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Aim: To mimic the ultrastructural morphology of the meniscus with nanofiber scaffolds coupled with controlled growth factor delivery to modulate cellular performance for tissue engineering of menisci. Methods: The authors functionalized collagen nanofibers by conjugating heparin to the following growth factors for sustained release: PDGF-BB, TGF-β1 and CTGF. Results: Incorporating growth factors increased human meniscal and synovial cell viability, proliferation and infiltration in vitro, ex vivo and in vivo; upregulated key genes involved in meniscal extracellular matrix synthesis and enhanced generation of meniscus-like tissue. Conclusion: The authors' results indicate that functionalizing collagen nanofibers can create a cell-favorable micro- and nanoenvironment and can serve as a system for sustained release of bioactive factors.

Objectives Successful tissue regeneration requires a clinically viable source of MSC. We explored ALK5 inhibitors to rapidly derive an MSC-like phenotype with high cartilage forming capacity from a xeno-free human embryonic cell line. Methods ESC cell lines (H9 and HADC100) were treated with ALK-5 inhibitor SB431542; HADC100 cells were additionally treated with ALK-5 inhibitors SB525334 or GW788388. Cells were then seeded upon human fibronectin in the presence of FGF in serum free medium. Flow cytometry was used to assess MSC markers (positive for CD73, CD90, CD105; negative for CD34, CD45). Differentiation status was assessed via qPCR. Cartilage forming capacity was determined in high density pellet cultures, in fibrin gels containing extracellular matrix (fibrin-ECM), and after implantation in ex vivo human osteoarthritic cartilage. Gene expression, histology and immunostaining was used to assess cartilage phenotype, tissue regeneration and integration. Results Exposure to all 3 ALK5 inhibitors lead to expression of mesodermal gene markers and differentiation into MSC-like cells (ES-MSC) based on surface marker expression. ES-MSC in pellet cultures or in fibrin-ECM gels expressed high levels of chondrogenic genes: COL2A1, ACAN, COMP; and low levels of COL1A1 and RUNX2. Cell pellets or fibrin constructs implanted into ex vivo human osteoarthritic cartilage defects produced GAG-rich (Safranin O positive) and collagen type II positive neo-cartilage tissues that integrated well with native diseased tissue. Conclusions We developed a protocol for rapid differentiation of xeno-free ESC into MSC-like cells with high cartilage forming capacity with potential for clinical applications.

There are various methods for reconstructing the anterior cruciate ligament (ACL) from other muscles or tendons. Initial tension of the reconstructed ACL is one of the key elements affecting postoperative outcomes. However, tension cannot be measured after graft fixation. The only intraoperative assessment is pull probing, which is performed by pulling joint soft tissues with the arthroscopic probe and can be measured quantitatively. Therefore, its value might be used as an alternative value for the mechanical property of the ACL. Using a probing device one author developed to measure the resistance force of soft tissues quantitatively while probing, we measured the resistance force of dissected ACLs and used tensile testing to investigate the correlation between the resistance force and the mechanical property of the ligaments. According to the results, when a certain amount of tension (strain; 16.6%) was applied, its mechanical properties were moderately correlated (r = 0.56 [p = 0.045]) with the probing force. Therefore, the tension of the reconstructed ACL after fixation under real ACL reconstruction surgery can be derived from the value of the probing device.

This study was designed to analyze the effects of type of activity and cruciate ligament resection on knee kinematics and ligament balance after total knee arthroplasty (TKA), and to determine if intraoperative passive kinematics are associated with active kinematics. Fresh-frozen human cadaveric knees were examined. The knees were mounted on a quadriceps-driven simulator. Cruciate-retaining (CR-TKA) and posterior-substituting (PS-TKA) TKA was performed using a contemporary knee system. Active flexion (closed-kinetic chain (CKC) and open-kinetic-chain (OKC)) and passive flexion were analyzed by recording the knee kinematics using a specifically developed application of an imageless navigation system. An electronic ligament balancer was used to measure the tibiofemoral gap under constant distraction pressure. The femur rotated externally relative to the tibia during passive and active CKC flexion. The femur translated anteriorly from 10° to 50° of flexion after TKA. Beyond 50° of flexion, the femur translated posteriorly in all surgical conditions. The femoral location during active CKC flexion was posterior relative to that during active OKC. Femoral rotation and translation during passive knee flexion correlated significantly with that during active knee flexion. Posterior tilt of the electronic ligament balancer was greater with CR-TKA than with PS-TKA and correlated significantly with the anteroposterior position of the femur. Statement of Clinical Significance: Intraoperative knee kinematics measured by computer-assisted navigation and intraoperative ligament balance have the potential to predict postoperative knee kinematics. This article is protected by copyright. All rights reserved.

ObjectivesSingle-cell level analysis of articular cartilage and meniscus tissues from human healthy and osteoarthritis (OA) knees.MethodsSingle-cell RNA sequencing (scRNA-seq) analyses were performed on articular cartilage and meniscus tissues from healthy (n=6, n=7) and OA (n=6, n=6) knees. Expression of genes of interest was validated using immunohistochemistry and RNA-seq and function was analysed by gene overexpression and depletion.ResultsscRNA-seq analyses of human knee articular cartilage (70 972 cells) and meniscus (78 017 cells) identified a pathogenic subset that is shared between both tissues. This cell population is expanded in OA and has strong OA and senescence gene signatures. Further, this subset has critical roles in extracellular matrix (ECM) and tenascin signalling and is the dominant sender of signals to all other cartilage and meniscus clusters and a receiver of TGFβ signalling. Fibroblast activating protein (FAP) is also a dysregulated gene in this cluster and promotes ECM degradation. Regulons that are controlled by transcription factor ZEB1 are shared between the pathogenic subset in articular cartilage and meniscus. In meniscus and cartilage cells, FAP and ZEB1 promote expression of genes that contribute to OA pathogenesis, including senescence.ConclusionsThese single-cell studies identified a senescent pathogenic cell cluster that is present in cartilage and meniscus and has FAP and ZEB1 as main regulators which are novel and promising therapeutic targets for OA-associated pathways in both tissues.

Background While patellar resurfacing can affect patellofemoral kinematics, the effect on tibiofemoral kinematics is unknown. We hypothesized that patellar resurfacing would affect tibiofemoral kinematics during deep knee flexion due to biomechanical alteration of the extensor mechanism. Methods We performed cruciate-retaining TKA in fresh-frozen human cadaveric knees (N = 5) and recorded fluoroscopic kinematics during deep knee flexion before and after the patellar resurfacing. To simulate deep knee flexion, cadaver knees were tested on a dynamic, quadriceps-driven, closed-kinetic chain simulator based on the Oxford knee rig design under loads equivalent to stair climbing. To measure knee kinematics, a 2-dimensional to 3-dimensional fluoroscopic registration technique was used. Component rotation, varus-valgus angle, and anteroposterior translation of medial and lateral contact points of the femoral component relative to the tibial component were calculated over the range of flexion. Results There were no significant differences in femoral component external rotation (before patellar resurfacing: 6.6 ± 2.3°, after patellar resurfacing: 7.2 ± 1.8°, p = 0.36), and less than 1° difference in femorotibial varus-valgus angle between patellar resurfacing and non-resurfacing (p = 0.01). For both conditions, the medial and lateral femorotibial contact points moved posteriorly from 0° to 30° of flexion, but not beyond 30° of flexion. At 10° of flexion, after patellar resurfacing, the medial contact point was more anteriorly located than before patellar resurfacing. Conclusion Despite the potential for alteration of the knee extensor biomechanics, patellar resurfacing had minimal effect on tibiofemoral kinematics. Patellar resurfacing, if performed adequately, is unlikely to affect postoperative knee function.

Hydrogels are commonly used in wound dressing, as they retain moisture, accelerate healing, and break down necrotic tissue. This process enhances patient comfort levels while simultaneously reducing pain caused by dead tissue. The purpose of this study was to investigate the in vivo toxicity of a dual hydrogel consisting of type I atelocollagen cross-linked with sodium hyaluronate hydrogel used for wound dressing. Porcine type I atelocollagen was cross-linked with sodium hyaluronate to form the hydrogel. For subcutaneous implantation, 0.5 ml of dual hydrogel was injected into two different sites of twenty rats per group. High density polyethylene rods were implanted subcutaneously to serve as a control material. Hematological assessment, blood biochemistry, histopathological, and histological evaluations were scored and graded after 4 weeks. A bioreactivity rating was used for evaluation of subacute toxicity. Differences observed in blood chemical analysis and hematological analysis between control and test groups were within normal variations and considered unrelated to the test article implantation. No significant implantation-related lesions were observed in any of the major organs of all test animals. The overall histopathological index of the test article implantation sites was evaluated as 0. The bioreactivity rating was evaluated as non-irritant after 4-week subcutaneous implantation. Overall, these results indicate that the dual hydrogel of type I atelocollagen and sodium hyaluronate is biologically and chemically safe for clinical application as a wound dressing.

AimsThe extensive variation in axial rotation of tibial components can lead to coronal plane malalignment. We analyzed the change in coronal alignment induced by tray malrotation.MethodsWe constructed a computer model of knee arthroplasty and used a virtual cutting guide to cut the tibia at 90° to the coronal plane. The virtual guide was rotated axially (15° medial to 15° lateral) and with posterior slopes (0° to 7°). To assess the effect of axial malrotation, we measured the coronal plane alignment of a tibial tray that was axially rotated (25° internal to 15° external), as viewed on a standard anteroposterior (AP) radiograph.ResultsAxial rotation of the cutting guide induced a varus-valgus malalignment up to 1.8° (for 15° of axial rotation combined with 7° of posterior slope). Axial malrotation of tibial tray induced a substantially higher risk of coronal plane malalignment ranging from 1.9° valgus with 15° external rotation, to over 3° varus with 25° of internal rotation. Coronal alignment of the tibial cut changed by 0.07° per degree of axial rotation and 0.22° per degree of posterior slope (linear regression, R2> 0.99).ConclusionWhile the effect of axial malalignment has been studied, the impact on coronal alignment is not known. Our results indicate that the direction of the cutting guide and malalignment in axial rotation alter coronal plane alignment and can increase the incidence of outliers. Cite this article: Bone Joint J 2020;102-B(6 Supple A):43–48.

INTRODUCTION Three-dimensional (3-D) CT volumetric filling ratio (VFR) is a better predictor of proximal humerus stress shielding after short-stem anatomic total shoulder arthroplasty (aTSA) than using plain radiographs. METHODS Forty-four patients with short-stem aTSAs, preoperative CT scans, and a minimum 3-year radiographic follow-up were included. Patients were divided into group A (stress shielding) and group B (no stress shielding) based on the radiographic analysis. Standard implant filling ratios were measured on plain radiographs. The 3-D VFR of the metaphyseal and diaphyseal segments of the aTSA stem was measured using MIMICS (Materialise). The area under a receiver operator characteristic curve was used to determine the predictive strength of the 3-D VFR method. RESULTS The average age and radiographic follow-up was 69 years and 44 months. Group A had 19 patients and statistically higher filling ratios using 3-D VFR method than group B, whereas no notable differences were found between the groups using standard techniques. The 3-D VFR had an area under a receiver operator characteristic curve of 92%, which supports it as a good predictor of stress shielding. CONCLUSIONS These methods enable early identification of patients at risk for stress shielding and can also be valuable in improving humeral stem designs. LEVEL OF EVIDENCE Level III. Case-control study.

Background Meniscal cysts are not uncommon in clinical practice, with reported incidence rates varying from 1 to 22%. Most meniscal cysts are parameniscal cysts, which are created by extravasation of synovial fluid through the meniscal tear into the adjacent soft tissue. In contrast, intrameniscal cysts in which the fluid collects in the meniscus are very rare. We encountered a teenager with a huge intrameniscal cyst accompanied by a small vertical meniscal tear in the red-white zone of the upper surface of the medial meniscus. A literature search revealed no information regarding the appropriate treatment methods and results for this type of lesion. Case presentation A 14-year-old boy presented to our outpatient clinic because of right knee pain that had been present for the previous 2 months. The patient participated in Hapkido, but had no specific trauma history. Magnetic resonance imaging revealed a huge intrameniscal cyst located in the central parenchyma of the posteromedial corner of the medial meniscus. In addition, one sagittal slice on MRI revealed a vertical tear in the red-white zone of the upper surface of the medial meniscus. The presence of such a tear accompanied by a huge intrameniscal cyst is very unusual. The patient was treated via arthroscopic inside-out meniscal suture repair and open cystic debridement with additional meniscocapsular suturing. During 4 years of magnetic resonance imaging follow-up, the lesion has completely disappeared and the meniscus has successfully recovered its normal form. Conclusions Our treatment method may be considered as the first choice for young patients who require surgical treatment for large intrameniscal cysts with accompanying small vertical meniscal tears.

Electrospinning is an attractive method of fabricating nanofibers that replicate the ultrastructure of the human meniscus. However, it is challenging to approximate the mechanical properties of meniscal tissue while maintaining the biocompatibility of collagen fibers. Our objective was to determine if functionalizing polylactic acid (PLA) nanofibers with collagen would enhance their biocompatibility. We therefore used coaxial electrospinning to generate core–shell nanofibers with a core of PLA for mechanical strength and a shell of collagen to enhance cell attachment and matrix synthesis. We characterized the nanostructure of the engineered scaffolds and measured the hydrophilic and mechanical properties. We assessed the performance of human meniscal cells seeded on coaxial electrospun scaffolds to produce meniscal tissue by gene expression and histology. Finally, we investigated whether these cell-seeded scaffolds could repair surgical tears created ex vivo in avascular meniscal explants. Histology, immunohistochemistry, and mechanical testing of ex vivo repair provided evidence of neotissue that was significantly better integrated with the native tissue than with the acellular coaxial electrospun scaffolds. Human meniscal cell-seeded coaxial electrospun scaffolds may have potential in enhancing repair of avascular meniscus tears. IMPACT STATEMENT: The success of any tissue-engineered meniscus graft relies on its ability to mimic native three-dimensional microstructure, support cell growth, produce tissue-specific matrix, and enhance graft integration into the repair site. Polylactic acid scaffolds possess the desired mechanical properties, whereas collagen scaffolds induce better cell attachment and enhanced tissue regeneration. We therefore fabricated nanofibrous scaffolds that combined the properties of two biomaterials. These novel coaxial scaffolds more closely emulated the structure, mechanical properties, and biochemical composition of native meniscal tissue. Our findings of meniscogenic tissue generation and integration in meniscus defects have the potential to be translated to clinical use.

The relative impact of soft tissue balance and knee laxity on clinical outcomes after total knee arthroplasty (TKA) is not fully understood. We analyzed associations among knee laxity, kinematics, and patient-reported outcomes.Knee Society Scores were recorded in 67 patients before and after primary TKA for osteoarthritis with varus deformity (N = 78). Varus and valgus laxity was measured in 78 knees using stress radiographs. Knee kinematics were measured fluoroscopically during stair ascent in 16 knees.On average, varus laxity decreased significantly, and valgus laxity increased significantly after TKA, although the net combined varus-valgus laxity did not change significantly. Postoperatively, the magnitude of valgus laxity correlated significantly with greater patient symptoms and satisfaction scores. Patients with medial pivot kinematics scored higher on patient satisfaction and standard activities.We found that postoperative valgus laxity and medial pivot kinematics were significantly associated with better clinical outcomes. These results emphasize the importance of careful preoperative planning and attention to intraoperative alignment and ligament balancing.

We analyzed the implantation effects on cruciate ligament force in unicompartmental knee arthroplasty (UKA) and determined whether kinematics is associated with the cruciate ligament force. We examined 16 patients (17 knees) undergoing medial UKA. Under fluoroscopy, each participant performed a deep knee bend before and after UKA. A two-dimensional/three-dimensional registration technique was employed to measure tibiofemoral kinematics. Forces in the anteromedial and posterolateral bundles of both the anterior cruciate ligament (aACL and pACL) and the anterolateral and posteromedial bundles of the posterior cruciate ligament (aPCL and pPCL) during knee flexion were analyzed pre- and post-UKA. Correlations between changes in kinematics and ligament forces post-UKA were also analyzed. Preoperatively, the aACL forces were highly correlated with anteroposterior (AP) translation of the lateral condyles (Correlation coefficient [r] = 0.59). The pPCL forces were highly correlated with the varus–valgus angulation (r = − 0.57). However, postoperatively, the PCL forces in both bundles were highly correlated with the AP translation of the medial femoral condyle (aPCL: r = 0.62, pPCL: r = 0.60). The ACL and PCL forces of the knees post-UKA were larger than those of the knees pre-UKA. Kinematic changes were significantly correlated with the cruciate ligament force changes.

PurposeThe development of ultrashort echo time (UTE) MRI sequences has led to improved imaging of tissues with short T2 relaxation times, such as the deep layer cartilage and meniscus. UTE combined with adiabatic T1ρ preparation (UTE-Adiab-T1ρ) is an MRI measure with low sensitivity to the magic angle effect. This study aimed to investigate the sensitivity of UTE-Adiab-T1ρ to mechanical load-induced deformations in the tibiofemoral cartilage and meniscus of human cadaveric knee joints.MethodsEight knee joints from young (42±12years at death) donors were evaluated on a 3T scanner using the UTE-Adiab-T1ρ sequence under four sequential loading conditions: load=0N (Load0), load=300N (Load1), load=500N (Load2), and load=0N (Unload). UTE-Adiab-T1ρ was measured in the meniscus (M), femoral articular cartilage (FAC), tibial articular cartilage (TAC), articular cartilage regions uncovered by meniscus (AC-UC), and articular cartilage regions covered by meniscus (AC-MC) within region of interests (ROIs) manually selected by an experienced MR scientist. The Kruskal-Wallis test, with corrected significance level for multiple comparisons, was used to examine the UTE-Adiab-T1ρ differences between different loading conditions.ResultsUTE-Adiab-T1ρ decreased in all grouped ROIs under both Load1 and Load2 conditions (-18.7% and-16.9% for M, -18.8% and-12.6% for FAC, -21.4% and-10.7% for TAC, -26.2% and-13.9% for AC-UC, and-16.9% and-10.7% for AC-MC). After unloading, average UTE-Adiab-T1ρ increased across all ROIs and within a lower range compared with the average UTE-Adiab-T1ρ decreases induced by the two previous loading conditions. The loading-induced differences were statistically non-significant.ConclusionsWhile UTE-Adiab-T1ρ reduction by loading is likely an indication of tissue deformation, the increase of UTE-Adiab-T1ρ within a lower range by unloading implies partial tissue restoration. This study highlights the UTE-Adiab-T1ρ technique as an imaging marker of tissue function for detecting deformation patterns under loading.

Purpose: Scaffold-free cartilage tissue engineering circumvents issues with scaffold seeding, potential toxicity response, and impaired host integration. However, precisely controlling and maintain...

In this study, we combined quantitative ultrashort echo time (UTE) magnetic resonance (MR) imaging and an investigation by a probing device with tri-axial force sensor to seek correlations with mechanical properties of human patellar cartilage for in situ evaluation of biomechanical properties. Cartilage blocks (15 × 20 × 5 mm3) were dissected from the patella of six donors, 5 mm square regions of interest from the cartilage blocks were imaged using UTE-MR imaging sequences (T2* and magnetization transfer ratio (MTR)), and mechanical properties were measured using a micro indentation device. Then, the vertical reaction force on the cartilage surface was measured while push-probing forward 3 mm with the probing device at a 30° tilt to the horizontal plane. The results showed a positive correlation between stiffness/elastic modulus and each predictor variable (UTE-T2* (r = 0.240 and 0.255, respectively, UTE-MTR (r = 0.378 and 0.379, respectively), and probing device force (r = 0.426 and 0.423, respectively). Furthermore, multiple linear regression analysis showed the combination of the three predictors had stronger correlation (adjusted r2 = 0.314 (stiffness), 0.323 (elastic), respectively). Our results demonstrate the potential for these non- and less- invasive methods for in situ evaluation of the mechanical properties of cartilage tissue.

Rotator cuff tears continue to be at risk of retear or failure to heal after surgical repair, despite the use of various surgical techniques, which stimulate development of novel scaffolding strategies. They should be able to address the known causes of failure after the conventional rotator cuff repair: (1) failure to reproduce the normal tendon healing process, (2) resultant failure to reproduce four zones of the enthesis, and (3) failure to attain sufficient mechanical strength after repair. Nanofiber scaffolds are suited for this application because they can be engineered to mimic the ultrastructure and properties of the native rotator cuff tendon. Among various methods for tissue-engineered nanofibers, electrospinning has recently been highlighted in the rotator cuff field. Electrospinning can create fibrous and porous structures that resemble natural tendon's extracellular matrix. Other advantages include the ability to create relatively large surface-to-volume ratios, the ability to control fiber size from the micro to the nano scale, and the flexibility of material choices. In this review, we will discuss the anatomical and mechanical features of the rotator cuff tendon, their potential impacts on improper healing after repair, and the current knowledge of the use of electrospinning for rotator cuff tissue engineering.

Meniscus tears common injuries of the knee joint and a major osteoarthritis (OA) risk factor. Knowledge gaps that limit development of therapeutic approaches for meniscus injury and degeneration concern transcription factors that control the meniscus cell phenotype. Analysis of RNA-sequencing data from 37 human tissues in the Genotype-Tissue Expression (GTEx) database and RNA-sequencing data from meniscus and articular cartilage showed that transcription factor Mohawk (MKX) is highly enriched in meniscus. In human meniscus cells, MKX regulates expression of meniscus marker genes, OA-related genes and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). In mesenchymal stem cells, the combination of adenoviral MKX (Ad-MKX) and Transforming growth factor-β3 (TGF-β3) induced a meniscus cell phenotype. When Ad-MKX-transduced mesenchymal stem cells (MSCs) were seeded on TGF-β3-conjugated decellularized meniscus scaffold (DMS) and inserted into experimental tears in meniscus explants, they increased glycosaminoglycan content, extracellular matrix interconnectivity, cell infiltration into the DMS and improved biomechanical properties. Ad-MKX injection into mouse knee joints with experimental OA induced by surgical destabilization of the meniscus suppressed meniscus and cartilage damage, reducing OA severity. Ad-MKX injection into human OA meniscus tissue explants corrected pathogenic gene expression. These results identify MKX as a previously unidentified key transcription factor that regulates the meniscus cell phenotype. The combination of Ad-MKX with TGF-β3 is effective for differentiation of MSCs to a meniscus cell phenotype and useful for meniscus repair. MKX is a promising therapeutic target for meniscus tissue engineering, repair and prevention of OA.

The knee menisci are critical to the long-term health of the knee joint. Because of the high incidence of injury and degeneration, replacing damaged or lost meniscal tissue is extremely clinically relevant. The multiscale architecture of the meniscus results in unique biomechanical properties. Nanofibrous scaffolds are extremely attractive to replicate the biochemical composition and ultrastructural features in engineered meniscus tissue. We review recent advances in electrospinning to generate nanofibrous scaffolds and the current state-of-the-art of electrospun materials for meniscal regeneration. We discuss the importance of cellular function for meniscal tissue engineering and the application of cells derived from multiple sources. We compare experimental models necessary for proof of concept and to support translation. Finally, we discuss future directions and potential for technological innovations.

The extensive variation in axial rotation of tibial components can lead to coronal plane malalignment. We analyzed the change in coronal alignment induced by tray malrotation.We constructed a computer model of knee arthroplasty and used a virtual cutting guide to cut the tibia at 90° to the coronal plane. The virtual guide was rotated axially (15° medial to 15° lateral) and with posterior slopes (0° to 7°). To assess the effect of axial malrotation, we measured the coronal plane alignment of a tibial tray that was axially rotated (25° internal to 15° external), as viewed on a standard anteroposterior (AP) radiograph.Axial rotation of the cutting guide induced a varus-valgus malalignment up to 1.8° (for 15° of axial rotation combined with 7° of posterior slope). Axial malrotation of tibial tray induced a substantially higher risk of coronal plane malalignment ranging from 1.9° valgus with 15° external rotation, to over 3° varus with 25° of internal rotation. Coronal alignment of the tibial cut changed by 0.07° per degree of axial rotation and 0.22° per degree of posterior slope (linear regression, RWhile the effect of axial malalignment has been studied, the impact on coronal alignment is not known. Our results indicate that the direction of the cutting guide and malalignment in axial rotation alter coronal plane alignment and can increase the incidence of outliers. Cite this article

INTRODUCTION Three-dimensional (3-D) CT volumetric filling ratio (VFR) is a better predictor of proximal humerus stress shielding after short-stem anatomic total shoulder arthroplasty (aTSA) than using plain radiographs. METHODS Forty-four patients with short-stem aTSAs, preoperative CT scans, and a minimum 3-year radiographic follow-up were included. Patients were divided into group A (stress shielding) and group B (no stress shielding) based on the radiographic analysis. Standard implant filling ratios were measured on plain radiographs. The 3-D VFR of the metaphyseal and diaphyseal segments of the aTSA stem was measured using MIMICS (Materialise). The area under a receiver operator characteristic curve was used to determine the predictive strength of the 3-D VFR method. RESULTS The average age and radiographic follow-up was 69 years and 44 months. Group A had 19 patients and statistically higher filling ratios using 3-D VFR method than group B, whereas no notable differences were found between the groups using standard techniques. The 3-D VFR had an area under a receiver operator characteristic curve of 92%, which supports it as a good predictor of stress shielding. CONCLUSIONS These methods enable early identification of patients at risk for stress shielding and can also be valuable in improving humeral stem designs. LEVEL OF EVIDENCE Level III. Case-control study.

Background Periprosthetic tibial fracture after unicompartmental knee replacement is a challenging post-operative complication. Patients have an increased risk of mortality after fracture, the majority undergo further surgery, and the revision operations are less successful. Inappropriate surgical technique increases the risk of fracture, but it is unclear which technical aspects of the surgery are most problematic and no research has been performed on how surgical factors interact. Methods Firstly, this study quantified the typical variance in surgical cuts made during unicompartmental knee replacement (determined from bones prepared by surgeons during an instructional course). Secondly, these measured distributions were used to create a probabilistic finite element model of the tibia after replacement. A thousand finite element models were created using the Monte Carlo method, representing 1000 virtual operations, and the risk of tibial fracture was assessed. Findings Multivariate linear regression of the results showed that excessive resection depth and making the vertical cut too deep posteriorly increased the risk of fracture. These two parameters also had high variability in the prepared synthetic bones. The regression equation calculated the risk of fracture from three cut parameters (resection depth, vertical and horizonal posterior cuts) and fit the model results with 90% correlation. Interpretation This study introduces for the first time the application of a probabilistic approach to predict the aetiology of fracture after unicompartmental knee replacement, providing unique insight into the relative importance of surgical saw cut variations. Targeted changes to operative technique can now be considered to seek to reduce the risk of periprosthetic fracture.

The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.

Mechanical and microstructural evaluations of cortical bone using ultrashort echo time magnetic resonance imaging (UTE-MRI) have been performed increasingly in recent years. UTE-MRI acquires considerable signal from cortical bone and enables quantitative bone evaluations. Fitting bone apparent transverse magnetization (T2*) decay using a bicomponent model has been regularly performed to estimate bound water (BW) and pore water (PW) in the quantification of bone matrix and porosity, respectively. Human cortical bone possesses a considerable amount of fat, which appears as MRI T2* signal oscillation and can subsequently lead to BW overestimation when using a bicomponent model. Tricomponent T2* fitting model has been developed to improve BW and PW estimations by accounting for fat contribution in the MRI signal. This study aimed to investigate the correlations of microstructural and mechanical properties of human cortical bone with water pool fractions obtained from a tricomponent T2* model. 135 cortical bone strips (~4 × 2 × 40 mm3 ) from tibial and femoral midshafts of 37 donors (61 ± 24 years old) were scanned using ten sets of dual-echo 3D-UTE-Cones sequences (TE = 0.032-24.0 ms) on a 3 T MRI scanner for T2* fitting analyses. Average bone porosity and pore size were measured using microcomputed tomography (μCT) at 9 μm voxel size. Bone mechanical properties were measured using 4-point bending tests. Using a tricomponent model, bound water fraction (FracBW ) showed significant strong (R = 0.70, P < 0.01) and moderate (R = 0.58-0.62, P < 0.01) correlations with porosity and mechanical properties, respectively. Correlations of bone microstructural and mechanical properties with water pool fractions were higher for tricomponent model results compared with the bicomponent model. The tricomponent T2* fitting model is suggested as a useful technique for cortical bone evaluation where the MRI contribution of bone fat is accounted for.

Cortical bone shows as a signal void when using conventional clinical magnetic resonance imaging (MRI). Ultrashort echo time MRI (UTE-MRI) can acquire high signal from cortical bone, thus enabling quantitative assessments. Magnetization transfer (MT) imaging combined with UTE-MRI can indirectly assess protons in the organic matrix of bone. This study aimed to examine UTE-MT MRI techniques to estimate the mechanical properties of cortical bone. A total of 156 rectangular human cortical bone strips were harvested from the tibial and femoral midshafts of 43 donors (62 ± 22 years old, 62 specimens from females, 94 specimens from males). Bone specimens were scanned using UTE-MT sequences on a clinical 3 T MRI scanner and on a micro-computed tomography (μCT) scanner. A series of MT pulse saturation powers (400°, 600°, 800°) and frequency offsets (2, 5, 10, 20, 50 kHz) was used to measure the macromolecular fraction (MMF) utilizing a two-pool MT model. Failure mechanical properties of the bone specimens were measured using 4-point bending tests. MMF from MRI results showed significant strong correlations with cortical bone porosity (R = -0.72, P, Highlights • Correlations between two-pool UTE-MT MRI modeling and cortical bone mechanical properties was investigated. • UTE-MT MRI modeling showed significant moderate correlations with mechanical properties. • UTE-MT MRI also showed strong correlations with μCT-based bone porosity and BMD.

The aim of this study was to examine the potential of platelet-derived growth factor (PDGF)-coated decellularized meniscus scaffold in mediating integrative healing of meniscus tears by inducing endogenous cell migration. Fresh bovine meniscus was chemically decellularized and covalently conjugated with heparin and PDGF-BB. In vitro PDGF release kinetics was measured. The scaffold was transplanted into experimental tears in avascular bovine meniscus explants and cultured for 2 and 4 weeks. The number migrating and proliferating cells at the borderline between the scaffold and injured explant and PDGF receptor-β (PDGFRβ) expressing cells were counted. The alignment of the newly produced ECM and collagen was analyzed by Safranin-O, picrosirius red staining, and differential interference contrast (DIC). Tensile testing of the explants was performed after culture for 2 and 4 weeks. Heparin conjugated scaffold showed immobilization of high levels of PDGF-BB, with sustained release over 2 weeks. Insertion of the PDGF-BB treated scaffold in defects in avascular meniscus led to increased PDGFRβ expression, cell migration and proliferation into the defect zone. Safranin-O, picrosirius red staining and DIC showed tissue integration between the scaffold and injured explants. Tensile properties of injured explants treated with PDGF-BB coated scaffold were significantly higher than in the scaffold without PDGF. In conclusion, PDGF-BB-coated scaffold increased PDGFRβ expression and promoted migration of endogenous meniscus cells to the defect area. New matrix was formed that bridged the space between the native meniscus and the scaffold and this was associated with improved biomechanical properties. The PDGF-BB-coated scaffold will be promising for clinical translation to healing of meniscus tears. Statement of Significance Meniscus tears are the most common injury of the knee joint. The most prevalent forms that occur in the inner third typically do not spontaneously heal and represent a major risk factor for the development of knee osteoarthritis. The goal of this project was to develop an approach that is readily applicable for clinical use. We selected a natural and readily available decellularized meniscus scaffold and conjugated it with PDGF, which we had previously found to have strong chemotactic activity for chondrocytes and progenitor cells. The present results show that insertion of the PDGF-conjugated scaffold in defects in avascular meniscus led to endogenous cell migration and proliferation into the defect zone with tissue integration between the scaffold and injured explants and improved tensile properties. This PDGF-conjugated scaffold will be promising for a translational approach to healing of meniscus tears.

To compare the stresses at bone–arthroplasty interface of constrained and semi-constrained knee prostheses, using the finite element (FE) method as a predictor of the survivorship of the implants. Three-dimensional FE models of the knee implanted with rotating hinge (RHK) and legacy constrained condylar (LCCK) prostheses were generated to study the loads and stresses for two situations: medial- and lateral collateral ligament deficiencies in full extension. On average, the shear stress developed at bone–implant interface dropped from 16.9 to 13.7 MPa (18.9%), and the interface von Mises stress lowered from 37.6 to 30.2 MPa (19.6%) in RHK compared to those in LCCK prostheses. RHK design also resulted in a more uniform stress distribution at the interfaces in both femur and tibia. The average polyethylene liner stress dropped from 9.6 to 2.6 MPa (a 72.7% decrease) in RHK design when compared to that in LCCK design. The more uniform interface stress suggests fewer density changes at the periprosthetic regions due to bone remodelling. Moreover, the lower polyethylene stresses are likely to reduce wear and damage. These findings reveal that the RHK design may have more favorable mechanical features compared to LCCK design in full extension boundary conditions, implying a potentially better survivorship. However, the findings should be interpreted cautiously as other configurations were not investigated.

Avascular (Avas) meniscus regeneration remains a challenge, which is partly a consequence of our limited knowledge of the cells that maintain this tissue region. In this study, we utilized microarrays to characterize gene expression profiles of intact human Avas meniscus tissue and of cells following culture expansion. Using these data, we examined various 3D culture conditions to redifferentiate Avas cells toward the tissue phenotype. RNA was isolated from either the tissue directly or following cell isolation and 2 weeks in monolayer culture. RNA was hybridized on human genome arrays. Differentially expressed (DE) genes were identified by ranking analysis. DAVID pathway analysis was performed and visualized using STRING analysis. Quantitative PCR (qPCR) on additional donor menisci (tissues and cells) were used to validate array data. Avas cells cultured in 3D were subjected to qPCR to compare with the array-generated data. A total of 387 genes were DE based on differentiation state (>3-fold change; p

Background Failure rates after rotator cuff repair remain high in patients with massive tears. Although superior translation of the humeral head has been used to assess the severity of rotator cuff tears, the relevance of anterior migration of the humeral head to clinical outcomes has not been established. The purpose of this study was to investigate the potential role of the T-scale, a measure of the anterolateral translation of the humeral head, as a prognostic factor for rotator cuff repair. Methods One hundred twenty consecutive patients with full-thickness rotator cuff tears underwent primary rotator cuff repair. The T-scale and acromiohumeral interval (AHI) were measured preoperatively on axial computed tomography scans and radiographs, respectively. The correlations of the T-scale and AHI with previously published scores and active forward elevation (FE) were investigated. The outcome of rotator cuff repairs was compared between patients with positive and patients with negative preoperative T-scale values. Results The preoperative T-scale but not AHI correlated significantly with postoperative FE and clinical scores in patients with large to massive tears but not in those with small to medium tears. Postoperative FE and clinical scores were significantly higher in patients with positive T-scale values than in those with negative T-scale values. The relative risk of retear was 2.0 to 7.9 times greater in patients with negative T-scale values. Conclusion Patients with large to massive tears and negative T-scale values had poorer clinical outcomes and higher retear rates. A negative T-scale value represents a useful prognostic factor for considering reverse shoulder arthroplasty in patients at greater risk of retear after rotator cuff repair.

Hydrogel and electrospun scaffold materials support cell attachment and neotissue development and can be tuned to structurally and mechanically resemble native extracellular matrix by altering either electrospun fiber or hydrogel properties. In this study, we examined meniscus tissue generation from different human cell sources including meniscus cells derived from vascular and avascular regions, human bone marrow-derived mesenchymal stem cells, synovial cells, and cells from the infrapatellar fat pad (IPFP). All cells were seeded onto aligned electrospun collagen type I scaffolds and were optionally encapsulated in a tricomponent hydrogel. Single or multilayered constructs were generated and cultivated in defined medium with selected growth factors for 2 weeks. Cell viability, cell morphology, and gene-expression profiles were monitored using confocal microscopy, scanning electron microscopy, and quantitative polymerase chain reaction (qPCR), respectively. Multilayered constructs were examined with histology, immunohistochemistry, qPCR, and for tensile mechanical properties. For all cell types, TGFβ1 and TGFβ3 treatment increased COL1A1, COMP, Tenascin C (TNC), and Scleraxis (SCX) gene expression and deposition of collagen type I protein. IPFP cells generated meniscus-like tissues with higher meniscogenic gene expression, mechanical properties, and better cell distribution compared to other cell types studied. We show proof of concept that electrospun collagen scaffolds support neotissue formation and IPFP cells have potential for use in cell-based meniscus regeneration strategies.

Summary Objective Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage. Methods Constitutive activation of autophagy during aging was measured in GFP-LC3 transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage. Results In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage. Conclusion Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity.

Since dislocation of total hip replacements (THR) remains a clinical problem, its mechanisms are still in the focus of research. Previous studies ignored the impact of soft tissue structures and dynamic processes or relied on simplified joint contact mechanics, thus, hindered a thorough understanding. Therefore, the purpose of the present study was to use hardware-in-the-loop (HiL) simulation to analyze systematically the impact of varying implant positions and designs as well as gluteal and posterior muscle function on THR instability under physiological-like loading conditions during dynamic movements. A musculoskeletal multibody model emulated the in situ environment of the lower extremity during deep sit-to-stand with femoral adduction maneuver while a six-axis robot moved and loaded a THR accordingly to feed physical measurements back to the multibody model. Commercial THRs with hard-soft bearings were used in the simulation with three different head diameters (28, 36, 44 mm) and two offsets (M, XL). Cup inclination of 45°, cup anteversion of 20°, and stem anteversion of 10° revealed to be outstandingly robust against any instability-related parameter variation. For the flexion motion, higher combined anteversion angles of cup and stem seemed generally favorable. Total hip instability was either deferred or even avoided even in the presence of higher cup inclination. Larger head diameters (>36 mm) and femoral head offsets (8 mm) deferred occurrence of prosthetic and bone impingement associated with increasing resisting torques. In summary, implant positioning had a much higher impact on total hip stability than gluteal insufficiency and impaired muscle function. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2557-2566, 2017.

Objective:The aim of this study was to evaluate the results of autologous bone marrow cell stimulation and allogenic chondrocyte implantation using 3-dimensional gel-type fibrin matrix in an animal model.Design:Eighteen rabbits were divided into 2 treatment groups. One group was treated with a microfracture and covering of it with gel-type fibrin (AutoBMS; n = 9), and the other group was treated with allogenic chondrocytes mixed gel-type fibrin at the cartilage defect (AlloCI; n = 9). The control group was untreated cartilage defect at the other side knee of each object. Twelve weeks after treatment, the cartilage was evaluated using the International Cartilage Repair Society (ICRS) scoring system, immunohistochemical staining, and modified O’Driscoll grading system.Results:The ICRS scores were similar in the AutoBMS (9.44 ± 2.44) and the AlloCI (9.33 ± 1.67) groups ( P < 0.05). Immunohistochemical staining confirmed higher expression of cartilaginous collagen for both groups. The average difference (AutoBMS, 31.89 ± 6.54; AlloCI, 32.89 ± 5.25) in the modified O’Driscoll scores appeared to be nonsignificant ( P > 0.05); however, both treatment groups showed significantly higher scores with respect to their control group (18.45 ± 1.65; 18.97 ± 1.58) ( P < 0.05).Conclusion:This experimental study suggests autologous bone marrow cells stimulation and implantation of allogenic chondrocytes are both useful methodologies for regenerating hyaline-like cartilage in full-thickness cartilage defects in animal model.