Aims. Animal models have been developed that allow simulation of post-traumatic joint contracture. One such model involves contracture-forming surgery followed by surgical capsular release. This model allows testing of antifibrotic agents, such as rosiglitazone. Methods. A total of 20 rabbits underwent contracture-forming surgery. Eight weeks later, the animals underwent a surgical capsular release. Ten animals received rosiglitazone (intramuscular initially, then orally). The animals were sacrificed following 16 weeks of free cage mobilisation. The joints were tested biomechanically, and the posterior capsule was assessed histologically and via genetic microarray analysis. Results. There was no significant difference in post-traumatic contracture between the rosiglitazone and control groups (33° (standard deviation (. sd. ) 11) vs 37° (. sd. 14), respectively; p = 0.4). There was no difference in number or percentage of myofibroblasts. Importantly, there were ten genes and 17 pathways that were significantly modulated by rosiglitazone in the posterior capsule. Discussion. Rosiglitazone significantly altered the genetic expression of the posterior capsular tissue in a rabbit model, with ten genes and 17 pathways demonstrating significant modulation. However, there was no significant effect on biomechanical or histological properties. Cite this article: M. P. Abdel. Effectiveness of rosiglitazone in reducing flexion contracture in a rabbit model of arthrofibrosis with surgical capsular release: A biomechanical, histological, and genetic analysis. Bone Joint Res 2016;5:11–17. doi: 10.1302/2046-3758.51.2000593

Summary. Based upon genetic analysis, decorin is an exciting pharmacologic agent of potential anti-fibrogenic effect on arthrofibrosis in our animal model. Introduction. While the pathophysiology of arthrofibrosis is not fully understood, some anti-fibrotic molecules such as decorin could potentially be used for the prevention or treatment of joint stiffness. The goal of this study was to determine whether intra-articular administration of decorin influences the expression of genes involved in the fibrotic cascade ultimately leading to less contracture in an animal model. Material and Methods. Eighteen rabbits had their right knees operated on to form contractures. The left knees served as controls. The 6 right limbs in the experimental group (Group 1) received four 500 ug/ml intra-articular injections of decorin over 8 days starting at 8 week, for a total of 2 mg. The 6 right limbs in the first control group (Group 2) received four intra-articular injections of bovine serum albumin (BSA) over 8 days starting at 8 weeks as well. The 6 six right limbs in the second control group (Group 3) received no injections. The contracted limbs of rabbits in Group 1 were biomechanically and genetically compared to the contracted limbs of rabbits in Groups 2 and 3 with the use of a calibrated joint measuring device and custom microarray, respectively. Results. There was no statistical difference in the flexion contracture angles between those right limbs that received intra-articular decorin versus those that received intra-articular BSA (66° vs. 69°; p = 0.41). Likewise, there was no statistical difference between those right limbs that received intra-articular decorin as opposed to those who had no injection (66° vs. 72°; p = 0.27). The lack of significance remained when the control left limbs were taken into account (p > 0.40). When compared to bovine serum albumin (BSA), decorin led to a statistically significant increase in the mRNA expression of 5 genes: substance P, neuropeptide γ, and neurokinin A, cyclin E2, and MMP-9 (p < 0.001). In addition, there was a statistically significant decrease in fibroblast growth factor receptor-2 (FGFR-2), rho-associated coiled-coil containing protein kinase-1 (ROCK-1), and vascular cell adhesion molecule-1 (VCAM-1) genes when intra-articular decorin was compared to no injection (p < 0.001). Conclusions. In this model, when administered intra-articularly at 8 weeks, 2 mg of decorin had no significant effect on joint contractures. However, our genetic analysis revealed a significant alteration in the expression of several fibrotic genes. Further studies investigating the route of administration, dosing, frequency, and timing are required before definitive conclusions may be drawn on the effects of decorin on joint contractures

Xiapex is a novel non-surgical intervention for the treatment of Dupuytren's contracture. It comprises a fixed-ratio mixture of two purified collagenolytic enzymes (AUX-I [clostridial type I collegenase] and AUX II [clostridial type II collagenase]) isolated from the medium of Clostridium histolyticum. Xiapex targets the contracture through the injection of enzymes into the pathologic diseased cords. The objectives of this study were to evaluate the safety and efficacy of Xiapex in patients with Dupuytren's Contracture, the recovery and associated use of health care resources. The study commenced in June 2011 and was completed in 11 months. 15 patients were screened for the study, 12 patients were eligible (10 male:2 female). All 12 patients completed the trial and 2 patients received multiple injections, one had two fingers affected and the other had two joints affected in one finger. Following screening visit to determine patient suitability, the patient received their first injection usually within 7 days. Xiapex was injected directly into the palpable cord. 24 hours after injection patients were reviewed and a “finger extension procedure” was performed if the cord had not spontaneously ruptured. Patients were then followed up at 7 days, 30 days and 6 months. Assessments at each visits included: Finger Goniometry, Physician and Subject Global Assessment and Satisfaction, Health Care Resource Utilization and URAM (function assessment) and adverse events. Of the 14 cords injected all ruptured after finger extension. No patient experienced any serious adverse events, but a number of more minor adverse events were recorded including skin tears, pain at injection site, swelling and bruising. At the time of final follow-up recurrence rates were 14%. In conclusion, Xiapex is suitable for appropriately selected patients who are affected by Dupuytren's contractures and who have a well-developed palpable cord

Fixed flexion contracture (FFC) following total knee arthroplasty (TKA) is a source of morbidity for patients. This retrospective review of pre- and post-operative data for 811 total knee replacements with two year follow up aimed to identify pre-operative risk factors for developing FFC and quantify the effect of FFC on outcomes. The incidence of FFC two years post-operation was 3.6%. Advanced age was associated with increased rate of FFC (p=0.02) Males were 2.6 times more likely than females to have FFC at two years (p=0.012). Patients with pre-implant FFC were 2.95 times more likely than those without to have FFC (p=0.028). BMI was not a risk factor (p=0.968). Patients with FFC had poorer outcomes (Oxford Knee Score p=0.003, patient satisfaction p=0.036). The results of this study support the existing literature and clarify a previously contentious point by excluding BMI as a risk factor

Our aims were to describe the distribution of α-smooth muscle actin (SMA)-containing cells in Dupuytren’s tissue in vivo and to determine the effects of selected agents in regulating the expression of SMA in Dupuytren’s cells in vitro. In selected hypercellular zones of Dupuytren’s nodules up to 40% of the cells contained SMA, as shown by immunohistochemistry. A lower percentage (20%) of SMA-containing cells was found in regions of lower cellularity. A notable finding was that treatment in vitro of Dupuytren’s cells with platelet-derived growth factor significantly reduced the content of SMA. Cells from the same patients showed a significant increase in expression of SMA in response to treatment with transforming growth factor, which confirmed recent findings. In addition, interferon-γ, which has been previously used as a treatment for Dupuytren’s disease in a clinical study, had no reproducible effect on the expression of this actin isoform. Our findings are of significance for the conservative management of contractures

Objectives. Sustained intra-articular delivery of pharmacological agents is an attractive modality but requires use of a safe carrier that would not induce cartilage damage or fibrosis. Collagen scaffolds are widely available and could be used intra-articularly, but no investigation has looked at the safety of collagen scaffolds within synovial joints. The aim of this study was to determine the safety of collagen scaffold implantation in a validated in vivo animal model of knee arthrofibrosis. Materials and Methods. A total of 96 rabbits were randomly and equally assigned to four different groups: arthrotomy alone; arthrotomy and collagen scaffold placement; contracture surgery; and contracture surgery and collagen scaffold placement. Animals were killed in equal numbers at 72 hours, two weeks, eight weeks, and 24 weeks. Joint contracture was measured, and cartilage and synovial samples underwent histological analysis. Results. Animals that underwent arthrotomy had equivalent joint contractures regardless of scaffold implantation (-13.9° versus -10.9°, equivalence limit 15°). Animals that underwent surgery to induce contracture did not demonstrate equivalent joint contractures with (41.8°) or without (53.9°) collagen scaffold implantation. Chondral damage occurred in similar rates with (11 of 48) and without (nine of 48) scaffold implantation. No significant difference in synovitis was noted between groups. Absorption of the collagen scaffold occurred within eight weeks in all animals. Conclusion. Our data suggest that intra-articular implantation of a collagen sponge does not induce synovitis or cartilage damage. Implantation in a native joint does not seem to induce contracture. Implantation of the collagen sponge in a rabbit knee model of contracture may decrease the severity of the contracture. Cite this article: J. A. Walker, T. J. Ewald, E. Lewallen, A. Van Wijnen, A. D. Hanssen, B. F. Morrey, M. E. Morrey, M. P. Abdel, J. Sanchez-Sotelo. Intra-articular implantation of collagen scaffold carriers is safe in both native and arthrofibrotic rabbit knee joints. Bone Joint Res 2016;6:162–171. DOI: 10.1302/2046-3758.63.BJR-2016-0193

Distal arthrogryposis (DA) is a collection of rare developmental disorders characterized by congenital joint contractures. Most arthrogryposis mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal tissues. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Surprisingly, overactive PIEZO2 is likely to cause joint abnormalities via increased exocytosis from sensory neuron endings without involving motor circuitry. This reveals a role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development. We also present proof-of-concept that Botox injection or dietary treatment can counteract the effect of overactive PIEZO2 function to evade DA-like phenotypes in mice when applied during a developmental critical period. These approaches might have clinical applications. Beyond this, our findings call attention to the importance of considering sensory mechanotransduction when diagnosing and treating other musculoskeletal disorders. Acknowledgements: Our work is supported by National Institutes of Health grant (R35 NS105067, R01 DE022358, R25 SC3GM127195, R25 GM07138, R01GM133845, intramural) and Howard Hughes Medical Institute

In-office surgeries have the potential to offer high quality medical care in a more efficient, cost-effective setting than outpatient surgical centers for certain procedures. The primary concerns with operating on patients in the office setting are insufficient sterility and lack of appropriate resources in case of excessive bleeding or other surgical complications. This study serves to investigate these concerns and determine whether in-office hand surgeries are safe and clinically effective. A retrospective review of patients who underwent minor hand operations in the office setting between December 2020 and December 2021 was performed. The surgical procedures included in this analysis are needle aponeurotomy, trigger finger release, mass/foreign body removal and reduction of hand/wrist fracture with or without percutaneous pinning. No major complications requiring extended observation or hospital admission occurred. 122 of the 132 patients (92.4%) were successfully treated with no complications and only mild symptoms within one month of surgery. Five patients (3.8%) returned to the office for pain, inflammation and/or stiffness of the affected finger, with two of the five returning due to osteoarthritis and/or pseudogout flare-ups. Five additional patients returned due to incomplete treatment with continued presence of Dupuytren's contracture (3), trigger finger (1) or infected foreign body (1). One patient (0.8%) developed infection, due to incomplete removal of an infected foreign body, which was subsequently treated with antibiotics and complete foreign body removal. The absence of major complications and high success rate for minor hand procedures shows the high degree of safety and efficacy which can be achieved via the in-office setting for select procedures. While proper patient selection is key, our result shows the in-office procedure room setting can offer the necessary elements of sterility and hemostatic support for several common hand surgeries

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq. ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue. The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future. For any figures or tables, please contact the authors directly

In 2012 collagenase Clostridium histolyticum (Xiapex) was approved by the SMC for restricted use for the treatment of Dupuytren's contracture. Xiapex was approved on a case by case basis for patients with a palpable pretendinous cord, giving rise to MCPJ contracture of greater than 30 degrees. As of September 2012 we began to offer Xiapex injections to patients in Ayrshire who enquired about the injection, and met the SMC criteria. To date injections have been performed on 3 patients, in a total of 7 digits. Patients were assessed prior to injection and manipulation, with the degree of contracture recorded and DASH scores noted. Each patient then underwent a standard injection of 0.58 mg of Xiapex. 48 hours post injection each patient underwent manipulation under local anaesthetic, with contractures remeasured, pain scored using a visual analogue scale and complications noted. Each patient was then reviewed at 4 weeks post injection where the residual degree of contracture was recorded and a further DASH score completed. Mean contracture at the MCPJ prior to injection was 57° (range 34–80), and mean DASH score of 20.8 (range 16.7–24.2). Following manipulation mean residual contracture at the MCPJ measured 21° (range 18–28). The average pain score following was manipulation was rated at 1.1. Mild bruising and swelling were reported in all cases following injection, and manipulation resulted in 2 minor skin tears. At the 4 week review prolonged improvement of contracture was achieved with a mean residual contracture of 14° (range −2–40); with a significant improvement in DASH scores – mean 0.6 (range 0–1.8). Despite small numbers, we have found Xiapex injections to be a successful and well tolerated treatment for moderate Dupuytren's disease. Further follow up is required to assess the longevity of the correction and ensure the cost effectiveness of Xiapex

Summary. In contrast to the current literature, myofibroblasts are not present in chronic posttraumatic elbow contractures. However, myofibroblasts are present in the acute phase after an elbow fracture and/or dislocation. This suggests a physiological role in normal capsule healing and a potential role in the early phase of posttraumatic contracture formation. Introduction. Elbow stiffness is a common complication after elbow trauma. The elbow capsule is often thickened, fibrotic and contracted upon surgical release. The limited studies available suggest that the capsule is contracted because of fibroblast to myofibroblast differentiation. However, the timeline is controversial and data on human capsules are scarce. We hypothesise that myofibroblasts are absent in normal capsules and early after acute trauma and elevated in patients with posttraumatic elbow contracture. Patients & Methods. We obtained twenty-one human elbow joint capsules within fourteen days after an elbow fracture and/or dislocation and thirty-four capsules from thirty-four patients who had operative release of posttraumatic contractures greater than five months after injury. Myofibroblasts in the joint capsules were quantified using immunohistochemistry. Alpha-smooth muscle actin (α-SMA) was used as a marker for myofibroblasts. Samples were characterised and scored by an independent pathologist blinded for clinical data. Results. Eleven capsules were associated with the acute phase after trauma (hours to 7 days), and staining for α-SMA was negative in all eleven specimens. Ten specimens were associated with a later phase post trauma with myofibroblasts staining positive for α-SMA in all but two. All, but two, thirty-four long standing contractures showed a histological pattern consistent with chronic stages of fibrosis, characterised by increased fibroblast-like cell proliferation and higher cellular density of fibroblast-like cells with highly unstructured collagen. There was no staining of α-SMA in fibroblast-like cells in, all but two of these longstanding contractures suggesting absence of myofibroblasts. Conclusions. This study present ‘negative results’ on the hypothesis that myofibroblast numbers are elevated in longstanding (> 5 months) human posttraumatic elbow capsules. This is in contrast to all studies on human tissue in the literature to date. One recent animal study is in agreement withy our data. We did find some myofibroblasts in elbow capsules in the late-phase posttrauma (between 7 and 14 days) suggesting a potential role in early phase of posttraumatic contracture formation

Summary. Previous work in a rabbit model of post-traumatic joint contractures shows that the mast cell stabilizer ketotifen decreases contracture severity. We show here that ketotifen decreases collagen gel contraction mediated by rabbit joint capsule fibroblasts when mast cells are present. Introduction. Ketotifen was shown to decrease contracture severity and associated joint capsule fibrosis in an animal model of post-traumatic joint contractures. Ketotifen prevents the release of profibrotic growth factors from mast cells (MC). An in vitro collagen gel contraction assay is used to examine the effect of ketotifen on joint capsule fibroblasts obtained from this animal model. Methods. Six New Zealand White rabbits had a standardised procedure to induce post-traumatic joint contractures and the joint capsule was harvested 4 weeks later. The capsules were minced, placed into T75 culture flasks and incubated at 37. 0. C in a humidified atmosphere containing 5% CO. 2. The Joint Capsule fibroblasts (JC, 2.5 × 10. 5. cells/mL) were mixed with neutralised collagen solution composed of 59% neutralised PureCol collagen I, serum free DMEM/F12 with 1x serum replacement and 1x antibiotic-antimycotic. Aliquots of solution were then cast into wells of a tissue culture plate. Gelation occurred over 3h at 37°C in a humidified incubator. The collagen gel/cells were maintained with DMEM/F-12 plus 1% serum replacement and 1% antibiotic-antimycotic and incubated at 37°C for 12 h. The gels were released and gel area was calculated up to 72h post-release. Different experiments were conducted with various combinations of a human mast cell line (HMC-1, 7.5 × 10. 5. cells/mL), the neuropeptide Substance P (SP, 10. −6. M) and Ketotifen fumurate at 10. −4. , 10. −6. , 10. −8. and 10. −10. M. The various interventions were combined with the JC and collagen gel during the gelation step. Statistical comparisons used a two way ANOVA with a Posthoc Tukey test. Significance was set at p < 0.05. Results. The JC contracted the collagen gels in all conditions, with statistically significant differences between time intervals from 6 h to 72 h. When ketotifen alone was added to JC, there was no effect on collagen gel contraction in the range of doses tested. Adding MC to JC led to a significantly increased rate of gel contraction that was inhibited by ketotifen in a dose-dependent manner. The effect was maximal with a concentration of 10. −4. M while the effect was absent by the dose of 10. −10. M. There were statistically significant differences amongst different doses except for comparisons between doses closest to each other (10. −4. vs 10. −6. , 10. −6. vs 10. −8. , 10. −8. vs 10. −10. M). Including SP with MC and JC further increased the rate of gel contraction, which was also significantly inhibited by ketotifen in a similar dose-dependent fashion. Discussion/Conclusion. Fibroblasts from rabbit joint capsules contract collagen gels with the effect enhanced by the addition of mast cells. Ketotifen prevents the release of mediators by mast cells, and ketotifen modified the collagen gel assay. It appears that the inhibition of the gel contraction by the fibroblasts is via mast cell stabilization since ketotifen had no direct affect on the fibroblasts in the concentrations evaluated. Ketotifen is a medication used in the chronic treatment of asthma. It has a wide safety profile, it is already approved for human use and it is available in oral preparations

The collagenase of Clostridium Histolyticum enzyme infiltration is a mini-invasive treatment method for Dupuytren's disease which has emerged in recent years as an alternative to traditional surgery (selective aponeurectomy). Although both treatments are effective in the long term, a wider use of the enzyme is spreading worldwide. Indications and protocol of administration of collagenase are strictly regulated by the Italian Drug Administration Agency (AIFA). In the present study an off-label use of this medication has been experienced, in terms of wider indications and more numerous infiltration sites in the same cord (Multipoint technique) and in additional cords affecting other digits (Multicord technique). All patients suffering from Dupuytren's disease and accessing the Hand Surgery outpatient at Rizzoli Institute were considered for the study, between february 2014 and february 2016. Inclusion criteria were Dupuytren's disease and a positive tabletop test. The collagenase injection was indicated for degrees of passive extension deficit (PED) higher than AIFA regulations (MCPJoints >50° and PIPJoints >45°). These patients were compared with the same PED subgroup of surgical patients who were treated through aponeurectomy. Since the drug is dispensed in vials of 0.90 mg, but according to the protocol only 0.58 mg are to be infiltrated, the injection of the remaining 0.32 mg that would otherwise remain unused was experienced. Therefore, in patients who had only one pathological cord in the hand, the first point of the cord to be treated was inoculated with 0.58 mg, according to standards, while two additional points were selected along the fibrosis and injected with the remaining 0, 32 mg. This group was compared with patients treated with the traditional 0.58 mg only on a single cord. In patients in whom the presence of more than a single pathological cord was found, the worse lesion was injected with the usual 0.58 mg as by legislation and the second cord was infiltrated with the 0.32 mg residue and the results obtained within the second cord were compared with those achieved with the usual dose of 0.58 mg. The endpoints considered were the perioperative variations of passive extension deficit (PED) and range of motion (ROM), both expressed as degrees. Data were statistically analyzed in order to find any possible significance in the comparison of groups. Comparing the surgical patients with those treated with collagenase, for the same degrees but higher than AIFA reference, both methods showed a reduction of contracture by at least 50% at 30 days and an improvement of ROM (p>0.05), with fewer complications in those treated enzymatically (p<0.01). Infiltrating the whole dose of collagenase (0.90 mg) through the multipoint mode, has enabled an easier handling of the cord at 24 hours post-injection, a reduction in contracture of at least 50% at 30 days allowing a dowstaging of the disease and a better and faster recovery of hand function, than the classic treatment, although these results are not statistically significant (p>0.05). For degrees of contractures within AIFA indications for collagenase, the 0.32 mg dose is sufficient to cause the lysis of a cord with similar results compared to the greater AIFA-recommended dose of 0.58, in terms of all considered endpoints, with no statistically significant difference (p >0.01). This study confirms the success of treatment with collagenase compared to surgical treatment, in terms of efficacy, safety, more rapid recovery and less invasiveness. In addition, through further clinical studies, AIFA regulations can be gradually safely and effectively extended in terms of a progressive widening of indications and modalities including:. Indication to collagenase for PED higher than 50° (MCP joints) or 45° (PIP joints). Multiple injections in the same cord with the whole content of the vial (0.90 mg). Injections in multiple cords with the whole content of the vial (0.90 mg)

Dupuytren Disease (DD), the most common connective tissue disease in man, presents as a benign fibromatosis of the hands and fingers resulting in the formation of nodules and cords and often leading to flexion contractures in association with keloids or Peyronie disease. Surgical resection of the fibrotic nodules, and more recently intra-lesional collagenase injection are the main therapeutic options for these patients. While the exact cause of DD is still unknown, linkage and Genome Wide Association Studies (GWAS) showed molecular heterogeneity with at least 10 different susceptibility loci 6 of which are close to genes encoding proteins in the Wnt-signaling pathway. We aim to identify the molecular basis of Dupuytren Disease (DD). Twenty patients with Dupuytren disease (including 3 patients with autosomal dominant inheritance, 1 with keloids and congenital torticollis, 2 with Peronie disease), were included in this study. Chromosome Microarray Analysis (CMA), Whole Exome Sequencing (WES) of gDNA and proteomic analysis by LC-Tandem Mass Spectrometry (LC-MSMS) studies were performed. Expression and Network analysis of LCMSMS results was performed using Principal Component Analysis (PCA), ANOVA and Ingenuity Pathway Analysis (IPA). No pathogenic copy number variants (CNVs) were found in CMA (n = 3). WES showed potentially pathogenic variants in POSTN, WNT11, MMP1 and COL3A1. PCA showed three differentially expressed clusters and network-IPA identified ACTB, BAX, COL3A1, FBN1, FN1, MMP1 as potential biomarkers. Comprehensive multi-OMIC analysis of gDNA and tissue proteins in patients with DD identified several connective tissue biomarkers potentially important in the pathogenesis of DD

In patients with developmental dysplasia of the hip (DDH) chronic joint dislocation induces remodeling of the soft tissue with contractures, muscle atrophy, especially of the hip abductors muscles, leading to severe motor dysfunction, pain and disability (1). The aim pf the present work is to explore if a correct positioning of the prosthetic implants through 3D skeletal modeling surgical planning technologies and an adequate customized rehabilitation can be beneficial for patients with DDH in improving functional performance. The project included two branches: a methodology branch of software development for the muscular efficiency calculation, which was inserted in the Hip-Op surgical planning system (2), developed at IOR to allow surgical planning for patients with complex hip joint impairment; and a clinical branch which involved the use of the developed software as part of a clinical multicentric randomized trial. 50 patients with DDH were randomized in two groups: a simple surgical planning group and an advanced surgical planning with muscular study group. The latter followed a customized rehabilitation program for the strenghtening of hip abductor muscles. All patients were assessed before surgery (T0) and at 3 (T1) and 6 months (T2) postoperatively using clinical outcome (WOMAC, HHS, ROM, MMT, SF12, 10mt WT) and instrumental measures (Dynamometric MT). Pre- and post-operative musculoskeletal parameters obtained by the software (i.e., leg length discrepancy, hip abductor muscle lengths and lever arms) using Hip-Op during the surgical planning were considered. One Way ANOVA for ROM measurement showed a significant improvement at T2 in patients included in experimental group, as well as WOMAC, HHS and SF12 score. The Dynamometric MT score showed significant differences between at T2 (p<0.009). Spearman's rank correlation coefficients showed a significant correlation between both pre- and post-operative abductors lever arm (mm) and hip abductor muscle strength at T2 (ρ = −0.55 pre-op and ρ = −0.51 post-op, p p<0.012 and p<0.02 respectively) and between the operated pre-postoperative leg length variation (mm) and the hip abductor muscle strength (ρ = −0.55, p p<0.013). Results so far obtained showed an improvement of functional outcomes in patients undergoing hip replacement surgery who followed therapeutic diagnostic pathway sincluding a preoperative planning including the assessment of the abductiors lever arm and a dedicated rehabilitation program for the strenghtening of abductios. Particularly interesting is the inverse relationship between the strength of the hip abductor muscles and the variation of the postoperative abductor lever arm

A correct ligament loading following TKA surgery is believed to minimize instability and improve patient satisfaction. The evaluation of the ligament stress or strain is however impractical in a surgical setting. Alternatively, tibial trial components containing force sensors have the potential to indirectly assess the ligament loading. These instrumented components quantify the medial and lateral forces in the tibiofemoral joint. Although this method finds clinical application already, the target values for both the force magnitude and medial / lateral force ratio under surgical conditions remain uncertain. A total of eight non-arthritic cadaveric knees have been tested mimicking surgical conditions. Therefore, the specimens are mounted in a custom knee simulator. This simulator allows to test full lower limb specimens, providing kinematic freedom throughout the range of motion. Knee flexion is obtained by lifting the femur (thigh pull). Knee kinematics are simultaneously recorded by means of a navigation system and based on the mechanical axis of the femur and tibia. In addition, the load transferred through the medial and lateral compartment of the knee is monitored. Therefore, a 2.4 mm thick sawing blade is used to machine a slot in the tibia perpendicular to the mechanical axis, at the location of the tibial cut in TKA surgery. A complete disconnection was thereby assured between the tibial plateau and the distal tibia. To fill the created gap, custom 3D printed shims were inserted. Through their specific geometry, these shims create a load deviation between two Tekscan pressure pads on the medial and lateral side. Following the insertion of the shims, the knee was closed before performing the kinematic and kinetic tests. Seven specimens showed a limited varus throughout the range of motion (ranging from 1° to 7° varus). The other knee was in valgus (4° valgus). Amongst varus knees, the results were very consistent, indicating high loads in full extension. Subsequently, the loads decrease as the knee flexes and eventually vanishes on the lateral side. This leads to consistently high compartmental load ratios (medial load / total load) in flexion. In full extension the screw-home mechanism results in increased loads, both medially and laterally. Upon flexion, the lateral loads disappear. This is attributed to slackening of the lateral collateral ligament, in turn linked to the femoral rollback and slope of the lateral compartment. The isometry of the medial collateral ligament contributes on the other hand to the near-constant load in the medial compartment. The above particularly applies for varus knees. The single valgus knee tested indicated a higher load transmission by the lateral compartment, potentially attributed to a contracture of the lateral structures. With respect to TKA surgery, these findings are particularly relevant when considering anatomically designed implants. For those implants, this study concludes that a tighter medial compartment reflects that of healthy varus knees. Be aware however that in full extension, higher and up to equal loads can be acceptable for the medial and lateral compartment

Distal femur resection for correction of flexion contractures in total knee arthroplasty (TKA) can lead to joint line elevation, abnormal knee kinematics and patellofemoral problems. The aim of this retrospective study was to establish the contribution of soft tissue releases and bony cuts in the change in maximum knee extension in TKA. Data were available for 211 TKAs performed by a single surgeon using a medial approach. Intra-operatively pre- and post-implant extension angles and the size of bone resection were collected using a commercial navigation system. The thickness of polyethylene insert and the extent of soft tissue release performed (no release, moderate and extensive release) were collected from the patient record. A linear model was used to predict change in maximum extension from pre- to post-implant. The analysis showed that bone cuts (p<0.001), soft tissue release (p=0.001) and insert thickness (p=0.010) were all significant terms in the model (r. 2. adj. =0.170). This model predicted that carrying out a TKA with 19 mm bone cuts, 10 mm insert and no soft tissue release would give 4.2° increase in extension. It predicted that a moderate release would give a further 2.8° increase in extension with an extensive release giving 3.9°. For each mm increase in bone cuts the model predicted an 0.8° increase in extension and for each mm increase in insert size a decrease extension by 1.1°. The modelling results show that in general to increase maximum extension by the same as an extensive soft tissue release that bone cuts would have to be increased by 4–5 mm. However this model only accounted for 17% of the variation in change in extension pre- to post-implant so may not be accurate at predicting outcomes for specific patients

Summary Statement. We present a simple and useful geometrical equation system to carry out the pre-operative planning and intra-operative assessments for total knee arthroplasty. These methods are extremely helpful in severely deformed lower limbs. Introduction. Total knee arthroplasty is a highly successful surgery for most of the patients with knee osteoarthritis. With commercial instruments and jigs, most surgeons can correct the deformity and provided satisfactory results. However, in cases with severe extra-articular deformity, the instruments may mislead surgeons in making judgment of the true mechanical axis. We developed a geometrical equation system for pre-operative planning and intra-operative measurement to perform correct bony cuts and achieve good post-operative axis. Patients & Methods. From 2008 to 2012, twenty-four patients with severe extra-articular deformities of low limbs underwent total knee arthroplasties for osteoarthritis. The deformities included malunion of femoral or tibial shafts with angulation, non-union of femoral supracondylar fractures, failed high tibia osteotomies, severe bowing of femurs, and other post-traumatic sequelae. The intra-medullary or extra-medullary guide devices were not possible to provide correct axis in these cases. For pre-operative planning, we analyzed the deformities on triple-film scanography and standing anterior-posterior and lateral X-ray films. The angles needed to be corrected in coronal and sagittal planes were measured. A geometrical equation system was applied to calculate the thickness of the proximal tibia cut and distal femoral cut. If the flexion contracture was presented, the degree of necessary elevation of joint line was also calculated. Intra-operatively, the degree of rotation of anterior and posterior femoral cuts was assessed after proximal tibial and distal femoral cuts. The sizes of prosthesis were judged according to the balance between flexion and extension gaps. A 3-in-1 jig was used for chamfering of the femur. After fine-tuning of bony cuts and balancing of soft tissue, the prostheses were cemented. The conventional intra-medullary and extra-medullary guiding devices were not used during the whole procedure. Results. All of the patients achieved satisfactory results in the aspect of pain relief and functional outcomes. All patients had good post-operative axis in coronal plane (varus or valgus deformity < 3 degrees). Twenty-two patients (92%) achieved good sagittal alignments (deformity < 3 degrees). The results were compatible with those in the patient population without those severe deformities. There was no major complication among these patients. Discussion/Conclusion. In this series, we present a simple and useful geometrical equation system to carry out the pre-operative planning and intra-operative assessments for total knee arthroplasty. These methods are extremely helpful in severely deformed lower limbs. Optimal post-operative alignments were achieved in this series and no major complication was found

Frozen shoulder is a chronic fibrosing condition of the capsule of the joint. The predominant cells involved are fibroblasts and myofibroblasts which lay down a dense matrix of type-I and type-III collagen within the capsule. This subsequently contracts leading to the typical features of pain and stiffness. Cytokines and growth factors regulate the growth and function of the fibroblasts of connective tissue and remodelling of the matrix is controlled by the matrix metalloproteinases (MMPs) and their inhibitors. Our aim was to determine whether there was an abnormal expression or secretion of cytokines, growth factors and MMPs in tissue samples from 14 patients with frozen shoulder using the reverse transcription/polymerase chain reaction (RT/PCR) technique and to compare the findings with those in tissue from four normal control shoulders and from five patients with Dupuytren’s contracture. Tissue from frozen shoulders demonstrated the presence of mRNA for a large number of cytokines and growth factors although the frequency was only slightly higher than in the control tissue. The frequency for a positive signal for the proinflammatory cytokines Il-1β and TNF-α and TNF-β, was not as great as in the Dupuytren’s tissue. The presence of mRNA for fibrogenic growth factors was, however, more similar to that obtained in the control and Dupuytren’s tissue. This correlated with the histological findings which in most specimens showed a dense fibrous tissue response with few cells other than mature fibroblasts and with very little evidence of any active inflammatory cell process. Positive expressions of the mRNA for the MMPs were also increased, together with their natural inhibitor TIMP. The notable exception compared with control and Dupuytren’s tissue was the absence of MMP-14, which is known to be a membrane-type MMP required for the activation of MMP-2 (gelatinase A). Understanding the control mechanisms which play a part in the pathogenesis of frozen shoulder may lead to the development of new regimes of treatment for this common, protracted and painful chronic fibrosing condition