular and vascular area of the lateral rabbit meniscus were treated with polyurethane scaffolds either loaded or unloaded with mesenchymal stromal cells. Menisci were harvested at 6 and 12 weeks after initial surgery. Both cell-free and cell-loaded approaches led to well-integrated and stable meniscus-like repair tissue. However, an accelerated healing was achieved by the application of mesenchymal stromal cells. Dense vascularization was detected throughout the repair tissue of both treatment groups. Overall, the polyurethane scaffold seems to promote the vessel ingrowth. The application of mesenchymal stromal cells has the potential to speed up the healing process.
Extensive investigations over the recent decades have established the anatomical, biomechanical and functional importance of the meniscus in the knee joint. As a functioning part of the joint, it serves to prevent the deterioration of articular cartilage and subsequent osteoarthritis. To this end, meniscus repair and regeneration is of particular interest from the biomaterial, bioengineering and orthopaedic research community. Even though meniscal research is previously of a considerable volume, the research community with evolving material science, biology and medical advances are all pushing toward emerging novel solutions and approaches to the successful treatment of meniscal difficulties. This review presents a tactical evaluation of the latest biomaterials, experiments to simulate meniscal tears and the state-of-the-art materials and strategies currently used to treat tears.
Background
Treatment of meniscus tears within the avascular region represents a significant challenge, particularly in a situation of early osteoarthritis. Cell-based tissue engineering approaches have shown promising results. However, studies have not found a consensus on the appropriate autologous cell source in a clinical situation, specifically in a challenging degenerative environment. The present study sought to evaluate the appropriate cell source for autologous meniscal repair in a demanding setting of early osteoarthritis.
Methods
A rabbit model was used to test autologous meniscal repair. Bone marrow and medial menisci were harvested 4 weeks prior to surgery. Bone marrow-derived mesenchymal stem cells (MSCs) and meniscal cells were isolated, expanded, and seeded onto collagen-hyaluronan scaffolds before implantation. A punch defect model was performed on the lateral meniscus and then a cell-seeded scaffold was press-fit into the defect. Following 6 or 12 weeks, gross joint morphology and OARSI grade were assessed, and menisci were harvested for macroscopic, histological, and immunohistochemical evaluation using a validated meniscus scoring system. In conjunction, human meniscal cells isolated from non-repairable bucket handle tears and human MSCs were expanded and, using the pellet culture model, assessed for their meniscus-like potential in a translational setting through collagen type I and II immunostaining, collagen type II enzyme-linked immunosorbent assay (ELISA), and gene expression analysis.
Results
After resections of the medial menisci, all knees showed early osteoarthritic changes (average OARSI grade 3.1). However, successful repair of meniscus punch defects was performed using either meniscal cells or MSCs. Gross joint assessment demonstrated donor site morbidity for meniscal cell treatment. Furthermore, human MSCs had significantly increased collagen type II gene expression and production compared to meniscal cells (p < 0.05).
Conclusions
The regenerative potential of the meniscus by an autologous cell-based tissue engineering approach was shown even in a challenging setting of early osteoarthritis. Autologous MSCs and meniscal cells were found to have improved meniscal healing in an animal model, thus demonstrating their feasibility in a clinical setting. However, donor site morbidity, reduced availability, and reduced chondrogenic differentiation of human meniscal cells from debris of meniscal tears favors autologous MSCs for clinical use for cell-based meniscus regeneration.
Meniscectomy is one of the most popular orthopaedic procedures, but long-term results are not entirely satisfactory and the concept of meniscal preservation has therefore progressed over the years. However, the meniscectomy rate remains too high even though robust scientific publications indicate the value of meniscal repair or non-removal in traumatic tears and non-operative treatment rather than meniscectomy in degenerative meniscal lesions
In traumatic tears, the first-line choice is repair or non-removal. Longitudinal vertical tears are a proper indication for repair, especially in the red-white or red-red zones. Success rate is high and cartilage preservation has been proven. Non-removal can be discussed for stable asymptomatic lateral meniscal tears in conjunction with anterior cruciate ligament (ACL) reconstruction. Extended indications are now recommended for some specific conditions: horizontal cleavage tears in young athletes, hidden posterior capsulo-meniscal tears in ACL injuries, radial tears and root tears.
Degenerative meniscal lesions are very common findings which can be considered as an early stage of osteoarthritis in middle-aged patients. Recent randomised studies found that arthroscopic partial meniscectomy (APM) has no superiority over non-operative treatment. Thus, non-operative treatment should be the first-line choice and APM should be considered in case of failure: three months has been accepted as a threshold in the ESSKA Meniscus Consensus Project presented in 2016. Earlier indications may be proposed in cases with considerable mechanical symptoms.
The main message remains: save the meniscus!
Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160056. Originally published online at www.efortopenreviews.org
Purpose: This meta-analysis evaluates the mid- to long-term survival outcome of MAT (meniscal allograft transplantation). Potential prognosticators, with particular focus on chondral status and age of the patient at the time of transplantation, were also analysed.
Study design: Meta-analysis.
Methods: An online database search was performed using following search string: “meniscal allograft transplantation” and “outcome”. A total of 65 articles were analysed for a total of 3157 performed MAT with a mean follow-up of 5.4 years. Subjective and clinical data was analysed.
Results: The subjective and objective results of 2977 patients (3157 allografts) were analysed; 70% were male, 30% were female. Thirty-eight percent received an isolated MAT. All other patients underwent at least one concomitant procedure. Lysholm, Knee injury and Osteoarthritis Outcome (KOOS), International Knee Documentation Committee (IKDC) and Visual Analogue Scale (VAS) scores were analysed. All scores showed a good patient satisfaction at long-term follow-up. The mean overall survival rate was 80.9%. Complication rates were comparable to standard meniscal repair surgery. There was a degenerative evolution in osteoarthritis with at least one grade in 1760 radiographically analysed patients. Concomitant procedures seem to have no effect on the outcome. Age at transplantation is a negative prognosticator. The body mass index (BMI) of the patient shows a slightly negative correlation with the outcome of MAT.
Conclusions: MAT is a viable solution for the younger patient with chronic pain in the meniscectomised knee joint. The complications are not severe and comparable to meniscal repair. The overall failure rate at final follow-up is acceptable and the allograft heals well in most cases, but MAT cannot be seen as a definitive solution for post-meniscectomy pain. The correct approach to the chronic painful total meniscectomised knee joint thus requires consideration of all pathologies including alignment, stability, meniscal abnormality and cartilage degeneration. It requires possibly combined but appropriate action in that order.
Background:
Meniscus damage can be caused by trauma or degeneration and is therefore common among patients of all ages. Repair or regeneration of the menisci could be of great importance not only for pain relief or regaining function but also to prevent degenerative disease and osteoarthritis. Current treatment does not offer consistent long-term improvement. Although preclinical research focusing on augmentation of meniscal tear repair and regeneration after meniscectomy is encouraging, clinical translation remains difficult.
Purpose:
To systematically evaluate the literature on in vivo meniscus regeneration and explore the optimal cell sources and conditions for clinical translation. We aimed at thorough evaluation of current evidence as well as clarifying the challenges for future preclinical and clinical studies.
Study design:
Systematic review.
Methods:
A search was conducted using the electronic databases of MEDLINE, Embase, and the Cochrane Collaboration. Search terms included meniscus, regeneration, and cell-based.
Results:
After screening 81 articles based on title and abstract, 51 articles on in vivo meniscus regeneration could be included; 2 additional articles were identified from the references. Repair and regeneration of the meniscus has been described by intra-articular injection of multipotent mesenchymal stromal (stem) cells from adipose tissue, bone marrow, synovium, or meniscus or the use of these cell types in combination with implantable or injectable scaffolds. The use of fibrochondrocytes, chondrocytes, and transfected myoblasts for meniscus repair and regeneration is limited to the combination with different scaffolds. The comparative in vitro and in vivo studies mentioned in this review indicate that the use of allogeneic cells is as successful as the use of autologous cells. In addition, the implantation or injection of cell-seeded scaffolds increased tissue regeneration and led to better structural organization compared with scaffold implantation or injection of a scaffold alone. None of the studies mentioned in this review compare the effectiveness of different (cell-seeded) scaffolds.
Conclusion:
There is heterogeneity in animal models, cell types, and scaffolds used, and limited comparative studies are available. The comparative in vivo research that is currently available is insufficient to draw strong conclusions as to which cell type is the most promising. However, there is a vast amount of in vivo research on the use of different types of multipotent mesenchymal stromal (stem) cells in different experimental settings, and good results are reported in terms of tissue formation. None of these studies compare the effectiveness of different cell-scaffold combinations, making it hard to conclude which scaffold has the greatest potential.
Background:
Total meniscectomy leads to knee osteoarthritis in the long term. The poly(ε-caprolactone) (PCL) scaffold is a promising material for meniscal tissue regeneration, but cell-free scaffolds result in relatively poor tissue regeneration and lead to joint degeneration.
Hypothesis:
A novel, 3-dimensional (3D)-printed PCL scaffold augmented with mesenchymal stem cells (MSCs) would offer benefits in meniscal regeneration and cartilage protection.
Study design:
Controlled laboratory study.
Methods:
PCL meniscal scaffolds were 3D printed and seeded with bone marrow-derived MSCs. Seventy-two New Zealand White rabbits were included and were divided into 4 groups: cell-seeded scaffold, cell-free scaffold, sham operation, and total meniscectomy alone. The regeneration of the implanted tissue and the degeneration of articular cartilage were assessed by gross and microscopic (histological and scanning electron microscope) analysis at 12 and 24 weeks postoperatively. The mechanical properties of implants were also evaluated (tensile and compressive testing).
Results:
Compared with the cell-free group, the cell-seeded scaffold showed notably better gross appearance, with a shiny white color and a smooth surface. Fibrochondrocytes with extracellular collagen type I, II, and III and proteoglycans were found in both seeded and cell-free scaffold implants at 12 and 24 weeks, while the results were significantly better for the cell-seeded group at week 24. Furthermore, the cell-seeded group presented notably lower cartilage degeneration in both femur and tibia compared with the cell-free or meniscectomy group. Both the tensile and compressive properties of the implants in the cell-seeded group were significantly increased compared with those of the cell-free group.
Conclusion:
Seeding MSCs in the PCL scaffold increased its fibrocartilaginous tissue regeneration and mechanical strength, providing a functional replacement to protect articular cartilage from damage after total meniscectomy.
Clinical relevance:
The study suggests the potential of the novel 3D PCL scaffold augmented with MSCs as an alternative meniscal substitution, although this approach requires further improvement before being used in clinical practice.
In recent years it has become increasingly clear that articular cartilage harbours a viable pool of progenitor cells and interest has focussed on their role during development and disease. Analysis of progenitor numbers using fluorescence-activated sorting techniques has resulted in wide-ranging estimates, which may be the result of context-dependent expression of cell surface markers. We have used a colony-forming assay to reliably determine chondroprogenitor numbers in normal and osteoarthritic cartilage where we observed a 2-fold increase in diseased tissue (P < 0.0001). Intriguingly, cell kinetic analysis of clonal isolates derived from single and multiple donors of osteoarthritic cartilage revealed the presence of a divergent progenitor subpopulation characterised by an early senescent phenotype. Divergent sub-populations displayed increased senescence-associated β–galactosidase activity, lower average telomere lengths but retained the capacity to undergo multi-lineage differentiation. Osteoarthritis is an age-related disease and cellular senescence is predicted to be a significant component of the pathological process. This study shows that although early senescence is an inherent property of a subset of activated progenitors, there is also a pool of progenitors with extended viability and regenerative potential residing within osteoarthritic cartilage.
Background
Platelet-rich plasma (PRP) has emerged as a popular biologic treatment for musculoskeletal injuries and conditions. Despite numerous investigations on the efficacy of PRP therapy, current utilization of this treatment within the United States is not widely known.
Purpose
To investigate the national utilization of PRP, including the incidence and conditions for which it is used in the clinical setting, and to determine the current charges associated with this treatment.
Study Design
Descriptive epidemiology study.
Methods
Using a national database (PearlDiver) of private insurance billing records, we conducted a comprehensive search using Current Procedural Terminology (CPT) codes to identify patients who received PRP injections over a 2-year period (2010-2011). Associated International Classification of Diseases, 9th Revision (ICD-9) codes were identified to determine the specific conditions the injection was used to treat. The aggregate patient data were analyzed by yearly quarter, practice setting, geographic region, and demographics. PRP therapy charges were calculated and reported as per-patient average charges (PPACs).
Results
A total of 2571 patients who received PRP injections were identified; 51% were male and 75% were older than 35 years. The overall incidence ranged from 5.9 to 7.9 per 1000 patients over the study period. PRP was most commonly administered in hospitals (39%) and ambulatory surgical centers (37%) compared with in private offices (26%). The most common conditions treated were knee meniscus/plica disorders, followed by unspecified shoulder conditions, rotator cuff injuries, epicondylitis, and plantar fasciitis. Further evaluation revealed that 25% of all patients received injections for cartilage-related conditions, 25% meniscus, 25% unspecified, 12% tendon, 8% glenoid labrum, and 5% ligament. The PPAC for PRP treatment was US$1755 per injection.
Conclusion
Despite a lack of consensus regarding PRP indications and efficacy, we observed widespread application of this treatment for a myriad of musculoskeletal injuries. Most treated patients were older than 35 years, and the most commonly treated conditions included cartilage and meniscus disorders. Given the current controversy surrounding this treatment, further studies are necessary to guide clinicians on the value of this therapy for each clinical diagnosis.
The aim of the current in vitro study was to investigate if tissue surface modification with collagenase and addition of the TGF-β3 can increase the number of cells present in meniscus tears repaired with the use of newly developed tissue adhesives based on isocyanate-terminated block copolymers. Cylindrical explants were harvested from the inner part of bovine menisci. To simulate a full-thickness tear, the central core of the explants was removed and glued back into the defect, with or without incubation in collagenase solution prior to gluing. The repair constructs were then cultured with or without addition of TGF-β3, and assessed for their histological appearance. The histological staining of the constructs confirmed that both developed adhesives were not cytotoxic. After 28 days, meniscus cells were present in direct contact with the glues. The addition of TGF-β3 to the culture medium resulted in the presence of cells that formed a sheath inside the simulated tear and in increased cell numbers at the edges of annulus of the explants. In the group in which the tissue was incubated in collagenase and cultured in medium containing TGF-β3, thicker layers of cells were observed. These results suggest that repairing the torn meniscus with tissue adhesives after pre-treatment of the tissue with collagenase and stimulation with TGF-β3 is a very promising treatment method, especially when treating the inner avascular part of the meniscus. Nevertheless, longer-term in vitro and in vivo studies are needed to confirm the beneficial effects of this combination therapy.
Purpose . To determine the characteristics of MSCs from hip and compare them to MSCs from knee. Methods . Synovial tissues were obtained from both the knee and the hip joints in 8 patients who underwent both hip and knee arthroscopies on the same day. MSCs were isolated from the knee and hip synovial samples. The capacities of MSCs were compared between both groups. Results . The number of cells per unit weight at passage 0 of synovium from the knee was significantly higher than that from the hip ( P<0.05 ). While it was possible to observe the growth of colonies in all the knee synovial fluid samples, it was impossible to culture cells from any of the hip samples. In adipogenesis experiments, the frequency of Oil Red-O-positive colonies and the gene expression of adipsin were significantly higher in knee than in hip. In osteogenesis experiments, the expression of COL1A1 and ALPP was significantly less in the knee synovium than in the hip synovium. Conclusions . MSCs obtained from hip joint have self-renewal and multilineage differentiation potentials. However, in matched donors, adipogenesis and osteogenesis potentials of MSCs from the knees are superior to those from the hips. Knee synovium may be a better source of MSC for potential use in hip diseases.
OBJECTIVE To assess the ability to regenerate an equine meniscus by use of a collagen repair patch (scaffold) seeded with mesenchymal stem cells (MSCs) derived from bone marrow (BM) or adipose tissue (AT).
SAMPLE 6 female Hispano-Breton horses between 4 and 7 years of age; MSCs from BM and AT were obtained for the in vitro experiment, and the horses were subsequently used for the in vivo experiment.
PROCEDURES Similarities and differences between MSCs derived from BM or AT were investigated in vitro by use of cell culture. In vivo assessment involved use of a meniscus defect and implantation on a scaffold. Horses were allocated into 2 groups. In one group, defects in the medial meniscus were treated with MSCs derived from BM, whereas in the other group, defects were treated with MSCs derived from AT. Defects were created in the contralateral stifle joint but were not treated (control samples).
RESULTS Both types of MSCs had universal stem cell characteristics. For in vivo testing, at 12 months after treatment, treated defects were regenerated with fibrocartilaginous tissue, whereas untreated defects were partially repaired or not repaired.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that MSCs derived from AT could be a good alternative to MSCs derived from BM for use in regenerative treatments. Results also were promising for a stem cell-based implant for use in regeneration in meniscal lesions.
IMPACT FOR HUMAN MEDICINE Because of similarities in joint disease between horses and humans, these results could have applications in humans.
Objective:
the menisci are easily injured and difficult to repair. The aim of this study was to analyze the current state of meniscal surgery aimed at preserving morphology and conserving the biomechanics of the knee to prevent joint degeneration.
Methodology:
a search of the electronic medical literature database Medline was conducted, from http://www.ncbi.nlm.nih.gov/pubmed. The search was not limited by language. Candidate articles were identified by searching for those that included the keywords meniscus, surgery, suture, implant, allograft. The limits were included for clinical research and clinical trials. Basic research was not included. The studies selected were evaluated and classified in three different categories: basic science, reconstruction (suture and meniscectomy) and implants (scaffolds and allograft).
Results:
the consequences of meniscectomy performed at a young age can lead to a joint cartilage degeneration twenty years later. There are few surgical options for the repair of meniscal injuries in order both to preserve the meniscus and to ensure the long term survival of the knee joint, meniscectomy, repair, suturing the tear, or reconstruction, when a meniscal allograft or synthetic substitute is used to replace the meniscus, but the biomechanical properties of the native meniscus are not reproduced entirely by the scaffolds that exist today.
Conclusion:
therapies that successfully repair or replace the meniscus are therefore likely to prevent or delay osteoarthritis progression.
Transplantation of mesenchymal stem cells (MSCs) is a potential therapy for meniscus regeneration. However, when using single cell suspension injection, there is frequently a significant loss of cells, with only a small percentage of cells remaining at the target site. This issue may be solved with the use of MSC sheets. In the present study, we investigated whether the use of MSC sheets were able to regenerate the meniscus effectively in a rat meniscectomized model. The anterior half of the medial meniscus in 10 rats was excised and an MSC sheet was transplanted in the MSC sheet treatment group, while untreated rats served as the control. After 4 and 8 weeks, the knee joints were examined by gross and histological observation. Histological observation revealed that the anterior portion of meniscus was similar to the native tissue, showing typical fibrochondrocytes surrounded by richer extracellular matrix in the MSC sheet group. In addition, predominant collagen-rich matrix bridging the interface was observed and the neo-meniscus integrated well with its host meniscus. Furthermore, degenerative changes of tibial plateau and femoral condyle occurred in the two groups. MSC sheet transplantation alleviated the degenerative changes efficiently. In conclusion, transplantation of MSC sheets may efficiently promote meniscus regeneration, as well as inhibit the progression of osteoarthritis in knee joints.
Repair of a massive meniscal defect remains a challenge in the clinic. However, targeted magnetic cell delivery, an emerging technique, may be useful in its treatment. The present study aimed to determine the effect of targeted intra-articular injection of superparamagnetic iron oxide (SPIO)-labeled adipose-derived mesenchymal stem cells (ASCs) in a rabbit model of a massive meniscal defect. ASCs may be directly labeled and almost 100% of the ASCs were labeled with SPIO after 24 h; these SPIO-labeled ASCs may be orientated by magnet. The centrifuged SPIO-labeled ASCs precipitations may be detected by magnetic resonance imaging (MRI). The anterior half of the medial meniscus of 18 New Zealand Rabbits was excised. After 7 days, the rabbits were randomized to injections of 2×10(6) SPIO-labeled ASCs, 2×10(6) unlabeled ASCs or saline. Permanent magnets were fixed to the outside of the operated joints for one day, and after 6 and 12 weeks, the knee joints were examined using MRI, gross and histological observation, and Prussian blue staining. Marked hypointense artifacts caused by SPIO-positive cells in the meniscus were detected using MRI. Histological observation revealed that the anterior portion of the meniscus was similar to the native tissue, demonstrating typical fibrochondrocytes surrounded by richer extracellular matrix in the SPIO-ASCs group. Collagen-rich matrix bridging the interface and the neo-meniscus integrated well with its host meniscus. Furthermore, degenerative changes occurred in all groups, but intra-articular injection of SPIO-ASCs or ASCs alleviated these degenerative changes. Prussian blue staining indicated that the implanted ASCs were directly associated with the regenerated tissue. Overall, targeted intra-articular delivery of SPIO-ASCs promoted meniscal regeneration whilst providing protective effects from osteoarthritic damage.
Introduction:
management of intrasubstance meniscal lesions is still controversial. Intrasubstance meniscal lesions can lead to reduced sports activity and meniscal rupture. Physical therapy is often not satisfactory. Therefore new treatment methods are requested. Platelet Rich Plasma (PRP) has the ability to regenerate tissue; this was proved in several experimental studies. Whether percutaneous injections of PRP are effective in intrasubstance meniscal lesions is unknown. We hypothesize that percutaneous PRP injections lead to pain relief and halt of progression on MRI over 6 months in patients with grade 2 meniscal lesions.
Materials and methods:
ten recreational athletes with intrasubstance meniscal lesions (grade II according to Reicher) proven by MR-Imaging (MRI) were treated by percutaneous injections of PRP in the affected meniscal area. Three sequential injections in seven day intervals were performed in every patient. All injections were performed with image converter. Follow-up MRI was done six months after last injection in every patient. Level of sports activity and amount of pain at athletic loads according to numeric rating scale (NRS-11) were noted in each patient before injections and at the time of follow up MRI after six months. The t-test was used to determine statistical differences.
Results:
four of ten patients (40%) showed decrease of meniscal lesion in follow up MRI after six months. Nine of ten patients (90%) complained about short episodes of heavy pain after the injections with average NRS-Score of 7.9 at daily loads after the last injection. Six of ten patients (60%) showed Improvement of NRS-Score at final follow up. Average NRS-Score improved significantly (p=0.027) from 6.9 before injections to 4.5 six month after treatment. Six of ten patients (60%) reported increase of sports activity compared to the situation before injections. In four patients (40%) additional surgical treatment was necessary because of persistent knee pain or progression of meniscal lesion.
Conclusions:
percutaneous injections of PRP have the ability to achieve pain relief and halt of progression on MRI over 6 months in patients with grade 2 meniscal lesions. Therefore it could be considered as a treatment option in patients with persisting pain.
Level of evidence:
IV.
Articular cartilage is a complex tissue comprising phenotypically distinct zones. Research has identified the presence of a progenitor cell population in the surface zone of immature articular cartilage. The aim of the present study was to determine the in vivo plasticity of articular cartilage progenitor.
Chondropogenitor cells were isolated from bovine metacarpalphalangeal joints by differential adhesion to fibronectin. Cells were labeled with PKH26 and injected into the thigh muscle of severe-combined immunodeficient (SCID) mice. After 2 weeks, the muscles were dissected and cryosectioned. Sections were stained with safranin O and labeled for sox9 and collagen type II. Polymerase chain reaction analysis was carried out to determine plasticity for a number of tissue-specific markers. Full-depth chondrocytes acted as a control.
Fluorescent PKH26 labeled cells were detected after 2 weeks in all samples analyzed. A cartilage pellet was present after injection of freshly isolated chondrocytes. After injection with clonal and enriched populations of chondroprogenitors, no distinct pellet was detected, but diffuse cartilage nodules were found with regions of safranin O staining and Sox9. Low levels of collagen type II were also detected. Polymerase chain reaction analysis identified the presence of the endothelial cell marker PECAM-1 in one clonal cell line, demonstrating phenotypic plasticity into the phenotype of the surrounding host tissues.
The bovine articular cartilage progenitor cells were able to survive in vivo postimplantation, but failed to create a robust cartilage pellet, despite expressing sox9 and type II collagen. This suggests the cells require further signals for chondrogenic differentiation.
The restoration of damaged meniscus has always been a challenge due to its limited healing capacity. Recently, bone marrow-derived mesenchymal stem cells (BMSCs) provide a promising alternative to repair meniscal defects. However, BMSCs are not ideal chondroprogenitor cells for meniscus repair because they have a high propensity for cartilage hypertrophy and bone formation. Our hypothesis is that mesenchymal stem cells (MSCs) reside in meniscus maintain specific traits distinct from others which may be more conducive to meniscus regeneration.
MSCs were isolated from bone marrow and menisci of the rabbits. The similarities and differences between BMSCs and MMSCs were investigated in vitro by a cell culture model, ex vivo by a rabbit meniscus defect model and in vivo by a nude rat implantation model using histochemistry, immunocytochemistry, qRT-PCR and western blotting.
Our data showed that two types of MSCs have universal stem cell characteristics including clonogenicity, multi-potency and self-renewal capacity. They both express stem cell markers including SSEA-4, Nanog, nucleostemin, strol-1, CD44 and CD90.
However, MMSCs differed from BMSCs. MMSC colonies were much smaller and grew more slowly than BMSC colonies. Moreover, fewer MMSCs expressed CD34 than BMSCs. Finally, MMSCs always appeared a pronounced tendency to chondrogenic differentiation while BMSCs exhibited significantly greater osteogenic potential, whatever in vitro and in vivo.
This study shows the similarities and differences between MMSCs and BMSCs for the first time. MMSCs are a promising source of mesenchymal stem cells in repairing meniscus defect.
The induction of synovial tissue to the meniscal lesion is crucial for meniscal healing. Synovial MSCs are an attractive cell source because of their high proliferative and chondrogenic potentials. We examined whether transplantation of synovial MSCs promoted healing after meniscal repair of extended longitudinal tear of avascular area in a microminipig model.
Longitudinal tear lesion was made in medial menisci and sutured in both knees, and then a synovial MSC suspension was administered for 10 minutes only in unilateral knee. The sutured meniscus was evaluated morphologically and biomechanically at 2, 4, and 12 weeks. The behavior of transplanted MSCs was also examined.
The meniscal healing at 12 weeks was significantly better in the MSC group than in the control group; macroscopically, histologically and by T1rho mapping analysis. Transmission electron microscopic analysis demonstrated that the meniscus lesion was occupied by dense collagen fibrils only in the MSC group. Biomechanical analysis revealed that the tensile strength to failure of the meniscus higher in the MSC group than in the control group in each microminipig. Synovial tissue covered better along the superficial layer from the outer zone into the lesion of the meniscus in the MSC group at 2 and 4 weeks in each microminipig. Synovial MSCs labeled with ferucarbotran were detected in the meniscus lesion and adjacent synovium by MRI at 2 weeks.
Transplantation of synovial MSCs promoted healing after meniscal repair with induction of synovium into the longitudinal tear in the avascular zone of meniscus in pigs.
Copyright © 2015. Published by Elsevier Ltd.
Increased contact stresses after meniscectomy have led to an increased focus on meniscal preservation strategies to prevent articular cartilage degeneration. Platelet-rich plasma (PRP) has received attention as a promising strategy to help induce healing and has been shown to do so both in vitro and in vivo. Although PRP has been used in clinical practice for some time, to date, few clinical studies support its use in meniscal repair.
We sought to (1) evaluate whether PRP augmentation at the time of index meniscal repair decreases the likelihood that subsequent meniscectomy will be performed; (2) determine if PRP augmentation in arthroscopic meniscus repair influenced functional outcome measures; and (3) examine whether PRP augmentation altered clinical and patient-reported outcomes.
Between 2008 and 2011, three surgeons performed 35 isolated arthroscopic meniscus repairs. Of those, 15 (43%) were augmented with PRP, and 20 (57%) were performed without PRP augmentation. During the study period, PRP was used for patients with meniscus tears in the setting of no ACL reconstruction. Complete followup at a minimum of 2 years (mean, 4 years; range, 2-6 years) was available on 11 (73%) of the PRP-augmented knees and 15 (75%) of the nonaugmented knees. Clinical outcome measures including the International Knee Documentation Committee (IKDC) score, Tegner Lysholm Knee Scoring Scale, and return to work and sports/activities survey tools were completed in person, over the phone, or through the mail. Range of motion data were collected from electronic patient charts in chart review. With the numbers available, a post hoc power calculation demonstrated that we would have expected to be able to discern a difference using IKDC if we treated 153 patients with PRP and 219 without PRP assuming an alpha rate of 5% and power exceeding 80%. Using the Lysholm score as an outcome measure, post hoc power estimate was 0.523 and effect size was -1.1 (-2.1 to -0.05) requiring 12 patients treated with PRP and 17 without to find statistically significant differences at p = 0.05 and power = 80%.
There was no difference in the proportion of patients who underwent reoperation in the PRP group (27% [four of 15]) compared with the non-PRP group (25% [five of 20]; p = 0.89). Functional outcome measures were not different between the two groups based on the measures used (mean IKDC score, 69; SD, 26 with PRP and 76; SD, 17 without PRP; p = 0.288; mean, Tegner Lysholm Knee Scoring Scale, 66, SD, 32 with PRP and 89; SD, 10 without PRP; p = 0.065). With the numbers available there was no difference in the proportion of patients who returned to work in the PRP group (100% [six of six]) compared with the non-PRP group (100% [nine of nine]) or in the patients who returned to their regular sports/activities in the PRP group (71% [five of seven]) compared with the non-PRP group (78% [seven of nine]; p = 0.75).
Patients who sustain meniscus injuries should be counseled at the time of injury about the outcomes after meniscus repair. With our limited study group, outcomes after meniscus repair with and without PRP appear similar in terms of reoperation rate. However, given the lack of power and nature of the study, modest size differences in outcome may not have been detected. Future larger prospective studies are needed to definitively determine whether PRP should be used with meniscal repair. Additionally, studies are needed to determine if PRP and other biologics may benefit complex tear types.
Level III, therapeutic study.
This study analysed the influence of bone morphogenetic protein-7 (BMP-7) on cells and meniscal structure. The effect of treatment with BMP-7 was assessed in vitro and in vivo in lesions in the avascular area of the meniscus. Cells were extracted from the outer and inner part of eight menisci of four 2-year-old merino sheep. The menisci were digested with a collagenase mix, and meniscus cells of the synovium, vascular area and avascular area were extracted. The expression of genes for collagen (Col1 and Col2A), matrix metalloproteinases (MMP-2 and MMP-13) and aggrecan was analysed by real time quantitative polymerase chain reaction (qPCR) at baseline and after incubation with BMP-7. Eight sheep aged 2 years and weighing 35–40 kg were used for the in vivo study. Surgery was performed in both knees of every animal. Two holes were made in the avascular area of the medial meniscus of both knees and filled using Putty® (control groups) or OP-1 Putty®, which comprises BMP-7 mixed with a cellulose putty carrier (experimental groups). Animals were sacrificed at 6, 12 and 25 weeks.
Purpose
Many studies have demonstrated that injection of various growth factors including platelet-derived growth factor could increase meniscal cell activity and stimulate repair. The purpose of this study was to augment repair and promote meniscal healing by the use of platelet-rich plasma (PRP) within horizontal cleavage meniscal tears repaired via an open approach. The hypothesis was that the clinical outcomes and healing process would be improved using this meniscal healing augmentation technique.
Methods
In this case–control study, 34 consecutive young patients underwent an open meniscal repair to treat symptomatic Grade 2 or Grade 3 horizontal meniscal tears [median age 28 years (13–40)]. The median time between the onset of symptoms and surgery was 11.5 months (6–50). In the first group (17 consecutive patients, Group 1), a standard open meniscal repair was performed. In the second group (17 consecutive patients, Group 2), the same surgical repair was performed, but platelet-rich plasma was introduced into the lesion at the end of the procedure. Clinical outcomes were evaluated using KOOS and IKDC 2000 scores. MRI was performed at 1 year after surgery for objective evaluation.
Results
At a minimum of 24 months postoperatively (mean 32.2 months, 24–40), three patients underwent subsequent meniscectomy (two in Group 1, one in Group 2). The mean KOOS distribution (pain, symptoms, daily activities, sports, quality of life) was 78.4, 86.1, 93.8, 74.4, 74.6 in Group 1, and 93.3, 90.7, 97.1, 88.8, 78.3 in Group 2 (p
Meniscal lesions in the avascular zone are still a problem in traumatology. Tissue Engineering approaches with mesenchymal stem cells (MSCs) showed successful regeneration of meniscal defects in the avascular zone. However, in daily clinical practice, a single stage regenerative treatment would be preferable for meniscus injuries. In particular, clinically applicable bioactive substances or isolated growth factors like platelet-rich plasma (PRP) or bone morphogenic protein 7 (BMP7) are in the focus of interest. In this study, the effects of PRP and BMP7 on the regeneration of avascular meniscal defects were evaluated. In vitro analysis showed that PRP secretes multiple growth factors over a period of 8 days. BMP7 enhances the collagen II deposition in an aggregate culture model of MSCs. However applied to meniscal defects PRP or BMP7 in combination with a hyaluronan collagen composite matrix failed to significantly improve meniscus healing in the avascular zone in a rabbit model after 3 months. Further information of the repair mechanism at the defect site is needed to develop special release systems or carriers for the appropriate application of growth factors to support biological augmentation of meniscus regeneration.
Damage to cartilage represents one of the most challenging tasks of musculoskeletal therapeutics due to its limited propensity for healing and regenerative capabilities. Lack of current treatments to restore cartilage tissue function has prompted research in this rapidly emerging field of tissue regeneration of functional cartilage tissue substitutes. The development of cartilaginous tissue largely depends on the combination of appropriate biomaterials, cell source, and stimulating factors. Over the years, various biomaterials have been utilized for cartilage repair, but outcomes are far from achieving native cartilage architecture and function. This highlights the need for exploration of suitable biomaterials and stimulating factors for cartilage regeneration. With these perspectives, we aim to present an overview of cartilage tissue engineering with recent progress, development, and major steps taken toward the generation of functional cartilage tissue. In this review, we have discussed the advances and problems in tissue engineering of cartilage with strong emphasis on the utilization of natural polymeric biomaterials, various cell sources, and stimulating factors such as biophysical stimuli, mechanical stimuli, dynamic culture, and growth factors used so far in cartilage regeneration. Finally, we have focused on clinical trials, recent innovations, and future prospects related to cartilage engineering.
Meniscal injuries are recognized as a cause of significant musculoskeletal morbidity. The menisci are vital for the normal function and long-term health of the knee joint. The purpose of this review is to provide current knowledge regarding the anatomy and biomechanical functions of the menisci, incidence, injury patterns and the advancements in treatment options of meniscal injury. A literature search was performed by a review of PubMed, Google Scholar, MEDLINE, and OVID for all relevant articles published between 1897 and 2014. This study highlights the anatomical and biomechanical characteristics of the menisci, which may be relevant to injury patterns and treatment options. An understanding of the normal anatomy and biomechanical functions of the knee menisci is a necessary prerequisite to understanding pathologies associated with the knee. Clin. Anat., 2014. © 2014 Wiley Periodicals, Inc.
The use of platelet-rich plasma (PRP) to improve clinical outcome following a soft tissue injury, regeneration, and repair has been the subject of intense investigation and discussion. This article endeavors to relate clinical and basic science strategies focused on biological augmentation of the healing response in anterior cruciate ligament (ACL) and meniscus repair and replacement using PRP. Therein, a translational feedback loop is created in the literature and targeted towards the entire multidisciplinary team. Ultimately, it is hoped that the theoretical benefits of PRP on soft-tissue interfacial healing will emerge clinically following a careful, focused characterization at the benchtop, and prospective randomized controlled clinical study.
Treatment options for meniscal tears fall into three broad categories; non-operative, meniscectomy or meniscal repair. Selecting the most appropriate treatment for a given patient involves both patient factors (e.g., age, co-morbidities and compliance) and tear characteristics (e.g., location of tear/age/reducibility of tear). There is evidence suggesting that degenerative tears in older patients without mechanical symptoms can be effectively treated non-operatively with a structured physical therapy programme as a first line. Even if these patients later require meniscectomy they will still achieve similar functional outcomes than if they had initially been treated surgically. Partial meniscectomy is suitable for symptomatic tears not amenable to repair, and can still preserve meniscal function especially when the peripheral meniscal rim is intact. Meniscal repair shows 80% success at 2 years and is more suitable in younger patients with reducible tears that are peripheral (e.g., nearer the capsular attachment) and horizontal or longitudinal in nature. However, careful patient selection and repair technique is required with good compliance to post-operative rehabilitation, which often consists of bracing and non-weight bearing for 4-6 wk.
Cells of the meniscus are exposed to a wide range of time‐varying mechanical stimuli that may regulate their metabolic activity in vivo. In this study, the biological response of the meniscus to compressive stimuli was evaluated in vitro, using a well‐controlled explant culture system. Gene expression for relevant extracellular matrix proteins was quantified using real‐time RT‐PCR following a 24 h period of applied static (0.1 MPa compressive stress) or dynamic compression (0.08–0.16 MPa). Static and dynamic compression were found to differentially regulate mRNA levels for specific proteins of the extracellular matrix. Decreased mRNA levels were observed for decorin (∼︁2.1 fold‐difference) and type II collagen (∼︁4.0 fold‐difference) following 24 h of dynamic compression. Decorin mRNA levels also decreased following static compression (∼︁4.5 fold‐difference), as did mRNA levels for both types I (∼︁3.3 fold‐difference) and II collagen (∼︁4.0 fold‐difference). Following either static or dynamic compression, mRNA levels for aggrecan, biglycan and cytoskeletal proteins were unchanged. It is noteworthy that static compression was associated with a 2.6 fold‐increase in mRNA levels for collagenase, or MMP‐1, suggesting that the homeostatic balance between collagen biosynthesis and catabolism was altered by the mechanical stimuli. These findings demonstrate that the biosynthetic response of the meniscus to compression is regulated, in part, at the transcriptional level and that transcription of types I and II collagen as well as decorin may be regulated by common mechanical stimuli. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Objective
To determine the histologic changes that accompany the formation of cell clusters during the early stages of osteoarthritis development in the meniscus, and to characterize the expression phenotype of these cells.
Methods
Histologic sections of medial menisci from normal and anterior cruciate ligament (ACL)–deficient rabbit knees were immunolabeled with monoclonal antibodies for vimentin to highlight the cytoskeleton of meniscal cells, Ki‐67 to identify proliferating cells, and type X collagen to evaluate changes in the cell expression phenotype. Tissue mineralization was assessed by specific staining with alizarin red.
Results
Following ACL transection, there was an alteration in the normal interconnected network of meniscal cells in the fibrocartilaginous region of the tissue. This led to isolation of islands of cells within the extracellular matrix of the meniscal tissue. These islands of cells displayed 3 different morphologies based on cell composition: 1) stellate cells, 2) stellate as well as round cells, and 3) round cells. Islands composed solely of round cells were more prominent in the latter stages following ACL transection, and the size of these islands increased with time, apparently as the result of cell proliferation. These islands of cells corresponded to the “clusters” previously described in osteoarthritic cartilage. Strong expression of type X collagen colocalized with the deposition of calcium within the meniscal regions enriched with cell clusters.
Conclusion
Based on the observed changes in cell distribution, morphology, and cell proliferation as well as the previous detection of apoptosis in similar studies of rabbit knee joints, we propose a model for the development of cell clusters in the osteoarthritic meniscus. The morphologic appearance as well as the type X collagen expression phenotype of the meniscal cells forming the clusters is similar to that of hypertrophic chondrocytes. These findings provide a basis for understanding the origin of cell clusters in other joint connective tissues, such as osteoarthritic cartilage.
Background:
Radial tears of the meniscus are a common knee injury, frequently resulting in osteoarthritis. To date, there are no established, effective treatments for radial tears. Adipose-derived stem cells (ASCs) may be an attractive cell source for meniscal regeneration because they can be quickly isolated in large number and are capable of undergoing induced fibrochondrogenic differentiation mediated by transforming growth factor β3 (TGF-β3). However, the use of ASCs for meniscal repair is largely unexplored.
Hypothesis:
ASC-seeded hydrogels with preloaded TGF-β3 will improve meniscal healing of radial tears, as modeled in an explant model.
Study design:
Controlled laboratory study.
Methods:
With an institutional review board-exempted protocol, human ASCs were isolated from the infrapatellar fat pads of 3 donors, obtained after total knee replacement, and characterized. ASCs were encapsulated in photocrosslinkable methacrylated gelatin hydrogels to form 3-dimensional constructs, which were placed into tissue culture. The effect of TGF-β3-whether preloaded into the hydrogel or added as a soluble medium supplement-on matrix-sulfated proteoglycan deposition in the constructs was evaluated. A meniscal explant culture model was used to simulate meniscal repair. Cylindrical-shaped explants were excised from the inner avascular region of adult bovine menisci, and a radial tear was modeled by cutting perpendicular to the meniscal main fibers to the length of the radius. Six combinations of hydrogels-namely, acellular and ASC-seeded hydrogels supplemented with preloaded TGF-β3 (2 µg/mL) or soluble TGF-β3 (10 ng/mL) and without supplement-were injected into the radial tear and stabilized by photocrosslinking with visible light. At 4 and 8 weeks of culture, healing was assessed through histology, immunofluorescence staining, and mechanical testing.
Results:
ASCs isolated from the 3 donors exhibited colony-forming and multilineage differentiation potential. Hydrogels preloaded with TGF-β3 and those cultured in soluble TGF-β3 showed robust matrix-sulfated proteoglycan deposition. ASC-seeded hydrogels promoted superior healing as compared with acellular hydrogels, with preloaded or soluble TGF-β3 further improving histological scores and mechanical properties.
Conclusion:
These findings demonstrated that ASC-seeded hydrogels preloaded with TGF-β3 enhanced healing of radial meniscal tears in an in vitro meniscal repair model.
Clinical relevance:
Injection delivery of ASCs in a TGF-β3-preloaded photocrosslinkable hydrogel represents a novel candidate strategy to repair meniscal radial tears and minimize further osteoarthritic joint degeneration.
The meniscus is the most commonly injured structure in the human knee. Meniscus deficiency has been shown to lead to advanced osteoarthritis (OA) due to abnormal mechanical forces, and replacement strategies for this structure have lagged behind other tissue engineering endeavors. The challenges include the complex 3D structure with individualized size parameters, the significant compressive, tensile and shear loads encountered, and the poor blood supply. In this progress report, a review of the current clinical treatments for different types of meniscal injury is provided. The state-of-the-art research in cellular therapies and novel cell sources for these therapies is discussed. The clinically available cell-free biomaterial implants and the current progress on cell-free biomaterial implants are reviewed. Cell-based tissue engineering strategies for the repair and replacement of meniscus are presented, and the current challenges are identified. Tissue-engineered meniscal biocomposite implants may provide an alternative solution for the treatment of meniscal injury to prevent OA in the long run, because of the limitations of the existing therapies.
Interest in non-invasive injectable therapies has rapidly risen due to their excellent safety profile and ease of use in clinical settings. Injectable hydrogels can be derived from the extracellular matrix (ECM) of specific tissues to provide a biomimetic environment for cell delivery and enable seamless regeneration of tissue defects. We investigated the in situ delivery of human mesenchymal stem cells (hMSCs) in decellularized meniscus ECM hydrogel to a meniscal defect in a nude rat model. First, decellularized meniscus ECM hydrogel retained tissue-specific proteoglycans and collagens, and significantly upregulated expression of fibrochondrogenic markers by hMSCs versus collagen hydrogel alone in vitro. The meniscus ECM hydrogel in turn supported delivery of hMSCs for integrative repair of a full-thickness defect model in meniscal explants after in vitro culture and in vivo subcutaneous implantation. When applied to an orthotopic model of meniscal injury in nude rat, hMSCs in meniscus ECM hydrogel were retained out to eight weeks post-injection, contributing to tissue regeneration and protection from joint space narrowing, pathologic mineralization, and osteoarthritis development, as evidenced by macroscopic and microscopic image analysis. Based on these findings, we propose the use of tissue-specific meniscus ECM-derived hydrogel for the delivery of therapeutic hMSCs to treat meniscal injury.
The meniscus has poor intrinsic regenerative capacity and its damage inevitably leads to articular cartilage degeneration. We focused on evaluating the effects of Polyvinyl alcohol/Chitosan (PVA/Ch) scaffold seeded by adipose-derived mesenchymal stem cell (ASC) and articular chondrocytes (AC) in meniscus regeneration. The PVA/Ch scaffolds with different molar contents of Ch (Ch1, Ch2, Ch4 and Ch8) were cross-linked by pre-polyurethane chains. By increasing amount of Ch tensile modulus was increased from 83.51 MPa for Ch1 to 110 MPa for Ch8 while toughness showed decrease from 0.33 mJ/mm³ in Ch1 to 0.11 mJ/mm³ in Ch8 constructs. Moreover, swelling ratio and degradation rate increased with an increase in Ch amount. Scanning electron microscopy imaging was performed for pore size measurement and cell attachment. At day 21, Ch4 construct seeded by AC showed the highest expression with 24.3 and 22.64 folds increase in collagen II and aggrecan (p ≤ 0.05), respectively. Since, the mechanical properties, water uptake and degradation rate of Ch4 and Ch8 compositions had no statistically significant differences, Ch4 was selected for in vivo study. New Zealand rabbits were underwent unilateral total medial meniscectomy and AC/scaffold, ASC/scaffold, AC-ASC (co-culture)/scaffold and cell-free scaffold were engrafted. At 7 months post-implantation, macroscopic, histologic and immunofluorescent studies for regenerated meniscus revealed better results in AC/scaffold group followed by AC-ASC/scaffold and ASC/scaffold groups. In the cell-free scaffold group, there was no obvious meniscus regeneration. Articular cartilages were preserved in AC/scaffold group. Degenerative changes appeared to be more severe in ASC/scaffold followed by cell-free scaffold. The best histological score was observed in AC/scaffold group. Our results support Ch4 scaffold seeded by AC alone can successfully regenerate meniscus in tearing injury and ASC has no significant contribution in the healing process.
Objective:
To give a narrative overview of meniscal tears with a radiologic emphasis on the morphologic type, technical considerations, and on the relevance of the type of meniscal tear in the context of osteoarthritis (OA) research.
Design:
Total 20 years of the PubMed database were searched for epidemiological, radiological, arthroscopic and biomechanical reports, and review articles focusing on meniscal tears in middle-aged and older individuals, in the setting of OA. Case reports, publications on meniscal tears in young active individuals, and publications not in English were excluded.
Results:
Meniscal intra-substance signal abnormalities are associated with an increased risk of a degenerative meniscal tear in the same segment. Posterior radial tears of the medial meniscus appear to be a highly relevant event in OA of the knee, with associated cartilage loss and meniscal extrusion. Radial tears are more commonly missed on MRI than other types, and should be carefully looked for on coronal and axial images. While medial meniscus posterior root tears are of "radial" morphology, there is growing interest in looking at them as a separate entity, mainly because they require a different therapeutic approach.
Conclusion:
There is a lack of data on the relevance of different morphologic types of meniscal tears to the natural history of knee OA, both cross-sectionally and-especially-longitudinally. Further epidemiologic studies should focus on specific meniscal tears based on their morphology to better understand their relevance in the genesis and progression of knee OA.
Purpose:
To determine whether meniscal tissue could be healed histologically by the implantation of allogenic three-dimensional formed adipose-derived stem cells (ADSCs) in a rabbit model of partial meniscectomy.
Methods:
Forty Japanese white rabbits (aged 15-17 weeks) were assigned to 2 groups. Defects 1.5 mm in diameter were created in the anterior horn of the medial menisci. The defects were left empty in the control group and were filled with cylindrical plugs of allogenic ADSCs extracted from adipose tissue in the experimental group. Macroscopic scoring (range, 0-3), histological scoring (range, 0-12), and immunohistological stainability of type I collagen were evaluated at 2, 4, 8, and 12 weeks postoperatively (n = 5 rabbits for each week).
Results:
Macroscopically, the height of the healing tissue in the experimental group was significantly greater than that of the control group at 2 weeks (3 vs 0, P = .01), 4 weeks (3 vs 1, P = .01), and 8 weeks (3 vs 2, P = .02). Histologically, safranin-O staining was noted at 2 weeks and increased gradually over time in the experimental group. In contrast, the intensity of staining was lower in controls at all weeks. Tissue quality scores were significantly higher in the experimental group than in the controls at all weeks (3 vs 0 at 2 weeks [P = .00009], 4.5 vs 2 at 4 weeks [P = .00023], 9 vs 5 at 8 weeks [P = .0047], 10.5 vs 6 at 12 weeks [P = .00026]). The implanted tissue was positive for type I collagen, and stainability was increased gradually over time.
Conclusions:
Three-dimensional scaffold-free allogenic ADSCs implanted into a 1.5-mm avascular meniscal defect survived, adhered to the defect, and promoted histological meniscus healing in a rabbit model.
Clinical relevance:
ADSC implantation designed to promote meniscal healing may play an important role as a tool for meniscus healing.
In regenerative medicine, adult stem cells are the most promising cell types for cell-based therapies. As a new source for multipotent stem cells, human adipose tissue has been introduced. These so called adipose tissue-derived stem cells (ADSCs) are considered to be ideal for application in regenerative therapies. Their main advantage over mesenchymal stem cells derived from other sources, e.g. from bone marrow, is that they can be easily and repeatable harvested using minimally invasive techniques with low morbidity. ADSCs are multipotent and can differentiate into various cell types of the tri-germ lineages, including e.g. osteocytes, adipocytes, neural cells, vascular endothelial cells, cardiomyocytes, pancreatic β-cells, and hepatocytes. Interestingly, ADSCs are characterized by immunosuppressive properties and low immunogenicity. Their secretion of trophic factors enforces the therapeutic and regenerative outcome in a wide range of applications. Taken together, these particular attributes of ADSCs make them highly relevant for clinical applications. Consequently, the therapeutic potential of ADSCs is enormous. Therefore, this review will provide a brief overview of the possible therapeutic applications of ADSCs with regard to their differentiation potential into the tri-germ lineages. Moreover, the relevant advancements made in the field, regulatory aspects as well as other challenges and obstacles will be highlighted.
Background:
Clinical outcomes and survivorship of meniscus transplants remain unclear, especially when magnetic resonance imaging (MRI) and weightbearing radiographic findings are included as endpoints. Many studies calculate survivorship based only on subsequent operative procedures.
Purpose:
We prospectively determined long-term survivorship and functional outcomes of 72 consecutive meniscus transplants. The effects of articular cartilage damage, concurrent osteochondral autograft transfer (20 knees), patient age, and tibiofemoral compartment were evaluated.
Study design:
Case series; Level of evidence, 4.
Methods:
The long-term function and survival rates of 69 of 72 consecutive medial and lateral bone-meniscus-bone transplants (96% follow-up) were determined. Survival endpoints of reoperations, MRI failure (grade 3 signal intensity, extrusion >50% of meniscal width), meniscal tear on examination, and radiographic loss of joint space provided a worst-case outcome. Long-term functional analysis was performed in 58 transplants a mean of 11.9 ± 3.2 years postoperatively. The Cincinnati and International Knee Documentation Committee rating systems were used to evaluate outcomes.
Results:
For all transplants, the estimated probability of survival was 85% at 2 years, 77% at 5 years, 69% at 7 years, 45% at 10 years, and 19% at 15 years. There were significant improvements for pain, swelling, walking, stair climbing, and patient knee rating (P < .05). Further surgery was performed in 37 cases. Knees that had concurrent osteochondral autograft transfer had significantly lower survival rates beginning at the seventh postoperative year; however, there was no significant difference in the long-term symptom, function, and patient perception scores between these knees and the rest of the cohort. The factors of articular cartilage damage (grade 2B/3 vs none), patient age (<30 years vs 30-49 years), and tibiofemoral compartment (medial vs lateral) had no significant effect on the survival, symptom, or functional analyses.
Conclusion:
A survival analysis that includes reoperations, MRI, radiographs, and a comprehensive examination provides a worst-case but realistic analysis of transplant function. Many patients experienced a short- and long-term benefit of reduced symptoms and improved function. However, meniscus transplants undergo a deleterious remodeling process and eventually fail. Patients should be advised that the procedure is not curative in the long term, and additional surgery will likely be required.
Introduction: Cell-based therapies are becoming a valuable tool to treat osteoarthritis (OA). This study investigated and compared the regenerative potential of Bone Marrow Concentrate (BMC) and Mesenchymal Stem Cells (MSC), both engineered with Hyaff®-11 (HA) for OA treatment in a sheep model.
Methods: OA was induced via unilateral medial meniscectomy. Bone marrow was aspirated from the iliac crest, followed by concentration processes or cell isolation and expansion to obtain BMC and MSC respectively. Treatments consisted of autologous BMC and MSC seeded onto HA. The regenerative potential on bone, cartilage, menisci and synovia was monitored using macroscopy, histology, immunohistochemistry and micro-computed tomography, at 12 weeks post-op. Data were analyzed using the General Linear Model with adjusted Sidak’s multiple comparison and Spearman tests.
Results: BMC-HA treatment showed a greater repair ability in inhibiting OA progression compared to MSC-HA, leading to a reduction of inflammation in cartilage, meniscus and synovium. Indeed, the decrease of inflammation positively contributed to counteract the progression of fibrotic and hypertrophic processes, known to be involved in tissue failure. Moreover, the treatment with BMC-HA showed the best results in allowing meniscus regeneration. Minor healing effects were noticed at bone level for both cell strategies, however a down-regulation of Cross-sectional Subchondral Bone Thickness (Cs.Th) was found in both cell-treatments compared to OA group in femur. Conclusion: The transplantation of BMC-HA provided the best effects in supporting regenerative processes in cartilage,meniscus and synovium and at less extent in bone. On the whole, both MSC and BMC combined with HA reduced inflammation and contributed to switch-off fibrotic and hypertrophic processes. The observed regenerative potential by BMC-HA on meniscus could open new perspectives suggesting its use not only for OA care but also for the treatment of meniscal lesions, even if further analyses are necessary to confirm its healing potential at long-term follow-up.
Transplantation of aggregates of synovial mesenchymal stem cells (MSCs) enhanced meniscus regeneration in rats. Anatomy and biological properties of the meniscus depend on animal species. To apply this technique clinically, it is valuable to investigate the use of animals genetically close to humans. We investigated whether transplantation of aggregates of autologous synovial MSCs promoted meniscal regeneration in aged primates. Chynomolgus primates between 12-13 years old were used. After the anterior halves of the medial menisci in both knees were removed, an average of 14 aggregates consisting of 250,000 synovial MSCs were transplanted onto the meniscus defect. No aggregates were transplanted to the opposite knee for the control. Meniscus and articular cartilage were analyzed macroscopically, histologically, and by MRI T1rho mapping at 8 (n = 3) and 16 weeks (n = 4). The medial meniscus was larger and the modified Pauli's histological score for the regenerated meniscus was better in the MSC group than in the control group in each primate at 8 and 16 weeks. Mankin's score for the medial femoral condyle cartilage was better in the MSC group than in the control group in all primates at 16 weeks. T1rho value for both the regenerated meniscus and adjacent articular cartilage in the MSC group was closer to the normal meniscus than in the control group in all primates at 16 weeks. Transplantation of aggregates of autologous synovial MSCs promoted meniscus regeneration and delayed progression of degeneration of articular cartilage in aged primates. This is the first report dealing with meniscus regeneration in primates. This article is protected by copyright. All rights reserved.
Chondroprogenitor cells are a subpopulation of multipotent progenitors that are primed for chondrogenesis. They are believed to have the biological repertoire to be ideal for cell-based cartilage therapy. In addition to summarizing recent advances in chondroprogenitor cell characterization, this review discusses the projected pros and cons of utilizing chondroprogenitors in regenerative medicine and compares them to that of preexisting methods, including autologous chondrocyte implantation (ACI) and the utilization of bone marrow derived mesenchymal stem cells (MSCs) for the purpose of cartilage tissue repair.
Integration between tendon/ligament and bone occurs through a specialized tissue interface called enthesis. The complex and heterogeneous structure of the enthesis is essential to ensure smooth mechanical stress transfer between bone and soft tissues. Following injury, the interface is not regenerated, resulting in high rupture recurrence rates. Tissue engineering is a promising strategy for the regeneration of a functional enthesis. However, the complex structural and cellular composition of the native interface makes enthesis tissue engineering particularly challenging. Thus, it is likely that a combination of biomaterials and cells stimulated with appropriate biochemical and mechanical cues will be needed. The objective of this review is to describe the current state-of-the-art, challenges and future directions in the field of enthesis tissue engineering focusing on four key parameters: (1) scaffold and biomaterials, (2) cells, (3) growth factors and (4) mechanical stimuli.
Copyright © 2015. Published by Elsevier B.V.
Regenerative therapies using adult stem cells have attracted great interest in the recent years and offer a promising alternative to current surgical practices. In this report, we evaluated the safety and efficacy of an autologous cell-based treatment of osteoarthritis using mesenchymal stromal cells expanded from bone marrow aspirates that were administered intra-articularly.
Ten 2-year old ewes were divided in two groups (for analysis at 6 and 12 months, respectively). Full thickness articular cartilage defects of approximately 60 mm2 were created arthroscopically in the medial femorotibial condyles and a meniscal tear in the anterior horn of the medial meniscus in the 20 hind legs. Intra-articular injection of 4 mL of either treatment (a suspension of cells) or control (same as treatment, without cells) were applied one month after generating a chronic condition similar to human pathology. Animals were monitored radiographically, by MRI and ultrasound scanning; and macroscopic and histological analyses were conducted at 6 and 12 months. Furthermore a full necropsy was performed at 12 months post-treatment. The intra-articular injection of autologous MSC was safe, as judged by the lack of local or systemic adverse effects during the clinical follow-up and by a full necropsy performed at 12 months post-treatment. Evidence of regeneration of articular cartilage and meniscus was case-dependent but statistically significant improvement was found in specific macroscopic and histological parameters. Such parameters included colour, rigidity, cell distribution and hyaline quality of the refill tissue as well as the structure of subchondral bone.
