Validation of CT image-based software for three-dimensional measurement of acetabular coverage profile.

BACKGROUND: Plain radiography, 2-dimensional (2D) magnetic resonance imaging (MRI), and computed tomography (CT) do not precisely display morphology and acetabular coverage in developmental dysplasia of the hip or pincer-type femoroacetabular impingement. Pelvic position and pelvic tilt affect assessment of the acetabular parameters, leading to misinterpretation. OBJECTIVE: We tested a 3-dimensional (3D) CT evaluation script to calculate the crossover sign (COS), acetabular coverage and morphology. METHODS: To test the method, we constructed a phantom pelvic model, in which the acetabulum was mounted at different coverages of the femoral head, and simulated a COS and the acetabular morphology. Additionally we examined the reliability and objectivity of this method in ten patients with CT scans of the pelvis for conditions unrelated to hip disorders. RESULTS: We obtained an average accuracy of the 3D CT evaluation script of -0.37∘ (range -3.84 to 3.88; SD ± 1.43) for morphology, and 0.002% (range -7.28% to 6.90%; SD ± 1.60%) for coverage of the femoral head. Significant correlation between the expected and calculated COS (p= 0.01) was found. CONCLUSIONS: Our 3D CT evaluation script permits precise evaluation of the acetabular coverage profile, the presence or absence of a COS and acetabular morphology, independent of patient positioning or pelvic tilt.

Exploring inter-subject anatomic variability using a population of patient-specific femurs and a statistical shape and intensity model.

This paper is motivated by the need to accurately and efficiently measure key periosteal and endosteal parameters of the femur, known to critically influence hip biomechanics following arthroplasty. The proposed approach uses statistical shape and intensity models (SSIMs) to represent the variability across a wide range of patients, in terms of femoral shape and bone density. The approach feasibility is demonstrated by using a training dataset of computer tomography scans from British subjects aged 25-106 years (75 male and 34 female). For each gender, a thousand new virtual femur geometries were generated using a subset of principal components required to capture 95% of the variance in both female and male training datasets. Significant differences were found in basic anatomic parameters between females and males: anteversion, CCD angle, femur and neck lengths, head offsets and radius, cortical thickness, densities in both Gruen and neck zones. The measured anteversion for female subjects was found to be twice as high as that for male subjects: 13 ± 6.4° vs. 6.3 ± 7.8° using the training datasets compared to 12.96 ± 6.68 vs. 5.83 ± 9.2 using the thousand virtual femurs. No significant differences were found in canal flare indexes. The proposed methodology is a valuable tool for automatically generating a large specific population of femurs, targeting specific patients, supporting implant design and femoral reconstructive surgery.

Inter-subject variability effects on the primary stability of a short cementless femoral stem.

This paper is concerned with the primary stability of the Furlong Evolution(®) cementless short stem across a spectrum of patient morphology. A computational tool is developed that automatically selects and positions the most suitable stem from an implant system made of a total of 48 collarless stems to best match a 3D model based on a library of CT femur scans (75 males and 34 females). Finite Element contact models of reconstructed hips, subjected to physiologically-based boundary constraints and peak loads of walking mode, were simulated using a coefficient of friction of 0.4 and an interference-fit of 50 µm. Maximum and average implant micromotions across the subpopulation were predicted to be 100±7 µm and 7±5 µm with ranges [15 µm, 350 µm] and [1 µm, 25 µm], respectively. The computed percentage of implant area with micromotions greater than reported critical values of 50 µm, 100 µm and 150 µm never exceeded 14%, 8% and 7%, respectively. To explore the possible correlations between anatomy and implant performance, response surface models for micromotion metrics were constructed. Detailed morphological analyses were conducted and a clear nonlinear decreasing trend was observed between implant average micromotion and both the metaphyseal canal flare indices and average densities in Gruen zones. The present study demonstrates that the primary stability and tolerance of the short stem to variability in patient anatomy were high, reducing the need for patient stratification. In addition, the developed tool could be utilised to support implant design and planning of femoral reconstructive surgery.

Chromodomain antagonists that target the polycomb-group methyllysine reader protein chromobox homolog 7 (CBX7).

We report here a peptide-driven approach to create first inhibitors of the chromobox homolog 7 (CBX7), a methyllysine reader protein. CBX7 uses its chromodomain to bind histone 3, lysine 27 trimethylated (H3K27me3), and this recognition event is implicated in silencing multiple tumor suppressors. Small trimethyllysine containing peptides were used as the basic scaffold from which potent ligands for disruption of CBX7-H3K27me3 complex were developed. Potency of ligands was determined by fluorescence polarization and/or isothermal titration calorimetry. Binding of one ligand was characterized in detail using 2D NMR and X-ray crystallography, revealing a structural motif unique among human CBX proteins. Inhibitors with a ∼200 nM potency for CBX7 binding and 10-fold/400-fold selectivity over related CBX8/CBX1 proteins were identified. These are the first reported inhibitors of any chromodomain.

The difference between stretching and splitting muscle trauma during THA seems not to play a dominant role in influencing periprosthetic BMD changes.

BACKGROUND: Periprosthetic bone adaptation in the proximal femur after total hip arthroplasty can result in reduced bone mineral density that may contribute to increased risk of aseptic loosening or fracture. Functional loading of the proximal femur postoperatively may depend upon the type of surgical muscle trauma - splitting or stretching - and is likely to influence the preservation of periprosthetic bone mineral. Since the maintenance of bone is known to be highly age and gender dependent, the aim of this study was to investigate the interplay between muscle trauma and age and gender influences on periprosthetic bone adaptation. METHODS: Ninet y-three patients were consecutively recruited into either a transgluteal (splitting) or anterolateral (stretching) surgical approach and examined 7 days and 12 months after an elective primary hip arthroplasty (Zweymüller Alloclassic stem), using dual-energy X-ray absorptiometry measurements to quantify proximal femoral bone mineral density. FINDINGS: The results indicate that neither gender, age nor surgical trauma type, but only the combination of age and gender, were significant predictors of postoperative remodelling rate, with younger men (<65) and older women exhibiting the largest bone atrophy. INTERPRETATION: This study has demonstrated that the difference between stretching and splitting surgical trauma to the muscles during total hip replacement does not play a dominant role in influencing periprosthetic bone mineral changes. However, this data does suggest that certain patient populations may particularly benefit from muscle and bone preserving procedures.

The direct lateral approach: impact on gait patterns, foot progression angle and pain in comparison with a minimally invasive anterolateral approach.

INTRODUCTION: Minimally invasive total hip arthroplasty has been successfully introduced in the past decade. Nevertheless, standard approaches such as the direct lateral approach are still commonly used in orthopaedic surgery due to easy handling, good intra-operative overview and low complication rates. However, a frequent occurrence of fatty atrophy within the anterior third of the gluteus medius muscle has been demonstrated when using the modified direct-lateral approach (mDL), which may be associated with a reduction in function, limitation of internal leg rotation, gait disorders and pain. The question addressed in this study is whether mDL-approach leads to unfavourable changes in foot progression angle (FPA), gait and to more postoperative pain compared with a minimally invasive anterolateral approach (ALMI). METHODS: Thirty patients with primary osteoarthritis of the hip were recruited for this study. All subjects received an uncemented THA (Alloclassic-Zweymüller stem, Allofit Cup, FA Zimmer), 15 through an ALMI-approach and 15 via the mDL-approach. Gait analyses were performed both preoperatively and 3 months after surgery to measure FPA, step length, stance duration, cadence and walking speed. Additionally, the Harris-Hip Score, pain according to the visual analogue scale and the Trendelenburg sign were evaluated. RESULTS: No influence of the surgical approach could be observed on the gait patterns or FPA. Furthermore, neither increased external rotation of the limb nor restriction of internal rotation during walking could be established. Pain and Harris-Hip Score did not diVer significantly between the two groups. CONCLUSION: In comparison with an ALMI approach, the mDL approach did not lead to a change in FPA postoperatively. No detrimental effect could be found on the gait pattern or pain after surgery. Based on these measurements, the minimally invasive anterolateral approach did not appear to provide functional benefits in outcome over the mDL approach. Consequently, both surgical approaches seem to be equally applicable approaches with good to very good functional results.

Ultrasound-based computer navigation of the acetabular component: a feasibility study.

INTRODUCTION: This feasibility study investigated the accuracy of anterior pelvic reference plane (APP) registration and acetabular cup orientation in two cadavers with different BMIs. METHOD: Five observers each registered the APP five times in the 2 cadavers (BMIs: 32 kg/m(2) and 25 kg/m(2)) using an ultrasound-based navigation system. By comparison against the CT-derived reference landmarks, the errors in determining the individual landmarks defining the APP, as well as the resulting errors in the orientation of the APP and the acetabular cup orientation were determined. RESULTS: Across all measurements obtained with the ultrasound navigation system, the errors in rotation and version in determining the APP were 0.5° ± 1.0° and -0.4° ± 2.0°, respectively. The cup abduction and anteversion errors determined from all measurements of the five investigators for both cadavers together were -0.1° ± 1.0° and -0.4° ± 2.7°, respectively. The data further demonstrated a high reproducibility of the measurements for the resulting cup adduction and anteversion angle. CONCLUSION: Our preliminary results confirm that ultrasound navigation is a highly accurate tool that allows a reproducible registration of the APP and thereby enables accurate and precise intraoperative determination of the acetabular cup orientation also in patients with increased BMI.

Reverse shoulder arthroplasty leads to significant biomechanical changes in the remaining rotator cuff.

OBJECTIVE: After reverse shoulder arthroplasty (RSA) external and internal rotation will often remain restricted. A postoperative alteration of the biomechanics in the remaining cuff is discussed as a contributing factor to these functional deficits. METHODS: In this study, muscle moment arms as well as origin-to-insertion distance (OID) were calculated using three-dimensional models of the shoulder derived from CT scans of seven cadaveric specimens. RESULTS: Moment arms for humeral rotation are significantly smaller for the cranial segments of SSC and all segments of TMIN in abduction angles of 30 degrees and above (p ≤ 0.05). Abduction moment arms were significantly decreased for all segments (p ≤ 0.002). OID was significantly smaller for all muscles at the 15 degree position (p ≤ 0.005), apart from the cranial SSC segment. CONCLUSIONS: Reduced rotational moment arms in conjunction with the decrease of OID may be a possible explanation for the clinically observed impaired external and internal rotation.

Influence of prosthesis design and implantation technique on implant stresses after cementless revision THR.

BACKGROUND: Femoral offset influences the forces at the hip and the implant stresses after revision THR. For extended bone defects, these forces may cause considerable bending moments within the implant, possibly leading to implant failure. This study investigates the influences of femoral anteversion and offset on stresses in the Wagner SL revision stem implant under varying extents of bone defect conditions. METHODS: Wagner SL revision stems with standard (34 mm) and increased offset (44 mm) were virtually implanted in a model femur with bone defects of variable extent (Paprosky I to IIIb). Variations in surgical technique were simulated by implanting the stems each at 4° or 14° of anteversion. Muscle and joint contact forces were applied to the reconstruction and implant stresses were determined using finite element analyses. RESULTS: Whilst increasing the implant's offset by 10 mm led to increased implant stresses (16.7% in peak tensile stresses), altering anteversion played a lesser role (5%). Generally, larger stresses were observed with reduced bone support: implant stresses increased by as much as 59% for a type IIIb defect. With increased offset, the maximum tensile stress was 225 MPa. CONCLUSION: Although increased stresses were observed within the stem with larger offset and increased anteversion, these findings indicate that restoration of offset, key to restoring joint function, is unlikely to result in excessive implant stresses under routine activities if appropriate fixation can be achieved.

In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer.

The objective of this study was to evaluate the tolerability, to establish a dosing regimen, and to evaluate the efficacy of intravesical docetaxel (DTX) formulations in a mouse model of bladder cancer. DTX in commercial formulation (Taxotere, DTX in Tween 80) or loaded in hyperbranched polyglycerols (HPGs) was evaluated. The synthesis and characterization of HPGs with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) in the shell and further functionalized with amine groups (HPG-C(8/10)-MePEG and HPG-C(8/10)-MePEG-NH(2)) is described. Intravesical DTX in either commercial or HPGs formulations (up to 1.0 mg/mL) was instilled in mice with orthotopic bladder cancer xenografts and was well tolerated with no apparent signs of local or systemic toxicities. Furthermore, a single dose of intravesical DTX (0.5 mg/mL) loaded in HPGs was significantly more effective in reducing the tumor growth in an orthotopic model of bladder cancer than the commercial formulation of Taxotere. In addition, DTX-loaded HPG-C(8/10)-MePEG-NH(2) was found to be more effective at lower instillation dose than DTX (0.2 mg/mL)-loaded HPG-C(8/10)-MePEG. Overall, our data show promising antitumor efficacy and safety in a recently validated orthotopic model of bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard intravesical therapy.

Synthesis and characterization of carboxylic acid conjugated, hydrophobically derivatized, hyperbranched polyglycerols as nanoparticulate drug carriers for cisplatin.

Hyperbranched polyglycerols (HPGs) with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) were synthesized and further functionalized with carboxylate groups to bind and deliver cisplatin. Low and high levels of carboxylate were conjugated to HPGs (HPG-C(8/10)-MePEG(6.5)-COOH(113) and HPG-C(8/10)-MePEG(6.5)-COOH(348)) and their structures were confirmed through NMR and FTIR spectroscopy and potentiometric titration. The hydrodynamic diameter of the HPGs ranged from 5-10 nm and the addition of COOH groups decreased the zeta potential of the polymers. HPG-C(8/10)-MePEG(6.5)-COOH(113) bound up to 10% w/w cisplatin, whereas HPG-C(8/10)-MePEG(6.5)-COOH(348) bound up to 20% w/w drug with 100% efficiency. Drug was released from HPG-C(8/10)-MePEG(6.5)-COOH(113) over 7 days at the same rate, regardless of the pH. Cisplatin release from HPG-C(8/10)-MePEG(6.5)-COOH(348) was significantly slower than HPG-C(8/10)-MePEG(6.5)-COOH(113) at pH 6 and 7.4, but similar at pH 4.5. Release of cisplatin into artificial urine was considerably faster than into buffer. Carboxylated HPGs demonstrated good biocompatibility, and drug-loaded HPGs effectively inhibited proliferation of KU-7-luc bladder cancer cells.

Release of membrane-bound vesicles and inhibition of tumor cell adhesion by the peptide Neopetrosiamide A.

BACKGROUND: Neopetrosiamide A (NeoA) is a 28-amino acid tricyclic peptide originally isolated from a marine sponge as a tumor cell invasion inhibitor whose mechanism of action is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that NeoA reversibly inhibits tumor cell adhesion, disassembles focal adhesions in pre-attached cells, and decreases the level of beta1 integrin subunits on the cell surface. NeoA also induces the formation of dynamic, membrane-bound protrusions on the surface of treated cells and the release of membrane-bound vesicles into the culture medium. Proteomic analysis indicates that the vesicles contain EGF and transferrin receptors as well as a number of proteins involved in adhesion and migration including: beta1 integrin and numerous alpha integrin subunits; actin and actin-binding proteins such as cofilin, moesin and myosin 1C; and membrane modulating eps15 homology domain (EHD) proteins. Surface labeling, trafficking inhibition, and real-time imaging experiments all suggest that beta1 integrin-containing vesicles are released directly from NeoA-induced cell surface protrusions rather than from vesicles generated intracellularly. The biological activity of NeoA is dependent on its disulfide bond pattern and NMR spectroscopy indicates that the peptide is globular with a continuous ridge of hydrophobic groups flanked by charged amino acid residues that could facilitate a simultaneous interaction with lipids and proteins in the membrane. CONCLUSIONS/SIGNIFICANCE: NeoA is an anti-adhesive peptide that decreases cell surface integrin levels through a novel, yet to be elucidated, mechanism that involves the release of adhesion molecule-containing vesicles from the cell surface.

Femoral neck cut level affects positioning of modular short-stem implant.

A trend in total hip arthroplasty surgery has been to design more bone-preserving procedures, especially for younger patients. This study investigated the final implant positioning of a short metaphyseal femoral neck type of implant to determine whether leg length, caput collum diaphysis (CCD) angle, and offset could be re-created with different levels of femoral neck resection. Ten cadaveric hips in 6 whole-body specimens were used, with 3 fiducial markers to allow registration of computer navigation points to computed tomography scan data. Three femoral neck resection levels were investigated: 0 mm, +5 mm (the recommended level of resection), and +10 mm from the base of the femoral neck. Results showed that the CCD angle was significantly higher with 0-mm neck cut and the offset was lower, whereas the highest neck cut had longer leg-length results. Surgeons who use a short metaphyseal stem need to realize the importance of a proper femoral neck cut to restore anatomic parameters as well as the possible benefit of computer-assisted surgery to restore these anatomic parameters during surgery.

Phage display and crystallographic analysis reveals potential substrate/binding site interactions in the protein secretion chaperone CsaA from Agrobacterium tumefaciens.

The protein CsaA has been proposed to function as a protein secretion chaperone in bacteria that lack the Sec-dependent protein-targeting chaperone SecB. CsaA is a homodimer with two putative substrate-binding pockets, one in each monomer. To test the hypothesis that these cavities are indeed substrate-binding sites able to interact with other polypeptide chains, we selected a peptide that bound to CsaA from a random peptide library displayed on phage. Presented here is the structure of CsaA from Agrobacterium tumefaciens (AtCsaA) solved in the presence and absence of the selected peptide. To promote co-crystallization, the sequence for this peptide was genetically fused to the amino-terminus of AtCsaA. The resulting 1.65 A resolution crystal structure reveals that the tethered peptide from one AtCsaA molecule binds to the proposed substrate-binding pocket of a symmetry-related molecule possibly mimicking the interaction between a pre-protein substrate and CsaA. The structure shows that the peptide lies in an extended conformation with alanine, proline and glutamine side chains pointing into the binding pocket. The peptide interacts with the atoms of the AtCsaA-binding pocket via seven direct hydrogen bonds. The side chain of a conserved pocket residue, Arg76, has an "up" conformation when the CsaA-binding site is empty and a "down" conformation when the CsaA-binding site is occupied, suggesting that this residue may function to stabilize the peptide in the binding cavity. The presented aggregation assays, phage-display analysis and structural analysis are consistent with AtCsaA being a general chaperone. The properties of the proposed CsaA-binding pocket/peptide interactions are compared to those from other structurally characterized molecular chaperones.

Influence of changes in stem positioning on femoral loading after THR using a short-stemmed hip implant.

BACKGROUND: Short-stemmed hip implants were introduced to conserve proximal bone mass and may facilitate the use of minimally invasive surgery, in which smaller incisions limit access to the joint. This limited access may increase the risk of surgical mal-positioning of the implant, however the sensitivity of femoral loading to such mal-positioning of a short-stemmed implant has not been studied. METHODS: Finite element models were developed of a femur and a short-stemmed implant positioned to reproduce the intact hip centre, as well as with the implant placed in increased anteversion or offset. The effect of these surgical variables on femoral loading was examined for walking and stair climbing using loads from a validated musculoskeletal model. Results of the implanted models were compared with an intact model to evaluate stress shielding. FINDINGS: Implant position had little influence on cortical strains along the length of the diaphysis, although strains decreased by up to 95% at the neck resection level compared to the intact femur. In the proximal Gruen zones I and VII strain energy density among the implanted models varied by up to 0.4 kJ/m(3) (28%) and 0.6 kJ/m(3) (24%) under walking and stair climbing, respectively. All implanted models showed characteristic proximal stress shielding, indicated by a decrease in strain energy density of up to 5.4 kJ/m(3) (69%) compared to the intact femur. INTERPRETATION: Small changes in stem placement would likely have little influence on the internal loading of the femur after bone ingrowth has been achieved, however a reduction in strain energy density and therefore stress shielding was seen even for a short-stemmed implant, which may have consequences for longer-term bone remodelling.

Intrinsic inhibition of the Hsp90 ATPase activity.

The molecular chaperone Hsp90 is required for the folding and activation of a large number of substrate proteins. These are involved in essential cellular processes ranging from signal transduction to viral replication. For the activation of its substrates, Hsp90 binds and hydrolyzes ATP, which is the key driving force for conformational conversions within the dimeric chaperone. Dimerization of Hsp90 is mediated by a C-terminal dimerization site. In addition, there is a transient ATP-induced dimerization of the two N-terminal ATP-binding domains. The resulting ring-like structure is thought to be the ATPase-active conformation. Hsp90 is a slow ATPase with a turnover number of 1 ATP/min for the yeast protein. A key question for understanding the molecular mechanism of Hsp90 is how ATP hydrolysis is regulated and linked to conformational changes. In this study, we analyzed the activation process structurally and biochemically with a view to identify the conformational limitations of the ATPase reaction cycle. We showed that the first 24 amino acids stabilize the N-terminal domain in a rigid state. Their removal confers flexibility specifically to the region between amino acids 98 and 120. Most surprisingly, the deletion of this structure results in the complete loss of ATPase activity and in increased N-terminal dimerization. Complementation assays using heterodimeric Hsp90 show that this rigid lid acts as an intrinsic kinetic inhibitor of the Hsp90 ATPase cycle preventing N-terminal dimerization in the ground state. On the other hand, this structure acts, in concert with the 24 N-terminal amino acids of the other N-terminal domain, to form an activated ATPase and thus regulates the turnover number of Hsp90.

The holo-form of the nucleotide binding domain of the KdpFABC complex from Escherichia coli reveals a new binding mode.

P-type ATPases are ubiquitously abundant enzymes involved in active transport of charged residues across biological membranes. The KdpB subunit of the prokaryotic Kdp-ATPase (KdpFABC complex) shares characteristic regions of homology with class II-IV P-type ATPases and has been shown previously to be misgrouped as a class IA P-type ATPase. Here, we present the NMR structure of the AMP-PNP-bound nucleotide binding domain KdpBN of the Escherichia coli Kdp-ATPase at high resolution. The aromatic moiety of the nucleotide is clipped into the binding pocket by Phe(377) and Lys(395) via a pi-pi stacking and a cation-pi interaction, respectively. Charged residues at the outer rim of the binding pocket (Arg(317), Arg(382), Asp(399), and Glu(348)) stabilize and direct the triphosphate group via electrostatic attraction and repulsion toward the phosphorylation domain. The nucleotide binding mode was corroborated by the replacement of critical residues. The conservative mutation F377Y produced a high residual nucleotide binding capacity, whereas replacement by alanine resulted in low nucleotide binding capacities and a considerable loss of ATPase activity. Similarly, mutation K395A resulted in loss of ATPase activity and nucleotide binding affinity, even though the protein was properly folded. We present a schematic model of the nucleotide binding mode that allows for both high selectivity and a low nucleotide binding constant, necessary for the fast and effective turnover rate realized in the reaction cycle of the Kdp-ATPase.

Structure-activity relationship studies optimizing the antiproliferative activity of novel cyclic somatostatin analogues containing a restrained cyclic beta-amino acid.

The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural alpha- and beta-amino acids. The N- fluorenylmethoxycarbonyl protected cyclic beta-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cbetaAA), for the replacement of the Phe(6)-Pro(1) moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] with the structure of l-363,301, a nearly perfect match of the betaII'-turn region with d-Trp in the i + 1 position was observed. The cyclic beta-amino acid cbetaAA is likely needed for the bioactive conformation of the peptide.

The influence of alignment on the musculo-skeletal loading conditions at the knee.

BACKGROUND AND AIM: High tibial osteotomies attempt to recreate physiologically normal joint loading. Previous studies have discussed the influence of mal-alignment on the distribution of static loads to the medial and lateral compartments of the knee. The aim of this study was to determine the influence of mal-alignment on the tibio-femoral loading conditions during dynamic activities. MATERIAL AND METHODS: Using a musculo-skeletal model of the lower limb, which had been previously validated with in vivo data, in this study we modified the alignment of the knee in four patients, from a normal position to the extremes of 8 degrees valgus and 10 degrees varus mal-alignment. The resulting tibio-femoral joint contact forces were examined while patients were walking and stair climbing. RESULTS: Varying the mal-alignment resulted in a highly individual response in joint loads. Deviations from the normal alignment produced an increase in loading, with valgus generating a more rapid increase in loading than a varus deformity of the same amount. Varus deformities of 10 degrees resulted in increases in peak contact force from an average of 3.3-times bodyweight (BW) up to a peak of 7.4 BW (+45% to +114%) while patients were walking, whilst increases of 15% up to 35% were determined for stair climbing. Increases of up to 140% were calculated at 8 degrees valgus during walking and up to 53% for stair climbing. CONCLUSION: This study demonstrated a clear dependence of the individual joint loads on axial knee alignment. Based on the sensitivity of joint loading to valgus mal-alignment, more than 3 degrees of over-correction of a varus deformity to valgus should be carefully reconsidered.