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Bone & Joint Research
Vol. 6, Issue 12 | Pages 640 - 648
1 Dec 2017
Xia B Li Y Zhou J Tian B Feng L

Objectives. Osteoporosis is a chronic disease. The aim of this study was to identify key genes in osteoporosis. Methods. Microarray data sets GSE56815 and GSE56814, comprising 67 osteoporosis blood samples and 62 control blood samples, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in osteoporosis using Limma package (3.2.1) and Meta-MA packages. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify biological functions. Furthermore, the transcriptional regulatory network was established between the top 20 DEGs and transcriptional factors using the UCSC ENCODE Genome Browser. Receiver operating characteristic (ROC) analysis was applied to investigate the diagnostic value of several DEGs. Results. A total of 1320 DEGs were obtained, of which 855 were up-regulated and 465 were down-regulated. These differentially expressed genes were enriched in Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, mainly associated with gene expression and osteoclast differentiation. In the transcriptional regulatory network, there were 6038 interactions pairs involving 88 transcriptional factors. In addition, the quantitative reverse transcriptase-polymerase chain reaction result validated the expression of several genes (VPS35, FCGR2A, TBCA, HIRA, TYROBP, and JUND). Finally, ROC analyses showed that VPS35, HIRA, PHF20 and NFKB2 had a significant diagnostic value for osteoporosis. Conclusion. Genes such as VPS35, FCGR2A, TBCA, HIRA, TYROBP, JUND, PHF20, NFKB2, RPL35A and BICD2 may be considered to be potential pathogenic genes of osteoporosis and may be useful for further study of the mechanisms underlying osteoporosis. Cite this article: B. Xia, Y. Li, J. Zhou, B. Tian, L. Feng. Identification of potential pathogenic genes associated with osteoporosis. Bone Joint Res 2017;6:640–648. DOI: 10.1302/2046-3758.612.BJR-2017-0102.R1


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 4 | Pages 520 - 526
1 Apr 2008
Yau WP Leung A Liu KG Yan CH Wong LS Chiu KY

We have investigated the errors in the identification of the transepicondylar axis and the anteroposterior axis between a minimally-invasive and a conventional approach in four fresh-frozen cadaver knees. The errors in aligning the femoral prosthesis were compared with the reference transepicondylar axis as established by CT. The error in the identification of the transepicondylar axis was significantly higher in the minimal approach (4.5° of internal rotation, . sd. 4) than in the conventional approach (3° of internal rotation, . sd. 4; p < 0.001). The errors in identifying the anteroposterior axis in the two approaches were 0° (. sd. 5) and 1.8° (. sd. 5) of internal rotation, respectively (p < 0.001)


Bone & Joint Research
Vol. 5, Issue 12 | Pages 594 - 601
1 Dec 2016
Li JJ Wang BQ Fei Q Yang Y Li D

Objectives. In order to screen the altered gene expression profile in peripheral blood mononuclear cells of patients with osteoporosis, we performed an integrated analysis of the online microarray studies of osteoporosis. Methods. We searched the Gene Expression Omnibus (GEO) database for microarray studies of peripheral blood mononuclear cells in patients with osteoporosis. Subsequently, we integrated gene expression data sets from multiple microarray studies to obtain differentially expressed genes (DEGs) between patients with osteoporosis and normal controls. Gene function analysis was performed to uncover the functions of identified DEGs. Results. A total of three microarray studies were selected for integrated analysis. In all, 1125 genes were found to be significantly differentially expressed between osteoporosis patients and normal controls, with 373 upregulated and 752 downregulated genes. Positive regulation of the cellular amino metabolic process (gene ontology (GO): 0033240, false discovery rate (FDR) = 1.00E + 00) was significantly enriched under the GO category for biological processes, while for molecular functions, flavin adenine dinucleotide binding (GO: 0050660, FDR = 3.66E-01) and androgen receptor binding (GO: 0050681, FDR = 6.35E-01) were significantly enriched. DEGs were enriched in many osteoporosis-related signalling pathways, including those of mitogen-activated protein kinase (MAPK) and calcium. Protein-protein interaction (PPI) network analysis showed that the significant hub proteins contained ubiquitin specific peptidase 9, X-linked (Degree = 99), ubiquitin specific peptidase 19 (Degree = 57) and ubiquitin conjugating enzyme E2 B (Degree = 57). Conclusion. Analysis of gene function of identified differentially expressed genes may expand our understanding of fundamental mechanisms leading to osteoporosis. Moreover, significantly enriched pathways, such as MAPK and calcium, may involve in osteoporosis through osteoblastic differentiation and bone formation. Cite this article: J. J. Li, B. Q. Wang, Q. Fei, Y. Yang, D. Li. Identification of candidate genes in osteoporosis by integrated microarray analysis. Bone Joint Res 2016;5:594–601. DOI: 10.1302/2046-3758.512.BJR-2016-0073.R1


Orthopaedic Proceedings
Vol. 99-B, Issue SUPP_2 | Pages 68 - 68
1 Jan 2017
Schneiderova P Kriegova E Gajdos P Vasinek M Mrazek F Kudelka M Gallo J
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The most common reasons for total joint arthroplasty (TJA) failure are aseptic loosening (AL) and prosthetic joint infection (PJI). There is a big clinical challenge to identify the patients with high risk of AL/PJI before the TJA surgery. Although there is evidence that genetic factors contribute to the individual susceptibility to AL/PJI, a predictive model for identification of patients with a high genetic risk of TJA failure has not been developed yet. We aimed to develop a risk evaluation tool utilising the AL/PJI-associated polymorphisms for identification of patients with high genetic risk of TJA failure based on inflammation-gene polymorphism panel. Based on allele and genotype frequencies of twenty-five single nucleotide polymorphisms (SNPs) in TNF, IL2, IL6, IL10, IL1b, IL-1Ra, MBL2, MMP1, FTO genes and those influencing the serum levels of biomarkers of TJA outcomes (IL6, CCL2/MCP-1, CRP, ESR) in peripheral blood obtained from patients with TJA (AL, n=110; PJI, n=93; no complications, n=123), we calculated a hazard ratio and a relative entropy of alleles and genotypes associated with AL and PJI and their combinations in patient subgroups. We conducted a risk evaluation tool based on the presence of risk alleles and genotypes in TNF (rs361525, rs1800629), DARC (rs12075), MBL2 (rs11003125) and FTO (rs9939609, rs9930506) genes associated with implant failure (AL/PJI). Of these, FTO gene variations (rs9939609, rs9930506) were associated mainly with PJI (P=0.001, OR=2.04, 95%CI=1.132–2.603; P=0.011, OR=1.72, 95%CI=1.338–3.096) and DARC (rs12075) with AL (P=0.005, OR=1.79, 95%CI=1.193–2.696). This tool calculates a hazard ratio of a combination of SNPs associated with AL and PJI for identification of patients with high and low risk of AL/PJI TJA failure. We proposed a risk evaluation tool for stratification of patients before the TJA surgery based on the genetic risk of AL/PJI development. The effect size for each genotype combination described in the study is small. Further multiparametric data analysis and studies on an extended patient cohort and other non-genetic and genetic parameters are ongoing. Grant support: AZV MZ CR VES16-131852A, VES15-27726A, IGA LF UP_2016_011


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_9 | Pages 76 - 76
17 Apr 2023
Hulme C Roberts S Gallagher P Jermin P Wright K
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Stratification is required to ensure that only those patients likely to benefit, receive Autologous Chondrocyte Implantation (ACI); ideally by assessing a biomarker in the blood. This study aimed to assess differences in the plasma proteome of individuals who respond well or poorly to ACI.

Isobaric tag for relative and absolute quantitation (ITRAQ) mass spectrometry and label-free proteomics analyses were performed in tandem as described previously by our group (Hulme et al., 2017; 2018; 2021) using plasma collected from ACI responders (n=10) compared with non-responders (n=10) at each stage of surgery (Stage I, cartilage harvest and Stage II, cell implantation).

iTRAQ using pooled plasma detected 16 proteins that were differentially abundant at baseline in ACI responders compared with non-responders (n=10) (≥±2.0 fold; p<0.05). Responders demonstrated a mean Lysholm (patient reported functional score from 0–100) improvement of 33±13 and non-responders a mean worsening of −13±13 points. The most pronounced plasma proteome shift was seen in response to Stage I surgery in ACI non-responders, with 48 proteins being differentially abundant between the two surgical procedures. We have previously noted this marked shift in response to initial surgery in the SF of ACI non-responders, several of these proteins were associated with the Acute Phase Response. One of these proteins, clusterin, could be confirmed in patients’ plasma using an independent immunoassay using individual samples. Label-free proteomic data from individual samples identified only cartilage acidic protein-1 (known to associate with osteoarthritis progression) to be significantly more abundant at Stage I in the plasma of non-responders.

This study indicates that proteins can be identified within the plasma that have potential use in ACI patient stratification. Further work is required to validate the findings of this discovery-phase work in larger ACI cohorts.


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_16 | Pages 45 - 45
17 Nov 2023
Rix L Tushingham S Wright K Snow M
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Abstract

Objective

A common orthopaedic pain found in a wide spectrum of individuals, from young and active to the elderly is anterior knee pain (AKP). It is a multifactorial disorder which is thought to occur through muscular imbalance, overuse, trauma, and structural malalignment. Over time, this can result in cartilage damage and subsequent chondral lesions. Whilst the current gold standard for chondral lesion detection is MRI, it is not a highly sensitive tool, with around 20% of lesions thought to be mis-diagnosed by MRI. Single-photon emission computerised tomography with conventional computer tomography (SPECT/CT) is an emerging technology, which may hold clinical value for the detection of chondral lesions. SPECT/CT may provide valuable diagnostic information for AKP patients who demonstrate absence of structural change on other imaging modalities. This review systematically assessed the value of SPECT/CT as an imaging modality for knee pain, and its ability to diagnose chondral lesions for patients who present with knee pain.

Methods

Using PRISMA guidelines, a systematic search was carried out in PubMed, Science Direct, and Web of Knowledge, CINAHL, AMED, Ovid Emcare and Embase. Inclusion criteria consisted of any English language article focusing on the diagnostic value of SPECT/CT for knee chondral lesions and knee pain. Furthermore, animal or cadaver studies, comparator technique other than SPECT/CT or patients with a pathology other than knee chondral lesions were excluded from the study. Relevant articles underwent QUADAS-2 bias assessment.


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_9 | Pages 79 - 79
17 Apr 2023
Stockmann A Grammens J Lenz J Pattappa G von Haver A Docheva D Zellner J Verdonk P Angele P
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Partial meniscectomy patients have a greater likelihood for the development of early osteoarthritis (OA). To prevent the onset of early OA, patient-specific treatment algorithms need to be created that predict patient risk to early OA after meniscectomy. The aim of this work was to identify patient-specific risk factors in partial meniscectomy patients that could potentially lead to early OA.

Partial meniscectomy patients operated between 01/2017 and 12/2019 were evaluated in the study (n=317). Exclusion criteria were other pathologies or surgeries for the evaluated knee and meniscus (n = 114). Following informed consent, an online questionnaire containing demographics and the “Knee Injury and Osteoarthritis Outcome Score” (KOOS) questionnaire was sent to the patient. Based on the KOOS pain score, patients were classified into “low” (> 75) and “high” (< 75) risk patients, indicating risk to symptomatic OA. The “high risk” patients also underwent a follow-up including an MRI scan to understand whether they have developed early OA.

From 203 participants, 96 patients responded to the questionnaire (116 did not respond) with 61 patients considered “low-risk” and 35 “high-risk” patients. Groups that showed a significant increased risk for OA were patients aged > 40 years, females, overweight (BMI >25 kg/m2 ≤ 30 kg/m2), and smokers (*p < 0.05). The “high-risk”-follow-up revealed a progression of early osteoarthritic cartilage changes in seven patients, with the remaining nineteen patients showing no changes in cartilage status or pain since time of operation. Additionally, eighteen patients in the high-risk group showed a varus or valgus axis deviation.

Patient-specific factors for worse postoperative outcomes after partial meniscectomy and indicators for an “early OA” development were identified, providing the basis for a patient-specific treatment approach. Further analysis in a multicentre study and computational analysis of MRI scans is ongoing to develop a patient-specific treatment algorithm for meniscectomy patients.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVI | Pages 87 - 87
1 Aug 2012
Williams R Khan I Richardson K Nelson L Baird D Roberts S Dudia J Briggs T Fairclough J Archer C
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Hyaline cartilage defects are a significant clinical problem for which a plethora of cartilage repair techniques are used. One such technique is cartilage replacement therapy using autologous chondrocyte or mesenchymal stem cell (MSC) implantation (ACI). Mesenchymal stem cells are increasingly being used for these types of repair technique because they are relatively easy to obtain and can be expanded to generate millions of cells. However, implanted MSCs can terminally differentiate and produce osteogenic tissue which is highly undesirable, also, MSCs generally only produce fibrocartilage which does not make biomechanically resilient repair tissue, an attribute that is crucial in high weight-bearing areas. Tissue-specific adult stem cells would be ideal candidates to fill the void, and as we have shown previously in animal model systems [Dowthwaite et al, 2004, J Cell Sci 117;889], they can be expanded to generate hundreds of millions of cells, produce hyaline cartilage and they have a restricted differential potential. Articular chondroprogenitors do not readily terminally differentiate down the osteogenic lineage. At present, research focused on isolating tissue-specific stem cells from articular cartilage has met with modest success. Our results demonstrate that using differential adhesion it is possible to easily isolate articular cartilage progenitor populations from human hyaline cartilage and that these cells can be subsequently expanded in vitro to a high population doubling whilst maintaining a normal karyotype. Articular cartilage progenitors maintain telomerase activity and telomere length that are a characteristic of progenitor/stem cells and differentiate to produce hyaline cartilage. In conclusion, we propose the identification and characterisation of a novel articular cartilage progenitor population, resident in human cartilage, which will greatly benefit future cell-based cartilage repair therapies


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 1 | Pages 124 - 129
1 Jan 2001
Lofthouse RA Davis JR Frondoza CG Jinnah RH Hungerford DS Hare JM

Caveolae, specialised regions of the cell membrane which have been detected in a wide range of mammalian cells, have not been described in bone cells. They are plasmalemmal invaginations, 50 to 100 nm in size, characterised by the presence of the structural protein, caveolin, which exists as three subtypes. Caveolin-1 and caveolin-2 are expressed in a wide range of cell types whereas caveolin-3 is thought to be a muscle-specific subtype. There is little information on the precise function of caveolae, but it has been proposed that they play an important role in signal transduction. As the principal bone-producing cell, the osteoblast has been widely studied in an effort to understand the signalling pathways by which it responds to extracellular stimuli. Our aim in this study was to identify caveolae and their structural protein caveolin in normal human osteoblasts, and to determine which subtypes of caveolin were present. Confocal microscopy showed staining which was associated with the plasma membrane. Transmission electron microscopy revealed the presence of membrane invaginations of 50 to 100 nm, consistent with the appearance of caveolae. Finally, we isolated protein from these osteoblasts, and performed Western blotting using anti-caveolin primary antibodies. This revealed the presence of caveolin-1 and -2, while caveolin-3 was absent. The identification of these structures and their associated protein may provide a significant contribution to our further understanding of signal transduction pathways in osteoblasts


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_14 | Pages 16 - 16
1 Dec 2022
Ragni E Orfei CP Colombini A Viganò M De Luca P Libonati F de Girolamo L
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In the context of regenerative medicine for the treatment of musculoskeletal pathologies mesenchymal stromal cells (MSCs) have shown good results thanks to secretion of therapeutic factors, both free and conveyed within the extracellular vesicles (EV), which in their totality constitute the “secretome”. The portfolio and biological activity of these molecules can be modulated by both in vitro and in vivo conditions, thus making the analysis of these activities very complex. A deep knowledge of the targets regulated by the secretome has become a matter of fundamental importance and a homogeneous and complete molecular characterization is still lacking in the field of applications for the musculoskeletal system. Therefore, the aim of this work was to characterize the secretome obtained from adipose-derived MSCs (ASCs), and its modulation after pre-conditioning of the ASCs. Pre-conditioning was done by culturing cells in the presence of i) high levels of IFNγ, as proposed for the production of clinical grade secretome with enhanced regenerative potential, ii) low levels of inflammatory stimuli, mimicking conditions found in the osteoarthritis (OA) synovial fluid. Furthermore, EVs ability to migrate within cartilage, chondrocyte and synoviocytes obtained from OA patients was evaluated.

The data showed that more than 50 cytokines / chemokines and more than 200 EV-microRNAs are detectable at various intensity levels in ASCs secretomes. The majority of the most abundantly present molecules are involved in the remodelling of the extracellular matrix and in the homeostasis and chemotaxis of inflammatory cells including macrophages, which in OA are often characterized by an M1 inflammatory polarization, promoting their transition to an M2 anti-inflammatory phenotype. Inflammatory priming with IFNγ and synovial fluid-like conditions were able to further increase the ability of the secretome to interact with inflammatory cells and modulate their migration. Finally, the penetration of the EVs in the cartilage explants resulted a rapid process, which begins a few minutes after administration of the EVs that are able to reach a depth of 30-40 μm in 5 hours. The same capacity for interaction was also verified in chondrocytes and synoviocytes isolated from the cartilage and synovial membrane of OA patients.

Thanks to the soluble factors and EV-microRNAs, the ASCs secretome has shown a strong propensity to modulate the inflammatory and degenerative processes that characterize OA. The inflammatory pre-conditioning through high concentrations of inflammatory molecules or in conditions similar to the synovial fluid of OA patients was able to increase this capacity by increasing their chemotactic power. The microscopy data also support the hypothesis of the ability of MSC-EVs to influence the chondrocytes residing in the ECM of the cartilage and the synovial cells of the synovial membrane through active interaction and the release of their therapeutic content.


Orthopaedic Proceedings
Vol. 102-B, Issue SUPP_11 | Pages 80 - 80
1 Dec 2020
Kahveci A Cengiz BC Alcan V Zinnuroğlu M Gürses S
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Differences at motor control strategies to provide dynamic balance in various tasks in diabetic polyneuropatic (DPN) patients due to losing the lower extremity somatosensory information were reported in the literature. It has been stated that dynamics of center of mass (CoM) is controlled by center of pressure (CoP) during human upright standing and active daily movements. Indeed analyzing kinematic trajectories of joints unveil motor control strategies stabilizing CoM. Nevertheless, we hypothesized that imbalance disorders/CoM destabilization observed at DPN patients due to lack of tactile information about the base of support cannot be explained only by looking at joint kinematics, rather functional foot usage is proposed to be an important counterpart at controlling CoM.

In this study, we included 14 DPN patients, who are diagnosed through clinical examination and electroneuromyography, and age matched 14 healthy subjects (HS) to identify control strategies in functional reach test (FRT). After measuring participants’ foot arch index (FAI) by a custom-made archmeter, they were tested by using a force plate, motion analysis system, surface electromyography and pressure pad, all working in synchronous during FRT. We analyzed data to determine effect of structural and functional foot pathologies due to neuropathy on patient performance and postural control estimating FAI, reach length (FR), FR to height (H) ratio (FR/H; normalized FR with respect to height), displacement of CoM and CoP in anteroposterior direction only, moment arm (MA, defined as the difference between CoP and CoM at the end of FRT), ankle, knee and hip joint angles computed at the sagittal plane for both extremities. Kinematic metrics included initial and final joint angles, defined with respect to start and end of reaching respectively. Further difference in the final and initial joint angles was defined as Δ.

FAI was founded significantly lower in DPN patients (DPN: 0.3404; HS: 0.3643, p= <0.05). The patients’ FR, FR/H and absolute MA and displacement of CoM were significantly shorter than the control group (p= <0.05). Displacement of CoP between the two groups were not significant. Further we observed that CoM was lacking CoP in DPN patients (mean MA: +0.88 cm), while leading CoP in HS (mean MA: −1.59 cm) at the end of FRT. All initial angles were similar in two groups, however in DPN patients final right and left hip flexion angle (p=0.016 and p=0.028 respectively) and left ankle plantar flexion angle (p=0.04) were smaller than HS significantly. DPN patients had significantly less (p=0.029) hip flexion (mean at right hip angle, Δ=25.0°) compared to HS (Δ=33.53°) and ankle plantar flexion (DPN mean at right ankle angle, Δ=6.42°, HS mean Δ=9.07°; p=0.05).

The results suggest that movement of both hip and ankle joints was limited simultaneously in DPN patients causing lack of CoM with respect to CoP at the end of reaching with significantly lower FAI. These results lead to the fact that cutaneous and joint somatosensory information from foot and ankle along with the structure of foot arch may play an important role in maintaining dynamic balance and performance of environmental context. In further studies, we expect to show that difference at control strategies in DPN patients due to restricted functional foot usage might be a good predictor of how neuropathy evolves to change biomechanical aspects of biped erect posture.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_4 | Pages 81 - 81
1 Apr 2018
Ripmeester E Caron MMJ van Rhijn LW Welting TJM
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Osteoarthritis (OA) is the most common degenerative joint disease causing joint immobility and chronic pain. Treatment is mainly based on alleviating pain and reducing disease progression. During OA progression the chondrocyte undergoes a hypertrophic switch in which extracellular matrix (ECM) -degrading enzymes are released, actively degrading the ECM. However, cell biological based therapies to slow down or reverse this katabolic phenotype are still to be developed. Bone morphogenetic protein 7 (BMP-7) has been shown to have OA disease-modifying properties. BMP-7 suppresses the chondrocyte hypertrophic and katabolic phenotype and may be the first biological treatment to target the chondrocyte phenotype in OA. However, intra-articular use of BMP-7 is at risk in the proteolytic and hydrolytic joint-environment. Weekly intra-articular injections are necessary to maintain biological activity, a frequency unacceptable for clinical use. Additionally, production of GMP-grade BMP-7 is challenging and expensive. To enable its clinical use, we sought for BMP-7 mimicking peptides better compatible with the joint-environment while still biologically active and which potentially can be incorporated in a drug-delivery system. We hypothesized that human BMP-7 derived peptides are able to mimic the disease modifying properties of the full-length human BMP-7 protein on the OA chondrocyte phenotype.

A BMP-7 peptide library was synthesized consisting of overlapping 20-mer peptides with 18 amino-acids overlap between sequential peptides. OA human articular chondrocytes (HACs) were isolated from OA cartilage from total knee arthroplasty (n=18 donors). HACs were exposed to BMP-7 (1 nM) or BMP-7 library peptides at different concentrations (1, 10, 100 or 1000 nM). Gene-expression levels of important chondrogenic-, hypertrophic-, cartilage degrading- and inflammatory mediators were determined by RT-qPCR. GAG and ALP activity were determined using a colorimetric assay and PGE levels were measured by EIA.

During the BMP-7 peptide library screening human BMP-7 derived peptides were screened for their full-length human BMP-7 mimicking properties at different concentrations (1, 10, 100 or 1000nM) on a pool of human chondrocytes. Gene expression as well as GAG, ALP and PGE2 level analysis revealed two distinct peptide regions in the BMP-7 protein based on their pro-chondrogenic and anti-OA phenotype actions on human OA chondrocytes. The two most promising peptides were further analysed for their OA chondrocyte disease modifying properties in the presence of OA synovial fluid, showing similar OA phenotype suppressive activity.

Conclusively, we successfully identified two peptide regions in the BMP-7 protein with in vitro OA suppressive actions. Further biochemical fine-tuning of the peptides, and in vivo evaluation, will potentially result in the first peptide-based experimental OA treatment, addressing the hypertrophic and katabolic chondrocyte phenotype in OA.


Orthopaedic Proceedings
Vol. 98-B, Issue SUPP_16 | Pages 29 - 29
1 Oct 2016
Komaris DS Govind C Riches P Murphy A Ewen A Picard F Clarke J
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Patients with osteoarthritis (OA) of the knee commonly alter their movement to compensate for deficiencies. This study presents a new numerical procedure for classifying sit-to-walk (STW) movement strategies.

Ten control and twelve OA participants performed the STW task in a motion capture laboratory. A full body biomechanical model was used. Participants were instructed to sit in a comfortable self-selected position on a stool height adjusted to 100% of their knee height and then stand and pick up an object from a table in front of them. Three matrices were constructed defining the progression of the torso, feet and hands in the sagittal plane along with a fourth expressing the location of the hands relative to the knees. Hierarchical clustering (HC) was used to identify different strategies. Trials were also classified as to whether the left (L) and right (R) extremities used a matching strategy (bilateral) or not (asymmetrical). Fisher's exact test was used to compare this between groups.

Clustering of the torso matrix dichotomised the trials in two major clusters; subjects leaning forward (LF) or not. The feet and hands matrices revealed sliding the foot backward (FB) and moving an arm forward (AF) strategies respectively. Trials not belonging in the AF cluster were submitted to the last HC of the fourth matrix exposing three additional strategies, the arm pushing through chair (PC), arm pushing through knee (PK) and arm not used (NA). The control participants used the LF+FBR+PK combination most frequently whereas the OA participants used the AFR+PCL. OA patients used significantly more asymmetrical arm strategies, p=0.034.

The results demonstrated that control and OA participants favour different STW strategies. The OA patients asymmetrical arm behaviour possibly indicates compensating for weakness of the affected leg. These strategy definitions may be useful to assess post-operative outcomes and rehabilitation progress.


Orthopaedic Proceedings
Vol. 97-B, Issue SUPP_11 | Pages 7 - 7
1 Oct 2015
Lehner C Gehwolf R Ek CJ Korntner S Bauer H Bauer HC Traweger A Tempfer H
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Introduction

Tendon cells originate from yet poorly described precursor cells and develop in a particular “niche” close to vascular walls. Several factors have been described to determine this niche such as mechanical stimuli, oxygen tension, composition and structure of the extracellular matrix (ECM). Also, the vasculature is considered to play a crucial role for tendon cell development, yet evidence of how this is accomplished is lacking. In this study we therefore focussed on the endothelium of tendon vessels postulating the existence of a paracellular barrier.

Materials and Methods

By electron microscopy, immunohistochemistry, and RT-PCR we investigated the presence of constituents making up such an endothelial barrier which we subsequently tested for its functionality by tracer injection. Moreover, we performed differentiation experiments into the adipogenic, chondrogenic and osteogenic lineage on tendon derived cells in the presence and absence of serum. Expression levels and activity of matrixmetalloproteinases (MMPs) were assessed by western blot and zymography.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXVIII | Pages 35 - 35
1 Jun 2012
Spencer S Clarke J Deakin A
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Range of motion (ROM) is a well recognised outcome measure following TKA and combines both knee flexion and extension. In contrast to achieved flexion, fewer studies have recognised the importance of fixed flexion deformity (FFD). A post-operative FFD can adversely affect pain and functional knee scores and so its detection is important. The aim of this study was to investigate the accuracy of standard clinical ROM measurement techniques following TKA and determine their reliability for recognising FFD.

Thirty patients six weeks post-TKA had knee ROM measurements performed with an infrared (IR) tracking system of ±1 accuracy. The patients were also assessed independently by experienced arthroplasty practitioners using a standardised goniometric measurement technique. For goniometric clinically-measured flexion (Clinflex) and extension (Clinext) linear models were generated using IR-measured flexion and extension (IRflex and IRext), BMI and gender as covariables. Data for extension was categorised as FFD present or absent based on Ritter's criteria and agreement was assessed using Kappa.

For both models neither BMI nor gender were significant variables. Models were Clinflex = 0.54 + 0.66∗IRflex (r2adj=0.521) and Clinext = 0.23 + 0.50∗IRext (r2adj=0.247), showing that for every 10° increase in flexion, clinical measurement only increased by 7° and for every 10° increase in FFD angle, clinical measurement only increased by 5°. In identifying FFD there was moderate agreement between the two measurements (κ=0.44) with disagreement for nine patients all being patients with FFD that were not identified clinically.

For both flexion and extension there was a greater tendency for the goniometric clinical measurements to underestimate the actual angle. In the context of TKA outcome for maximum flexion this may be preferable to overestimating. In contrast, underestimating the degree of flexion when the knee is in the extended position is not desirable as it will potentially underreport the frequency and magnitude of FFD.


The Journal of Bone & Joint Surgery British Volume
Vol. 91-B, Issue 4 | Pages 552 - 556
1 Apr 2009
Hannouche D Ballis R Raould A Nizard RS Masquelet AC

We describe a lateral approach to the distal humerus based on initial location of the superficial branches of the radial nerve, the inferior lateral cutaneous nerve of the arm and the posterior cutaneous nerve of the forearm. In 18 upper limbs the superficial branches of the radial nerve were located in the subcutaneous tissue between the triceps and brachioradialis muscles and dissected proximally to their origin from the radial nerve, exposing the shaft of the humerus. The inferior lateral cutaneous nerve of the arm arose from the radial nerve at the lower part of the spiral groove, at a mean of 14.2 cm proximal to the lateral epicondyle. The posterior cutaneous nerve of the forearm arose from the inferior lateral cutaneous nerve at a mean of 6.9 cm (6.0 to 8.1) proximal to the lateral epicondyle and descended vertically along the dorsal aspect of the forearm. The size and constant site of emergence between the triceps and brachioradialis muscles constitute a readily identifiable landmark to explore the radial nerve and expose the humeral shaft.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 8 | Pages 1106 - 1113
1 Aug 2008
Richards L Brown C Stone MH Fisher J Ingham E Tipper JL

Nanometre-sized particles of ultra-high molecular weight polyethylene have been identified in the lubricants retrieved from hip simulators. Tissue samples were taken from seven failed Charnley total hip replacements, digested using strong alkali and analysed using high-resolution field emission gun-scanning electron microscopy to determine whether nanometre-sized particles of polyethylene debris were generated in vivo. A randomised method of analysis was used to quantify and characterise all the polyethylene particles isolated.

We isolated nanometre-sized particles from the retrieved tissue samples. The smallest identified was 30 nm and the majority were in the 0.1 μm to 0.99 μm size range. Particles in the 1.0 μm to 9.99 μm size range represented the highest proportion of the wear volume of the tissue samples, with 35% to 98% of the total wear volume comprised of particles of this size. The number of nanometre-sized particles isolated from the tissues accounted for only a small proportion of the total wear volume. Further work is required to assess the biological response to nanometre-sized polyethylene particles.


In severe cases of total knee & hip arthroplasty, where off-the-shelf implants are not suitable (i.e., in cases with extended bone defects or periprosthetic fractures), 3D-printed custom-made knee & hip revision implants out of titanium or cobalt-chromium alloy represent one of the few remaining clinical treatment options. Design verification and validation of such custom-made implants is very challenging. Therefore, a methodology was developed to support surgeons and engineers in their decision on whether a developed design is suitable for the specific case. A novel method for the pre-clinical testing of 3D-printed custom-made knee implants has been established, which relies on the biomechanical test and finite element analysis (FEA) of a comparable clinically established reference implant. The method comprises different steps, such as identification of the main potential failure mechanism, reproduction of the biomechanical test of the reference implant via FEA, identification of the maximum value of the corresponding FEA quantity of interest at the required load level, definition of this value as the acceptance criterion for the FEA of the custom-made implant, reproduction of the biomechanical test with the custom-made implant via FEA, decision making for realization or re-design based on the acceptance criterion is fulfilled or not. Exemplary cases of custom-made knee & hip implants were evaluated with this new methodology. The FEA acceptance criterion derived from the reference implants was fulfilled in both custom-made implants and subsequent biomechanical tests verified the FEA results. The suggested method allows a quantitative evaluation of the biomechanical properties of custom-made knee & hip implant without performing physical bench testing. This represents an important contribution to achieve a sustainable patient treatment in complex revision total knee & hip arthroplasty with custom-made 3D printed implants in a safe and timely manner


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_8 | Pages 120 - 120
11 Apr 2023
Hettich G Weiß J Grupp T
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In severe cases of total knee arthroplasty which cannot be treated with off-the-shelf implants anymore custom-made knee implants may serve as one of the few remaining options to restore joint function or to prevent limb amputation. Custom-made implants are specifically designed and manufactured for one individual patient in a single-unit production, in which the surgeon is responsible for the implant design characteristics in consultation with the corresponding engineer. The mechanical performance of these custom-made implants is challenging to evaluate due to the unique design characteristics and the limited time until which the implant is needed. Nevertheless, the custom-made implant must comply with clinical and regulatory requirements. The design of custom-made implants is often based on a underlying reference implant with available biomechanical test results and well-known clinical performance. To support surgeons and engineers in their decision whether a specific implant design is suitable, a method is proposed to evaluate its mechanical performance. The method uses finite element analysis (FEA) and comprises six steps: (1) Identification of the main potential failure mechanism and its corresponding FEA quantity of interest. (2) Reproduction of the biomechanical test of the reference implant via FEA. (3) Identification of the maximum value of the corresponding FEA quantity of interest at the required load level. (4) Definition of this value as the acceptance criteria for the FEA of the custom-made implant. (5) Reproduction of the biomechanical test with the custom-made implant via FEA. (6) Conclusion whether the acceptance criteria is fulfilled or not. The method was applied to two exemplary cases of custom-made knee implants. The FEA acceptance criteria derived from the reference implants were fulfilled in both custom-made implants. Subsequent biomechanical tests verified the FEA results. This study suggests and applies a non-destructive and efficient method for pre-clinical testing of a single-unit custom-made knee implant to evaluate whether the design is mechanically suitable


Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_2 | Pages 29 - 29
2 Jan 2024
Klatte-Schulz F Gehlen T Bormann N Tsitsilonis S Manegold S Schmock A Melzer J Schmidt-Bleek K Geißler S Duda G Sawitzki B Wildemann B
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Early identification of patients at risk for impaired tendon healing and corresponding novel therapeutic approaches are urgent medical needs. This study aimed to clarify the role of CD3+ T-cells during acute Achilles tendon (AT) healing. Blood and hematoma aspirate were taken from 26 patients during AT reconstruction, and additional blood samples were obtained during clinical follow-up at 6, 26 and 52 weeks after surgery. T-cell subsets were analyzed by flow cytometry using CD3, CD4, CD8, CD11a, CD57 and CD28 antibodies. Clinical follow-up included functional tests, MRI assessments, and subjective questionnaires. In vitro, the functional behavior of patient-derived tenocytes was investigated in co-cultures with autologous unpolarized CD4+ or CD8+ T-cells, or IFNy-polarized CD8+ or IL17-polarized CD4+ Tcells (n=5-6). This included alterations in gene expression (qPCR), MMP secretion (ELISA), migration rate (scratch wound healing assay) or contractility (collagen gels). Analysis revealed that elevated CD4+ T-cell levels and reduced CD8+ T-cell levels (increased CD4/CD8 ratio) in hematoma aspirate and pre-operative blood were associated with inferior clinical outcomes regarding pain and function at 26 and 52 weeks. Increased levels of CD8+ -memory T-cell subpopulations in blood 6 weeks after surgery were associated with less tendon elongation. In vitro, tenocytes showed increased MMP1/2/3 levels and collagen III/I ratio in co-culture with unpolarized and/or IL17-polarized CD4+ T-cells compared to unpolarized CD8+ T-cells. This coincided with increased IL17 receptor expression in tenocytes co-cultured with CD4+ T-cells. Exposure of tenocytes to IL17-polarized CD4+ T-cells decreased their migration rate and increased their matrix contractility, especially compared to IFNy-polarized CD8+ T-cells. The CD4+ /CD8+ T-cell ratio could serve as prognostic marker for early identification of patients with impaired AT healing potential. Local reduction of CD4+ T-cell levels or their IL17 secretion represent a potential therapeutic approach to improve AT healing and to prevent weakening of the tendon ECM