The December 2024 Children’s orthopaedics Roundup360 looks at: Establishing best practice for managing idiopathic toe walking in children: a UK consensus; Long-term outcomes of below-elbow casting in paediatric diaphyseal forearm fractures; Residual dysplasia risk persists in developmental dysplasia of the hip patients after Pavlik harness treatment; 3D printing in paediatricorthopaedics: enhancing surgical efficiency and patient outcomes; Pavlik harness treatment for hip dysplasia does not delay motor skill development in children; High prevalence of hip dysplasia found in adolescents with idiopathic scoliosis on routine spine radiographs; Minifragment plates as effective growth modulation for ulnar deformities of the distal radius in children; Long-term success of Chiari pelvic osteotomy in preserving hip function: 30-year follow-up study.
Chondrocytes are enveloped within the pericellular matrix (PCM), a structurally intricate network primarily demarcated by the presence of collagen type VI microfibrils and perlecan, resembling a protective cocoon. The PCM serves pivotal functions in facilitating cell mechanoprotection and mechanotransduction. The progression of osteoarthritis (OA) is associated with alterations in the spatial arrangement of chondrocytes, transitioning from single strings to double strings, small clusters, and eventually coalescing into large clusters in advanced OA stages. Changes in cellular patters coincide with structural degradation of the PCM and loss of biomechanical properties. Here, we systematically studied matrix metalloproteinases (MMPs), their distribution, activity, and involvement in PCM destruction, utilizing chondrocyte arrangement as an OA biomarker. Cartilage specimens were obtained from 149 osteoarthritis (OA) patients, and selected based on the predominant spatial pattern of chondrocytes. Immunoassays were employed to screen for the presence of various MMPs (-1, -2, -3, -7, -8, -9, -10, -12, -13). Subsequently, the presence and activity of elevated MMPs were further investigated through immunolabeling, western blots and zymograms. Enzymatic assays were utilized to demonstrate the direct involvement of the targeted MMPs in the PCM destruction.Introduction
Methods
Metabolic bone diseases, such as osteoporosis and osteopetrosis, result from an imbalanced bone remodeling process. In vitro bone models are often used to investigate either bone formation or resorption independently, while in vivo, these processes are coupled. Combining these processes in a co-culture is challenging as it requires finding the right medium components to stimulate each cell type involved without interfering with the other cell type's differentiation. Furthermore, differentiation stimulating factors often comprise growth factors in supraphysiological concentrations, which can overshadow the cell-mediated crosstalk and coupling. To address these challenges, we aimed to recreate the physiological bone remodeling process, which follows a specific sequence of events starting with cell activation and bone resorption by osteoclasts, reversal, followed by bone formation by osteoblasts. We used a mineralized silk fibroin scaffold as a bone-mimetic template, inspired by bone's extracellular matrix composition and organization. Our model supported osteoclastic resorption and osteoblastic mineralization in the specific sequence that represents physiological bone remodeling. We also demonstrated how culture variables, such as different cell ratios, base media, and the use of osteogenic/osteoclast supplements, and the application of mechanical load, can be adjusted to represent either a high bone turnover system or a self-regulating system. The latter system did not require the addition of osteoclastic and osteogenic differentiation factors for remodeling, therefore avoiding growth factor use. Our in vitro model for bone remodeling has the potential to reduce animal experiments and advance in vitro drug development for bone remodeling pathologies like osteoporosis. By recreating the physiological bone remodeling cycle, we can investigate cell-cell and cell-matrix interactions, which are essential for understanding bone physiology and pathology. Furthermore, by tuning the culture variables, we can investigate bone remodeling under various conditions, potentially providing insights into the mechanisms underlying different bone disorders.
Extracellular matrix (ECM) mechanical cues guide healing in tendons. Yet, the molecular mechanisms orchestrating the healing processes remain elusive. Appropriate tissue tension is essential for tendon homeostasis and tissue health. By mapping the attainment of tensional homeostasis, we aim to understand how ECM tension regulates healing. We hypothesize that diseased tendon returns to homeostasis only after the cells reach a mechanically gated exit from wound healing. We engineered a 3D mechano-culture system to create tendon-like constructs by embedding patient-derived tendon cells into a collagen I hydrogel. Casting the hydrogel between posts anchored in silicone allowed adjusting the post stiffness. Under this static mechanical stimulation, cells remodel the (unorganized) collagen representing wound healing mechanisms. We quantified tissue-level forces using post deflection measurements. Secreted ECM was visualized by metabolic labelling with non-canonical amino acids, click chemistry and confocal microscopy. We blocked cell-mediated actin-myosin contractility using a ROCK inhibitor (Y27632) to explore the involvement of the Rho/ROCK pathway in tension regulation. Tissue tension forces reached the same homeostatic level at day 21 independent of post compliance (p = 0.9456). While minimal matrix was synthesized in early phases of tissue formation (d3-d5), cell-deposited ECM was present in later stages (d7-d9). More ECM was deposited by tendon constructs cultured on compliant (1Nm) compared to rigid posts (p = 0.0017). Matrix synthesized by constructs cultured on compliant posts was less aligned (greater fiber dispersion, p = 0.0021). ROCK inhibition significantly decreased tissue-level tensional forces (p < 0.0001). Our results indicate that tendon cells balance matrix remodeling and synthesis during tissue repair to reach an intrinsically defined “mechanostat setpoint” guiding tension-mediated exit from wound healing towards homeostasis. We are identifying specific molecular mechanosensors governing tension-regulated healing in tendon and investigate the Rho/ROCK system as their possible downstream pathway.
Young patients receiving metallic bone implants after surgical resection of bone cancer require implants that last into adulthood, and ideally life-long. Porous implants with similar stiffness to bone can promote bone ingrowth and thus beneficial clinical outcomes. A mechanical remodelling stimulus, strain energy density (SED), is thought to be the primary control variable of the process of bone growth into porous implants. The sequential process of bone growth needs to be taken into account to develop an accurate and validated bone remodelling algorithm, which can be employed to improve porous implant design and achieve better clinical outcomes. A bone remodelling algorithm was developed, incorporating the concept of bone connectivity (sequential growth of bone from existing bone) to make the algorithm more physiologically relevant. The algorithm includes adaptive elastic modulus based on apparent bone density, using a node-based model to simulate local remodelling variations while alleviating numerical checkerboard problems. Strain energy density (SED) incorporating stress and strain effects in all directions was used as the primary stimulus for bone remodelling. The simulations were developed to run in MATLAB interfacing with the commercial FEA software ABAQUS and Python. The algorithm was applied to predict bone ingrowth into a porous implant for comparison against data from a sheep model.Abstract
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Methods
The effect of high-fat diet and testosterone replacement therapy upon bone remodelling was investigated in orchiectomised male APOE-/- mice. Mice were split in to three groups: sham surgery + placebo treatment (control, n=9), orchiectomy plus placebo treatment (n=8) and orchiectomy plus testosterone treatment (n=10). Treatments were administered via intramuscular injection once a fortnight for 17 weeks before sacrifice at 25 weeks of age. Tibiae were scanned ex-vivo using µCT followed by post-analysis histology and immunohistochemistry. Previously presented µCT data demonstrated orchiectomised, placebo treated mice exhibited significantly reduced trabecular bone volume, number, thickness and BMD compared to control mice despite no significant differences in body weight. Trabecular parameters were rescued back to control levels in orchiectomised mice treated with testosterone. No significant differences were observed in the cortical bone. Assessment of TRAP stained FFPE sections revealed no significant differences in osteoclast or osteoblast number along the endocortical surface. IHC assessment of osteoprotegerin (OPG) expression in osteoblasts is to be quantified alongside markers of osteoclastogenesis including RANK and RANKL. Results support morphological analysis of cortical bone where no change in cortical bone volume or density between groups is in line with no significant change in osteoblast or osteoclast number and percentage across all three groups. Future work will include further IHC assessment of bone remodelling and adiposity, as well as utilisation of mechanical testing to establish the effects of observed morphological differences in bone upon mechanical properties. Additionally, the effects of hormone treatments upon murine-derived bone cells will be investigated to provide mechanistic insights.
Aims. Fixation techniques used in the treatment of slipped capital femoral epiphysis (SCFE) that allow continued growth of the femoral neck, rather than inducing epiphyseal fusion in situ, have the advantage of allowing remodelling of the deformity. The aims of this study were threefold: to assess whether the Free-Gliding (FG) SCFE screw prevents further slip; to establish whether, in practice, it enables lengthening and gliding; and to determine whether the age of the patient influences the extent of glide. Methods. All patients with SCFE who underwent fixation using FG SCFE screws after its introduction at our institution, with minimum three years’ follow-up, were reviewed retrospectively as part of ongoing governance. All pre- and postoperative radiographs were evaluated. The demographics of the patients, the grade of slip, the extent of lengthening of the barrel of the screw and the restoration of Klein’s line were recorded. Subanalysis was performed according to sex and age. Results. A total of 19 hips in 13 patients were included. The mean age of the patients at the time of surgery was 11.5 years (9 to 13) and the mean follow-up was 63 months (45 to 83). A total of 13 FG SCFE screws were used for the fixation of mild or moderate SCFE, with six contralateral prophylactic fixations. No hip with SCFE showed a further slip after fixation and there were no complications. Lengthening occurred in 15 hips (79%), with a mean lengthening of the barrel of 6.8 mm (2.5 to 13.6) at final follow-up.
Large acetabular bone defects encountered in revision total hip arthroplasty (THA) are challenging to restore. Metal constructs for structural support are combined with bone graft materials for restoration. Autograft is restricted due to limited volume, and allogenic grafts have downsides including cost, availability, and operative processing. Bone graft substitutes (BGS) are an attractive alternative if they can demonstrate positive remodelling. One potential product is a biphasic injectable mixture (Cerament) that combines a fast-resorbing material (calcium sulphate) with the highly osteoconductive material hydroxyapatite. This study reviews the application of this biomaterial in large acetabular defects. We performed a retrospective review at a single institution of patients undergoing revision THA by a single surgeon. We identified 49 consecutive patients with large acetabular defects where the biphasic BGS was applied, with no other products added to the BGS. After placement of metallic acetabular implants, the BGS was injected into the remaining bone defects surrounding the new implants. Patients were followed and monitored for functional outcome scores, implant fixation, radiological graft site remodelling, and revision failures.Aims
Methods
Knowledge of the premorbid glenoid shape and the morphological changes the bone undergoes in patients with glenohumeral arthritis can improve surgical outcomes in total and reverse shoulder arthroplasty. Several studies have previously used scapular statistical shape models (SSMs) to predict premorbid glenoid shape and evaluate glenoid erosion properties. However, current literature suggests no studies have used scapular SSMs to examine the changes in glenoid surface area in patients with glenohumeral arthritis. Therefore, the purpose of this study was to compare the glenoid articular surface area between pathologic glenoid cavities from patients with glenohumeral arthritis and their predicted premorbid shape using a scapular SSM. Furthermore, this study compared pathologic glenoid surface area with that from virtually eroded glenoid models created without influence from internal bone remodelling activity and osteophyte formation. It was hypothesized that the pathologic glenoid cavities would exhibit the greatest glenoid surface area despite the eroded nature of the glenoid and the medialization, which in a vault shape, should logically result in less surface area. Computer tomography (CT) scans from 20 patients exhibiting type A2 glenoid erosion according to the Walch classification [Walch et al., 1999] were obtained. A scapular SSM was used to predict the premorbid glenoid shape for each scapula. The scapula and humerus from each patient were automatically segmented and exported as 3D object files along with the scapular SSM from a pre-operative planning software. Each scapula and a copy of its corresponding SSM were aligned using the coracoid, lateral edge of the acromion, inferior glenoid tubercule, scapular notch, and the trigonum spinae. Points were then digitized on both the pathologic humeral and glenoid surfaces and were used in an iterative closest point (ICP) algorithm in MATLAB (MathWorks, Natick, MA, USA) to align the humerus with the glenoid surface. A Boolean subtraction was then performed between the scapular SSM and the humerus to create a virtual erosion in the scapular SSM that matched the erosion orientation of the pathologic glenoid. This led to the development of three distinct glenoid models for each patient: premorbid, pathologic, and virtually eroded (Fig. 1). The glenoid surface area from each model was then determined using 3-Matic (Materialise, Leuven, Belgium). Figure 1. (A) Premorbid glenoid model, (B) pathologic glenoid model, and (C) virtually eroded glenoid model. The average glenoid surface area for the pathologic scapular models was 70% greater compared to the premorbid glenoid models (P < 0 .001). Furthermore, the surface area of the virtual glenoid erosions was 6.4% lower on average compared to the premorbid glenoid surface area (P=0.361). The larger surface area values observed in the pathologic glenoid cavities suggests that sufficient bone remodelling exists at the periphery of the glenoid bone in patients exhibiting A2 type glenohumeral arthritis. This is further supported by the large difference in glenoid surface area between the pathologic and virtually eroded glenoid cavities as the virtually eroded models only considered humeral anatomy when creating the erosion. For any figures or tables, please contact the authors directly.
Excision of chronic osteomyelitic bone creates a dead space which must be managed to avoid early recurrence of infection. Systemic antibiotics cannot penetrate this space in high concentrations, so local treatment has become an attractive adjunct to surgery. The aim of this study was to present the mid- to long-term results of local treatment with gentamicin in a bioabsorbable ceramic carrier. A prospective series of 100 patients with Cierny-Mader Types III and IV chronic ostemyelitis, affecting 105 bones, were treated with a single-stage procedure including debridement, deep tissue sampling, local and systemic antibiotics, stabilization, and immediate skin closure. Chronic osteomyelitis was confirmed using strict diagnostic criteria. The mean follow-up was 6.05 years (4.2 to 8.4).Aims
Methods
Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors. Cite this article:
Abstract. Introduction. After remodelling, loss of bone density beside the keel of cementless UKR tibial components has been observed as a potential cause of concern. How this affects patient-reported outcomes, and further clinical implications, is unclear. This study aims to assess the effect of cementless UKR implantation on tibial bone density, and to explore its relationship to patient demographics and outcomes. Method. This prospective study assesses 115 anterior-posterior radiographs from cementless UKR postoperatively and five years after surgery. Grey values from nine regions around each keel were collected and standardised to enable inter-radiograph comparison. Change between the post-operative and 5-year radiographs (indicating bone density) was calculated, and effect on 5-year patient demographics and pain and functional outcomes was assessed. Repeat measurements were performed by two operators to assess reliability. Results. There was excellent inter-operator correlation. There was increased bone density directly below the keel (9.1% vs 3.3%: p<0.0001), and reduced density beside the keel (−5.9% vs -1.0%, p<0.0001); comparisons to adjacent regions. Overall remodelling was significantly greater in smaller tibias (p=0.006), and females (p=0.01).
Introduction. Fibula contributes to weight bearing and serves as a lateral buttress to the talus. Fibular shortening leads to ankle valgus, distal tibial epiphyseal wedging and ankle instability. Trauma, infection and skeletal dyplasias are the common causes of fibular shortening in children. Aim was to review this cohort who underwent fibular lengthening and ankle reconstruction. Materials and Methods. Retrospective review from a prospective database of clinical and radiographic data of all children who underwent fibular lengthening for correction of ankle valgus. Distraction osteogenesis with external fixator was performed for all cases. Results. Eight children with 10 fibulae (average age: 10 years) were followed up for an average of 75.6 months. In older children, corrective tibial osteotomy was performed in addition to fibular lengthening. TSF frame mounted with mini-rail fixator was used in seven children who required adjuvant tibial correction and mini-rail was used for bilateral fibular lengthening in one.
Global prevalence of obesity has risen almost three-fold between 1975 and 2016. Alongside the more well-known health implications of obesity such as cardiovascular disease, cancer and type II diabetes, is the effect of male obesity on testosterone depletion and hypogonadism. Hypogonadism is a well-known contributor to the acceleration of bone loss during aging, and obesity is the single biggest risk factor for testosterone deficiency in men. Understanding the micro and macro structural changes to bone in response to testosterone depletion in combination with a high fat ‘Western’ diet, will advance our understanding of the relationship between obesity and bone metabolism. This study investigated the impact of surgically induced testosterone depletion and subsequent testosterone treatment upon bone remodelling in mice fed a high fat diet. Male ApoE−/− mice were split into 3 groups at 7 weeks of age and fed a high fat diet: Sham surgery with placebo treatment, orchiectomy surgery with placebo treatment, and orchiectomy surgery with testosterone treatment. Surgeries were performed at 8 weeks of age, followed by fortnightly testosterone treatment via injection. Mice were sacrificed at 25 weeks of age. Tibiae were collected and scanned ex-vivo at 4.3μm on a SkyScan 1272 Micro-CT scanner (Bruker). Left tibiae were used for assessment of trabecular and cortical Volumes of Interest (VOIs) 0.2mm and 1.0mm respectively from the growth-plate bridge break. Tibiae were subsequently paraffin embedded and sectioned at 4μm prior to immunohistochemical evaluation of alkaline phosphatase.Introduction and Objective
Materials and Methods
Bone remodelling is a continuous process whereby osteocytes regulate the activity of osteoblasts and osteoclasts to repair loading-induced microdamage. While many in vitro studies have established the role of paracrine factors (e.g., RANKL/OPG) and cellular pathways involved in bone homeostasis, these techniques are generally limited to two-dimensional cell culture, which neglects the role of the native extracellular matrix in maintaining the phenotype of osteocyte. Recently, ex vivo models have been used to understand cell physiology and mechanobiology in the presence of the native matrix. Such approaches could be applicable to study the mechanisms of bone repair, whilst also enabling exploration of biomechanical cues. However, to date an ex vivo model of bone remodelling in cortical bone has not been developed. In this study, the objective was to develop an ex vivo model where cortical bone was subjected to cyclic strains to study the remodelling of bone. Ex vivo model of bone remodelling induced by cyclic loading: At the day of culling, beam-shape bovine bone samples were cut and preserved in PBS + 5% Pen/Strep + 2 mM L-Glut overnight at 37°C. Cyclic strains were applied with a three-point bend system to induce damage with a regime at 16.66 mm/min for 5,000 cycles in sterile PBS in Evolve® bags (maximum strain 6%). A control group was cultured under static conditions. Metabolic activity: Alamar Blue assays were performed after 1 and 7 days of ex vivo culture for each group (Static, Loaded) and normalized to weight. Bone remodelling: ALP activity was assessed in the media at day 1 and 7. After 24 hours cell culture conditioned media (CM) was collected from each group and stored at −80°C. RAW264.7 cells were cultured with CM for 6 days, after which the samples were stained for TRAP, to determine osteoclastogenesis, and imaged. Histomorphometry: Samples were cultured with calcein for 3 days to label bone formation between day 4 and 7. Fluorescent images were captured at day 7. μCT scanning was performed at 3 μm resolution after labelling samples with BaSO4 precipitate to quantify bone damage.Introduction and Objective
Materials and Methods
The aim of this study was to define the complications and long-term outcome following adolescent mid-shaft clavicular fracture. We retrospectively reviewed a consecutive series of 677 adolescent fractures in 671 patients presenting to our region (age 13 to 17 years) over a ten-year period (2009 to 2019). Long-term patient-reported outcomes (abbreviated version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) score and EuroQol five-dimension three-level (EQ-5D-3L) quality of life score) were undertaken at a mean of 6.4 years (1.2 to 11.3) following injury in severely displaced mid-shaft fractures (Edinburgh 2B) and angulated mid-shaft fractures (Edinburgh 2A2) at a minimum of one year post-injury. The median patient age was 14.8 years (interquartile range (IQR) 14.0 to 15.7) and 89% were male (n = 594/671).Aims
Methods
The management of completely displaced fractures of the distal radius in children remains controversial. This study evaluates the outcomes of surgical and non-surgical management of ‘off-ended’ fractures in children with at least two years of potential growth remaining. A total of 34 boys and 22 girls aged 0 to ten years with a closed, completely displaced metaphyseal distal radial fracture presented between 1 November 2015 and 1 January 2020. After 2018, children aged ten or under were offered treatment in a straight plaster or manipulation under anaesthesia with Kirschner (K-)wire stabilization. Case notes and radiographs were reviewed to evaluate outcomes. In all, 16 underwent treatment in a straight cast and 40 had manipulation under anaesthesia, including 37 stabilized with K-wires.Aims
Methods
After anterior cruciate ligament (ACL) rupture, reconstructive surgery with a hamstring tendon autograft is often performed. Despite overall good results, ACL re-rupture occurs in up to 10% of the patient population, increasing to 30% of the cases for patients aged under 20 years. This can be related to tissue remodelling in the first months to years after surgery, which compromises the graft's mechanical strength. Resident graft fibroblasts secrete matrix metalloproteinases (MMPs), which break down the collagen I extracellular matrix. After necrosis of these fibroblasts, myofibroblasts repopulate the graft, and deposit more collagen III rather than collagen I. Eventually, the cellular and matrix properties converge towards those of the native ACL, but full restoration of the ACL properties is not achieved. It is unknown how inter-patient differences in tissue remodelling capacity contribute to ACL graft rupture risk. This research measured patient-specific tissue remodelling-related properties of human hamstring tendon-derived cells in an in vitro micro-tissue platform, in order to identify potential biological predictors for graft rupture. Human hamstring tendon-derived cells were obtained from remnant autograft tissue after ACL reconstructions. These cells were seeded in collagen I gels on a micro-tissue platform to assess inter-patient cellular differences in tissue remodelling capacity.
To evaluate if union of clavicle fractures can be predicted at six weeks post-injury by the presence of bridging callus on ultrasound. Adult patients managed nonoperatively with a displaced mid-shaft clavicle were recruited prospectively. Ultrasound evaluation of the fracture was undertaken to determine if sonographic bridging callus was present. Clinical risk factors at six weeks were used to stratify patients at high risk of nonunion with a combination of Quick Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) ≥ 40, fracture movement on examination, or absence of callus on radiograph.Aims
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