Repression motif in HSF1 regulated by phosphorylation.

The heat shock factor 1 (HSF1) is a transcription factor that itself is a sensor for stress and integrates various intrinsic or environmental stress sensing pathways. Thus HSF1 orchestrates the heat shock response (HSR) by translating these pathways into a distinct transcriptional program that aids the cells to cope with and adapt to proteotoxic stress. Although heavily researched the regulation of HSF1 activation is still not completely understood. A conserved reaction to stress is the hyperphosphorylation of the otherwise confined constitutive phosphorylated HSF1. Therefore, this stress specific phosphorylation is believed to be involved in the regulatory mechanism and hence, was and is focus of many studies, ascribing various effects to single phosphorylation sites. To gain additional insight into effects of phosphorylation, HSF1 carrying amino acid substitutions on up to 18 amino acids were tested for their transactivation potential on an HSR reporter plasmid. A pattern of eleven phosphor-mimicking and diminishing amino acid substitutions on well-known phosphorylation sites of HSF1 were introduced to produce transcriptional active [11 M(+)] or repressed [11 M(-)] phenotypes. It could be confirmed that heat activates HSF1 regardless of phosphorylation. Distinct cellular stress, obtained by chemical HSR inducers or mimicked by a constitutively active HSF1, showed clear differences in the activation potential of HSF1-11 M(+) and 11 M(-). Further refinement to the single amino acid level identified the S303/307 double-phosphorylation motif, wherein phosphorylation of S303 was sole responsible for the repressing effect. The effect could be reproduced in different cell lines and is not entirely based on degradation. A small repression motif could be dissociated from the HSF1 context, which is still capable of repressing the background transcription of a specifically designed reporter plasmid. Taken together these results indicate, that besides already described mechanisms of pS303/307 mediated repression of HSF1 activation, an additional mechanism repressing the transcriptional output of the entire HSE containing promoter is mediated by this small repressive motif.

Effect of Active and Passive Function of the Posterosuperior Rotator Cuff on Compensatory Muscle Loads in the Shoulder.

Background: Irreparable posterosuperior rotator cuff (PSRC) tears have been shown to result in shoulder pain and loss of function. Purpose/Hypothesis: The purpose of this study was to determine the effect of the loss of active or passive function of the PSRC on compensatory muscle loads in the deltoid and the remaining rotator cuff. It was hypothesized that both deactivation and resection of the PSRC would result in load increases in the remaining muscles and that resection of the PSRC would result in even higher required compensatory forces than would mere deactivation. Study Design: Controlled laboratory study. Methods: A total of 7 cadaveric shoulders were tested using a biomechanical shoulder simulator with 10 independently controlled actuators for various muscles (anterior, middle, and posterior deltoid; inferior and superior subscapularis; latissimus dorsi; pectoralis major; teres minor; supraspinatus; and infraspinatus) and 3-dimensional motion tracking. The muscle loads representing the latissimus dorsi and pectoralis major were each held constant, and the remaining muscle actuator forces required to abduct the arm in the scapular plane were determined. The actuator forces corresponding with arm elevation from 20° to 65° were compared at 5° increments for 3 testing conditions: (1) intact, active PSRC; (2) intact, deactivated PSRC; and (3) resected PSRC and shoulder capsule. Results: In both the deactivated and resected states, the teres minor showed a significant increase in required muscle forces through nearly the entire tested range of arm elevation compared to the active state. This was also the case for the subscapularis but only at higher elevation angles. The deltoid demonstrated increased muscle forces of at least 1 of its subunits between 25° and 55° of elevation when comparing the deactivated state or resected state to the active state. However, through nearly the entire range of elevation, no statistically significant differences were found between the deactivated and resected states for any of the actuator loads representing muscle forces. Conclusion: The loss of active function of the PSRC led to compensatory loads on the remaining rotator cuff and deltoid, regardless of the passive presence of the PSRC as a supposed subacromial spacer. Clinical Relevance: The findings encourage the exploration of treatment procedures that mimic the active function of the PSRC when the rotator cuff itself is irreparable.

Quantitative Comparison of HSF1 Activators.

The heat shock response (HSR) pathway is a highly conserved rescue mechanism, which protects the cells from harmful insults disturbing the cellular protein homeostasis via expression of chaperones. Furthermore, it was demonstrated to play crucial roles in various diseases like neurodegeneration and cancer. For neurodegenerative diseases, an overexpression of chaperones is a potential therapeutic approach to clear the cells from non-functional protein aggregates. Therefore, activators of the HSR pathway and its master regulator HSF1 are under close observation. There are numerous HSR activators published in the literature using different model systems, experimental designs, and readout assays. The aim of this work was to provide a quantitative comparison of a broad range of published activators using a newly developed HSF responsive dual-luciferase cell line. Contrary to natural target genes, which are regulated by multiple input pathways, the artificial reporter exclusively reacts to HSF activity. In addition, the results were compared to endogenous heat shock protein expression. As a result, great differences in the intensity of pathway activation were observed. In addition, a parallel viability assessment revealed high variability in the specificity of the drugs. Furthermore, the differences seen compared to published data indicate that some activators exhibit tissue-specific differences leading to interesting assumptions about the regulation of HSF1.

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Development and Multisite Assessment of a Novel Shoulder Motion Joint Simulator.

Multiple biomechanical shoulder simulators have been described in the literature, with a trend toward increasing complexity to better simulate clinical scenarios. Our objective was to develop an advanced, novel shoulder joint simulator and compare outcomes at two separate institutions, for a typical shoulder joint motion simulation. Identical shoulder simulators were developed & deployed at both institutions. Eight cadaveric upper extremities were tested by simulating actively controlled, arm elevation in the plane of the scapula for two sequential test conditions (intact and nondestructive simulated cuff-tear), each repeated for a total of five trials. Muscle forces and joint translations were recorded for both conditions. The intact condition was repeated following simulated cuff-tear to assess effect of testing order. Statistical analyses were aimed at assessing repeatability and reproducibility of results within specimens, between specimens, and between institutions. The highest average forces were observed for the middle deltoid (233N or 32.5% body weight (BW)), followed by infraspinatus (99.0N), and posterior deltoid (93.7N) muscles. Differentiation between test conditions was unhindered by variability between repeated trials. Data from testing repeated over time, and between the two institutions were not significantly different. The novel shoulder simulator produced repeatable results with low trial-to-trial variation and outcomes were comparable between the two institutions. The results demonstrated a consistent response in muscle forces and humeral translation for the simulated rotator cuff tear condition. Such advanced shoulder simulators could thus be used for evaluating and optimizing surgical interventions and implant strategies.

Scapular motion in the presence of rotator cuff tears: a systematic review.

BACKGROUND: Rotator cuff tears (RCTs) remain a significant source of pain and disability in the shoulder. Although much work has been done in the study of the effects of rotator cuff tears on glenohumeral joint motion, much less has been done in understanding the effect of rotator cuff tearing on scapular motion or activation. It remains unknown whether scapular dyskinesis is causative or adaptive. The purpose of this study was to systematically review the literature to determine the relationship between rotator cuff tear presence and size on scapular motion, and if rotator cuff repair restored normal motion. METHODS: A systematic review using PRISMA guidelines was accomplished to include all studies with biomechanical or clinical outcomes of scapular motion in the presence of RCTs. Studies were excluded if they involved shoulder arthroplasty, rotator cuff tendinopathy, or shoulder impingement without an RCT. From 530 initial references, 42 manuscripts were selected for full review and cross referenced. All studies were evaluated for inclusion and exclusion criteria. RESULTS: Sixteen studies including 335 rotator cuff tears were included in the final review. There were several findings of interest in the literature. First, although all studies demonstrated scapular dyskinesis, they did not report a consistent pattern of motion in the presence of an RCT. In general, scapular posterior tilt was decreased, and scapular upward rotation was increased, especially in large tears, but the literature was unclear as to whether this was a result of the RCT or an adaptive attempt to maintain elevation. Larger RCTs resulted in more pronounced scapular dysfunction, but there was significant variability within studies. Further, dyskinesis was confounded by pain with more abnormal movement in symptomatic vs. asymptomatic RCTs, the latter of which were not different from normal healthy controls. Four studies addressed the effect of RCT on scapular mechanics and found that repair consistently improved it compared to the normal side, but the time to normalization varied between 5 months and 2 years. CONCLUSION: Scapular motion is abnormal in the presence of an RCT, but the literature is inconsistent regarding a universally affected variable or consistent degree of scapular dysfunction in this setting. Furthermore, it remains unknown which changes are adaptive vs. pathologic. Understanding the relationship between rotator cuff tearing and scapular dyskinesis will require better biomechanical models that consider scapular dyskinesis in their design.

Association of exposure to manganese and fine motor skills in welders - Results from the WELDOX II study.

The aim of this study was to evaluate the effect of exposure to manganese (Mn) on fine motor functions. A total of 48 welders and 30 unexposed workers as controls completed questionnaires, underwent blood examinations, and a motor test battery. The shift exposure of welders to respirable Mn was measured with personal samplers. For all subjects accumulations of Mn in the brain were assessed with T1-weighted magnetic resonance imaging. Welders showed normal motor functions on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale part III. Furthermore welders performed excellent on a steadiness test, showing better results than controls. However, welders were slightly slower than controls in motor tests. There was no association between fine motor test results and the relaxation rates R1 in globus pallidus and substantia nigra as MRI-based biomarkers to quantify Mn deposition in the brain.

Modelling of exposure to respirable and inhalable welding fumes at German workplaces.

The International Agency for Research on Cancer classified welding fumes as carcinogenic to humans, and occupational exposure limits should be established to protect welders. The aim of this study is to estimate exposure levels to inhalable and respirable welding fumes by welding process to use them for exposure assessment in epidemiological studies and to derive occupational exposure limits. In total, 15,473 mass concentrations of inhalable and 9,161 concentrations of respirable welding fumes could be analyzed along with welding-related and sampling information, which were compiled in the German database MEGA between 1983 and 2016. In both particle-size fractions, model-based geometric means of the concentrations were estimated by welding process and material for frequently used welding processes adjusted for sampling time and median-centered for calendar years. The inhalable concentrations were approximately twice the respirable concentrations, with medians of 3 mg/m3 (inter-quartile range: 1.2-7.0 mg/m3) and 1.5 mg/m3 (inter-quartile range: < limit of detection -3.8 mg/m3), respectively. The adjusted geometric means of flux-cored arc welding, metal inert and active gas welding, shielded metal arc welding and torch cutting ranged from 0.9 to 2.2 mg/m3 for respirable welding fumes and from 2.3 to 4.7 mg/m3 for inhalable fumes. In both particle-size fractions, geometric means were between 0.1 and 0.9 mg/m3 when performing tungsten inert gas, autogeneous, resistance, laser, and plasma welding or spraying. Results derived from this large dataset are useful for a quantitative exposure assessment to estimate health risks of welders.

HSF1 mediated stress response of heavy metals.

The heat shock response (HSR) pathway is a highly conserved cellular stress response and mediated by its master regulator HSF1. Activation of the pathway results in the expression of chaperone proteins (heat shock proteins; HSP) to maintain protein homeostasis. One of the genes strongest upregulated upon stress is HSPA1A (HSP72). Heavy metals are highly toxic to living organisms and known as environmental contaminants, due to industrialisation. Furthermore, many of them are well-described inducers of the HSR pathway. Here we compare the effect of different heavy metals, concerning their potential to activate HSF1 with a sensitive artificial heat shock reporter cell line, consisting of heat shock elements (HSE). In general the responses of the artificial promoter to heavy metal stress were in good agreement with those of well-established HSF1 target genes, like HSPA1A. Nevertheless, differences were observable when effects of heat and heavy metal stress were compared. Whereas heat stress preferentially activated the HSE promoter, heavy metals more strongly induced the HSPA1A promoter. We therefore analysed the HSPA1A promoter in more detail, by isolating and mutating the HSEs. The results indicate that the importance of the individual binding sites for HSF1 is determined by their sequence similarity to the consensus sequence and their position relative to the transcription start site, but they were not differentially affected by heat or heavy metal stress. In contrast, we found that other parts of the HSPA1A promoter have different impact on the response under different stress conditions. In this work we provide deeper insights into the regulation of HSP72 expression as a well as a method to quantitatively and sensitively evaluate different stressor on their potential to activate HSF1.

Exposure to hexavalent chromium in welders: Results of the WELDOX II field study.

Objectives: Exposure to hexavalent chromium (Cr(VI)) has been primarily studied in chromate production. Here, we measured personal exposure to respirable Cr(VI) together with airborne and urinary Cr and Ni in welders to explore levels and associations between various measures of exposure. Methods: Shift concentrations of Cr(VI), Cr, and Ni were measured in respirable welding fumes in 50 men who used either gas metal arc welding (GMAW) (n = 24) or tungsten inert gas welding (TIG) (n = 19) as their major technique. Cr and Ni were determined in pre- and post-shift urine samples. Concentrations below the limit of quantification (LOQ) were multiply imputed. Spearman correlation coefficients (rs) were calculated with 95% confidence intervals (CIs) to explore associations between the exposure variables, and regression models were applied to estimate the effect of the parent metal on the urinary concentration. Results: Regarding the respirable Cr(VI), 62% of the measurements were below the LOQ, the 75th percentile was 0.50 µg m-3, and 8 out of 50 (16%) welders exceeded 1 µg m-3. The highest shift concentration that occurred as a result of shielded metal arc welding (SMAW) was 180 µg m-3. The Cr(VI) content in total Cr ranged from 4 to 82% (median 20%), although the concentration correlated with total Cr (rs 0.55, 95% CI 0.46; 0.64). The correlation between Cr(VI) and Ni was weaker (rs 0.42, 95% CI 0.34; 0.51) than that between total Cr and Ni in welding fumes (rs 0.83, 95% CI 0.74; 0.92). Both Cr(VI) and total Cr influenced the urinary Cr concentrations in post-shift samples (P = 0.0008 and P ≤ 0.0001, respectively). The airborne shift exposure was a weaker determinant than the Cr content in pre-shift urine samples, which strongly correlated with post-shift urinary Cr (rs 0.78, 95% CI 0.69; 0.87). Conclusions: The Cr(VI) content in total Cr varied considerably in welding fumes. The majority of welders using GMAW or TIG presented with shift concentrations of respirable Cr(VI) below 1 µg m-3. However, very high Cr(VI) concentrations may occur, for example in SMAW. The urinary concentration of total Cr, cannot be used to precisely determine the shift concentration of respirable Cr(VI) in welders.

Metabolites of the PAH diol epoxide pathway and other urinary biomarkers of phenanthrene and pyrene in workers with and without exposure to bitumen fumes.

PURPOSE: This study investigates the diol epoxide pathway of phenanthrene (PHE) together with phenolic metabolites of PHE and pyrene (PYR) in workers with and without exposure to bitumen fumes. METHODS: The metabolite concentrations were determined in urine samples collected from 91 mastic asphalt workers and 42 construction workers as reference group before and after shift. During shift, vapours and aerosols of bitumen were measured according to a German protocol in the workers' breathing zone. RESULTS: The median concentration of vapours and aerosols of bitumen in mastic asphalt workers was 6.3 mg/m3. Metabolite concentrations were highest in post-shift urines of smokers with bitumen exposure and showed an increase during shift. The Spearman correlations between the creatinine-adjusted concentrations of metabolites and vapours and aerosols of bitumen in non-smokers were weak (e.g. sum of Di-OH-PYR: 0.28) or negligible (e.g. 1,2-PHE-diol: 0.08; PHE-tetrol: 0.12). Metabolites from the diol epoxide pathway of PHE were excreted in higher concentrations than phenolic metabolites (post-shift, non-smoking asphalt workers: 1,2-PHE-diol 2.59 µg/g crea vs. sum of all OH-PHE 1.87 µg/g crea). 1,2-PHE-diol was weakly correlated with PHE-tetrol (Spearman coefficient 0.30), an endpoint of the diol epoxide pathway. By contrast, we found a close correlation between the sum of 1,6-DiOH-PYR and 1,8-DiOH-PYR with 1-OH-PYR (Spearman coefficient 0.76). CONCLUSIONS: Most urinary PAH metabolites were higher after shift in bitumen-exposed workers, although the association with bitumen was weak or negligible likely due to the small PAH content. The additional metabolites of PHE and PYR complete the picture of the complex metabolic pathways. Nevertheless, none of the PAH metabolites can be considered to be a specific biomarker for bitumen exposure.

Hazard banding in compliance with the new Globally Harmonised System (GHS) for use in control banding tools.

Many control banding tools use hazard banding in risk assessments for the occupational handling of hazardous substances. The outcome of these assessments can be combined with advice for the required risk management measures (RMMs). The Globally Harmonised System of Classification and Labelling of Chemicals (GHS) has resulted in a change in the hazard communication elements, i.e. Hazard (H) statements instead of Risk-phrases. Hazard banding schemes that depend on the old form of safety information have to be adapted to the new rules. The purpose of this publication is to outline the rationales for the assignment of hazard bands to H statements under the GHS. Based on this, this publication proposes a hazard banding scheme that uses the information from the safety data sheets as the basis for assignment. The assignment of hazard bands tiered according to the severity of the underlying hazards supports the important principle of substitution. Additionally, the set of assignment rules permits an exposure-route-specific assignment of hazard bands, which is necessary for the proposed route-specific RMMs. Ideally, all control banding tools should apply the same assignment rules. This GHS-compliant hazard banding scheme can hopefully help to establish a unified hazard banding strategy in the various control banding tools.

Device-length changes and implant function following surgical implantation of the KineSpring in cadaver knees.

INTRODUCTION: The KineSpring implant system has been shown to provide load reductions at the medial compartment of the knee, and has demonstrated clinical success in reducing pain and increasing function in patients with medial knee osteoarthritis. These results depend on the ability of the KineSpring to rotate, lengthen, and shorten to accommodate knee motions, and in response to knee position and loading. PURPOSE: The present study was undertaken to determine length changes of the implanted KineSpring in response to a range of knee positions, external knee loads, and placements by different orthopedic surgeons. MATERIALS AND METHODS: KineSpring system components were implanted in ten cadaver leg specimens by ten orthopedic surgeons, and absorber-length changes were measured under combined loading and in different positions of the knee. RESULTS AND CONCLUSION: Spring compression consistent with knee-load reduction, and device lengthening and shortening to accommodate knee loads and motions were seen. These confirm the functionality of the KineSpring when implanted medially to the knee.

Matrix segregation as the major cause for sample inhomogeneity in MALDI dried droplet spots.

The segregation in dried droplet MALDI sample spots was analyzed with regard to the matrix-to-sample ratio using optical microscopy, MALDI imaging mass spectrometry (MALDI MSI) and IR imaging spectroscopy. In this context, different polymer/matrix/solvent systems usually applied in the analysis of synthetic polymers were investigated. The use of typical matrix concentrations (10 mg mL⁻¹) in almost every case resulted in ring patterns, whereas higher concentrated matrix solutions always led to homogeneous sample spot layers. The data revealed that segregation is predominantly caused by matrix transport in the drying droplet, whereas polymer segregation seems to be only secondary.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometric imaging of synthetic polymer sample spots prepared using ionic liquid matrices.

RATIONALE: Polymer sample spots for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) prepared by the dried-droplet method often reveal ring formation accompanied by possible segregation of matrix and sample molecules as well as of the polymer homologs itself. Since the majority of sample spots are prepared by this simple and fast method, a matrix or sample preparation method that excludes such segregation has to be found. METHODS: Three different ionic liquid matrices based on conventionally used aromatic compounds for MALDI-TOF MS were prepared. The formation of ionic liquids was proven by (1) H NMR spectroscopy. MALDI-Imaging mass spectrometry was applied to monitor the homogeneity. RESULTS: Our results show a superior sample spot homogeneity using ionic liquid matrices. Spots could be sampled several times without visible differences in the mass spectra. A frequently observed loss of matrix in the mass spectrometer vacuum was not observed. The necessary laser irradiance was reduced, which resulted in less polymer fragmentation. CONCLUSIONS: Ionic liquid matrices can be used to overcome segregation, a typical drawback of conventional MALDI dried-droplet preparations. Homogeneous sample spots are easy to prepare, stable in the MS vacuum and, thereby, improve the reproducibility of MALDI.

The KineSpring(®) Knee Implant System: an implantable joint-unloading prosthesis for treatment of medial knee osteoarthritis.

Symptomatic medial compartment knee osteoarthritis (OA) is the leading cause of musculoskeletal pain and disability in adults. Therapies intended to unload the medial knee compartment have yielded unsatisfactory results due to low patient compliance with conservative treatments and high complication rates with surgical options. There is no widely available joint-unloading treatment for medial knee OA that offers clinically important symptom alleviation, low complication risk, and high patient acceptance. The KineSpring(®) Knee Implant System (Moximed, Inc, Hayward, CA, USA) is a first-of-its-kind, implantable, extra-articular, extra-capsular prosthesis intended to alleviate knee OA-related symptoms by reducing medial knee compartment loading while overcoming the limitations of traditional joint-unloading therapies. Preclinical and clinical studies have demonstrated excellent prosthesis durability, substantial reductions in medial compartment and total joint loads, and clinically important improvements in OA-related pain and function. The purpose of this report is to describe the KineSpring System, including implant characteristics, principles of operation, indications for use, patient selection criteria, surgical technique, postoperative care, preclinical testing, and clinical experience. The KineSpring System has potential to bridge the gap between ineffective conservative treatments and irreversible surgical interventions for medial compartment knee OA.

Unloading the osteoarthritic knee with a novel implant system.

Medial knee osteoarthritis (OA) is a common disorder often associated with pathologic joint loading. Insoles, braces, and high tibial osteotomy are OA treatments aimed at reducing medial joint loads, but their use and effectiveness are limited. The KineSpring System implant also intends to reduce knee loads in OA patients while overcoming those limitations. The current study was undertaken to test the implant's effect on loads at the knee. Six cadaver knees with Outerbridge Grade I-II medial OA were subjected to simulated gait using a kinematic test system. Knees were tested with and without the medial knee implant while thin film sensors measured medial and lateral femorotibial contact pressures. Significant medial compartment load reductions (134 ± 53 N [P = .002]) were found throughout the stance phase of gait in the treated knee. Significant total joint load decreases (91 ± 40 N [P = .002]) were also observed without substantial changes in lateral compartment loads. These significant reductions of medial and total intra-articular loads are also within clinically effective ranges of other unloading systems. This suggests that the KineSpring System could be a viable treatment for medial knee OA.

Quantitative analysis of polymer additives with MALDI-TOF MS using an internal standard approach.

MALDI-TOF MS is used for the qualitative analysis of seven different polymer additives directly from the polymer without tedious sample pretreatment. Additionally, by using a solid sample preparation technique, which avoids the concentration gradient problems known to occur with dried droplets and by adding tetraphenylporphyrine as an internal standard to the matrix, it is possible to perform quantitative analysis of additives directly from the polymer sample. Calibration curves for Tinuvin 770, Tinuvin 622, Irganox 1024, Irganox 1010, Irgafos 168, and Chimassorb 944 are presented, showing coefficients of determination between 0.911 and 0.990.

Evaluation of the safety of a novel knee load-bypassing device in a sheep model.

BACKGROUND: Unloading treatments for osteoarthritis of the knee, such as valgus braces, have been shown to reduce medial joint-loading and pain. The purpose of this preclinical study was to investigate the tissue response to an extracapsular implantable device (KineSpring System; Moximed, Hayward, California) that is designed to reduce loading across the medial compartment of the knee. METHODS: Eleven sheep were implanted with the KineSpring System, consisting of bases secured to the medial femoral and tibial cortices with bone screws and also consisting of a joint-spanning load-absorber composed of a piston and spring assembly inside a polymeric sheath. In nine sheep, titanium alloy washers with either an uncoated or a plasma-sprayed titanium-hydroxyapatite (TPS-HA) coated undersurface were fixed with screws to the contralateral femur and tibia to investigate the effects of surface treatment on extracortical bone apposition. The functionality of the KineSpring System was assessed by fluoroscopy, tissue response was determined by gross and microscopic histology, and implant fixation was determined by radiography, microradiography, and histomorphometry at four, twelve, twenty-six, and fifty-two weeks. RESULTS: The function of the KineSpring System was confirmed in all sheep. Seventeen of eighteen TPS-HA coated bases and thirty-six of thirty-six washers had stable bone fixation; one coated base was loose with evidence of infection. At four weeks, there was an early, expected inflammatory response, but this response resolved by twelve weeks and a pseudosynovial membrane formed around the sheath. Bone apposition increased over time for the TPS-HA coated bases and for uncoated washers (p < 0.05). There was good apposition of the TPS-HA coated washers even at early time points, with no subsequent increase in apposition over time. CONCLUSIONS: The KineSpring System demonstrated safety in a simulated use model for periods of up to fifty-two weeks. Screws result in stable implant fixation and TPS-HA coating allows for early and long-lasting cortical bone apposition and integration. CLINICAL RELEVANCE: This implant warrants further investigation as a means of reducing medial compartment loading and pain in patients with osteoarthritis of the knee.