Bone metastases are common and severe complications of cancers. It is estimated to occur in 65–75% of breast and prostate cancer patients and cause 80% of breast cancer-related deaths. Metastasised cancer cells have devastating impacts on bone due to their ability to alter bone remodeling by interacting with osteoblasts and osteoclasts. Exercise, often used as an intervention for cancer patients, regulates bone remodeling via osteocytes. Therefore, we hypothesise that bone mechanical loading may regulate bone metastases via osteocytes. This provides novel insights into the impact of exercises on bone metastases. It will assist in designing cancer intervention programs that lowers the risk for bone metastases. Investigating the mechanisms for the observed effects may also identify potential drug targets. MLO-Y4 osteocyte-like cells (gift of Dr. Bonewald, University of Missouri-Kansas City) on glass slides were placed in flow chambers and subjected to oscillatory fluid flow (1Pa; 1Hz; 2 hours). Media were extracted (conditioned media; CM) post-flow. RAW264.7 osteoclast precursors were conditioned in MLO-Y4 CM for 7 days. Migration of MDA-MB-231 breast cancer cells and PC3 prostate cancer cells towards CM was assayed using Transwell. Viability, apoptosis, and proliferation of the cancer cells in the CM were measured with Fixable Viability Dye eFluor 450, APOPercentage, and BrDu, respectively. P-values were calculated using Student's t-test. Significantly more MDA-MB-231 and PC3 cells migrated towards the CM from MLO-Y4 cells with exposure to flow in comparison to CM from MLO-Y4 cells not exposed to flow. The preferential migration is abolished with anti-VEGF antibodies. MDA-MB-231 cells apoptosis rate was slightly lower in CM from MLO-Y4 cells exposed to flow, while proliferation rate was slightly higher. The current data showed no difference in cancer cells viability and adhesion to collagen between any two groups. On the other hand, it was observed that less MDA-MB-231 cells migrated towards CM from RAW264.7 cells conditioned in CM from MLO-Y4 cells stimulated with flow in comparison to those conditioned in CM from MLO-Y4 cells not stimulated with flow. TRAP staining results confirmed that there were less differentiated osteoclasts when RAW264.7 cells were cultured in CM from MLO-Y4 cells exposed to flow. Overall, this study suggests that when only osteocytes and cancer cells are involved, osteocytes subjected to mechanical loading can promote metastases due to the increased secretion of VEGF. However, with the incorporation of osteoclasts, mechanical loading on osteocytes seems to reduce MDA-MB-231 cell migration. This is likely because osteocytes reduce osteoclastogenesis in response to mechanical stimulation, and osteoclasts have been shown to support cancer cells. Animal studies will also be conducted to verify the pro- or anti-metastatic effect of mechanical loading that is observed in the in vitro part of this study

Introduction. The pathogenesis of primary knee osteoarthritis is due to excess mechanical loading of the articular cartilage. Previous studies have assessed the impact of muscle forces on tibiofemoral kinematics and force distribution. A cadaveric study was performed to evaluate the effect of altering the moment arm of the iliotibial band (ITB) on knee biomechanics. Method. A robotic system consisting of a 6-DOF manipulator capable of measuring forces on the medial and lateral condyle of a cadaveric knee at various flexion angles and muscle forces was utilized [1]. The system measured the compartment forces at flexion angles between 0° and 30° under 3 simulated loading conditions (300N quadriceps, 100N hamstrings and: i. 0N ITB; ii. 50N ITB; iii. 100N ITB). Eight fresh frozen human cadaver knee specimens (4 males, 4 females); age range 36 – 50 years; weight range 49 – 90 kg; height range 154 – 190 cm were used in the study. The ITB and associated lateral soft tissue structures were laterally displaced from the lateral femoral condyle by fixing a metal implant (like in Figure 1) to the distal lateral femur. Mechanical loads on the medial and lateral compartments (with and without the implant) were measured using piezoelectric pressure sensors. Results. For each specimen, lateral displacement of the ITB due to the implant was measured (15 – 20 mm). The % average unloading of the medial compartment for all the specimens ranged from 34% – 65% (Figure 2). Also observed was a concomitant increase in lateral compartment load. Medial unloading was even observed with no ITB force (0N) which indicates a role for other lateral structures attached to the ITB in unloading the medial compartment [2]. In addition, under these non-weight bearing conditions, on average, there was an increase in valgus tibial angulation through the flexion range. Discussion. Increasing mechanical leverage of muscles across a joint is accomplished in nature through sesamoid bones (e.g., patella) which increase the muscle moment arm. By increasing the moment arm of the ITB and lateral soft tissue structures by lateralizing these structures, our model demonstrates a 34–65% unloading of the medial compartment. Studies of knee braces and weight loss have shown that reducing mechanical load on the medial condyle by even 10% provides clinical benefits in terms of reduced pain and improved function. Based on the results of this study, unloading the medial compartment by displacing the ITB laterally may be a means of treating medial osteoarthritis (Figure 3). A prospective, multi-center, non-randomized, open label, single-arm study is currently underway to establish the safety and efficacy of providing medial osteoarthritis pain relief by displacing the ITB using Cotera, Inc.'s Latella™ Knee Implant

Introduction. Wolff's Law proposes that trabecular bone adapts in response to mechanical loading and that trabeculae align with the trajectory of predominant loads. The current study is aimed to investigate trabecular orientation in the tibia in patients with osteoarthritis of the knee. Consistent with Wolff's Law, it was hypothesised that orientation would reflect the mechanical loading of the joint and hence that there would be a correlation between the trabecular orientation and the mechanical axis of the lower limb. Methods. 51 anonymised radiographs from patients with osteoarthritis were analysed using ImageJ (National Institute of Health). Each patient had both a standard anteroposterior radiograph of the knee and a long leg view taken while weight bearing. For each anteroposterior radiograph, the angle of the femoral shaft and tibial shaft were measured. The femoral shaft – tibial shaft (FS -TS) angle was then calculated as the difference between the two, as described by Sheehy et al. (2011). A medial rectangle was selected with the top, bottom, medial and lateral borders being the sclerotic bone, the growth line, the bone edge and the centre of the medial tibial spine. Corresponding measurements were done on the lateral side. Trabecular orientation of both areas was measured using OrientationJ (an ImageJ plugin). In all cases the medial and lateral orientation angles were expressed relative to the angle of the tibial shaft. The mechanical axis of the lower limb was measured from the full length radiographs by calculating the angle formed by the femoral and tibial axes, as described by Goker and Block. All measurements were done independently by two observers, SAS and SL. Results. Except where indicated, the results are based on analysis of 51 radiographs. Inter-tester analysis indicated excellent reliability (ICC = 0.99) for the mechanical axis measurement and preliminary inter-tester analysis (based on 25 radiographs) indicated good reliability for the orientation measurements (ICC = 0.76). The FS-TS angle calculated from the anteroposterior radiographs was significantly correlated with the mechanical axis calculated from the full-leg views (r = 0.96, p < 0.01), with an average offset of 5.7°, which is consistent with previous research. There was a significant correlation between the lateral trabecular orientation and both the FS-TS angle measured from the anteroposterior radiographs (r = −0.48, p < 0.01) (Figure) and the mechanical axis measured from the long leg views (r = −0.39, p < 0.01). There was also a significant correlation between the medial trabecular orientation and the FS-TS angle (r = 0.35, p = 0.01). Discussion. There were significant correlations between leg alignment (both the mechanical axis and the FS − TS angle) and trabecular orientation in the human tibia. These findings were consistent with Wolff's Law, which proposes that trabecular bone adapts in response to mechanical loading. To the best of our knowledge, the current study is the first to investigate in vivo trabecular orientation in the human tibia and to establish a correlation with the mechanical axis of the lower limb. The findings also suggest that inspection of the trabecular orientation might provide valuable information on leg alignment and mechanical loading prior to surgery

Osteoarthritis (OA) is a debilitating disease and the most common joint disorder worldwide. Although the development of OA is considered multifactorial, the mechanisms underlying its initiation and progression remain unclear. A prominent feature in OA is cartilage degradation typified by the progressive loss of extracellular matrix components - aggrecan and type II collagen (Col II). Cartilage homeostasis is maintained by the anabolic and catabolic activities of chondrocytes. Prolonged exposure to stressors such as mechanical loading and inflammatory cytokines can alter the phonotype of chondrocytes favoring cartilage catabolism, and occurs through decreased matrix protein synthesis and upregulation of catabolic enzymes such as aggrecanases (ADAMTS-) 4 and 5 and matrix metalloproteinases (MMPs). More recently, the endoplasmic reticulum (ER) stress response has been implicated in OA. The ER-stress response protects the cell from misfolded proteins however, excessive activation of this system can lead to chondrocyte apoptosis. Acute exposure of chondrocytes to IL-1β has been demonstrated to upregulate ER-stress markers (GADD153 and GRP78), however, it is unclear whether the ER-stress response plays a role on chronic IL-1β exposure. The purpose of this study was to determine whether modulating the ER stress response with tauroursodeoxycholic acid (TUDCA) in human OA chondrocytes during prolonged IL-1β exposure can alter its catabolic effects. Articular cartilage was isolated from donors undergoing total hip or knee replacement. Chondrocytes were recovered from the cartilage of each femoral head or knee by sequential digestion with Pronase followed by Collagenase, and expanded in DMEM-low glucose supplemented with 10% FBS. Chondrocytes were expanded in flasks for one passage before being prepared for micropellet culture. Chondrocyte pellets were cultured in regular growth medium (Control), medium supplemented with IL-1β [10 ng/mL], TUDCA [100 uM] or IL-1β + TUDCA for 12 days. Medium was replaced every three days. Cartilage explants were prepared from the donors undergoing knee replacement, and included cartilage with the cortical bone approximately 1 cm2 in dimension. Explants were cultured in the above mentioned media, however, the incubation period was extended to 21 days. RNA was extracted using Geneaid RNA Mini Kit for Tissue followed by cDNA synthesis. QPCR was performed using Cyber Green mastermix and primers for the following genes: ACAN (aggreacan), COL1A1, COL2A1, COL10A1, ADAMTS-4, ADAMTS-5, MMP-3, and MMP-13, on an ABI 7500 fast qPCR system. Although IL-1β did not significantly decrease the expression of matrix proteins, it did increase the expression of ADAMTS-4, −5, and MMP3 and −13 when compared to controls (Kruskal-Wallis, p < 0 .05, n=3). TUDCA treatment alone did not significantly increase the expression of catabolic enzymes but it did increase the expression of collagen type II. When IL-1β was coincubated with TUDCA, the expression of ADAMTS-4, ADAMTS-5, and MMP-13 significantly decreased by ∼40-fold, ∼10-fold, and ∼3-fold, respectfully. We provide evidence that the catabolic activities of IL-1β on human cartilage can be abrogated through modulation of the ER stress response

Adherent cells are known to respond to physical characteristics of their surrounding microenvironment, adapting their cytoskeleton and initiating signaling cascades specific to the type of cue encountered. Scaffolds mimicking native biophysical cues have proven to differentiate stem cells towards tissue-specific lineages and to maintain the phenotype of somatic cells for longer periods of culture time. Although the characteristic anisotropy of tendon tissue is commonly replicated in scaffolds, relevant physical cues such as tendon rigidity or mechanical loading are often neglected. The objective of this study is to use tendons' main extracellular matrix component, collagen type I, to create scaffolds with an anisotropic surface topography and controlled rigidity, in an effort to engineer functional tendon tissue equivalents, with native organization and strength. Porcine collagen type I in solution was treated with one of the following cross-linkers: glutaraldehyde, genipin or 4-arm polyethylene glycol (4SP). The resulting mixture was poured on micro-grooved (2×2×2 μm) or planar polydimethylsiloxane (PDMS) molds and dried in a laminar flow hood to obtain 5 mg/ml collagen films. Surface topography and elastic modulus of the final scaffolds were analyzed using SEM/AFM and rheometry, respectively. Human tendon cells were isolated from adult tendon tissue and cultured on micro-grooved/planar scaffolds for 4, 7 and 10 days. Cell morphology, collagen III and tenascin C expression were analyzed by immunocytochemistry. Among the different cross-linkers used, only the treatment with 4SP resulted in scaffolds with a recognizable micro-grooved surface topography. Precise control over the micro-grooved topography and the rigidity of the scaffolds was achieved by cross-linking the collagen with varying concentrations of 4SP at low pH and temperature. The elastic modulus of the scaffolds cross-linked with the highest concentration of 4SP matched the physiological values reported in developing tendons (∼15 kPa). Around eighty percent of the human tendon cells cultured on the cross-linked collagen films aligned in the direction of the anisotropy for 10 days in culture. At 4 days, tenoyctes cultured on micro-grooved substrates presented a significant higher nuclei aspect ratio than tenocytes cultured on planar substrates for all the 4SP concentrations. Synthesis, deposition and alignment of collagen III and tenascin C, two important tenogenic markers, were up regulated selectively in the rigid micro-grooved scaffolds after 7 days in culture. These results highlight the synergistic effect of matrix rigidity and cell alignment on tenogenic cell lineage commitment. Collectively, this study provides new insights into how collagen can be modulated to create scaffolds with precise imprinted topographies and controlled rigidities. Gene expression analysis and a replicate study with hBMSCs will be carried out to support the first results and to further identify the optimal biophysical conditions for tenogenic cell lineage commitment. This potentially leads to the design of smart implants that not only restore immediate tendon functionality but also provide microscopic cues that drive cellular synthesis of organized tissue-specific matrix

Tendinopathy is one of the most common orthopaedic pathological conditions characterized by tendon degenerative changes. Excessive mechanical loading is considered as a major causative factor in the development of tendinopathy, but the mechanisms of pathogenesis remain unclear. High mobility group box-1 (HMGB1), a potent inflammatory mediator when released into the matrix, has been identified in the early stage tendinopathy patients. Since the release and contribution of HMGB1 in tendinopathy development due to mechanical overloading is unknown, we investigated the role of HMGB1 in tendinopathy using a mouse intensive treadmill running (ITR) model and injection of glycyrrhizin (GL), a specific inhibitor of HMGB1. A total of 48 mice were divided into four groups, Cage Control group: The animals were allowed to move freely in their cage, GL group: The animals were received daily IP injection of GL (50 mg/kg body weight) for 24 weeks, ITR group: The animals ran on treadmill at 15 meters/min for three h/ day, five days a week for 12 or 24 weeks, GL+ITR group: The animals ran the same protocol as that of ITR group plus daily IP injection of GL for 12 or 24 weeks. Six mice/group were sacrificed at 12 or 24 weeks and the Achilles and patellar tendon tissues were harvested and used for histochemical staining and immunostaining. Mechanical overloading induced HMGB1 released from the cell nuclei to the matrix (Fig. 1a, b) caused tendon inflammation (Fig. 1c, d) and led to tendon degenerative changes (Fig. 1e-j). After 12 weeks of ITR, the tendon tissue near the bone insertion site showed typical tendinopathic changes in cell shape, accumulation of glycosaminoglycans (GAG) (Fig. 1e, f), and increase in SOX-9 staining (Fig. 1g-j). After 24 weeks ITR, the distal site of Achilles tendon showed considerable changes in cell shape (Fig. 2A, g, arrows), which is round compared to more elongated in the control and GL groups (Fig. 2A, e, f). However, daily treatment with GL prior to ITR blocked the cell shape change (Fig. 2A, h) and, ITR induced extensive GAG accumulation in ITR group (Fig. 2B, bottom panel). Furthermore, GL inhibited ITR-induced expression of chondrogenic markers (SOX-9 and collagen II) in the tendons (Fig. 3). Our results showed that mechanical overloading-induced HMGB1 plays a critical role in the development of tendinopathy by initiating tendon inflammation and eventual degeneration characterized by the presence of chondrocyte-like cells, accumulation of proteoglycans, high levels of collagen type II production, and chondrogenic marker SOX-9 expression. These results provide the first evidence for the role of HMGB1 as a therapeutic target to prevent tendinopathy before its onset and block further development at its early inflammation stages. The inhibition of tendinopathy development by GL administration in this study also suggests the putative therapeutic potential of this natural triterpene that is already in clinical use to treat other inflammation-related diseases. For any figures or tables, please contact authors directly

Introduction. Highly crosslinked, ultra-high molecular weight polyethylene (HXLPE) acetabular liners inherently have a risk of fatigue failure associated with femoral neck impingement. One of the potential reasons for liner failure was reported as crosslinking formulations of polyethylene, increasing the brittleness and structural rigidity. In addition, the acetabular component designs greatly affect the mechanical loading scenario, such as the offset (lateralized) liners with protruded rim above the metal shells, which commonly induce a weak resistance to rim impingement. The purpose of the present study was to compare the influence of the liner offset length on the impingement resistance in the annealed (first generation) and vitamin E-blended (second-generation) HXLPE liners with a commercial design. Materials and Methods. The materials tested were the 95-kGy irradiated annealed GUR1020, and the 300-kGy irradiated vitamin E-blended GUR1050 HXLPE offset liners, which were referred to as “20_95” and “50E_300”, respectively. These liners had 2, 3, 4-mm rim offset, 2.45-mm rim thickness, and 36-mm internal diameter. Their rims were protruded above the metal rim at 2, 3, 4mm. Rim impingement testing was performed using an electrodynamic axial-torsional machine. The cyclic impingement load of 25–250N was applied on the rims through the necks of the femoral stems at 1Hz. The rotational torque was simultaneously generated by swinging the stem necks on the rims at 1Hz and its rotational angle was set at the range of 0–10˚. The percent crystallinity was analyzed on the as-received (intact) and impinged HXLPE acetabular rims by confocal Raman microspectroscopy. Results. The number of cycles to failure was dependent on the offset length (2, 3, 4-mm) in 20_95 and 50E_300 liners. Our results showed that the shorter the rim offset, the shorter the number of cycles to failure. In both HXLPEs, accumulation of impingement damages significantly decreased crystallinity in their near-surfaces, indicating the occurrence of crystallographic breakdown. In each offset length tested, the fracture always occurred much earlier in 50E_300 than 20_95. However, the magnitudes of the microstructural changes at the time of failure were much less in 50E_300 than 20_95. Conclusions. Although it is known that vitamin E blend into HXLPE can improve the fatigue resistance of HXLPE, the impingement resistance of 50E_300 was lower than vitamin-E free 20_95, indicating a larger negative contribution of high-dose radiation (300kGy) over a positive contribution of the vitamin E blend in 50E_300. Our results implied that the reduction of the protruded rim length in the offset liners may increase the neck-rim contact stresses at the time of impingement, causing a decrease in the fatigue durability. Therefore, if HXLPE offset liner is used, surgeons should take special care in maximizing the volume of the protruded lip section

Introduction. The process of wear and corrosion at the head-neck junction of a total hip replacement is initiated when the femoral head and stem are joined together during surgery. To date, the effects of the surface topography of the femoral head and metal stem on the contact mechanics during assembly and thus on tribology and fretting corrosion during service life of the implant are not well understood. Therefore, the objective of this study was to investigate the influence of the surface topography of the metal stem taper on contact mechanics and wear during assembly of the head-neck junction using Finite Element models. Materials and Methods. 2D axisymmetric Finite Element models were developed consisting of a simplified head-neck junction incorporating the surface topography of a threaded stem taper to investigate axial assembly with 1 kN. Subsequently, a base model and three modifications of the base model in terms of profile peak height and plateau width of the stem taper topography and femoral head taper angle were calculated. To account for the wear process during assembly a law based on the Archard equation was implemented. Femoral head was modeled as ceramic (linear-elastic), taper material was either modeled as titanium, stainless steel or cobalt-chromium (all elastic-plastic). Wear volume, contact area, taper subsidence, equivalent plastic strain, von Mises stress, engagement length and crevice width was analyzed. Results. Titanium tapers showed largest wear volume throughout all simulations, followed by stainless steel and cobalt-chromium. A larger head taper angle resulted in an increase of the wear volume for all taper materials while the increase of the plateau width resulted in a decrease of the wear volume. Taper subsidence, von Mises stress and equivalent plastic strain followed the same trends. Contact area was largest for the models with a large plateau width for all taper materials. Other taper parameters had little effect on contact area. A pure increase of the angular mismatch (AM) resulted in the strongest decrease of the engagement length, while a combined increase of the AM and plateau width showed only a moderate decrease. The smallest effect concerning the engagement length was found when a combined increase of the profile peak height and AM was simulated. Crevice width was largest for a pure increase of the AM and for a combined increase of the AM and profile peak height for all taper materials. Discussion. This study showed that depending on the surface topography and material of the stem taper, wear and taper mechanics during assembly could be affected. For the examined surface topographies wear is distinctively elevated by increasing the AM and the profile peak height due to the resulting higher mechanical loading. More parameter studies under in vivo loading and the study of other taper surface parameters like the peak-to-peak distance have to be conducted to get a deeper insight into taper mechanics and wear effects. However, this study demonstrates the importance of good manufacturing practice of components for hip replacement systems to guarantee reproducible taper mechanics. For any figures or tables, please contact authors directly

Introduction. Subject-specific finite element models (FEMs) allow for a variety of biomechanical conditions to be tested in a highly repeatable manner. Accuracy of FEMs is improved by mapping density using quantitative computed tomography (QCT) and choosing a constitutive relationship relating density and mechanical properties of bone. Although QCT-derived FEMs have become common practice in contemporary computational studies of whole bones, many density-modulus relationships used at the whole bone level were derived using mechanical loading of small trabecular or cortical bone cores. These cores were mechanically loaded to derive an apparent modulus, which is related to each core's mean apparent or ash density. This study used these relationships and either elemental or nodal material mapping strategies to elucidate optimal methods for scapular QCT-FEMs. Methods. Six cadaveric scapulae (3 male; 3 female; mean age: 68±10 years) were loaded within a micro-CT in a custom CT-compatible hexapod robot Pre- and post-loaded scans were acquired (spatial resolution = 33.5 µm) and DVC was used to quantify experimental full-field displacements (BoneDVC, Insigneo) (Figure 1).. Experimental reaction forces applied to the scapulae were measured using a 6-DOF load cell. FEMs were derived from corresponding QCT scans of each cadaver bone. These models were mapped with one of fifteen density-modulus relationships and elemental or nodal material mapping strategies. DVC-derived BCs were imposed on the QCT-FEMs using local displacement measurements obtained from the DVC algorithm. Comparisons between the empirical and computational models were performed using resultant reaction loads and full-field displacements (Figure 2). Results and Discussion. Reaction forces predicted by the QCT-FEMs showed large percentage error variations across all specimens and density-modulus relationships with elemental material mapping. The percentage errors were as large as 899%, but as low as 3=57% for the different specimens. Similarly, when using a nodal material mapping strategy, percentage errors were as large as 965%, but as low as 4=59% for the different specimens (Figure 3). For all specimens, minimal variation only occurred in the slope between the QCT-FEM and DVC displacements in the x and y directions for either elemental or nodal material mapping strategies. Slopes ranged from 0.86 to 1.06. This held true for 3 specimens in the z direction; however, for the remaining 3 specimens more pronounced variations occurred between the QCT-FEM and DVC displacements, dependent on density-modulus relationship. The r. 2. values were consistently between 0.82 and 1.00 for both material mapping strategies and density-modulus relationships for all three Cartesian components of displacement and all specimens. Conclusions. The results suggest that QCT-FEMs using DVC derived boundary conditions can replicate experimental loading of cadaveric specimens. It was also shown that only slight variations exist when either elemental or nodal material mapping strategies are adopted. Given the recent advancements provided by DVC-derived BCs, this study provides a basis for a common methodology that can be implemented in future studies comparing similar outcomes in all anatomic locations. Expanding the current sample size has the potential to determine if a single density-modulus relationship can exist or if specimen or anatomic location-specific relationships should be utilized. For any figures or tables, please contact the authors directly

Testing potential therapeutics in the regeneration of the disc requires the use of model systems. Although several animal models have been developed to test intervertebral disc (IVD) regeneration, application becomes costly when used as a screening method. The bovine IVD organ culture system offers an inexpensive alternative, however, in the current paradigm, the bony vertebrae is removed to allow for nutrient diffusion to disc cells. This provides limitations on the conditions and strategies one can employ in investigating IVD regeneration and mechanisms in degenerative disc disease (i.e. complex loading). Although one method has been attempted to extend the survival of bovine vertebrae containing IVDs (vIVD) cell viability declined after two weeks in culture. Our goal was to develop and validate a long-term organ culture model with vertebral bone, which could be used subsequently for studying biological repair of disc degeneration and biomechanics. Preparation of vIVDs: Bovine IVDs from the tails of 22–28-month-old steers were prepared for organ culture by parallel cuts through the adjacent vertebral bodies at 1cm from the endplates using an IsoMet®1000 Buehler precision sectioning saw. vIVDs were split into two groups: IVDs treated with PrimeGrowth Media kit (developed by Intervertech and licensed to Wisent Bioproducts) and IVDs with DMEM. The PrimeGrowth group was incubated for 1h in PrimeGrowth Isolation Medium (Cat# 319–511-EL) and the DMEM group for 1h in DMEM. After isolation, IVDs were washed in PrimeGrowth Neutralisation Medium (Cat# 319–512-CL) while the other IVDs were washed in DMEM. The discs isolated with PrimeGrowth and DMEM were cultured for up to 5 months in sterile vented 60 ml Leakbuster™ Specimen Containers in PrimeGrowth Culture Medium (Cat# 319–510-CL) and DMEM with no mechanical load applied. Live/Dead Assay: vIVDs cultured for 1 or 5 months were dissected and cell viability was assessed in different regions by confocal microscopy using Live/Dead® (Invitrogen) fluorescence assay. Glucose Diffusion: After one month of culture, vIVDs were incubated for 72h in diffusion medium containing PBS (1x), CaCl2 (1mM), MgCl2 (0.5mM), KCl2 (5mM), 0.1% BSA and 150µM 2-NDBG, a D-glucose fluorescent analogue. Discs were dissected and IVD tissues were incubated in guanidinium chloride extraction buffer. Extracts were measured for fluorescence. After 5 months in culture, vIVDs prepared with PrimeGrowth kit demonstrated approximately 95% cell viability in all regions of the disc. However, dramatic reductions (∼90%) in vIVD viability were measured in DMEM group after 1 month. vIVD viability was related to the amount of 2-NDBG incorporated into the disc tissue. We have developed a novel method for isolating IVDs with vertebral bone capable of long-term viability. This method may not only help in the discovery of novel therapeutics in disc regeneration, but could also advance our understanding on complex loading paradigms in disc degeneration

Back ground. In 1970's, condylar type knee prosthese with anatomic design appeared, however, joint flexion was not satisfactory. Y/S II total knee arthroplasty (TKA) was developed to obtain deep flexion together with bilateral ligament balance in 1980. The articular surface of the tibial component was flattened to permit femoral shift posteriorily during knee flexion. Medial and lateral soft tissue release was determined by a unique ligament tensor both at flexion and extension. A metal tray was embedded in polyethylene, which had a shape of glasses frame. Though the usage of Y/SII TKA was finished in 1984, we here studied its long term surgical results using the Kaplan-Meyer method. Study design. From 1988 to 1991, 122 knees were replaced by Y/SII TKA in 81 patients with rheumatoid arthritis (RA). Among them, 24 joints in 12 patients were examined directly. The average age of follow-up was 19.5 years. The survival rate was investigated according to medical records. Results. The HSS knee score was 53.6 prior to the operation and 76.8 at the final observation. The average flexion was improved from 110.7degrees to 124.0 degrees after the operation, and was 115.8 degrees at the follow up. Radiological analysis showed no distinct clear zone around the femoral and tibial components. There was no breakage of components or polyethylene wear that cause a metal contact. The survival rate was 99% at 4 years and 97% at 19 years after the operation. Three prostheses were removed due to loosening in 2 and infection in 1. Discussion. While modern knee prostheses are designed to get deep flexion and long-term durability, the purposes of TKA in the earlier era were pain relief, stability and correction of deformity. Y/SII TKA was developed in such period, and obtained fairly deep flexion probably by its design and soft tissue release using the special instrument. Another result was that Y/SII TKA had long durability with a high rate of survival. One of the reasons was considered as the structure of femoral component. The metal tray with a shape of glasses frame conducts mechanical load anatomically to the bone and prevent from metal contact when polyethylene wears. The number of the size of component was only 3 and was fewer compared to current-generation prostheses. While this requires some technique when an operator inserts Y/SII prostheses, only a few instruments are needed during operation. Conclusively, we showed the good long term results of Y/SII TKA developed in relatively early era of knee prostheses

Aims

Limb-lengthening nails have largely replaced external fixation in limb-lengthening and reconstructive surgery. However, the adverse events and high prevalence of radiological changes recently noted with the STRYDE lengthening nail have raised concerns about the use of internal lengthening nails. The aim of this study was to compare the prevalence of radiological bone abnormalities between STRYDE, PRECICE, and FITBONE nails prior to nail removal.

Conventional hip arthroplasty femoral stems bypass the femoral neck for fixation. The femoral neck and proximal femur has a complex anatomy and interosseous structure to facilitate transfer of mechanical load in axial, compression bending and torsion mechanisms. von Mises analysis suggests a short stem, fixed in the femoral neck would maintain proximal femoral biomechanics, achieve physiological load transfer to the femoral neck and preserve bone stock and function. The strong calcar bone provides excellent opportunities for implant fixation and load transfer. Method. The Muscle Sparing Arthroplasty (MSA™) is a short femoral stem designed to achieve implant fixation in the femoral neck. The specific design features including a trapezoidal cross section; proximal conical flare; porous coating and lateral T back enhance proximal fixation and compressive load transfer to the calcar and femoral neck. Results. We report 54 hip arthroplasties in 49 patients with an average follow up of 18 months. All hip arthroplasties showed evidence of new bone formation in the proximal femoral neck and calcar region. This consisted of new bone streaming from the original calcar bone, in a strut fashion up to the conical flare of the implant. In 18 patients additional new bone formation occurred proximal to the neck osteotomy. This pattern of bone formation is consistent with predictions. Conclusion. A short femoral stem, fixed in the femoral neck can maintain biomechanical function of the femoral neck and result in preservation of bone and new bone stock

Introduction. Some patients complain ingrown pain or discomfort after implanting Co-Cr conventional endprosthesis of the hip. Some of this complaint may be attributable for effect on cartilage metabolism. It have been reported that ceramic is bioinert for biological tissue. On the other hand, metal including cobalt-chrome (Co-Cr) have some detrimental effect on biological tissue. However, there is no report concerning acetabular cartilage metabolism after hip endprosthesis implantation. In the present study, we hypothesized that ceramic head have small detrimental effect on cartilage cell metabolism. Specific aim of the study is to compare the protein level of inflammation related cytokines, amount of hyaluronic acid (HA) in culture media, and cartilage mRNA expression in organ culture model of hip end prosthesis implanted using ceramic head and Co-Cr head. Materials and Methods. Six acetabulum of 3 matured crossbred pig (average weight: 36 +/− 3.6kg) was retrieved. Animal experiment was performed under the rules of ethical committee of animal experiment. Average diameter of pig acetabulum was 26.3 +/− 0.6 mm. Just after sacrifice, mechanical loading using Instron testing machine with 26mm diameter of Co-Cr in right hip and Ceramic heads in left hip was performed in culture media. Ten thousand cycles of cyclic compression and rotation load (1.5kN to 0.15kN of compression and 12 degrees of rotation) to cartilage was applied at 1Hz (Figure 1). Culture media was analyzed for protein levels of inflammation related cytokines and amount of HA. Relative quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) from acetabular cartilage was performed as previously reported using specific primer sets for type II collagen, aggrecan, TNF-alpha, Interleukine-1 and 6, and MMP-1, 3, 13. Results. IL-1 beta protein level from culture media was significantly higher in Co-Cr than that in Ceramic (155+/−25.2 pg/ml vs. 86.3+/−9.6 pg/ml respectively). MMP-3 protein level had tendency to be higher in culture media from Co-Cr than that from Ceramic (16.3+/−10.6 ng/ml vs. 10.0+/−0.1 ng/ml respectively, p<0.05), however there was no significant difference. There were no significant differences of protein levels from culture media in MMP-1, IL-1a, and TNF between two groups. Amount of HA from culture media of Co-Cr group was significantly higher than that from Ceramic group (337+/−38.4 mg/ml versus 257+/−11.1 mg/ml respectively, p<0.05). Type II collagen mRNA expression was 3 times higher in Ceramic group than that in Co-Cr group. IL-1 beta mRNA expression was 4 times higher in Co-Cr group than that in Ceramic group. Other gene expression had no significant differences. Discussion. The present study showed that Co-Cr affects cartilage metabolism than Ceramic. Co-Cr group had higher protein level and mRNA expression of inflammation related cytokine, IL-1 beta, and higher HA. Concerning the mRNA expression from cartilage, type II collagen was significantly higher in Ceramic group. It has been reported that HA level is high in osteoarthritic joint. These report and our results showed that ceramic head have small detrimental effect on cartilage cell metabolism. There are limitations of the present study. Firstly, the sample size is small. Secondly, we did not evaluate synovial membrane metabolism

Introduction. Highly crosslinked ultrahigh-molecular-weight polyethylene (XLPE) reduces wear and osteolysis in total hip arthroplasty, but it is unclear if XLPE will provide the same clinical benefit in total knee arthroplasty (TKA). Adhesive and abrasive wear generally dominate in polyethylene acetabular components, whereas fatigue wear is an important wear mechanism in polyethylene TKA tibial inserts. The wear resistance of XLPE depends on the crosslink density of the material, which may decrease during in vivo mechanical loading, leading to more wear and increased oxidation. To examine this possibility, we measured crosslink density and oxidation levels in loaded and unloaded locations of retrieved tibial inserts to evaluate the short-term performance of XLPE material in TKA. Materials and Methods. Forty retrieved XLPE tibial inserts (23 remelted, 17 annealed) retrieved after a mean time of 18 ± 14 months were visibly inspected to identify loaded (burnished) and unloaded (unburnished) locations on the plateaus of each insert using a previously published damage mapping method. For each insert, four cubes (3 mm3) were cut from loaded and unloaded surface and subsurface locations (Fig. 1). Swell ratio testing was done according to ASTM F2214 to calculate crosslink density of the cubes. With a microtome, 200 μm sections were taken adjacent to the cubes and oxidation was assessed with Fourier transform infrared spectroscopy following ASTM F2102 (Fig. 2). Surface oxidation was measured in the sections adjacent the surface cubes and subsurface oxidation was measured in sections adjacent to the subsurface cubes. The effects of location (surface vs. subsurface in the loaded and unloaded regions) and thermal treatment (annealed vs. remelted) on crosslink density and oxidation were assessed with repeated measures generalized estimating equations (GEEs), with the implant treated as the repeated factor. Results are presented as means and 95% confidence intervals and the level of significance was α=0.05. Results. Crosslink density was associated with location within the polyethylene tibial inserts (p<0.001), while oxidation was associated with both location (p<0.001) and heat treatment (p=0.003). The loaded surface (location 1 in Fig. 1) had 13% lower crosslink density than all other locations (p<0.001 for each), and greater oxidation than all other locations (Fig. 3). Specifically, oxidation of the loaded surface was 0.29[0.17,0.40] greater (two times greater) than that of the unloaded surface (p < 0.001), whereas subsurface areas of loaded and unloaded regions differed by only 0.03[0.00,0.07] (p<0.022). Additionally, surface oxidation was over 7-fold greater than subsurface oxidation in the loaded region (difference: 0.56[0.44,0.68], p<0.001). Annealed XLPE had 2-fold greater oxidation than remelted XLPE (difference 0.159, 95% CI = 0.045, 0.126), and this was independent of location within the inserts. Conclusions. In vivo loading of XLPE decreased the crosslink density and increased the oxidation in areas that underwent wear and deformation at the articular surface of TKA inserts. Nonetheless, in these short term retrievals, no clinical complications were attributed to the change in material properties. However, if crosslink density continues to decrease with load over time, XLPE may not provide a clinical advantage over conventional polyethylene in TKA

Introduction:. There has been widespread concern regarding the adverse tissue reactions after metal-on-metal (MoM) total hip replacements (THR). Concerns have also been expressed with mechanical wear from micromotion and fretting corrosion at the head/stem taper junction in total hip replacements. In order to understand the interface mechanism a study was undertaken in order to investigate the effect of surface finish and contact area associated with modular tapers in total hip replacements with a single combination of materials of modular tapers. Methods:. An inverted hip replacement setup was used (ASTM F1875-98). 28 mm Cobalt Chrome (CoCr) femoral heads were coupled with either full length (standard) or reduced length (mini) 12/14 Titanium (Ti) stem tapers. These Ti stem tapers had either a rough or smooth surface finish whilst all the head tapers had a smooth surface finish. Wear and corrosion of taper surfaces were compared after samples were sinusoidally loaded between 0.1 kN and 3.1 kN for 10 million cycles at 4 Hz. In test 1 rough mini stem tapers were compared with rough standard stem tapers whilst in test 2 rough mini stem tapers were compared with smooth mini stem tapers. Surface parameters and profiles were measured before and after testing. Electrochemical static and dynamic corrosion tests were performed between rough mini stem tapers and smooth mini stem tapers under loaded and non-loaded conditions. Results:. In test 1 following the mechanical loading test the surface roughness parameters on the head taper were significantly increased when they were coupled with the mini stem tapers compared to the standard stem tapers (p = 0.046). Similarly in test 2 the surface roughness parameters on the head tapers were significantly increased when mini rough stem tapers were used compared to smooth mini stem tapers (p = 0.04). Corrosion testing showed breaching of the passive film on the rough but not the smooth neck tapers. Conclusion:. This study has identified enhanced fretting corrosion at the modular taper junction associated with roughened surface finish and small neck tapers and points to the overall concern associated with the use of modular taper connections in orthopaedic implants. Crevice corrosion is identified as the predominant mechanism, with evidence of pitting in all rough mini neck tapers. The greatest wear and corrosion was in the plane where the greatest bending moments were generated, implicating fretting as a mechanism. The rough mini neck tapers have a reduced surface area at the interface and ultimately bending forces are concentrated here

R Appleyard, Murray Maxwell Biomechanics Lab, Royal North Shore Hospital, Sydney. The fundamental mechanisms that underlie tendon breakdown are ill understood. There is an emerging hypothesis that altered mechanical strain modulates the metabolism and/or phenotype of tenocytes, disrupting the balance of matrix synthesis and degradation, and that rupture then occurs through an abnormal tendon matrix. The critically regulated genes have not yet been determined. We have developed sheep model in sheep where both stress-deprived and over-stressed areas can be examined in the one tendon, to evaluate the pathological and molecular changes over time. We have also used ‘wild type’ and genetically modified mice to determine the role of specific enzymes and proteoglycans in tendon degeneration. Stress-deprived and over-stressed regions showed classical changes of increased cellularity and vascularity, rounded tenocytes and interfascicular matrix infiltration. These structural changes resolved for up to one year after injury. Resolution was more rapid in over-stressed regions. Irrespective of the initiating stress, proteoglycan staining and chondroid metaplasia increased in tendon with time. There were distinct molecular and temporal differences between regions, which are reviewed here. While tendon degeneration has traditionally been regarded as a single field of change, our studies show that at a molecular level, the injured tendon may be regarded as a number of distinct regions—overloaded and underloaded, adjacent to bone or adjacent to muscle. Each region manifests distinct molecular changes, driven by relevant gene expression. While collagen metabolism in pathological tendon has received much attention, accumulation of proteoglycan is also consistently induced by altered mechanical loading. We suggest that ADAMTS enzymes, which cleave aggrecan, versican and small proteoglycans, may play a significant role in tendon homeostasis and pathology. Regulating proteoglycan turnover may represent a novel target for treating tendon degeneration. We have initiated studies using mesenchymal stem cells (MSC), not to directly augment healing but to modify the molecular pathology in tendon resulting from altered loading. Preliminary data indicates that injection of MSC into an acute tendon defect significantly abrogates the increase in expression of aggrecan and collagen degrading metalloproteinases in the adjacent over-stressed tendon. This may decrease the resultant degeneration. The effects of MSC in treating tendon degeneration are reviewed here, as are the possible benefits of radiofrequency microtenotomy

Major aspects on long-term outcome in Total Knee Arthroplasty are the correct alignment of the implant with the mechanical load axis, the rotational alignment of the components as well as good soft tissue balancing. To reduce the variability of implant alignment and at the same time minimise the invasiveness different computer assisted systems have been introduced. To achieve accuracy as high as those of a robotic system but with a pure mechanically adjustable cutting block, the Exactech GPS system has been developed. The new concept comprises a seamlessly planning and navigation screen with an integrated optical tracking system for fast and accurate acquisition and verification of anatomical landmarks within the sterile field as well as a tiny cutting guide for accurate transfer of the planned bone resections. Using a conventional screwdriver the cutting block could be accurately aligned with the planned resection by controlling the current position of the cutting block on the navigation screen. To save time, to maximise the ease of use and to minimize the surgeon's mental workload during adjustment, a smart screwdriver (SSD) has been developed being able to automatically adjust the screws. The basic idea of the smart screwdriver is to have a system providing an automatic transfer of the planned data to the cutting guide similar to a robotic system, but with the actuators separated from the kinematic. The use of the SSD is as simple as follows: After planning of the intervention and rigid fixation of the cutting guide on the bone, the surgeon simply connects sequentially the screwdriver to all screws of the cutting guide. To further maximise the ease of use and to avoid a mix-up of different screws, an identification means has been integrated into the positioning screws as well as into the smart screwdriver. For an automated identification of the screws different technologies have been analysed as position tracking, optical recognition or wired/wireless electronics. A first prototype without screw identification has been used successfully on 4 cadaver knees. All guide positions could be adjusted automatically using the SSD. However, the absence of screw identification required that the surgeon follows indications given by the computer to turn screws sequentially. A second prototype of the smart screwdriver has successfully been built up and is able to identify the different positioning screws in less than 1s with high reliability. The identification is realised as inductive coupling of different small resonance circuits that are integrated into the screw heads and the screwdrivers tip. To adjust the cutting guide from neutral to the planned position, the screws have to be adjusted by 5 mm in average. The rotational speed of the current SSD implementation is 2 rounds per second, resulting in a mean time of about 3.5 s for each screw adjustment. The rotational accuracy of the screwdriver is ±5°. Taking into account a thread of the positioning screws of 0.7 mm, the theoretical translational error is about ±0.01 mm. Looking at the angular accuracy, the maximum distance of the screws of the current setup of the cutting block of 15 mm results in an angular error of less than ±0.05°

INTRODUCTION. Glenosphere disengagement can be a potential serious default in reverse shoulder arthroplasty [1]. To ensure a good clinical outcome, it is important for the surgeon to obtain an optimal assembly of the glenosphere - base plate system during surgery. However interpositioning of material particles (bone, soft tissue) between the contact surface of the glenosphere and the base plate and/or a misalignment of the glenosphere relative to the base plate can result in a suboptimal assembly of the glenosphere – base plate system [2]. This misalignment is typically caused by unwanted contact between the glenosphere and the scapula due to inadequate reaming. Both defects prevent the Morse taper from fully engaging, leading to a system configuration for which the assembly was not designed to be loaded in vivo. This study quantifies the influence these defects have on the relative movement between the glenosphere and metaglene. MATERIALS AND METHODS. A biaxial test setup [Fig. 1] was developed to mechanically load the glenoidal assembly (base plate + glenosphere) of 5 Depuy. ®. Delta Xtend 38 prostheses. The setup allows applying a cyclic loading pattern to the glenoidal component with a constant actuator load of 750 N. Each of the 5 samples was tested for 5000 cycles on 3 defects: an interpositioning of 150 µm thick (0.48 mm. 3). and two local underreaming defects, pushing one side of the glenosphere up 0.5 mm and 1 mm respectively, hence causing a misalignment. The relative movement was recorded using 4 Linear Variable Differential Transducers (LVDTs). The cycling frequency is 1 Hz. RESULTS. A mean increase in relative movement of 26.84% (standard deviation: +- 18.2 %) and 38.04% (standard deviation +- 28.73%) was measured for respectively the 0.5 and 1 mm misalignment defect. The interpositioning of material with a thickness of 150 µm thick caused the relative movement between glenosphere and metaglene to increase by 38.5 % (standard deviation +-26.56 %). For each sample and each defect the changes in relative movement between an optimal assembly and the suboptimal assemblies were significant at the 1% level. DISCUSSION AND CONCLUSIONS. Relative cyclic movement between two components is an important wear and fatigue parameter. An increase in this parameter might lead to increased wear and fatigue problems. The results show how interpositioning and misalignment defects are linked to an important increase in relative cyclic movement between the glenosphere and metaglene and thus underline the importance of avoiding both defects leading to a suboptimal assembly during surgery

Functional joint stability and accurate component alignment are crucial for a successful clinical outcome after TKA. However, there are few methods to evaluate joint stability during TKA surgery. Activities of daily living often cause mechanical load to the knee joint not only in full extension but also in mid-flexion. Computer navigation systems are useful for intra-operative monitoring of joint positioning and movements. The purpose of this study was to compare the varus-valgus stability between knees treated with cruciate-retaining (CR) and posterior-stabilized (PS) TKA at different angles in the range of motion (ROM) especially in mid-flexion, using the navigation technique. Thirty two knees that underwent TKA with computer navigation technology (precisionN Knee Navigation Software version 4.0, Stryker, Kalamazoo, MI) were evaluated (CR:16; PS:16). The investigator gently applied physiologically allowable maximal manual varus-valgus stress to the knee without angular acceleration, while moving the leg from full extension to flexion, and the mechanical femoral-tibial angle was measured automatically by the navigation system at every 10 degrees throughout the ROM. This measurement cycle was repeated for 3 to 4 times, and maximal varus-valgus laxity was determined as the sum of varus and valgus stress angles for each of the predetermined knee flexion angles. The results of the navigated measurements were used to evaluate varus-valgus instability throughout the ROM and the differences in varus-valgus laxity between pre-TKA (Prior to bone cutting, after navigation registration and suturing of the joint capsule) and post-TKA(After confirming that the TKA components and inserts were firmly placed in an appropriate position, the surgical incision was completely closed). The differences in varus-valgus laxity between the CR and PS groups were compared using the Student's t-test. The knees examined showed the greatest preoperative laxity at 20 to 40 degrees of flexion, with no statistically significant difference between the CR and PS groups (See Figure 1). However, postoperative assessment revealed that PS knees had more varus-valgus laxity than CR knees at all ROM angles examined, and the differences were statistically significant in the flexion range of 10 to 70 degrees (See Figure.2). The differences between preoperative and postoperative joint laxity were analyzed separately for the CR and PS groups. After CR-TKA, joint laxity decreased across all degrees of knee flexion. The differences between preoperative and postoperative joint laxity were statistically significant for the flexion range of 110 to 120 degrees (See Figure.3). On the other hand, knees treated with PS-TKA showed an increase in joint laxity for the flexion range of 10 to 90 degrees. The differences between the preoperative and postoperative values were statistically significant for the flexion range of 10 to 20 degrees in PS-TKA (See Figure.4). We successfully evaluated varus-valgus laxity in this study using a navigation system. The results showed that PS knees had greater varus-valgus laxity than CR knees throughout the ROM, and the differences were statistically significant for the flexion range of 10 to 70 degrees. Altogether, we conclude that PS knees have more mid-flexion laxity than CR knees