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1.  Peri-implant Bone Strains and Micro-motion Following In-Vivo Service: A Postmortem Retrieval Study of 22 Tibial Components from Total Knee Replacements 
Biological adaptation following placement of total knee replacements (TKR) is known to affect peri-implant bone mineral density (BMD) and implant fixation. The goals of this project were to quantify the proximal tibial bone strain and implant-bone micro-motion for functioning postmortem retrieved TKRs and to assess the strain/micro-motion relationships with chronological (donor age and time in service) and patient (body weight and BMD) factors. Twenty-two tibial constructs were functionally loaded to one body weight (60% medial/40% lateral) and the proximal tibial bone strains and tray/bone micro-motion were measured using a digital image correlation system. Donors with more time in service had higher bone strains (p=0.044), but there was not a significant (p=0.333) contribution from donor age. Donors with lower peri-implant BMD (p=0.0039) and higher body mass (p=0.0286) had higher bone strains. Long term implants (> 11 years) had proximal bone strains (900 με) that were almost twice as high as short term (< 5 years) implants (570 με). Micro-motion was greater for younger donors (p=0.0161) and longer time in service (p=0.0008). Increased bone strain with long term in-vivo service could contribute to loosening of TKRs by failure of the tibial peri-implant bone.
doi:10.1002/jor.22534
PMCID: PMC4100998  PMID: 24277230
knee replacement; loosening; bone strain; postmortem; micro-motion
2.  Local Tissue Properties of Human Osteoarthritic Cartilage Correlate with Magnetic Resonance T1rho Relaxation Times 
Objective
The objective of this study is to examine the local relationship between T1ρ relaxation times and the mechanical behavior of human osteoarthritic articular cartilage using high-resolution magnetic resonance imaging (MRI) and local in situ microindentation.
Methods
Seven human tibial plateaus were obtained from patients who underwent total knee arthroplasty due to severe OA. Three to six sites were selected from each sample for visual classification using the ICRS Outerbridge scale (total thirty-six sites). Samples were imaged by MR, and the local distribution of T1ρ relaxation times were obtained at these selected sites. The elastic and the viscoelastic characteristics of the tissue were quantified non-destructively using dynamic microindentation to measure peak dynamic modulus, energy dissipation, and phase angle.
Results
Measured Outerbridge scores, MR T1ρ relaxation times and mechanical properties were highly heterogeneous across each cartilage surface. Site-specific measures of T1ρ relaxation times correlated significantly with the phase angle (p < 0.001; R = 0.908), a viscoelastic mechanical behavior of the cartilage.
Conclusions
The novel combination of high resolution MR imaging and microindentation allows the investigation of the local relationship between quantitative MRI and biomechanical properties in highly heterogeneous OA cartilage. These findings suggest that MRI T1ρ can provide a functional assessment of articular cartilage.
doi:10.1002/jor.21381
PMCID: PMC4092115  PMID: 21445940
cartilage; osteoarthritis; magnetic resonance imaging; tissue viscoelasticity; T1rho
3.  Electrospun Fibers as a Scaffolding Platform for Bone Tissue Repair 
The purpose of the study is to investigate the effects of electrospun fiber diameter and orientation on differentiation and ECM organization of bone marrow stromal cells (BMSCs), in attempt to provide rationale for fabrication of a periosteum mimetic for bone defect repair. Cellular growth, differentiation, and ECM organization were analyzed on PLGA-based random and aligned fibers using fluorescent microscopy, gene analyses, electron scanning microscopy (SEM), and multiphoton laser scanning microscopy (MPLSM). BMSCs on aligned fibers had a reduced number of ALP+ colony at day 10 as compared to the random fibers of the same size. However, the ALP+ area in the aligned fibers increased to a similar level as the random fibers at day 21 following stimulation with osteogenic media. Compared with the random fibers, BMSCs on the aligned fibers showed a higher expression of OSX and RUNX2. Analyses of ECM on decellularized spun fibers showed highly organized ECM arranged according to the orientation of the spun fibers, with a broad size distribution of collagen fibers in a range of 40nm to 2.4µm. Taken together, our data support the use of submicron-sized electrospun fibers for engineering of oriented fibrous tissue mimetic, such as periosteum, for guided bone repair and reconstruction.
doi:10.1002/jor.22367
PMCID: PMC4083683  PMID: 23580466
Electrospinning; Extracellular Matrix (ECM); periosteum
4.  Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice 
The osteocyte network is crucial for the response of bone to mechanical force. Within this network, connexin43 (Cx43) is thought to mediate the communication of osteocytes and osteoblasts among themselves and the exchange of small molecules with the extracellular milieu. Despite recent advances in understanding Cx43 role for the response of bone cells to mechanical stimulation, the contribution of Cx43 specifically in osteocytes to mechanotransduction in vivo is not well-known. We examined the anabolic response to ulnar axial loading of mice lacking Cx43 in osteocytes (Cx43ΔOt). Loading induced a greater increase in periosteal bone formation rate in Cx43ΔOt mice compared to control littermates, resulting from higher mineralizing surface and enhanced mineral apposition rate. Expression of β-catenin protein, a molecule implicated in mechanotransduction, was higher in bones from Cx43ΔOt mice, compared to littermate controls. In addition, MLO-Y4 osteocytic cells knocked-down for Cx43 exhibited higher β-catenin protein expression and enhanced response to mechanical stimulation. These findings suggest that osteocytes lacking Cx43 are “primed” to respond to mechanical stimulation and that absence of Cx43 in osteocytes unleashes bone formation, by a mechanism that might involve accumulation of β-catenin.
doi:10.1002/jor.22341
PMCID: PMC3663897  PMID: 23483620
connexin43; bone formation; mechanical loading; osteocyte; β-catenin
5.  Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration 
Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O2) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O2). Human disc cells grown at 20% O2 showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O2. Importantly, we demonstrated that treatment of accelerated aging Ercc1−/Δmice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1−/Δmice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.
doi:10.1002/jor.22320
PMCID: PMC3668354  PMID: 23389888
Aging; oxidative stress; reactive oxygen species (ROS); intervertebral discs; radical scavenger; nitroxide; matrix proteoglycan
6.  Synovial Fluid Concentrations and Relative Potency of Interleukin-1 alpha and beta in Cartilage and Meniscus Degradation 
Cartilage degeneration with osteoarthritis (OA) is believed to involve the activities of interleukin-1 (IL-1), which exists as alpha and beta isoforms. The goal of this study was to measure the concentrations of both isoforms of IL-1 in the synovial fluid of normal and spontaneously osteoarthritic porcine knees, and to test the hypothesis that physiologic concentrations of IL-1α and IL-1β exhibit different potencies in activating calcium signaling, the production of matrix metalloproteinases and nitric oxide, and the loss of proteoglycans and tissue mechanical properties in cartilage and meniscus. Median concentrations of IL-1α were 0.043 ng/mL with mild OA and 0.288 ng/mL with moderate OA, whereas IL-1β concentrations were 0.109 ng/mL with mild OA and 0.122ng/mL with moderate OA. Both isoforms induced calcium signaling in chondrocytes and meniscal cells at all concentrations. Overall, cartilage and meniscus catabolism was significantly more sensitive to IL-1α than IL-1β at concentrations of 1 ng/mL or less, while few differences were observed between the two forms at 10 ng/mL. These data provide a range of physiologic IL-1 concentrations that can serve as a framework for the comparison of various in vitro studies, as well as providing further insight for the development of anti-cytokine therapies for OA.
doi:10.1002/jor.22334
PMCID: PMC4037157  PMID: 23483596
post-traumatic arthritis; inflammation; fibrochondrocyte; MMP; glycosaminoglycan
7.  In Vivo Efficacy of Fresh vs. Frozen Osteochondral Allografts in the Goat at 6 Months is Associated with PRG4 Secretion 
The long-term efficacy of osteochondral allografts is due to the presence of viable chondrocytes within graft cartilage. Chondrocytes in osteochondral allografts, especially those at the articular surface that normally produce the lubricant proteoglycan-4 (PRG4), are susceptible to storage-associated death. The hypothesis of this study was that the loss of chondrocytes within osteochondral grafts leads to decreased PRG4 secretion, after graft storage and subsequent implant. The objectives were to determine the effect of osteochondral allograft treatment (FROZEN vs. FRESH) on secretion of functional PRG4 after (i) storage, and (ii) 6months in vivo in adult goats. FROZEN allograft storage reduced PRG4 secretion from cartilage by ~85% compared to FRESH allograft storage. After 6months in vivo, the PRG4-secreting function of osteochondral allografts was diminished with prior FROZEN storage by ~81% versus FRESH allografts and by ~84% versus non-operated control cartilage. Concomitantly, cellularity at the articular surface in FROZEN allografts was ~96% lower than FRESH allografts and non-operated cartilage. Thus, the PRG4-secreting function of allografts appears to be maintained in vivo based on its state after storage. PRG4 secretion may be not only a useful marker of allograft performance, but also a biological process protecting the articular surface of grafts following cartilage repair.
doi:10.1002/jor.22319
PMCID: PMC4076778  PMID: 23362152
osteochondral allografts; animal models; proteoglycan-4; superficial zone
8.  Grand Challenge Competition to Predict In Vivo Knee Loads 
Impairment of the human neuromusculoskeletal system can lead to significant mobility limitations and decreased quality of life. Computational models that accurately represent the musculoskeletal systems of individual patients could be used to explore different treatment options and ultimately to optimize clinical outcome. The most significant barrier to model-based treatment design is validation of model-based estimates of in vivo contact and muscle forces. This paper introduces an annual “Grand Challenge Competition to Predict In Vivo Knee Loads” based on a series of comprehensive publicly available in vivo data sets for evaluating musculoskeletal model predictions of contact and muscle forces in the knee. The data sets come from patients implanted with force-measuring tibial prostheses. Following a historical review of musculoskeletal modeling methods used for estimating knee muscle and contact forces, we describe the first two data sets used for the first two competitions and summarize four subsequent data sets to be used for future competitions. These data sets include tibial contact force, video motion, ground reaction, muscle EMG, muscle strength, static and dynamic imaging, and implant geometry data. Competition participants create musculoskeletal models to predict tibial contact forces without having access to the corresponding in vivo measurements, which are not released until after each year’s competition submissions. These blinded predictions provide an unbiased evaluation of the capabilities and limitations of musculoskeletal modeling methods. The paper concludes with a discussion of how these unique data sets can be used by the musculoskeletal modeling research community to improve the estimation of in vivo muscle and contact forces and ultimately to help make musculoskeletal models clinically useful.
doi:10.1002/jor.22023
PMCID: PMC4067494  PMID: 22161745
Musculoskeletal model validation; Total knee arthroplasty; Instrumented implant; Gait; Biomechanics
9.  EFFECT OF AXIAL TIBIAL TORQUE DIRECTION ON ACL RELATIVE STRAIN AND STRAIN RATE IN AN IN VITRO SIMULATED PIVOT LANDING 
Anterior cruciate ligament (ACL) injuries most frequently occur under the large loads associated with a unipedal jump landing involving a cutting or pivoting maneuver. We tested the hypotheses that internal tibial torque would increase the anteromedial (AM) bundle ACL relative strain and strain rate more than would the corresponding external tibial torque under the large impulsive loads associated with such landing maneuvers.
Twelve cadaveric female knees [mean (SD) age: 65.0 (10.5) years] were tested. Pretensioned quadriceps, hamstring and gastrocnemius muscle-tendon unit forces maintained an initial knee flexion angle of 15°. A compound impulsive test load (compression, flexion moment and internal or external tibial torque) was applied to the distal tibia while recording the 3-D knee loads and tibofemoral kinematics. AM-ACL relative strain was measured using a 3mm DVRT. In this repeated measures experiment, the Wilcoxon Signed-Rank test was used to test the null hypotheses with p<0.05 considered significant.
The mean (± SD) peak AM-ACL relative strains were 5.4±3.7 % and 3.1±2.8 % under internal and external tibial torque, respectively. The corresponding mean (± SD) peak AM-ACL strain rates reached 254.4±160.1 %/sec and 179.4±109.9 %/sec, respectively. The hypotheses were supported in that the normalized mean peak AM-ACL relative strain and strain rate were 70% and 42% greater under internal than external tibial torque, respectively (p=0.023, p=0.041).
We conclude that internal tibial torque is a potent stressor of the ACL because it induces a considerably (70%) larger peak strain in the AM-ACL than does a corresponding external tibial torque.
doi:10.1002/jor.21572
PMCID: PMC4048060  PMID: 22025178
cruciate ligament; strain; rate; torque
10.  Resurfacing with Chemically Modified Hyaluronic Acid and Lubricin for Flexor Tendon Reconstruction 
We assessed surface coating with carbodiimide derivatized hyaluronic acid combined with lubricin (cd-HA-Lubricin) as a way to improve extrasynovial tendon surface quality and, consequently, the functional results in flexor tendon reconstruction, using a canine in vivo model. The second and fifth flexor digitorum profundus tendons from 14 dogs were reconstructed with autologs peroneus longus (PL) tendons 6 weeks after a failed primary repair. One digit was treated with cd-HA-Lubricin, and the other was treated with saline as the control. Six weeks following grafting, the digits and graft tendons were functionally and histologically evaluated. Adhesion score, normalized work of flexion, graft friction in zone II, and adhesion breaking strength at the proximal repair site in zone III were all lower in the cd-HA-Lubricin treated group compared to the control group. The strength at the distal tendon/bone interface was decreased in the cd-HA-Lubricin treated grafts compared to the control grafts. Histology showed inferior healing in the cd-HA-Lubricin group at both proximal and distal repair sites. However, cd-HA-Lubricin treatment did not result in any gap or rupture at either the proximal or distal repair sites. These results demonstrate that cd-HA-Lubricin can eliminate graft adhesions and improve digit function, but that treatment may have an adverse effect on tendon healing.
doi:10.1002/jor.22305
PMCID: PMC3628950  PMID: 23335124
flexor tendon; graft; hyaluronic acid; lubricin; surface modification
11.  An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints 
As human lifespan increases so does the incidence of age-associated degenerative joint diseases, resulting in significant negative socioeconomic consequences. Osteoarthritis (OA) and intervertebral disc degeneration (IDD) are the most common underlying causes of joint-related chronic disability and debilitating pain in the elderly. Current treatment methods are generally not effective and involve either symptomatic relief with non-steroidal anti-inflammatory drugs and physical therapy or surgery when conservative treatments fail. The limitation in treatment options is due to our incomplete knowledge of the molecular mechanism of degeneration of articular cartilage and disc tissue. Basic understanding of the age-related changes in joint tissue is thus needed to combat the adverse effects of aging on joint health. Aging is caused at least in part by time-dependent accumulation of damaged organelles and macromolecules, leading to cell death and senescence and the eventual loss of multipotent stem cells and tissue regenerative capacity. Studies over the past decades have uncovered a number of important molecular and cellular changes in joint tissues with age. However, the precise causes of damage, cellular targets of damage, and cellular responses to damage remain poorly understood. The objectives of this review are (1) to provide an overview of the current knowledge about the sources of endogenous and exogenous damaging agents and how they contribute to age-dependent degenerative joint disease, and (2) highlight animal models of accelerated aging that could potentially be useful for identifying causes of and therapies for degenerative joint diseases.
doi:10.1002/jor.22204
PMCID: PMC3628921  PMID: 23483579
Synovial joints; intervertebral disc; DNA repair; aging; oxidative damage
12.  Are External Knee Load and EMG Measures Accurate Indicators of Internal Knee Contact Forces during Gait? 
Mechanical loading is believed to be a critical factor in the development and treatment of knee osteoarthritis. However, the contact forces to which the knee articular surfaces are subjected during daily activities cannot be measured clinically. Thus, the ability to predict internal knee contact forces accurately using external measures (i.e., external knee loads and muscle EMG signals) would be clinically valuable. This study quantifies how well external knee load and EMG measures predict internal knee contact forces during gait. A single subject with a force-measuring tibial prosthesis and post-operative valgus alignment performed four gait patterns (normal, medial thrust, walking pole, and trunk sway) to induce a wide range of external and internal knee joint loads. Linear regression analyses were performed to assess how much of the variability in internal contact forces was accounted for by variability in the external measures. Though the different gait patterns successfully induced significant changes in the external and internal quantities, changes in external measures were generally weak indicators of changes in total, medial, and lateral contact force. Our results suggest that when total contact force may be changing, caution should be exercised when inferring changes in knee contact forces based on observed changes in external knee load and EMG measures. Advances in musculoskeletal modeling methods may be needed for accurate estimation of in vivo knee contact forces.
doi:10.1002/jor.22304
PMCID: PMC3628973  PMID: 23280647
Knee osteoarthritis; Instrumented knee implant; Gait modification; Biomechanics; Knee adduction moment
13.  CARTILAGE-ON-CARTILAGE VS. METAL-ON-CARTILAGE IMPACT CHARACTERISTICS AND RESPONSES 
A common in vitro model for studying acute mechanical damage in cartilage is to impact an isolated osteochondral or cartilage specimen with a metallic impactor. The mechanics of a cartilage-on-cartilage (COC) impact, as encountered in vivo, are likely different than those of a metal-on-cartilage (MOC) impact. The hypothesis of this study was that impacted in vitro COC and MOC specimens would differ in their impact behavior, mechanical properties, chondrocyte viability, cell metabolism, and histologic structural damage. Osteochondral specimens were impacted with either an osteochondral plug or a metallic cylinder at the same delivered impact energy per unit area, and processed after 14 days in culture. The COC impacts resulted in about half of the impact maximum stress and a quarter of the impact maximum stress rate of change, as compared to the MOC impacts. The impacted COC specimens had smaller changes in mechanical properties, smaller decreases in chondrocyte viability, higher total proteoglycan content, and less histologic structural damage, as compared to the impacted MOC specimens. If metal-on-cartilage impact conditions are to be used for modeling of articular injuries and post-traumatic osteoarthritis, the differences between COC and MOC impacts must be kept in mind.
doi:10.1002/jor.22311
PMCID: PMC3740544  PMID: 23335281
Articular cartilage; biochemical analysis; histology; impact testing; post-traumatic osteoarthritis
14.  Pathokinematics of Precision Pinch Movement Associated with Carpal Tunnel Syndrome 
Purpose
Carpal tunnel syndrome (CTS) can adversely affect fine motor control of the hand. Precision pinch between the thumb and index finger requires coordinated movements of these digits for reliable task performance. This study examined the impairment upon precision pinch function affected by CTS during digit movement and digit contact.
Methods
Eleven CTS subjects and 11 able-bodied (ABL) controls donned markers for motion capture of the thumb and index finger during precision pinch movement (PPM). Subjects were instructed to repetitively execute the PPM task, and performance was assessed by range of movement, variability of the movement trajectory, and precision of digit contact.
Results
The CTS group demonstrated shorter path-length of digit endpoints and greater variability in inter-pad distance and most joint angles across the PPM movement. Subjects with CTS also showed lack of precision in contact points on the digit-pads and relative orientation of the digits at contact.
Conclusions
Carpal tunnel syndrome impairs the ability to perform precision pinch across the movement and at digit-contact. The findings may serve to identify deficits in manual dexterity for functional evaluation of CTS.
doi:10.1002/jor.22600
PMCID: PMC4010872  PMID: 24536036
Carpal tunnel syndrome; precision pinch; kinematics
15.  Influence of Biochemical Composition on Endplate Cartilage Tensile Properties in the Human Lumbar Spine 
Endplate cartilage integrity is critical to spine health and is presumably impaired by deterioration in biochemical composition. Yet, quantitative relationships between endplate biochemical composition and biomechanical properties are unavailable. Using endplate cartilage harvested from human lumbar spines (six donors, ages 51–67 years) we showed that endplate biochemical composition has a significant influence on its equilibrium tensile properties and that the presence of endplate damage associates with a diminished composition–function relationship. We found that the equilibrium tensile modulus (5.9±5.7 MPa) correlated significantly with collagen content (559±147 μg/mg dry weight, r2=0.35) and with the collagen/GAG ratio (6.0±2.1, r2=0.58). Accounting for the damage status of the adjacent cartilage improved the latter correlation (r2=0.77) and indicated that samples with adjacent damage such as fissures and avulsions had a diminished modulus–collagen/GAG relationship (p=0.02). Quasi-linear viscoelastic relaxation properties (C, t1, and t2) did not correlate with biochemical composition. We conclude that reduced matrix quantity decreases the equilibrium tensile modulus of human endplate cartilage and that characteristics of biochemical composition that are independent of matrix quantity, that is, characteristics related to matrix quality, may also be important.
doi:10.1002/jor.22516
PMCID: PMC4039641  PMID: 24273192
cartilage endplate; spine; low back pain; intervertebral disc degeneration; biomechanical properties
16.  Histological Confirmation and Biological Significance of Cartilage Canals Demonstrated Using High Field MRI in Swine at Predilection Sites of Osteochondrosis 
Cartilage canal vessels in epiphyseal cartilage have a pivotal role in the pathogenesis of osteochondrosis/osteochondritis dissecans. The present study aimed to validate high field magnetic resonance imaging (MRI) methods to visualize these vessels in young pigs. Osteochondral samples from the distal femur and distal humerus (predilection sites of osteochondrosis) of piglets were imaged post-mortem: (1) using susceptibility-weighted imaging (SWI) in an MRI scanner, followed by histological evaluation; and (2) after barium perfusion using μCT, followed by clearing techniques. In addition, both stifle joints of a 25-day-old piglet were imaged in vivo using SWI and gadolinium enhanced T1-weighted MRI, after which distal femoral samples were harvested and evaluated using μCT and histology. Histological sections were compared to corresponding MRI slices, and three-dimensional visualizations of vessels identified using MRI were compared to those obtained using μCT and to the cleared specimens. Vessels contained in cartilage canals were identified using MRI, both ex vivo and in vivo; their locations matched those observed in the histological sections, μCT images, and cleared specimens of barium-perfused tissues. The ability to visualize cartilage canal blood vessels by MRI, without using a contrast agent, will allow future longitudinal studies to evaluate their role in developmental orthopedic disease.
doi:10.1002/jor.22449
PMCID: PMC4034470  PMID: 23939946
cartilage; cartilage canal; susceptibility weighted imaging; MRI; osteochondrosis
17.  Modulation of Endochondral Development of the Distal Femoral Condyle by Mechanical Loading 
Although previous theoretical modeling studies have predicted that various mechanical stresses accelerate or inhibit the ossification process of the neonatal chondroepiphysis, there is a paucity of experimental data to verify these models. The present study was designed to provide experimental evidence on whether the ossification of the chondroepiphysis is modulated by mechanical loading on the distal femoral condyle explant of the neonatal (5-day-old) rabbit in organ culture. Upon aseptic dissection, the right condyle explant was immersed in and fixated to an organ culture system, and received cyclic forces at 200 mN and 1 Hz for 12 h (N = 8) directly on its slightly convex articular surface, whereas the contralateral, left condyle explant was immersed separately in organ culture (N = 8). Subsequently, both loaded and control explants were placed in a bioreactor rotating at 20 rpm for 72 h. In each mechanically loaded specimen, a structure reminiscent of the secondary ossification center (SOC) appeared with an average area of 1.17 ± 0.13 mm2, or 15.2 ± 8.2% of the total epiphysis area. In contrast, no SOC was detected in any of the unloaded contralateral control specimens. The SOC in mechanically loaded specimens was stained intensively with fast green, whereas either the rest of the loaded epiphysis or the entire control epiphysis was stained intensely to safranin-O but lacked fast green staining. Immunolocalization revealed that the SOC of the mechanically loaded specimens expressed Runx 2 and osteopontin, both of which were absent in the unloaded control specimens. Type X collagen was expressed surrounding hypertrophic chondrocytes adjacent to the SOC, but was absent in the control specimen. Type II collagen and decorin were absent in the SOC of the loaded specimen, but were expressed throughout the rest of the loaded epiphysis and the unloaded control epiphysis. The intensity of type II collagen and decorin expression was significantly stronger among hypertrophic chondrocytes surrounding the SOC than the control. The numbers of hypertrophic chondrocytes surrounding the SOC and superior to metaphyseal bone were significantly higher in the loaded specimens than the unloaded controls. Taken together, mechanical stresses accelerate the formation of the secondary ossification center, and therefore modulate endochondral ossification.
doi:10.1002/jor.20024
PMCID: PMC4035017  PMID: 16435356
osteoblast; chondrocyte; joint; Runx2; decorin
18.  Mechanical effectiveness of lateral foot wedging in medial knee osteoarthritis after one year of wear 
Purpose
The use of lateral foot wedging in the management of medial knee osteoarthritis is under scrutiny. Interestingly, there have been minimal efforts to evaluate biomechanical effectiveness with long term use. Therefore, we aimed to evaluate dynamic knee loading (assessed using the knee adduction moment) and other secondary gait parameters in patients with medial knee osteoarthritis wearing lateral foot wedging at a baseline visit and after 1 year of wear.
Methods
3-dimensional gait data were captured in an intervention group of 19 patients with symptomatic medial knee osteoarthritis wearing their prescribed laterally wedged foot orthoses at 0 and 12 months. Wedge amounts were prescribed based on symptom response to a step-down test. A control group of 19 patients wearing prescribed neutral orthoses were also captured at 0 and 12 months. The gait of the intervention group wearing neutral orthoses was additionally captured. Walking speed and shoes were controlled. Analyses of variance were conducted to examine for group-by-time (between the groups in their prescribed orthoses) and condition-by-time (within the intervention group) interactions, main effects, and simple effects.
Results
We observed increased knee adduction moments and frontal plane motion over time in the control group but not the intervention group. Further, within the intervention group, the mechanical effectiveness of the lateral wedging did not decrease.
Conclusions
In patients with medial knee osteoarthritis, the effects of lateral foot wedging on pathomechanics associated with medial knee osteoarthritis were favorable and sustained over time.
doi:10.1002/jor.22252
PMCID: PMC4026192  PMID: 23097326
19.  Periprosthetic Osteolysis: Characterizing the innate immune response to titanium wear-particles 
Osteolysis of bone following total hip replacements is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1β (IL-1β). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, has been shown to signal the cleavage of pro-IL-1β into its mature, secreted form, IL-1β. Here we show that titanium particles stimulate the NALP3 inflammasome. We demonstrate that titanium induces IL-1β secretion from macrophages and this response is dependent on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also show that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response is dependent on the expression of the IL-1 receptor and IL-1α/β. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle-induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1β secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist based-therapies for implant osteolysis.
doi:10.1002/jor.21149
PMCID: PMC4011639  PMID: 20872576
Titanium; inflammasome; neutrophils; IL-1; NALP3
20.  Effect of Return to Overuse Activity Following an Isolated Supraspinatus Tendon Tear on Adjacent Intact Tendons and Glenoid Cartilage in a Rat Model 
Rotator cuff tears are common conditions that can alter shoulder mechanics and may lead to damage of intact joint tissues. These injuries are of particular concern in populations who perform tasks requiring repetitive overhead activity (e.g., athletes and laborers) and who are likely to return to aggressive pre-injury activity levels despite limited understanding of the potentially damaging effects on the remaining tissues. Therefore, we investigated the effect of returning to overuse activity following a supraspinatus tear on shoulder function and the mechanical properties of the remaining intact tendons and glenoid cartilage. Forty rats underwent 4 weeks of overuse activity to create a tendinopathic condition followed by detachment of the supraspinatus tendon and were then randomized into two groups: continued overuse or cage activity. Ambulatory measurements were performed throughout the 8 weeks prior to euthaniasia, and properties of the adjacent tendons and cartilage were evaluated. Results demonstrated that shoulder function was not compromised in the return to overuse group. However, alterations of the glenoid cartilage and biceps tendon properties occurred. Our results help define the contributory roles of common mechanical injury mechanisms and provide a framework by which physicians could better prescribe long-term treatment strategies for patients.
doi:10.1002/jor.22295
PMCID: PMC3641891  PMID: 23280495
rotator cuff; animal model; overuse injury
21.  Evaluation of factors affecting tibial bone strain after unicompartmental knee replacement 
Persistent pain is an important cause of patient dissatisfaction after unicompartmental knee replacement (UKR) and has been correlated with localised tibial strain. However, the factors that influence these strains are not well understood. To address this issue, we created finite element models to examine the effect on tibial strain of: (1) muscle forces (estimated using instrumented knee data) acting on attachment sites on the proximal tibia, (2) UKR implantation, (3) loading position, and (4) changes in gait pattern. Muscle forces acting on the tibia had no significant influence on strains within the periprosthetic region, but UKR implantation increased strain by 20%. Strain also significantly increased if the region of load application was moved >3 mm medially. The strain within the periprosthetic region was found to be dependent on gait pattern and was influenced by both medial and lateral loads, with the medial load having a greater effect (regression coefficients: medial=0.74, lateral=0.30). These findings suggest that tibial strain is increased after UKR and may be a cause of pain. It may be possible to reduce pain through modification of surgical factors or through altered gait patterns.
doi:10.1002/jor.22283
PMCID: PMC3602347  PMID: 23192787
Finite Element; Pain; Simulation; Unicompartmental; Knee
22.  Disruption of the Anterior–Posterior Rotator Cuff Force Balance Alters Joint Function and Leads to Joint Damage in a Rat Model 
The rotator cuff assists in shoulder movement and provides dynamic stability to the glenohumeral joint. Specifically, the anterior–posterior (AP) force balance, provided by the subscapularis anteriorly and the infraspinatus and teres minor posteriorly, is critical for joint stability and concentric rotation of the humeral head on the glenoid. However, limited understanding exists of the consequences associated with disruption of the AP force balance (due to tears of both the supraspinatus and infraspinatus tendons) on joint function and joint damage. We investigated the effect of disrupting the APforce balance on joint function and joint damage in an overuse rat model. Twenty-eight rats underwent 4 weeks of overuse to produce a tendinopathic condition and were then randomized into two surgical groups: Detachment of the supraspinatus only or detachment of the supraspinatus and infraspinatus tendons. Rats were then gradually returned to their overuse protocol. Quantitative ambulatory measures including medial/lateral, propulsion, braking, and vertical forces were significantly different between groups. Additionally, cartilage and adjacent tendon properties were significantly altered. These results identify joint imbalance as a mechanical mechanism for joint damage and demonstrate the importance of preserving rotator cuff balance when treating active cuff tear patients.
doi:10.1002/jor.22586
PMCID: PMC4006275  PMID: 24464961
force couple; rotator cuff; animal model
23.  Effect of rhBMP-2 and VEGF in a Vascularized Bone Allotransplant Experimental Model Based on Surgical Neoangiogenesis 
We have demonstrated survival of living allogeneic bone without long-term immunosuppression using short-term immunosuppression and simultaneous creation of an autogenous neoagiogenic circulation. In this study bone morphogenic protein-2 (rhBMP-2), and/or vascular endothelial growth factor (VEGF), were used to augment this process. Femoral diaphyseal bone was transplanted heterotopically from 46 Dark Agouti to 46 Lewis rats. Microvascular repair of the allotransplant nutrient pedicle was combined with intra-medullary implantation of an autogenous saphenous arteriovenous (AV) bundle and biodegradable microspheres containing buffer (control), rhBMP-2 or rhBMP-2 + VEGF. FK-506 given daily for 14 days maintained nutrient pedicle flow during angiogenesis. After an 18 weeks survival period, we measured angiogenesis (capillary density) from the AV bundle and cortical bone blood flow. Both measures were greater in the combined (rhBMP-2 + VEGF) group than rhBMP-2 and control groups (p<0.05). Osteoblast counts were also higher in the rhBMP-2 + VEGF group (p<0.05). A trend towards greater bone formation was seen in both rhBMP2 + VGF and rhBMP2 groups as compared to controls (p=0.059). Local administration of VEGF and rhBMP-2 augments angiogenesis, osteoblastic activity and bone blood flow from implanted blood vessels of donor origin in vascularized bone allografts.
doi:10.1002/jor.22277
PMCID: PMC3972920  PMID: 23192572
bone; allotransplantation; microspheres; BMP; VEGF
24.  Structural, Compositional, and Biomechanical Alterations of the Lumbar Spine in Rats with Mucopolysaccharidosis Type VI (Maroteaux–Lamy Syndrome) 
Mucopolysaccharidosis (MPS) VI is an inherited lysosomal storage disorder resulting from deficiency of N-acetylgalactosamine-4-sulfatase activity and subsequent accumulation of incompletely degraded dermatan sulfate (DS) containing glycosaminoglycans (GAGs). Painful spinal deformities are commonly found in MPS VI patients. We characterized lumbar spine structure, composition, and biomechanics in a naturally occurring rat MPS VI model and evaluated the role of MMP-13, ADAMTS-5 and TNF-α in modulating the observed changes. MPS VI rats had discs with large vacuolated cells and sizable nuclear defects. MPS spine segments also had structural and functional changes suggestive of spinal instability, including decreased nuclear pressurization, increased joint laxity and increased disc height index. These functional changes were at least partly associated with elevated ADAMTS-5, MMP-13, and TNF-α. Vertebral and endplate biomechanics were also affected by MPS VI with decreased failure load and stiffness. The discal and vertebral dysfunctions observed in MPS VI rats are likely to be associated with pathological spinal conditions, similar to those that afflict MPS patients. Our findings also suggest more broadly that abnormal accumulation of GAGs and the associated chronic pro-inflammatory and catabolic cascade may also be a source of spinal dysfunction.
doi:10.1002/jor.22281
PMCID: PMC3645935  PMID: 23192728
mucopolysaccharidosis VI; biomechanical properties; TNF-α; MMP-13; ADAMTS-5
25.  The Native Cell Population Does Not Contribute to Central-Third Graft Healing at 6, 12 or 26 Weeks in the Rabbit Patellar Tendon 
Investigators do not yet understand the role of intrinsic tendon cells in healing at the tendon-to-bone enthesis. Therefore, our first objective was to understand how the native cell population influences tendon autograft incorporation in the central-third patellar tendon defect site. To do this, we contrasted the histochemical and biomechanical properties of de-cellularized patellar tendon autograft (dcPTA) and patellar tendon autograft (PTA) repairs in the skeletally mature New Zealand white rabbit. Recognizing that soft tissues in many animal models require up to 26 weeks to incorporate into bone, our second objective was to investigate how recovery time affects enthesis formation and graft tissue biomechanical properties. Thus, we examined graft structure and mechanics at 6, 12, and 26 weeks post-surgery. Our results showed that maintaining the native cell population produced no histochemical or biomechanical benefit at 6, 12 or 26 weeks. These findings suggest that PTA healing is mediated more by extrinsic rather than intrinsic cellular mechanisms. Moreover, while repair tissue biomechanical properties generally increased from 6 to 12 weeks after surgery, no further improvements were noted up to 26 weeks.
doi:10.1002/jor.22261
PMCID: PMC3586979  PMID: 23138453
Patellar tendon; intrinsic healing; enthesis

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