Objectives: It is disputed whether arthroscopic meniscectomy is an (cost-) effective treatment for degenerative meniscus tears in day-to-day clinical practice. The objective of this study was to assess the cost-effectiveness of arthroscopic meniscectomy in subjects with knee osteoarthritis, in routine clinical practice, while taking into account the increased risk for future knee replacement surgery. We compared cost-effectiveness of arthroscopic meniscectomy compared to no surgery. Design: We used a state transition (Markov) simulation model to evaluate the cost-effectiveness of arthroscopic meniscectomy compared to no surgery in subjects with knee osteoarthritis (age range 45-79 years). Data used in the preparation of the current study were obtained from the Osteoarthritis Initiative (AOI) database. We applied a 9 years' time horizon (which is equal to the current OAI study follow up period), and evaluated cost-effectiveness from a societal perspective. The main outcome measure was the incremental cost-effectiveness ratio (Euros per quality adjusted life-year (QALY) gained). Results: Arthroscopic meniscectomy was associated with 8.09 (SD +/- 0.07) QALYs at a cost of (sic) 21,345 (SD +/- 841), whereas the no surgery was associated with 8.05 (SD +/- 0.07) QALYs at a cost of (sic) 16,284 (SD +/- 855). For arthroscopic meniscectomy, the incremental cost per QALY gained was (sic) 150,754. Conclusions: In day-to-day clinical practice, arthroscopic meniscectomy in subjects with knee osteoarthritis is associated with (sic) 150,754 per QALY gained, which exceeds the generally accepted willingness to pay (WTP) (range (sic) 20,000-V 80,000). (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Current treatment methods to repair meniscal tears do not bring fully satisfactory results. Tissue adhesives are considered promising alternatives, since they are easy to apply and cause minimal tissue trauma. The first aim of this study was to analyze the adhesive properties of and tissue response to two recently developed biodegradable block copolymeric three-armed- and hyper-branched tissue adhesives. The second aim was to investigate if tissue surface modification with collagenase improves the attachment of the adhesives and increases the healing potential of the tissue. Cylindrical explants were harvested from bovine menisci. The central core of the explants was removed and glued back into the defect, with or without incubation in collagenase solution prior to gluing, using one of the novel glues, Dermabond® or fibrin glue. The repair constructs were cultured in vitro for 1 and 28 days. Adhesion tests and histology were performed to analyze the effects of the glue in combination with the additional treatment. The adhesive strength of the novel glues was 40-50 kPa, which was significantly higher than that of fibrin glue (15 kPa). Cells were present in direct contact with the glues, and the tissue remained vital during the whole culture period. Increased cellularity around the tear in the collagenase treated explants was observed after 1 day. The two newly developed tissue adhesives are attractive materials to be used for repair of meniscal tears. The beneficial influence of collagenase treatment in treating meniscal tears with glues still needs to be confirmed in more clinical relevant studies. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1405-1411, 2017.

Tissue adhesives are attractive materials with potential to replace the use of sutures and staples in the repair of the injured tissues. The research field of tissue adhesives is dynamically growing, and different methods and tissue models are employed to evaluate the adhesive properties of newly developed materials. It is thus difficult to directly compare the properties of materials developed by researchers from different groups. Moreover, the extrapolation of results obtained using different tissue models to the targeted human tissues is often not possible. Therefore, the purpose of the current study was to evaluate the adhesive properties of the three different tissues adhesives: the clinically used Dermabond® and fibrin glues, and the recently developed isocyanate‐terminated three‐armed adhesive block copolymers. Different biological substrates were used to assess their adhesion strengths: bovine Achilles tendon, meniscus tissue and skeletal muscle, chamois leather, and collagen films. Comparisons of the adhesive properties of the glues with these substrates were made. The obtained results were analyzed in terms of the chemistry and the adhesion mechanisms of the glues, and the composition and properties of the substrates like their hydrophilicity and surface morphology. We conclude that standardized procedures and models should be developed to allow direct comparison between the different (developed) tissue adhesives and to enable extrapolation of the results towards the targeted human tissues. Copyright © 2016 John Wiley & Sons, Ltd.

OBJECTIVE:The primary objective was to assess whether patients with knee osteoarthritis and whom undergo arthroscopic meniscectomy have an increased risk for future knee replacement surgery. DESIGN:Data used were obtained from the Osteoarthritis Initiative (OAI) study. SETTING:Participants were enrolled, in four clinical centers, between February 2004 and May 2006 and were followed up on an annual basis up to and including 108-months from enrollment. PARTICIPANTS:4674 participants (58.4% female), aged 45-79, of all ethnic groups, who had, and those who were at high risk for developing, symptomatic knee osteoarthritis were included, of which 3337 (71.4%) were included in the final follow up visit. MAIN OUTCOME MEASURES:Hazard ratio of knee replacement surgery for participants who underwent arthroscopic meniscectomy during follow up compared to propensity score matched participants who did not undergo arthroscopic meniscectomy during follow up. RESULTS:335 participants underwent arthroscopic meniscectomy during follow up, of which 63 (18.8%) underwent knee replacement surgery in the same knee. Of the 335 propensity score matched participants 38 (11.1%) underwent knee replacement surgery during follow up. Results from the Cox-proportional hazards model demonstrated that the hazard ratio of knee replacement surgery was 3.03 (95% CI (1.67-5.26)) for participants who underwent arthroscopic meniscectomy relative to the propensity score matched participants who did not undergo arthroscopic meniscectomy. CONCLUSIONS:In patients with knee osteoarthritis arthroscopic knee surgery with meniscectomy is associated with a three fold increase in the risk for future knee replacement surgery.

Menisci are crucial structures in the knee joint as they play important functions in load transfer, maintaining joint stability and in homeostasis of articular cartilage. Unfortunately, ones of the most frequently occurring knee injuries are meniscal tears. Particularly tears in the avascular zone of the meniscus usually do not heal spontaneously and lead to pain, swelling and locking of the knee joint. Eventually, after a (partial) meniscectomy, they will lead to osteoarthritis. Current treatment modalities to repair tears and by that restore the integrity of the native meniscus still carry their drawbacks and a new robust solution is desired. A strong tissue adhesive could provide such a solution and could potentially improve on sutures, which are the current gold standard. Moreover, a glue could serve as a carrier for biological compounds known to enhance tissue healing. Only few tissue adhesives, e.g., Dermabond(®) and fibrin glue, are already successfully used in clinical practice for other applications, but are not considered suitable for gluing meniscus tissue due to their sub-optimal mechanical properties or toxicity. There is a growing interest and research field focusing on the development of novel polymer-based tissue adhesives, but up to now, there is no material specially designed for the repair of meniscal tears. In this review, we discuss the current clinical gold standard treatment of meniscal tears and present an overview of new developments in this field. Moreover, we discuss the properties of different tissue adhesives for their potential use in meniscal tear repair. Finally, we formulate recommendations regarding the design criteria of material properties and adhesive strength for clinically applicable glues for meniscal tears.

OBJECTIVE:Recently it was shown that loading of articular cartilage explants activates TGFβ signaling. Here we investigated if in vivo chondrocytes express permanently high TGFβ signaling, and the consequence of the loss of compressive loading-mediated TGFβ signaling on chondrocyte function and phenotype. METHOD:Bovine articular cartilage explants were collected within 10 min post mortem and stained immediately and after 30, 60 and 360 min for phosphorylated-Smad2, indicating active TGFβ signaling. Explants were unloaded for 48 h and subsequently repeatedly loaded with a compressive load of 3 MPa. In addition, explants were cultured unloaded for 2 weeks and the effect of loading or exogenous TGFβ on proteoglycan level and chondrocyte phenotype (Col10a1 mRNA expression) was analyzed. RESULTS:Unloading of articular cartilage results in rapid loss of TGFβ signaling while subsequent compressive loading swiftly restored this. Loading and exogenous TGFβ enhanced expression of TGFβ1 and ALK5. Unloading of explants for 2 weeks resulted in proteoglycan loss and increased Col10a1 expression. Both loading and exogenous TGFβ inhibited elevated Col10a1 expression but not proteoglycan loss. CONCLUSION:Our data might imply that in vivo regular physiological loading of articular cartilage leads to enduring TGFβ signaling and TGFβ-induced gene expression. We propose a hypothetical model in which loading activates a self-perpetuating system that prevents hypertrophic differentiation of chondrocytes and is crucial for cartilage homeostasis.

Objective: Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression.Design: Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis.Results: Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed.Conclusions: We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA). (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Meniscus tears are one of the most commonly occurring injuries of the knee joint. Current meniscus repair techniques are challenging and do not bring fully satisfactory results. Tissue adhesives are a promising alternative, since they are easy to apply and cause minimal tissue trauma.In this study, a series of amphiphilic copolymers based on polyethylene glycol, trimethylene carbonate and citric acid were synthesized and subsequently end-functionalized with hexamethylene diisocyanate to form reactive adhesive materials.The shear adhesive strength of the networks to bovine meniscus tissue measured in a lap-shear adhesion test ranged between 20 and 80 kPa, which was better than for fibrin glue (10 kPa). The elastic modulus of the networks depended on composition and was in the same range as that of human meniscus. Cell compatibility was assessed using Alamar Blue staining after incubation of the bovine meniscus cells with different concentrations of the glues for 7 days. Cell viability was not affected after adding up to 3 mg of the adhesive/mL of medium.The proposed materials are suitable candidates to be used as resorbable tissue adhesives for meniscus repair. They have excellent mechanical and adhesive properties that can be adjusted by varying the composition of the copolymers.Statement of SignificanceMeniscal tears often occur and current treatment strategies do not bring fully satisfactory results. Use of biodegradable tissue adhesives would be an interesting option, but currently available adhesives are not suited due to toxicity or poor mechanical properties.Here, we describe the development of novel biodegradable, hyper-branched, adhesive copolymers. These adhesives cure upon contact with water forming flexible networks. Their adhesion to bovine meniscus tissue was significantly better than that of clinically used fibrin glue. The tensile properties of the cured networks were in the same range of values of the human meniscus. When physiologically relevant amounts were added to cells in culture, not toxic effects were observed. Therefore, the proposed materials are interesting resorbable tissue adhesives for meniscus repair. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Purpose: The development of osteoarthritis (OA) is associated with the expression of hypertrophy-related genes by articular chondrocytes. The acquired hypertrophy-like phenotype is characterized by increased expression of Collagen type X (Col10a1) and production of catabolic enzymes like MMP13. TGF-β signaling via Smad2/3P can potently prevent this shift in phenotype and its catabolic effects. Recently, we have shown that loading of intact articular cartilage activates TGF β/Smad2/3P signaling. Moreover, since decades it is known that the absence of joint loading leads to cartilage atrophy and degeneration, both in humans and animal models. Based on these facts we hypothesized that in vivo chondrocytes are exposed to permanent, loading mediated, TGF-β/Smad2/3P signaling and that loss of loading will result in rapid loss of TGF-β signaling. Subsequently, this lack of active TGF-β/Smad2/3P signaling will promote the shift of chondrocytes towards a hypertrophic-like stage and eventually result in cartilage damage. Methods: To show if in vivo chondrocytes express high, loading mediated, TGF β/Smad2/3P signaling and to investigate how rapidly this is lost, bovine articular cartilage explants were collected within 10 minutes post mortem and stained immediately and after 30, 60 and 360 minutes for phosphorylated-Smad2 (Smad2P). Furthermore, the expression of TGF β/Smad2/3P signaling reporter genes was analyzed within 3 hours and after 24 and 48 hours post mortem. To show if loading can restore TGF-β/Smad2/3P in cartilage, first explants were unloaded for 48 hours and subsequently loaded with a physiological load of 3 MPa. TGF-β/Smad2/3P signaling was monitored by immunohistochemistry for Smad2P and by expression analysis of signaling reporter genes. To analyze if loading can repeatedly induce TGF β/Smad2/3P signaling, this protocol was repeated several times on the same explants. In addition, to analyze if a lack of active TGF-β/Smad2/3P signaling causes a shift in chondrocyte phenotype, cartilage explants were cultured in unloaded conditions for 2 weeks and the effect of loading or exogenous TGF-β on sulfated glycosaminoglycan (GAG) and chondrocyte phenotype was analyzed. Results: In freshly isolated samples, Smad2P was abundantly present throughout all layers of the cartilage. However, already 2 h after cartilage unloading Smad2P levels were decreased and from 6 h on hardly detectable. After unloading, the expression of the Smad2/3P reporter genes Pai1, Smad7 and Alk5 dropped significantly over time. This drop was as severe as when the ALK4/5/7inhibitor ( = Smad2/3P inhibitor) SB-505124 was used. Compressive loading of articular cartilage resulted in swift restoration of Smad2P levels as well as potent up-regulation of Pai1, Smad7, Alk5 and Tgfb1 and down-regulation of Alk1. Moreover, this process was repeatable but it could be inhibited by the ALK4/5/7inhibitor SB 505124, indicating TGF-β or Activin signaling as the driver. However, exogenous rhTGF β (1 10 ng/ml) was able to induce similar gene expression and pSmad2 activation as compression, whereas, in contrast, exogenous rhActivin A (1–10 ng/ml) was not. Unloading of explants for 2 weeks resulted in profound GAG loss and increased Col10a1 expression. Remarkably, repeated loading nor exogenous TGF-β did not counteract GAG loss, but repeated loading inhibited the elevation of Col10a1 expression as effective as exogenous TGF-β. Conclusions: Our data strongly indicate that in vivo articular cartilage when regularly loaded has enduring TGF-β-induced signaling and gene expression. Based on our results we propose the following model for loading-induced TGF-β signaling in articular chondrocytes. Loading of cartilage leads to release of active TGF-β form the extracellular matrix (ECM). Subsequently, activated TGF-β signals via ALK-5 and activates Smad2/3P signaling which subsequently inhibits the hypertrophic shift of chondrocytes. Additionally, Smad2/3P activates a positive feedback loop by inducing expression of its own activating receptor: ALK5 and lowering deleterious ALK1. Moreover, Smad2/3P induces the expression of (inactive) TGF-β1, which after production will bind to the ECM and return the system to its original stage. We think that, these results, in combination with our earlier findings that loading-induced TGF-β signaling is impaired in aged cartilage, indicate that the (age dependent) loss of this system could contribute to OA development.

PURPOSE:To evaluate the functional biomechanical performance of a novel anatomically shaped, polycarbonate urethane total meniscus implant.METHODS:Five human cadaveric knees were flexed between 0° and 90° under compressive loads mimicking a squat movement. Anteroposterior (AP) laxity tests were performed in 30° and 90° flexion. Meniscal kinematics and knee laxity were quantified using roentgen stereophotogrammetric analysis. Tibial cartilage contact mechanics were determined in 90° flexion. Measurements were repeated for the native medial meniscus, the implant, after total medial meniscectomy and allograft transplantation.RESULTS:The implant and allograft displayed increased posterior and medial displacements compared to the native meniscus, yet no differences were found between the implant and allograft. Meniscal condition did not affect rotational laxity. Compared to the native joint, AP laxity for the implant was increased in 30° flexion, but not in 90°. The implant reduced the mean contact pressure compared to meniscectomy but could not restore contact pressures to native meniscus levels. Compared to the native meniscus, the implant significantly increased the peak pressure, while the contact area was reduced. Contact mechanics of the implant and allograft were never statistically different.CONCLUSIONS:Biomechanical performance was similar for the implant and allograft. However, both meniscal replacements could not restore outcomes to native meniscus levels or sufficiently improve outcomes after meniscectomy. This was presumably caused by the mobility allowed by the suture-only horn fixation. The similarity of implant and allograft performance suggests that the novel implant has the biomechanical potential to serve as an alternative to meniscal allograft transplantation.

Since meniscal geometry affects the cartilage contact pressures, it is essential to carefully define the geometry of the synthetic meniscal implant that we developed. Recently, six independent modes of size- and shape-related geometry variation were identified through 3D statistical shape modeling (SSM) of the medial meniscus. However, this model did not provide information on the functional importance of these geometry characteristics. Therefore, in this study finite element simulations were performed to determine the influence of anatomically-based meniscal implant size and shape variations on knee cartilage contact pressures. Finite element simulations of the knee joint were performed for a total medial meniscectomy, an allograft, the average implant geometry, six implant sizes and ten shape variations. The geometries of the allograft and all implant variations were based on the meniscus SSM. Cartilage contact pressures and implant tensile strains were evaluated in full extension under 1200 N of axial compression. The average implant induced cartilage peak pressures intermediate between the allograft and meniscectomy and also reduced the cartilage area subjected to pressures >5 MPa compared to the meniscectomy. The smaller implant sizes resulted in lower cartilage peak pressures and compressive strains than the allograft, yet high implant tensile strains were observed. Shape modes 2, 3 and 6 affected the cartilage contact stresses but to a lesser extent than the size variations. Shape modes 4 and 5 did not result in changes of the cartilage stress levels. The present study indicates that cartilage contact mechanics are more sensitive to implant size than to implant shape. Down-sizing the implant resulted in more favorable contact mechanics, but caused excessive material strains. Further evaluations are necessary to balance cartilage contact pressures and material strains to ensure cartilage protection and longevity of the implant.

PURPOSE:Since the treatment options for symptomatic total meniscectomy patients are still limited, an anatomically shaped, polycarbonate urethane (PCU), total meniscus replacement was developed. This study evaluates the in vivo performance of the implant in a goat model, with a specific focus on the implant location in the joint, geometrical integrity of the implant and the effect of the implant on synovial membrane and articular cartilage histopathological condition.METHODS:The right medial meniscus of seven Saanen goats was replaced by the implant. Sham surgery (transection of the MCL, arthrotomy and MCL suturing) was performed in six animals. The contralateral knee joints of both groups served as control groups. After three months follow-up the following aspects of implant performance were evaluated: implant position, implant deformation and the histopathological condition of the synovium and cartilage.RESULTS:Implant geometry was well maintained during the three month implantation period. No signs of PCU wear were found and the implant did not induce an inflammatory response in the knee joint. In all animals, implant fixation was compromised due to suture breakage, wear or elongation, likely causing the increase in extrusion observed in the implant group. Both the femoral cartilage and tibial cartilage in direct contact with the implant showed increased damage compared to the sham and sham-control groups.CONCLUSION:This study demonstrates that the novel, anatomically shaped PCU total meniscal replacement is biocompatible and resistant to three months of physiological loading. Failure of the fixation sutures may have increased implant mobility, which probably induced implant extrusion and potentially stimulated cartilage degeneration. Evidently, redesigning the fixation method is necessary. Future animal studies should evaluate the improved fixation method and compare implant performance to current treatment standards, such as allografts.

Objective: Transforming growth factor beta (TGF-beta) in articular cartilage can signal via two routes, the ALK5/Smad2/3P and the ALK1/Smad1/5/8P route, the first being protective and the latter favoring chondrocyte terminal differentiation. Since biomechanical factors are known to play an essential role in osteoarthritis (OA) initiation and progression, we investigated if excessive mechanical compression can alter TGF-beta signaling in cartilage shifting it from ALK5/Smad2/3P to ALK1/Smad1/5/8P pathway, favoring terminal differentiation of chondrocytes.Design: Articular cartilage explants were harvested from bovine metacarpophalangeal joints. After equilibration, explants were subjected to unconfined dynamic mechanical compression (1 Hz) with 3 MPa (physiological) or 12 MPa (excessive) stress. After different time intervals samples were frozen and mRNA levels of selected genes were examined using real-time polymerase chain reaction.Results: In articular cartilage compressed with 3 MPa and also 12 MPa stress the expression of Smad2/3P responsive genes bSerpine1, bSmad7 and bAlk5 was up-regulated, whereas the expression of Smad1/5/8P responsive gene bId1 was down-regulated. Furthermore, the expression of bTgfb1 was significantly up-regulated in both compression groups. When ALK5/Smad2/3P pathway was blocked with a selective ALK4/5/7 inhibitor, the effect of excessive mechanical compression on bSmad7 and bAlk5 expression was prevented.Conclusions: Here we show that excessive mechanical compression alone is not able to shift TGF-beta signaling toward the ALK1/Smad1/5/8P pathway. In contrast, we show that mechanical compression not only with physiological but also with excessive stress can activate Smad2/3P signaling, which is known to be protective for articular cartilage and to block chondrocyte terminal differentiation. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The geometry-dependent functioning of the meniscus indicates that detailed knowledge on 3D meniscus geometry and its inter-subject variation is essential to design well functioning anatomically shaped meniscus replacements. Therefore, the aim of this study was to quantify 3D meniscus geometry and to determine whether variation in medial meniscus geometry is size-or shape-driven. Also we performed a cluster analysis to identify distinct morphological groups of medial menisci and assessed whether meniscal geometry is gender-dependent. A statistical shape model was created, containing the meniscus geometries of 35 subjects (20 females, 15 males) that were obtained from MR images. A principal component analysis was performed to determine the most important modes of geometry variation and the characteristic changes per principal component were evaluated. Each meniscus from the original dataset was then reconstructed as a linear combination of principal components. This allowed the comparison of male and female menisci, and a cluster analysis to determine distinct morphological meniscus groups. Of the variation in medial meniscus geometry, 53.8% was found to be due to primarily size-related differences and 29.6% due to shape differences. Shape changes were most prominent in the cross-sectional plane, rather than in the transverse plane. Significant differences between male and female menisci were only found for principal component 1, which predominantly reflected size differences. The cluster analysis resulted in four clusters, yet these clusters represented two statistically different meniscal shapes, as differences between cluster 1, 2 and 4 were only present for principal component 1. This study illustrates that differences in meniscal geometry cannot be explained by scaling only, but that different meniscal shapes can be distinguished. Functional analysis, e. g. through finite element modeling, is required to assess whether these distinct shapes actually influence the biomechanical performance of the meniscus.

Purpose: (Partial) Meniscectomy causes dramatic changes in knee joint biomechanics. As a consequence, this surgical intervention generally leads to the development of osteoarthritis (OA). Furthermore, the majority of reports show that age is one of the most important risk factors for OA development after meniscectomy. However, the mechanisms how changed loading patterns lead to OA and how age related changes in articular cartilage influence its response for increased loading remains largely unknown. Our previous findings showed that in young and healthy articular cartilage, when subjected to compression, TGF-beta signals via type I receptor ALK5 causing activation of downstream genes specific for Smad2/3 signaling pathway. Since in aged articular cartilage there is loss of type ALK5 leading to shift towards Smad1/5/8 signaling pathway, we wanted to investigate how TGF-beta signals in aged articular cartilage when subjected to physiological and excessive loading. Methods: Full-thickness articular cartilage specimens were cored from metacarpophalangeal joint surface of two different age groups of cows(juvenile of 1 year old and aged of 8- 12 years old) . All explants were allowed to equilibrate for 48 h in static, serum free culture conditions. Explants were divided into two stimulation groups: 30 min stimulation with 3 MPa (physiological load) and 30 min stimulation with 12 MPa (excessive load). Unloaded cartilage was used as controls. Stimulation groups were subjected to sinusoidal compression (1Hz) using BOSE ElectroForce® BioDynamic® test system, in culture conditions. After 2 and 6 hours cartilage samples were frozen and mRNA levels of selected genes were examined using real-time polymerase chain reaction (RT-PCR). Results: In 2 hours after the stimulation there was significant upregulation of TGF-beta1 in both age groups when stimulated with 3 MPa but also with 12 MPa compared to the static control. However, in young articular cartilage this upregulation was more pronounced than in old. In 6 hours after the stimulation, in young cartilage, TGF-beta was upregulated in control group (when compared to 2 hours time point), therefore the effect of stimulation was less pronounced. This was not the case in aged cartilage where in both stimulation groups TGF-beta was upregulated when compared to static control. Examination of TGF-beta signaling pathways downstream genes expression demonstrated that in 2 hours after the stimulation in both age groups, 3 MPa and 12 MPa stimulation caused upregulation of PAI-1. The level of upregulation was higher in young articular cartilage but this could be related to lower PAI1 expression in static controls of young cartilage. In aged articular cartilage, PAI-1 upregulation was caused only by 12 MPa stimulation. Stimulation with both physiological (3 MPa) and excessive loading (12 MPa) showed no effect on ID1 expression when measured in 2 hours in both age groups. However in 6 hours after the stimulation in 12 MPa compression group ID1 was down-regulated in both age groups. Conclusions: Unexpectedly many changes in expression of genes caused by repetitive loading did not depend on the amount of force that was applied in our experiments. Mechanical compression with physiological and excessive forces affected similar TGF-beta-signaling related genes in young and old cartilage, however, in young cartilage with a greater magnitude. Although ALK5 expression is decreased in aged articular cartilage, loading is still able to activate PAI-1, indicating activation of the Smad2/3 signalling pathway. This indicates similar but not equal stimulation of TGF-beta signaling in different age groups. Since activation of protective TGF-beta signalling by loading was higher in young cartilage this might indicate that the protective effects of laoding are more pronounced in young cartilage than in old cartilage.

Clinically used scaffolds are suboptimal in regenerating the highly oriented meniscus fiber structure in full meniscal defects. The objective of this study was to test whether anisotropic porous scaffolds with channels resulted in a more meniscus like matrix organization compared to isotropic porous scaffolds. Isotropic polyurethane scaffolds were made via standard solvent leaching techniques. Anisotropic porous scaffolds with channels were made via modified thermal induced phase separation. Both scaffold types were analyzed with light microscopy, scanning electron microscopy and computed nano-tomography. Finally, isotropic and anisotropic scaffolds were bilaterally and subcutaneously implanted on the back of 32 Wistar rats for 1, 4, 8 and 24 weeks to assess tissue ingrowth and matrix organization. Isotropic scaffolds had a pore diameter of 35±14.7 μm and a degree of anisotropy of 0.18, while anisotropic scaffolds had a channel diameter of 20±6.0 μm and a degree of anisotropy of 0.39. After implantation full tissue ingrowth was achieved after 8 and 24 weeks for isotropic and anisotropic, respectively. Isotropic scaffolds had a random tissue infiltration with unorganized collagen deposition, whereas anisotropic scaffolds showed tissue infiltration and collagen alignment in the direction of the channels. Anisotropic scaffolds resulted in a matrix organization that resembled the tissue in the vascularized zone of the meniscus, while isotropic scaffolds resembled the tissue in the avascular zone of the meniscus.

The aim of this review was to discuss the current state of research of combining bisphosphonates with allograft bone for implant fixation. The allograft bone can only be reached by the bisphosphonate once it has been revascularized. However, this can be circumvented by local administration of bisphosphonates. Several animal studies showed that local application of bisphosphonates might protect the graft from resorption. There seems to be an optimum concentration for local application, however, this optimum varies for all different bisphosphonates. It can be concluded that local administration of bisphosphonates might play an important role in improving stability after surgery in which a prosthesis is combined with allograft bone to restore bony defects, however caution should be taken when extrapolating results of animal research to the human clinical situation. More research is needed to study the effect of local bisphophonate use in humans and to study possible side effects.