Synchronized mechanical oscillations at the cell-matrix interface in the formation of tensile tissue.

The formation of uniaxial fibrous tissues with defined viscoelastic properties implies the existence of an orchestrated mechanical interaction between the cytoskeleton and the extracellular matrix. This study addresses the nature of this interaction. The hypothesis is that this mechanical interplay underpins the mechanical development of the tissue. In embryonic tendon tissue, an early event in the development of a mechanically robust tissue is the interaction of the pointed tips of extracellular collagen fibrils with the fibroblast plasma membrane to form stable interface structures (fibripositors). Here, we used a fibroblast-generated tissue that is structurally and mechanically matched to embryonic tendon to demonstrate homeostasis of cell-derived and external strain-derived tension over repeated cycles of strain and relaxation. A cell-derived oscillatory tension component is evident in this matrix construct. This oscillatory tension involves synchronization of individual cell forces across the construct and is induced in each strain cycle by transient relaxation and transient tensioning of the tissue. The cell-derived tension along with the oscillatory component is absent in the presence of blebbistatin, which disrupts actinomyosin force generation of the cell. The time period of this oscillation (60-90 s) is well-defined in each tissue sample and matches a primary viscoelastic relaxation time. We hypothesize that this mechanical oscillation of fibroblasts with plasma membrane anchored collagen fibrils is a key factor in mechanical sensing and feedback regulation in the formation of tensile tissues.

Fibroblasts Promote Inflammation and Pain via IL-1α Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2.

Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Herein, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea, we used a human model of surgery-induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics, we discovered that many months after TKA, the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators, including the monocyte chemoattractant, chemokine (C-C motif) ligand (CCL) 2, and the innate immune trigger, IL-1α. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL-1α polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-κB prevented IL-1α-induced monocyte recruitment. Clinical investigations discovered that levels of patient-reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue, such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1α-NF-κB-CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.

Nonmuscle myosin II powered transport of newly formed collagen fibrils at the plasma membrane.

Collagen fibrils can exceed thousands of microns in length and are therefore the longest, largest, and most size-pleomorphic protein polymers in vertebrates; thus, knowing how cells transport collagen fibrils is essential for a more complete understanding of protein transport and its role in tissue morphogenesis. Here, we identified newly formed collagen fibrils being transported at the surface of embryonic tendon cells in vivo by using serial block face-scanning electron microscopy of the cell-matrix interface. Newly formed fibrils ranged in length from ~1 to ~30 µm. The shortest (1-10 µm) occurred in intracellular fibricarriers; the longest (~30 µm) occurred in plasma membrane fibripositors. Fibrils and fibripositors were reduced in numbers when collagen secretion was blocked. ImmunoEM showed the absence of lysosomal-associated membrane protein 2 on fibricarriers and fibripositors and there was no effect of leupeptin on fibricarrier or fibripositor number and size, suggesting that fibricarriers and fibripositors are not part of a fibril degradation pathway. Blebbistatin decreased fibricarrier number and increased fibripositor length; thus, nonmuscle myosin II (NMII) powers the transport of these compartments. Inhibition of dynamin-dependent endocytosis with dynasore blocked fibricarrier formation and caused accumulation of fibrils in fibripositors. Data from fluid-phase HRP electron tomography showed that fibricarriers could originate at the plasma membrane. We propose that NMII-powered transport of newly formed collagen fibrils at the plasma membrane is fundamental to the development of collagen fibril-rich tissues. A NMII-dependent cell-force model is presented as the basis for the creation and dynamics of fibripositor structures.

Quantification and severity grading of femoral vessel compression by adverse reactions to metal debris in metal-on-metal total hip arthroplasty.

INTRODUCTION: Metal-on-metal (MoM) total hip arthroplasty (THA) may cause adverse reactions to metal debris (ARMD). ARMD causing femoral vessel compression with serious complications has been described in case reports, but the rate of compression by ARMD is not known. This study aims to investigate the rate, and quantify the severity, of femoral vessel compression in MoM hips with ARMD lesions. METHODS: Patients under surveillance for MoM THA investigated with MRI were studied. In patients with confirmed ARMD, femoral artery (FA) and vein (FV) diameters were measured at the point of maximal compression and compared to contralateral vessels. The primary outcome measure was presence or absence of compression. Cases were then classified by compression ratios. Secondary outcome measures were rates of deep vein thrombosis, revision surgery and time to ARMD from index procedure. RESULTS: MRI scans for 436 patients with MoM THA were screened. Of these, 211/436 (48.4%) showed evidence of ARMD. Measurements were obtained on 133/211 (63.0%) patients. The FV was compressed in 102/133 (76.7%) and FA in 58/133 (43.6%), while 31/133 (23.3%) patients had no compression. In FVs, 42 demonstrated mild compression, 39 moderate and 21 severe. In FAs, none were severely compressed, 6 were moderate and 52 showed mild compression. There were 3 DVT cases, 2 in patients with moderate FV compression and 1 in patients without FV compression. Revision rates were highest in patients with severe FV compression (14/21, 66.7%). The mean time for MRI-diagnosed ARMD from index procedure was 8 years and 1 month (range 11 months-14.5 years). CONCLUSIONS: Extra-luminal compression of the femoral vessels was found in >75% of patients with ARMD. Although it is not clear whether revision for femoral vessel compression is required, quantification of FV compression may be useful for surgeons and radiologists considering revision for ARMD.

Low readmission and reattendance rate in day-case total knee arthroplasties.

Aims: The rate of day-case total knee arthroplasty (TKA) in the UK is currently approximately 0.5%. Reducing length of stay allows orthopaedic providers to improve efficiency, increase operative throughput, and tackle the rising demand for joint arthroplasty surgery and the COVID-19-related backlog. Here, we report safe delivery of day-case TKA in an NHS trust via inpatient wards with no additional resources. Methods: Day-case TKAs, defined as patients discharged on the same calendar day as surgery, were retrospectively reviewed with a minimum follow-up of six months. Analysis of hospital and primary care records was performed to determine readmission and reattendance rates. Telephone interviews were conducted to determine patient satisfaction. Results: Since 2016, 301/7350 TKAs (4.1%) in 290 patients at our institution were discharged on the day of surgery. Mean follow-up was 31.4 months (6.2 to 70.0). In all, 28 patients (9.3%) attended the emergency department or other acute care settings within 90 days of surgery, most often with wound concerns or leg swelling; six patients (2.0%) were readmitted. No patients underwent a subsequent revision procedure, and there were no periprosthetic infections. Two patients (0.7%) underwent secondary patella resurfacing, and one patient underwent arthroscopic arthrolysis after previous manipulation under anaesthetic (MUA). Three patients (1.0%) underwent MUA alone. Primary care consultation records, available for 206 patients, showed 16 patients (7.8%) contacted their general practitioner within two weeks postoperatively; two (1.0%) were referred to secondary care. Overall, 115/121 patients (95%) telephoned stated they would have day-case TKA again. Conclusion: Day-case TKA can be safely delivered in the NHS with no additional resources. We found low incidence of contact with primary and secondary care in the postoperative period, and high patient satisfaction.

Slow stretching that mimics embryonic growth rate stimulates structural and mechanical development of tendon-like tissue in vitro.

A distinctive feature of embryonic tendon development is the steady increase in collagen fibril diameter and associated improvement of tissue mechanical properties. A potential mechanical stimulus for these changes is slow stretching of the tendon during limb growth. Testing this hypothesis in vivo is complicated by the presence of other developmental processes including muscle development and innervation. Here we used a cell culture tendon-like construct to determine if slow stretch can explain the increases in fibril diameter and mechanical properties that are observed in vivo. Non-stretched constructs had an ultrastructural appearance and mechanical properties similar to those of early embryonic tendon. However, slowly stretching during 4 days in culture increased collagen fibril diameter, fibril packing volume, and mechanical stiffness, and thereby mimicked embryonic development. 3D EM showed cells with improved longitudinal alignment and elongated nuclei, which raises the hypothesis that nuclear deformation could be a novel mechanism during tendon development.

Destructive synovial hemangioma of the hip resembling pigmented villonodular synovitis.

We report a case of synovial hemangioma of the hip causing joint destruction severe enough to warrant arthroplasty in a 32-year-old man who presented with a 2-year history of hip pain and worsening limp. Plain radiographs demonstrated advanced degenerative changes of the hip articular surface. Magnetic resonance imaging revealed changes consistent with pigmented villonodular synovitis throughout the joint and erosion of the acetabular bone. A total hip arthroplasty was performed, and histopathologic examination of the resected tissue demonstrated synovial hemangioma. This case, unique in the literature, demonstrates the destructive capacity and diagnostic pitfalls of synovial hemangioma.

Do changes in gastro-intestinal blood flow explain high-altitude anorexia?

BACKGROUND: Gastrointestinal symptoms are common on acute exposure to high-altitude (HA). Underlying mechanisms are not understood, but vascular shunting away from the gut could be responsible. Therefore, blood flow in the superior mesenteric artery (SMA) and hepatic portal vein (HPV) was examined at sea level (SL) and after ascent to 4392 m (HA). MATERIALS AND METHODS: Twelve subjects [eight male, mean age 40 (22-72) years] were studied following an overnight fast and a standard meal. Cross-sectional vessel area and blood velocity were measured by ultrasound, systolic and diastolic flow calculated for the SMA (HR x vessel area x velocity, cm(3) min(-1)) and mean flow for the HPV. RESULTS: All subjects experienced reduced appetite at HA. Blood flow in the SMA and HPV increased following food at SL (mean SMA systolic flow 1024 vs. 3316 cm(3) min(-1), P < 0.001; HPV 505 vs. 1789, P < 0.001) and at HA (2020 vs. 3767, P < 0.001; HPV 708 vs. 1727, P < 0.001). Pre-prandial flow in the SMA and HPV was significantly increased at HA compared with SL. The changes were due to increased vessel diameter and increased flow velocity. There was no difference in post-prandial flow between SL and HA in the HPV, although the increase in post-prandial flow was greater at SL than HA (254% increase vs. 144%). CONCLUSIONS: These results show that resting blood flow in the gastrointestinal tract is increased during exposure to high-altitude hypoxia, and that the vascular response of increased blood flow following food ingestion is maintained. Therefore, reduced flow is unlikely to cause gastrointestinal symptoms and reduced appetite at HA.

Top ten research priorities for problematic knee arthroplasty.

AIMS: The James Lind Alliance aims to bring patients, carers, and clinicians together to identify uncertainties regarding care. A Priority Setting Partnership was established by the British Association for Surgery of the Knee in conjunction with the James Lind Alliance to identify research priorities related to the assessment, management, and rehabilitation of patients with persistent symptoms after knee arthroplasty. METHODS: The project was conducted using the James Lind Alliance protocol. A steering group was convened including patients, surgeons, anaesthetists, nurses, physiotherapists, and researchers. Partner organizations were recruited. A survey was conducted on a national scale through which patients, carers, and healthcare professionals submitted key unanswered questions relating to problematic knee arthroplasties. These were analyzed, aggregated, and synthesized into summary questions and the relevant evidence was checked. After confirming that these were not answered in the current literature, 32 questions were taken forward to an interim prioritization survey. Data from this survey informed a shortlist taken to a final consensus meeting. RESULTS: A total of 769 questions were received during the initial survey with national reach across the UK. These were refined into 32 unique questions by an independent information specialist. The interim prioritization survey was completed by 201 respondents and 25 questions were taken to a final consensus group meeting between patients, carers, and healthcare professionals. Consensus was reached for ranking the top ten questions for publication and dissemination. CONCLUSIONS: The top ten research priorities focused on pain, infection, stiffness, health service configuration, surgical and non-surgical management strategies, and outcome measures. This list will guide funders and help focus research efforts within the knee arthroplasty community. Cite this article: Bone Joint J 2020;102-B(9):1176-1182.

Quantification of intra-articular fibrosis in patients with stiff knee arthroplasties using metal-reduction MRI.

AIMS: Stiffness is a common complication after total knee arthroplasty (TKA). Pathogenesis is not understood, treatment options are limited, and diagnosis is challenging. The aim of this study was to investigate if MRI can be used to visualize intra-articular scarring in patients with stiff, painful knee arthroplasties. METHODS: Well-functioning primary TKAs (n = 11), failed non-fibrotic TKAs (n = 5), and patients with a clinical diagnosis of fibrosis1 (n = 8) underwent an MRI scan with advanced metal suppression (Slice Encoding for Metal Artefact Correction, SEMAC) with gadolinium contrast. Fibrotic tissue (low intensity on T1 and T2, low-moderate post-contrast enhancement) was quantified (presence and tissue thickness) in six compartments: supra/infrapatella, medial/lateral gutters, and posterior medial/lateral. RESULTS: Fibrotic tissue was identified in all patients studied. However, tissue was significantly thicker in fibrotic patients (4.4 mm ± 0.2 mm) versus non-fibrotic (2.5 mm ± 0.4 mm) and normal TKAs (1.9 mm ± 0.2 mm, p = < 0.05). Significant (> 4 mm thick) tissue was seen in 26/48 (54%) of compartments examined in the fibrotic group, compared with 17/30 (57%) non-fibrotic, and 10/66 (15%) normal TKAs. Although revision surgery did improve range of movement (ROM) in all fibrotic patients, clinically significant restriction remained post-surgery. CONCLUSION: Stiff TKAs contain intra-articular fibrotic tissue that is identifiable by MRI. Studies should evaluate whether MRI is useful for surgical planning of debridement, and as a non-invasive measurement tool following interventions for stiffness caused by fibrosis. Revision for stiffness can improve ROM, but outcomes are sub-optimal and new treatments are required. Cite this article: Bone Joint J 2020;102-B(10):1331-1340.

The effect of angiotensin-converting enzyme genotype on acute mountain sickness and summit success in trekkers attempting the summit of Mt. Kilimanjaro (5,895 m).

The I-allele rather than the D-allele of the human angiotensin converting enzyme (ACE) gene has been associated with high-altitude mountaineering success. We investigated whether the I-allele was associated with summit success, and also with AMS development, in altitude-naïve trekkers. Subjects ascended from 1,860 m to the summit over 4 days (n = 34, 'direct-profile') or 5 days (n = 82, 'slower-profile'). Proportionally more II direct-profile subjects were successful than ID or DD, although the difference was not significant (100% of II subjects, 52% ID and 43% DD, P = 0.09). There was no difference in success amongst subjects on the slower-profile (50% II, 45% ID and 58% DD, P = 0.54). There was a non-significant trend for increasing AMS scores in ID/DD subjects. Amongst tourist trekkers on Mt. Kilimanjaro the I-allele is not associated with summit success. No evidence is found to support an association between ACE genotype and AMS development.

Determinants of summiting success and acute mountain sickness on Mt Kilimanjaro (5895 m).

OBJECTIVE: To determine the incidence of acute mountain sickness (AMS), the frequency of summiting success, and the factors that affect these in trekkers on Kilimanjaro, one of the world's most summitted high-altitude peaks. METHODS: The study group comprised 312 trekkers attempting Mt Kilimanjaro summit by the Marango Route. Trekkers ascended over 4 or 5 days along a fixed ascent profile, stopping at 3 huts on ascent (2700 m, 3700 m, and 4700 m) before attempting the summit. Researchers were stationed at each hut for 16 days. Each night we measured heart rate, respiratory rate, blood pressure, oxygen saturation, and Lake Louise Score. We recorded the highest altitude that trekkers reached on the mountain. RESULTS: Of 181 complete sets of data, 111 (61%) trekkers reached the summit, and 139 (77%) developed AMS. Physiological results were not related to summit success. The incidence of AMS and summiting success were similar in those on the 4- or 5-day route. Trekkers on the 5-day route who used acetazolamide were less likely to develop AMS and more likely to summit than were those not taking acetazolamide (P = <.05); this difference was not present with trekkers on the 4-day route. CONCLUSIONS: The risk of developing AMS is high on Mt Kilimanjaro. Although taking an extra day to acclimatize with the use of acetazolamide did provide some protection against AMS, ideally trekkers need a more gradual route profile for climbing this mountain.

V-Y advancement flap coverage of toe-tip injuries.

UNLABELLED: Toe-tip injury presents a challenging problem. There are few techniques that provide cover for distal toe defects, and most injuries are usually treated with terminalization or a skin graft. In patients with toe-tip injuries where there is preservation of the plantar toe pulp, V-Y flap advancement is a therapeutic option. In this article, we describe the surgical technique used and present the results of 10 patients with dorsal oblique or transverse toe injuries that underwent V-Y flap advancement for defect coverage. Eight patients had distal great toe injuries, 1 had a dorsal oblique amputation of the third toe, and 1 had a transverse amputation at the metatarsophalangeal joint level. Mean follow-up was 5 months, at which time all patients had returned to their previous activity level, and showed acceptable levels of scarring. The V-Y advancement flap, commonly used in fingertip injuries, when indicated and carefully performed gives excellent contour and padding, maintains toe length, and provides good cosmesis for treatment of toe amputations. LEVEL OF CLINICAL EVIDENCE: 4.

Chronic, Active Inflammation in Patients With Failed Total Knee Replacements Undergoing Revision Surgery.

Chronic pain and restricted knee motion is a significant problem following the total knee arthroplasty (TKA). The molecular pathogenesis of pain post-TKA is not known and no targeted therapeutic intervention is available. The aim of this study was to investigate whether pro-inflammatory mediators are elevated in revision knee patients, indicating an active, ongoing inflammatory process that may contribute to pain. Twelve key markers (pro-inflammatory cytokines granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin 5 [IL-5], IL-8 and IL-10, chemokines CCL2, CCL3, CCL4, and CCL13, mediators of angiogenesis Flt-1, vascular endothelial growth factor, and cell migration vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) were measured in knee tissue and synovial fluid (SF) from primary TKA (n = 29) and revision patients (n = 32). Indications for surgery were osteoarthritis (OA) for primary TKA, and component loosening (n = 11), stiffness (n = 11), laxity pattern (n = 8), or progression of OA in patella resurfacing (n = 3) for revision surgery. Pain levels (WOMAC score) were higher in revision than primary patients (p ≤ 0.05). Time from primary to revision ranged from 8 months to 30 years (median 10 years). All markers were elevated in revision TKA; there was no trend toward decreasing levels with greater time from primary surgery for any marker studied in SF. Similar results were seen in knee tissue. We found no differences comparing indications for revision surgery (p ≥ 0.05). The elevation of inflammatory mediators in painful post-TKA knees requiring revision suggests active, chronic inflammation. Characterization of upregulated markers provides rationale for targeted therapy, even many years from the primary surgery. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2316-2324, 2019.

Post-radiation sciatic neuropathy: a case report and review of the literature.

BACKGROUND: Post-radiation peripheral neuropathy has been reported in brachial and cervical plexuses and the femoral nerve. CASE PRESENTATION: We describe a patient who developed post-radiation sciatic neuropathy after approximately 3 years and discuss the pathophysiology, clinical course and treatment options available for the deleterious effects of radiation to peripheral nerves. CONCLUSION: This is the first case of post-radiation involvement of the sciatic nerve reported in the literature.

Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis.

OBJECTIVE: Joint fibrosis affects many synovial joints (including hip, knee and shoulder) causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease. Here we tested the hypothesis that joint fibrosis and other soft tissue fibrotic conditions are also associated with telomere length. PATIENTS AND METHODS: 5,200 participants in the TwinsUK registry had data on telomere length (measured by qPCR) and the traits of interest (hip and knee stiffness, total joint replacement (TJR, hip or knee) and fibrotic conditions (Dupuytren's disease, frozen shoulder). RESULTS: Multivariable logistic regression analyses showed a significant association between telomere length and fibrotic conditions (hip stiffness, knee stiffness and frozen shoulder, p = ≤0.002) even after taking age into account. No association was found between TJR and telomere length. CONCLUSION: These findings suggest that defects in telomere repair contribute to joint fibrosis, and that fibrosis shares a common mechanistic pathway in different organs. Therapeutic strategies to combat telomere shortening may offer novel treatments for fibrotic joint disease.

Joint Stiffness Is Heritable and Associated with Fibrotic Conditions and Joint Replacement.

OBJECTIVE: Joint stiffness is a common, debilitating, age-related symptom, which may be seen after total joint replacement (TJR). Stiffness also occurs in fibrotic conditions such as shoulder capsulitis and Dupuytren's contracture. We speculated that the two traits (TJR and fibrotic disease) are linked pathogenically. METHODS: Using the TwinsUK NIHR BRC BioResource we tested the hypotheses that 1) joint (hip and knee) stiffness, TJR (hip and knee), and fibrotic conditions are associated and 2) genetic factors contribute to them. RESULTS: Participating twins (n = 9718) had completed self-reported questionnaires on the traits of interest. All three traits were significantly associated with increasing age and body mass index (BMI), as well as female sex, on univariate analysis. Multivariable logistic regression analyses showed a significant association between TJR and joint stiffness (OR = 3.96, 95% confidence interval, CI 2.77-5.68) and between fibrotic conditions and joint stiffness (OR = 2.39, 1.74-3.29), adjusting for age, sex, BMI and twin relatedness. Monozygotic versus dizygotic intraclass correlations gave heritability estimates for TJR = 46% and joint stiffness = 32%. CONCLUSION: That fibrotic conditions, joint stiffness and TJR are significantly associated suggests a common disease process, possibly fibrosis, which is genetically mediated.

A structure-based extracellular matrix expansion mechanism of fibrous tissue growth.

Embryonic growth occurs predominately by an increase in cell number; little is known about growth mechanisms later in development when fibrous tissues account for the bulk of adult vertebrate mass. We present a model for fibrous tissue growth based on 3D-electron microscopy of mouse tendon. We show that the number of collagen fibrils increases during embryonic development and then remains constant during postnatal growth. Embryonic growth was explained predominately by increases in fibril number and length. Postnatal growth arose predominately from increases in fibril length and diameter. A helical crimp structure was established in embryogenesis, and persisted postnatally. The data support a model where the shape and size of tendon is determined by the number and position of embryonic fibroblasts. The collagen fibrils that these cells synthesise provide a template for postnatal growth by structure-based matrix expansion. The model has important implications for growth of other fibrous tissues and fibrosis.