Osteoarthritis (OA) leads to articular cartilage degradation, following complex dysregulation of chondrocyte's metabolism towards a catabolic state. Mechanical and biochemical signals are involved and need to be considered to understand the condition. Regulatory network-based models (RNM) successfully simulated the biological activity of the chondrocyte and the transduction of mechanical signals at the molecular and cell levels. However, the knowledge gap between single-cell regulation and intercellular communication in tissue volumes hinders the interpretability of such models at larger scales. Accordingly, a novel tissue-level biochemical model is proposed. We hypothesise that it is possible to simulate interacting network effects through the transport of diluted species in a finite-element model, to grasp relevant dynamics of cell and tissue regulation in OA. Chondrocyte RNM equations were translated into a reaction term of 18 multi-species diffusion model (e.g., 3 anti-inflammatory and 8 pro-inflammatory interleukins, 3 pro-anabolic and 1 pro-catabolic growth factors, 2 nociceptive factors and 2 pro-inflammatory cytokines). Elements with RNM reaction terms represented the chondrocytes and were distributed randomly through the model, according to known cellular density in the knee cartilage, and could both react to and produce diffusive entities through the pericellular matrix, associated with reduced diffusion coefficients. The model was constructed over a 2D square of 0.47 mm sides considered to be in the middle of the cartilage, so boundary conditions were settled as periodic. Different simulations were initialised with initial concentrations of either healthy or pro-OA mediators. Preliminary results showed that, independently of the initial conditions, the chondrocytes successfully evolved into anabolic states, in absence of sustained pro-catabolic external stimulations, in contrast to single-cell RNM [2]. Our intercellular model suggests that paracrine communication may increase robustness towards cartilage maintenance, and future tests shall reveal new OA dynamics. Acknowledgements: Funding was provided by the European Commission (ERC-2021-CoG-O-Health-101044828)

The purpose of the this survey study was twofold: 1) to examine different aspects of satisfaction with post-operative care in injured workers who have undergone rotator cuff surgery and 2) to examine the relationship between receiving a newly implemented summary report and the overall satisfaction with surgery and recovery. The clinical communication summary report was given to injured workers following their review assessment to share with the family doctor or other health care providers. The form indicated a need for further assessments or investigations and return to work recommendations. The study involved using a satisfaction survey that examined different aspects of follow-up visit and workers’ opinion about their understanding of the nature of surgery, their progress, clinical management, and usefulness of the newly implemented summery report. Eighty patients completed the questionnaire (mean age: 54 (8), 62(78%) males, of whom 26 (34%) had a rotator cuff decompression and 31 (40%) had a rotator cuff repair with 20 (26%) having both procedures and three missing data. There were no statistically significant relationships between the patient demographics (age, sex or type of surgery) and satisfaction. However, there was a significant correlation between how patients perceived the summary report in terms of helpfulness and the overall satisfaction with surgery (FTE<0.0004, p=0.001) and the satisfaction with recovery (FTE<0.0001, p=0.001). This may indicate that improvement in worker's understanding of their treatment recommendations and restrictions is associated with higher levels of overall satisfaction in this population. Our results indicate a positive linear relationship between expressing a high satisfaction and the helpfulness of the summary report. As part of improving care, adding a summary report may facilitate sharing information with the injured workers, their care providers and their workplace

Few doctors answer their bleep by stating who they are. Answering the phone in a formal manner is of utmost importance in the hospital setting especially by on-call teams who are normally referred patients by other specialties, general practitioners and in some cases by other hospitals. An audit to evaluate the internal hospital communication was completed. In the first part of this audit, junior doctors within the orthopaedic department at the RAH were bleeped. Doctors were expected to answer by initiating the conversation by stating (1) name, (2) department, (3) grade and (4) a greeting. A list of omissions was recorded. If the call went through switchboard, it was expected that the hospital name was stated. The second part of the audit extended to other specialties in the RAH as well as orthopaedic departments in hospitals within the Greater Glasgow and Clyde health board (NHS GGC). Forty-three bleeps were made to doctors of various grades over a period of two months. Nine bleeps (two from other hospitals) were not answered. Five doctors answered their bleep in full. Only twenty-one doctors stated their name whilst eleven stated their grade. In both instances the department was not necessarily stated. The results were similar between the different departments as well as between the seven hospitals offering an orthopaedic service within NHS GGC. Of the thirteen on-call doctors that were bleeped as an external call through switchboard, only one doctor stated the hospital name. This has implications since most hospitals within NHS GGC share a common switchboard. These results emphasise the need for a protocol within NHS GGC for a standard etiquette for intra and inter hospital communication to ensure that patient safety and confidentiality is safeguarded

Multiple myeloma (MM) is an incurable hematological tumor stemming from malignant plasma cells. MM cells accumulate in the bone marrow (BM) and shape the BM niche by establishing complex interactions with normal BM cells, boosting osteoclasts (OCLs) differentiation and causing bone disease. This unbalance in bone resorption promotes tumor survival and the development of drug resistance. The communication between tumor cells and stromal cells may be mediated by: 1) direct cell-cell contact; 2) secretion of soluble factors, i.e. chemokines and growth factors; 3) release of extracellular vesicles/exosomes (EVs) which are able to deliver mRNAs, miRNAs, proteins and metabolites in different body district. Primary CD138+ MM cells were isolated from patients BM aspirates. MM cell lines were cultured alone in complete RPMI-1640 medium or co-cultured with murine (NIH3T3) or human (HS5) BMSC cell lines or murine Raw264.7 monocytes in DMEM medium supplemented with 10% V/V FBS. Silencing of Jagged1 and Jagged2 was obtained by transient expression of specific siRNAs or by lentiviral transduction using a Dox-inducible system (pTRIPZ). EVs were isolated using differential ultracentrifugation. EVs concentration and size were analyzed using Nano Track Analysis (NTA) system. The uptake of PKH26-labelled MM-derived EVs by HS5 or Raw264.7 was measured after 48 hours by confocal microscopy and flow cytometry. Osteoclast (OCL) differentiation of Raw264.7 cells was induced by 50ng/ml mRANKL, co-culturing with MM cells, CM or EVs. OCLs were stained by TRAP Kit and counted. Bone resorption was assessed by Osteo Assay Surface plates. Flow cytometric detection of apoptotic cells was performed after staining with Annexin V. Gene expression was analyzed by qRT-PCR, while protein levels were determined using flow cytometry ELISA or WB. Notch oncogenic signaling is dysregulated in several hematological and solid malignancies. Notch receptors and ligands are key players in the crosstalk between tumor cells and BM cells. We have demonstrated that: 1) the dysregulated Jagged ligands on MM cells trigger the activation of Notch receptors in the nearby stromal cells by cell-cell contact. This results in the release of anti-apoptotic and growth stimulating factors, i.e. IL6 and SDF1; 2) MM cells promote the development of bone lesions boosting osteoclast differentiation by secreting soluble factors (i.e. RANKL) and by the activation of Notch signaling mediated by direct contact with osteoclast precursors; 3) Finally, we present evidences that EVs play a crucial role in the dysregulated interactions of MM cells with the microenvironment and that Notch signaling regulates their release and participate in this cross-talk. These evidences supports the hypothesis that Jagged targeting on MM cells may interrupt the communication between tumor cells and the surrounding milieu, blocking the activation of the oncogenic Notch pathway and finally resulting in the a reduction of MM-associated bone disease and drug resistance

Abstract. INTRODUCTION. Knee tactile afferents act as synovial joint limit detectors, eliciting signalling upon excessive fibrous tissue strain but play little role in joint function as disruption of their activity does not induce impairments in movement or sensation. In contrast, knee nociceptive afferents gain activity upon inflammation producing painful sensation in pathology such as osteoarthritis. We hypothesize that similar in origin, fast-conducting tactile afferents become sensitized by inflammatory mediators and gain activity causing proprioceptive sensation impairment in patients with knee pathology, driving gait abnormalities and osteoarthritis progression. To investigate the activity of these neurons, we will produce a co-culture model using our existing 3D bone mimetic and iPSC derived tactile sensory neurons by utilizing the NGN2-BRN3A plasmid produced by Nickolls et al producing a model of these tactile neurons at their position within the joint at the fibrous/bony interface. METHODS. Human Y201 MSC cells embedded in type I collagen gels (0.05 × 106 cell/gel) were differentiated to osteocytes andmechanically loaded in silicone plates (5000 µstrain, 10Hz, 3000 cycles) (n=5). RNA quantified by RNAseq analysis (NovaSeq S1) and neuronal communication pathways identified using DEseq2 analysis. RESULTS. Over 20 genes involved in neural communication were expressed in 100% of bone cultures, and most of these showed regulation under mechanical strain including receptors for Substance P (p= 0.91), CGRP (p=0.05), Norepinepherin (p=0.002), NPY (p=0.0002), Sema3A (p=0.01), Leptin (p=0.00005), Neutrophin3A (p=0.23), BDNF (p=0.5), GDNF (p=0.02), and glutamate(p=0.024) and signalling molecules Neutrophin3 (p=0.73), NGF (p=0.02), Sema3A (p=0.003), BDNF (p=0.02) and GDNF (p=0.006). DISCUSSION. The production of this 3D neural co-culture model is still in its infancy. However, preliminary RNAseq data has shown our Y201 bone model expresses all the signalling pathways known to exert neural regulatory responses and therefore is now ready to move forward to neural inclusion

Abstract. Objectives. In the human knee, the cells of the articular cartilage (AC) and subchondral bone (SB) communicate via the secretion of biochemical factors. Chondrocyte-based AC repair strategies, such as articular chondrocyte implantation, are widely used but there has been little investigation into the communication between the native SB cells and the transplanted chondrocytes. We hypothesise that this communication depends on the health state of the SB and could influence the composition and quality of the repair cartilage. Methods. An indirect co-culture model was developed using transwell inserts, representing a chondrocyte/scaffold-construct for repair of AC defects adjoining SB with varying degrees of degeneration. Donor-matched populations of human bone-marrow derived mesenchymal stromal cells (BM-MSCs) were isolated from the macroscopically and histologically best and worst osteochondral tissue, representing “healthy” and “unhealthy” SB. The BM-MSCs were co-cultured with normal chondrocytes suspended in agarose, with the two cell types separated by a porous membrane. After 0, 7, 14 and 21 days, chondrocyte-agarose scaffolds were assessed by gene expression and biochemical analyses. Results. Matched healthy and unhealthy BM-MSCs from five patients undergoing knee arthroplasty (2 male, 3 female; 72.8±2.2. SD. years-old) were used, together with normal chondrocytes from a healthy patient (male; 24 years-old). At day 21, there was significantly more glycosaminoglycan per chondrocyte in the scaffolds co-cultured with healthy BM-MSCs (4.37×10. −4. μg/cell±2.69×10. −5. SEM. ) than in those cultured with unhealthy BM-MSCs (3.52×10. −4. μg/cell±2.19×10. −5. SEM. ; p<0.001). Co-culture with unhealthy BM-MSCs caused a difference in expression of COL2A1 (day 0–21 fold change; unhealthy:-32.8±12.9. SEM. ; healthy:-7.82±4.46. SEM. ; p<0.001) and ACAN (unhealthy:+1.51±0.51. SEM. ; healthy:+4.05±0.49. SEM. ; p=0.002). Conclusions. Co-culture with unhealthy BM-MSCs caused a reduction in GAG deposition and expression of genes encoding matrix-specific proteins, compared to culturing with healthy BM-MSCs. There are clinical implications for cell-based cartilage repair, where the health of the SB may influence the outcome of chondrocyte-based therapies

Regenerative medicine (RM) promises to restore both the mechanical functionality and the biological composition of tissues after damage. Three-dimensional scaffolds are used in RM to host cells and let them produce proteins that are the building blocks of the native tissues. While regenerating tissues evolve over time through dynamic biomechanical and biochemical changes, current scaffolds’ generation are passive causing mechanical mismatch, suboptimal growth, and pain. Furthermore, current scaffolds ignore the complexity of the reciprocal bio-mechanics regulation, hindering the design of the next-gen scaffolds. To regenerate tissues and organs, biofabrication strategies that impart spatiotemporal control over cell-cell and cell-extracellular matrix communication, often through control over cell and material deposition and placement, are being developed. To achieve these targets, the spatiotemporal control over biological signals at the interface between cells and materials is often aimed for. Alternatively, biological activity can be triggered through the control of mechanical cues, harnessing more fundamental know-how in mechanobiology that could be combined with biofabrication strategies. Here, I present some of our most recent advancements in merging mechanobiology with biofabrication that enabled the control of cell activity, moving towards enhanced tissue regeneration as well as the possibility to create more complex 3D in vitro models to study biological processes

Variations in pelvic anatomy are a major risk factor for misplaced percutaneous sacroiliac screws used to treat unstable posterior pelvic ring injuries. A better understanding of pelvic morphology improves preoperative planning and therefore minimises the risk of malpositioned screws, neurological or vascular injuries, failed fixation or malreduction. Hence a classification system which identifies the clinically important anatomical variations of the sacrum would improve communication among pelvic surgeons and inform treatment strategy. 300 Pelvic CT scans from skeletally mature trauma patients that did not have pre-existing posterior pelvic pathology were identified. Axial and coronal transosseous corridor widths at both S1 and S2 were recorded. Additionally, the S1 lateral mass angle were also calculated. Pelvises were classified based upon the sacroiliac joint (SIJ) height using the midpoint of the anterior cortex of L5 as a reference point. Four distinct types could be identified:. Type-A – SIJ height is above the midpoint of the anterior cortex of the L5 vertebra. Type-B – SIJ height is between the midpoint and the lowest point of the anterior cortex of the L5 vertebra. Type-C – SIJ height is below the lowest point of the anterior cortex of the L5 vertebra. Type-D – a subgroup for those with a lumbosacral transitional vertebra, in particular a sacralised L5. Differences in transosseous corridor widths and lateral mass angles between classification types were assessed using two-way ANOVAs. Type-B was the most common pelvic type followed by Type-A, Type-C, and Type-D. Significant differences in the axial and coronal corridors was observed for all pelvic types at each level. Lateral mass angles increased from Types-A to C, but were smaller in Type-D. This classification system offers a guide to surgeons navigating variable pelvic anatomy and understanding how it is associated with the differences in transosseous sacral corridors. It can assist surgeons’ preoperative planning of screw position, choice of fixation or the need for technological assistance

Worldwide, tendon disorders are one of the main causes of disability that decrease the quality of life of individuals and represent a substantial economic burden on society. Currently, the main therapies used for tendon injuries are not able to restore tendon functionality, and due to tendons' hypovascular and hypocellular nature, they present a reduced healing capacity, which also limits the success of the available therapies. In order to discover new therapies, extracellular vesicles (EVs), key players in cell-cell communication, have been widely explored for tissue engineering and regenerative medicine applications. Thus, the aim of this study is to assess the role of EVs derived from platelets in stem cell tenogenic commitment using a bioengineered tendon in vitro model for potential use as tendon therapeutic agents. Biomimetic platelet-derived EVs were produced by freeze-thaw cycles of platelets and isolation at different centrifugation speed. To recreate the architecture of tendons, a 3D system consisting of electrospun anisotropic nanofiber scaffolds coated with collagen encapsulating human adipose stem cells (hASCs) and different types of platelet-derived EVs, were produced. Then, the influence of the tendon-mimetic constructs and the distinct EVs populations in the hASCs tenogenic differentiation were assessed over culture time. We observed that the hASCs on the nanofibrous tendon scaffolds, show high cytoskeleton anisotropic organization that is characteristic of tenocytes. Moreover, acting as biological cues, platelet-derived EVs boosted hASCs tenogenic commitment, supported by the increased gene expression of tendon-related markers (SCX and TNMD). Additionally, EVs enhanced the deposition of tendon like extracellular matrix (ECM), as evidenced by the increased gene expression of ECM-related markers such as COL1, COL3, DCN, TNC, and MMP-3, which are fundamental for ECM synthesis and degradation balance. Moreover, EVs induced lower collagen matrix contraction on hASCs, which has been related with lower myofibroblast differentiation. Overall, the results revealed that EVs are capable of modulating stem cells' behavior boosting their tenogenic commitment, through the increased expression of healthy tendon cell markers, potentiating ECM deposition and decreasing cell contractility. Therefore, platelet EVs are a promising biochemical tool, worthy to be further explored, as paracrine signaling that might potentiate tendon repair and regeneration

Distal radius fractures are common, particularly in post-menopausal women. Several factors have been identified such as osteopenia and an increased risk of falling. We hypothesised that increased soft tissue padding from muscle and fat in the volar hand may confer an element of protection against fractures more in men than women and more in younger than older patients. The aim of the study was to assess for thenar and hypothenar thickness and assess whether it varies between sexes and changes with age. We retrospectively evaluated hand MRI scans performed for non-acute conditions in adults without previous injury or surgery. Using the Patient Archiving and Communication System (PACS) we measured the distance (mm) from the volar surface of the trapezium to the skin, the hook of the hamate to skin and the pisiform to skin as measures of thenar and hypothenar thickness. We also recorded the sex and age of the subjects. Soft tissue thickness was corrected for hand size by dividing by capitate length which we measured; we have already established this as a surrogate measure of hand size. The scans of 51 men (mean age 35, range 19–66) years and 27 women (mean age 49, range 19–79) years were reviewed. Men had significantly thicker soft tissues compared to women over both the thenar and hypothenar eminences (p=0.0001). Soft tissue thickness did not change significantly with age (p> 0.05). The study confirms a significant difference in volar hand soft tissue thickness between men and women accounting for differences in hand size. Our previous research has shown how we fall onto our outstretched hands in the upper limb falling reflex and we have shown that padding the thenar and hypothenar eminences reduces force transmission to the forearm bones. In theory thicker thenar and hypothenar musculature would help protect against distal radius fractures following a fall on an outstretched hand. The thinner musculature on women may further predispose them to an increased risk of distal radius fractures. Further research is needed to assess for any loss of volar hand soft tissue thickness beyond age 75 years

Pericytes are contractile, motile cells that surround the capillary. Recent studies have shown that pericytes promoted joint fibrosis and induced subchondral bone angiogenesis, indicating the role of pericytes in osteoarthritis (OA). However, whether pericytes are involved in regulating inflammatory and catabolic response, as well as fibrotic repair of cartilage is still unclear. Here we used 2D and 3D models to investigate the communication of pericytes and chondrocytes under inflammatory osteoarthritis conditions. CD34-CD146+ pericytes were isolated and sorted from human bone marrow. Human OA chondrocytes were isolated from OA joints. In 2D studies, monolayer cultured chondrocytes were treated +/- pericyte conditioned media, +/- 1ng/ml IL1β for 24h. In 3D studies, pericytes and chondrocytes were cultured within fibrin gel in 3D polyurethane scaffolds, separately or combined for 7 days, followed by treatment of +/- IL1β for another 7 days (Fig 2A). The inflammatory response, catabolic activity and expression of fibrosis markers of chondrocytes and pericytes were measured by ELISA and/or q-rtPCR. Pericytes had weak inflammatory, catabolic and fibrotic response to IL1β (data not shown). The 2D study showed that pericyte conditioned media promoted inflammation, catabolism and fibrosis markers of chondrocytes, in the absence of IL1β treatment (Figure 1). However, study in 3D showed that coculture of chondrocytes and pericytes reduced the inflammatory and catabolic response of chondrocytes to IL1β and induced fibrosis markers in chondrocytes (Figure 2). Pericytes are involved in regulating inflammatory response, catabolic response and fibrosis of chondrocytes. The opposite results from 2D and 3D experiments indicate the variety of the regulatory role of pericytes in the interaction with chondrocytes within different culture models. The underlying mechanism is under evaluation with on-going studies. Acknowledgements. This study was funded by SINPAIN project, from European Union's Horizon Europe research and innovation programme under Grant Agreement NO. 101057778. Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. For any figures or tables, please contact the authors directly

Calcium is an important element for a wide range of physiological functions including muscle contraction, neuronal activity, exocytosis, blood coagulation and cell communication. In the musculoskeletal system calcium is crucial for the structural integrity of bones, teeth, intervertebral disc and articular cartilage. At the cellular level calcium acts as a second messenger. Calcium signalling uses intracellular calcium ions to drive intracellular communication and signal transduction processes. When calcium enters the cell it exerts allosteric regulatory effects on many enzymes and proteins. Examining the role of calcium in chondrocyte biology is important for understanding the role for this divalent ion in the metabolic modulation of chondrocyte function in health and disease. This includes the study of calcium transport systems such as channels, transporters and pumps involved in calcium homeostasis in chondrocytes and how existing pharmacological drugs act on these transport systems. L-type calcium channel blockers are drugs used as cardiac antiarrhythmics or antihypertensives, depending on whether the drugs have higher affinity for the heart (the phenylalkylamines, like verapamil), or for the blood vessels (the dihydropyridines, like nifedipine). L-type calcium channels are present in many musculoskeletal tissues including skeletal muscle, smooth muscle, bone and cartilage. L-type calcium channel inhibitors like nifedipine used for the treatment of some forms of hypertension modulate calcium-mediated events in chondrocytes under dynamic loading, thus affecting metabolism, osmotic responses and extracellular matrix turnover in cartilage. The aim of our work is to understand the impact of L-type calcium channel inhibitors used for the treatment of hypertension on chondrocytes and on the chondrogenic differentiation of bone marrow derived mesenchymal stem cells (MSCs). This knowledge will enhance our understanding of the development of osteoarthritis (OA) and may lead to new opportunities for chondroprotection and regenerative medicine for OA. We have used electrophysiology to demonstrate L-type calcium currents in chondrocytes immediately after pharmacological activation with the calcium channel opener Bay-K8644. We have also used immunohistochemistry to demonstrate expression of the a1C subunit Ca. v. 1.2 (CACNA1C) in human chondrocytes and MSCs. Inhibitors of L-type calcium channels such as nifedipine downregulate mitochondrial respiration and ATP production in MSCs but not in chondrocytes. Nifedipine inhibits proliferation of chondrocytes and enhances glycolytic capacity in chondrocytes, promoting glycolytic reserve in both MSCs and chondrocytes. Nifedipine can also stimulate chondrogenic differentiation in MSCs (with or without growth factors). Metabolic responses to nifedipine differs in mesenchymal stem cells and chondrocytes highlighting important metabolic differences between these cells. In summary, antihypertensive drugs such as nifedipine can affect the biological function of chondrocytes and MSCs and may modulate the course of OA progression and impact on cartilage repair

Remodeling of the cancellous bone is more active than that of the cortical bone. It is known that the remodeling is governed by the intracancellous fluid pressure. Particularly, the lacunocanalicular pore (PLC) fluid pressure (FP) is essential for survival of the osteocyte and communication of remodeling signals between the PLC and intertrabecular pore (PIT). As a result, knowledge about the PLCFP generation of trabeculae is required to understand human cancellous bone biology. At this moment, the PLCFP measurement of human trabeculae is not reported. The purpose of this study was a direct measurement of PLCFP generation of human proximal femoral trabeculae in the direction of superior-to-fovea. Twenty one microscopic cylindrical trabecular specimens from trabeculae of five fresh human proximal femur (75 to 77 years) were fabricated using a micro-milling machine composed of the laser (Teemphotonics: 532nm), 3-dimensional PZT stage (PI Gmbh, resolution: 0.5nm), and microscope (lens: Navitar, and CCD: Hitachi) with the image processor. The fabrication resolution of the micro-milling machine was 0.4 um. Based on the trabecular trajectory of femoral head, the specimens were obtained in the direction of superior-to-fovea. The cylindrical specimen size had 120 um in diameter and 240 um in length. The test methods described in the previous study were utilized. The used undrained uniaxial strain condition could induce the maximum PLCFP within the trabecular elastic limit. The measured trabecular PLCFP (±SD) at the strain of 0.4% was 693.7±79.1 kPa. Since this experiment is equivalent to the instantaneous response of PLCFP with free flow boundaries after application of an extremely fast loading speed such an ideal step loading, a PLCFP generation in the physiological condition will be much less than the results obtained in this study. Base on the linear isotropic poroelasticity, the obtained Skempton's coefficient is almost 0. Thus, the load bearing capability by trabecular PLC fluid is negligible. The Biot coefficient is 0.35 which is higher than that of the cortical tissue (0.14). As a result, the intraosseous fluid communication through trabecular surfaces is active compared to that through Haversian canal surfaces. This imply that mass transports from the trabecular PLC into the PIT and from the PIT into the trabecular PLC could be significantly affected by the PITFP (the physiological blood systolic and diastolic pressure: 16 and 11 kPa, respectively) that acts as the FP boundary condition for the PLC flow. It is known that the PLC flow generates the electrical charges on the trabecular surface (‘+’ for being spouted into the PIT and ‘−’ for being flown into the PLC), which control differentiation and proliferation of the osteoblast and mesenchymal stem cell. Thus, significant changes in the PITFT could cause changes in the intra-trabecular PLC flow characteristics, mass transports between the PLC and PIT, and electrical charges on the trabeculae. Eventually, these could result in pathologies related to the trabecular remodeling

Intervertebral disc degeneration (IDD) affects more than 80% of the population all over the world. Current strategies for the treatment of IDD are based on conservative or surgical procedures with the aim of relieving pain. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy in recent decades, but studies showed that the particularly hostile microenvironment in the intervertebral disc (IVD) can compromise cells survival rate. The use of exosomes, extracellular vesicles released by various cell types, possess considerable economic advantages including low immunogenicity and toxicity. Exosomes allow intercellular communication by conveying functional proteins, RNA, miRNA and lipids between cells. The purpose of this study is to assess the therapeutic effects of exosomes derived from Wharton Jelly mesenchymal stromal cells (WJ-MSC) on human nucleuspulposus cells (hNPC) in an in vitro 3D culture model. Exosomes (exos) were isolated by tangential flow filtration of WJ-MSC conditioned media and characterized by: quantification with BCA test; morphological observation with TEM, surface marker expression by WB and size evaluation by NTA. Confocal microscopy has been used to identify exosomes marked with PKH26 and monitor fusion and/or incorporation in hNPC. hNPC were isolated from waste surgical material from patients undergoing discectomy (n = 5), expanded, encapsulated in alginate beads and treated with: culture medium (control group); WJ-MSC exos (WJ-exos) at different concentrations (10 μg/ml, 50 μg/ml and 100 μg/ml). They were then analysed for: cell proliferation (Trypan Blu); viability (Live/Dead Assay); quantification of nitrites (Griess) and glycosaminoglycans, GAG (DMBB). The hNPC in alginate beads treated for 7 days were included in paraffin and histologically analysed to determine the presence of extracellular matrix (ECM) components. Finally, the expression levels of catabolic and anabolic genes were evaluated through real-time polymerase chain reaction (qPCR). All concentrations of WJ-exos under exam were capable to induce a significant increase in cell proliferation after 10 and 14 days of treatment (p < 0.01 and p < 0.001, respectively). Live/Dead assay showed a decrease in cell death at 50 μg/ml of WJ-exos (p < 0.05). While cellular oxidative stress indicator, nitrite production, was reduced in a dose-dependent way and statistically significant only with 100 μg/ml of WJ-exos (p < 0.05). WJ-exos at 10 and 100 μg/ml induced a significant increase in GAG content (p < 0.05; p < 0.01, respectively) confirmed by Alcian Blu staining. Exos derived from WJ-MSC modulated gene expression levels by increasing expression of ACAN and SOX-9 genes and reducing significantly of IL-6, MMP-1, MMP-13 and ADAMTS-5 levels (p < 0.05; p < 0.01) compared to the control group. Our results supported the potential use of exosomes from WJ-MSC for the treatment of IDD. Exosomes improved hNPC growth, attenuated ECM degradation and reduced oxidative stress and inflammation. This study offers a new scenario in IVD regeneration, promoting the potential use of extracellular vesicles as an alternative strategy to cell therapy

Among the advanced technology developed and tested for orthopaedic surgery, the Rizzoli (IOR) has a long experience on custom-made design and implant of devices for joint and bone replacements. This follows the recent advancements in additive manufacturing, which now allows to obtain products also in metal alloy by deposition of material layer-by-layer according to a digital model. The process starts from medical image, goes through anatomical modelling, prosthesis design, prototyping, and final production in 3D printers and in case post-production. These devices have demonstrated already to be accurate enough to address properly the specific needs and conditions of the patient and of his/her physician. These guarantee also minimum removal of the tissues, partial replacements, no size related issues, minimal invasiveness, limited instrumentation. The thorough preparation of the treatment results also in a considerable shortening of the surgical and of recovery time. The necessary additional efforts and costs of custom-made implants seem to be well balanced by these advantages and savings, which shall include the lower failures and revision surgery rates. This also allows thoughtful optimization of the component-to-bone interfaces, by advanced lattice structures, with topologies mimicking the trabecular bone, possibly to promote osteointegration and to prevent infection. IOR's experience comprises all sub-disciplines and anatomical areas, here mentioned in historical order. Originally, several systems of Patient-Specific instrumentation have been exploited in total knee and total ankle replacements. A few massive osteoarticular reconstructions in the shank and foot for severe bone fractures were performed, starting from mirroring the contralateral area. Something very similar was performed also for pelvic surgery in the Oncology department, where massive skeletal reconstructions for bone tumours are necessary. To this aim, in addition to the standard anatomical modelling, prosthesis design, technical/technological refinements, and manufacturing, surgical guides for the correct execution of the osteotomies are also designed and 3D printed. Another original experience is about en-block replacement of vertebral bodies for severe bone loss, in particular for tumours. In this project, technological and biological aspects have also been addressed, to enhance osteointegration and to diminish the risk of infection. In our series there is also a case of successful custom reconstruction of the anterior chest wall. Initial experiences are in progress also for shoulder and elbow surgery, in particular for pre-op planning and surgical guide design in complex re-alignment osteotomies for severe bone deformities. Also in complex flat-foot deformities, in preparation of surgical corrections, 3D digital reconstruction and 3D printing in cheap ABS filaments have been valuable, for indication, planning of surgery and patient communication; with special materials mimicking bone strength, these 3D physical models are precious also for training and preparation of the surgery. In Paediatric surgery severe multi planar & multifocal deformities in children are addressed with personalized pre-op planning and custom cutting-guides for the necessary osteotomies, most of which require custom allografts. A number of complex hip revision surgeries have been performed, where 3D reconstruction for possible final solutions with exact implants on the remaining bone were developed. Elective surgery has been addressed as well, in particular the customization of an original total ankle replacement designed at IOR. Also a novel system with a high-tibial-osteotomy, including a custom cutting jig and the fixation plate was tested. An initial experience for the design and test of custom ankle & foot orthotics is also in progress, starting with 3D surface scanning of the shank and foot including the plantar aspect. Clearly, for achieving these results, multi-disciplinary teams have been formed, including physicians, radiologists, bioengineers and technologists, working together for the same goal

Introduction and Objective. Low back pain (LBP) is a disorder strongly associated with intervertebral disc degeneration (IDD) with an important impact on the quality of life of affected people. To date, LBP treatment is based on conservative methods with the aim to reduce back pain without restoring the degenerative environment of the disc. The main cause of IDD is the drastic reduction of the proteoglycan content within the nucleus pulposus (NP), eventually leading to the loss of disc water content, micro-architecture, biochemical and mechanical properties. A promising approach for disc regeneration is represented by the transplantation of mesenchymal stromal cells (MSCs). The exact mechanism remains unknown. Growing evidence suggests that MSCs can influence cells and modulate cells’ behaviour by secreting a set of bioactive factors. MSCs secretome is composed of several molecules such as soluble protein, lipids, nucleic acids and extracellular vesicles (EVs) involved in inflammation, immunomodulation, cell survival and intercellular communication. The aim of this study was to evaluate the in vitro effects of MSCs secretome on human NP cells (hNPCs) in a 3D culture model with and without inflammatory stimulus. Materials and Methods. MSCs secretome was collected from bone marrow-MSCs (BM-MSCs) and adipose tissue-MSCs (ASCs) after centrifugation and obtained by culturing cells without fetal bovine serum (FBS) for 48 hours. hNPCs were isolated from surgical specimens through digestion with type II collagenase, culture expanded in vitro, encapsulated in alginate beads (three-dimensional culture system) and treated with growth medium (controls), BM-MSCs or ASCs secretome with or without interleukin-1 beta (IL-1b). After 7 days, total RNA was extracted and reverse-transcribed. Gene expression levels of catabolic and anabolic genes were analyzed through real time-polymerase chain reaction (qPCR). Cell proliferation and glycosaminoglycan (GAG) production was assessed by flow cytometry and 1,9-dimethylmethylene blue (DMMB), respectively. hNPCs in alginate beads were stained with Live/Dead assay and detected using confocal immunofluorescence microscopy. Data were analyzed using Graphpad prism 8 and expressed as mean ± S.D. One-way ANOVA analysis was used to compare differences among the groups under exam. Results. Our results reported an increase of hNPCs proliferation after treatment with both MSCs-secretomes. In detail, cell proliferation levels increased at 7 days after ASC-secretome (p ≤ 0,05) and BM-secretome (p ≥ 0,05) treatment compared to control. Live/dead staining showed that cell death was reduced by BM-secretome (p ≤ 0,05); in combined treatment of BM-secretome with IL1b 10ng/mL (p ≤ 0,05) at 7 days compared to control. There is not a significant difference between treated and untreated hNPCs’ GAG synthesis. In addition, gene expression levels resulted to be modulated by MSCs-secretomes under study compared to controls. Conclusions. Although the cell-therapy may be considered an attractive and safe option, MSCs require long and expensive processes. In conclusion, our experimental conditions supported as BM-MSCs and ASCs secretomes could represent cell-free alternative approaches in IDD, overcoming translational limits of cell therapy to the clinical practice

Increasing incidence of osteoporosis, obesity and an aging population have led to an increase in low energy hip fractures in the elderly. Perceived lower blood loss and lower surgical time, media coverage of minimal invasive surgery and patient expectations unsurprisingly have led to a trend towards intramedullary devices for fixation of extracapsular hip fractures. This is contrary to the Cochrane review of random controlled trials of intramedullary vs extramedullary implants which continues recommends the use of a sliding hip screw (SHS) over other devices. Furthermore, despite published literature of minimally invasive surgery (MIS) of SHS citing benefits such as reduced soft tissue trauma, smaller scar, faster recovery, reduced blood loss, reduced analgesia needs; the uptake of these approaches has been poor. We describe a novel technique one which remains minimally invasive, that not only has a simple learning curve but easily reproducible results. All patients who underwent MIS SHS fixation of extracapsular fractures were included in this study. Technique is shown in Figure 1. We collated data on all intertrochanteric hip fractures that were treated by a single surgeon series during period Jan 2014 to July 2015. Data was collected from electronic patient records and radiographs from Picture Archiving and Communication System (PACS). Surgical time, fluoroscopy time, blood loss, surgical incision length, post-operative transfusion, Tip Apex Distance (TAD) were analyzed. There were 10 patients in this study. All fractures were Orthopaedic Trauma Association (OTA) type A1 or A2. Median surgical time was 36 minutes (25–54). Mean fluoroscopy time was similar to standard incision sliding hip screw fixation. Blood loss estimation with MIS SHS can be undertaken safely and expeditiously for extracapsular hip fractures

Telemedicine is the delivery of healthcare from a remote location using integrated computer/communication technology. This systematic review aims to explore evidence for telemedicine in orthopaedics to determine its advantages, validity, effectiveness and utilisation particularly during our current pandemic where patient contact is limited. Databases of PubMed, Scopus and CINHAL were systematically searched and articles were included if they involved any form of telephone or video consultation in an orthopaedic population. Findings were synthesised into four themes: patient/clinician satisfaction, accuracy and validity of examination, safety and patient outcomes and cost effectiveness. Quality assessment was undertaken using Cochrane and Joanna Briggs Institute appraisal tools. Twenty studies were included consisting of nine RCTs across numerous orthopaedic subspecialties including fracture care, elective orthopaedics and oncology. Studies revealed high patient satisfaction with telemedicine for convenience, less waiting and travelling time. Telemedicine was cost effective particularly if patients had to travel long distances, required hospital transport or time off work. No clinically significant differences were found in patient examination nor measurement of patient reported outcome measures. Telemedicine was reported to be a safe method of consultation. However, studies were of variable methodological quality with selection bias. In conclusion, evidence suggests that telemedicine in orthopaedics can be safe, cost effective, valid in clinical assessment with high patient/clinician satisfaction. Further work with high quality RCTs is required to elucidate long term outcomes. This systematic review presents up-to-date evidence on the use of telemedicine and provides data for organisations considering its use in the current COVID-19 pandemic and beyond

Distal radius fractures (DRF) are very common injuries. National recommendations (British Orthopaedic Association, National Institute for Health and Care Excellence (NICE)) exist in the UK to guide the management of these injuries. These guidelines provide recommendations about several aspects of care including which type of injuries to treat non-operatively and surgically, timing of surgery and routine follow-up. In particular, current recommendations include considering immobilizing patients for 4 weeks in plaster for those managed conservatively, and operating on fractures within 72 hours for intra-articular injuries and 7 days for extra-articular fractures. With increased demands for services and an ageing population, prompt surgery for those presenting with distal radius fractures is not always possible. A key factor is the need for prompt surgery for hip fracture patients. This study is an audit of the current standard of care at a busy level 2 trauma unit against national guidelines for the management of DRFs. This retrospective audit includes all patients presenting to our emergency department from June to September 2018. Patients over 18 years of age with a diagnosis of a closed distal radius fracture and follow-up in our department were included in the study. Those with open fractures were excluded. Data was retrieved from clinical coding, electronic patient records, and IMPAX Client (Picture archiving and communication system). The following data was collected on patients treated conservatively and those managed surgically:- (1)Time to surgery for surgical management; (2)Period of immobilization for both conservative and operative groups. 45 patients (13 male, 32 female) with 49 distal radius fractures (2 patients had bilateral injuries) were included. Patients had mean age 63 years (range 19 to 92 years) 30 wrists were treated non-operatively and 19 wrists treated surgically (8 K-wires, 10 ORIF, 1 MUA). Mean time to surgery in the operative group was 8 days (range 1 – 21 days, median 7 days). Mean time to surgery for intra-articular fractures was 7 days (range 1 – 21) and 12 days for extra-articular fractures (range 4 – 20). Mean immobilization period in those treated in plaster is 6 weeks (range 4 – 13 weeks, median 5.6 weeks). At busy level 2 trauma units with limited theatre capacity and a high volume of hip fracture admissions, time to surgery for less urgent injuries such as wrist fractures is often delayed. National guidelines are useful in helping to guide management however their standards are often difficult to achieve in the context of increasing populations in urban areas and an ageing population

Summary Statement. The purpose is to evaluate the effects of internet usage on new patient referral patterns to identify optimal patient recruitment and communication. Overall, social networking and internet may be an effective way for surgeons to recruit a wider patient population. Introduction. Prior studies in other medical specialties have shown that social networking and internet usage has become an increasingly important means of patient communication and referral. However, this information is lacking in the orthopaedics literature. In this study, we evaluate the means by which new patients arrive at orthopaedic clinics in a major academic center. The purpose is to evaluate the effects of internet or social media usage on new patient referral patterns to identify avenues to optimise patient recruitment and communication. Patients and Methods. New patients were recruited in a major academic orthopaedic clinic to complete a 15-item questionnaire with demographic information, social media use/networking and referral method. Data was collected for all orthopaedic sub-specialties and analyzed accordingly. Statistical analysis was performed. Results. Of the 752 responses, there were 66% female and 34% male responses. Responses were obtained from hand (142), sports medicine (303), foot and ankle (129), joints/tumor (95) and trauma (83) services. Overall, 51% report using social networking sites such as Facebook or Twitter. Of the patients that report not using social network sites, 92% are over the age of 40. Joints/tumor patients most commonly had seen another orthopaedic surgeon prior to their visit (59%) and had prior surgery (42%). Most patients traveled under 60 miles and were referred by their primary care physicians. Between 18–26% of all patients used a physician review website before consultation. The majority of the patients prefer communicating with their physician via the phone(68%) compared to email(32%). Independent associations found that sports medicine patients tend to be higher social networking users (35.9%) relative to other services (9.8–17.9%) and was statistically higher when compared to the joints/tumor service (P<.0001). The multivariate logistic regression model showed that the sports service was generally more likely to have social networking users with the exception of the foot/ankle service), however these differences were not statistically significant. The biggest indicator predicting social media usage in the orthopaedic population was age. The older the patient population, the less likely patients will use social networking sites. Non-doctorate patients were more likely to be social media users compared to doctorate level individuals, but was not statistically significant. Patients that lived from 120 to 180 miles from the hospital were significantly more likely to be social media users, as were patients that did research on their condition prior to their new patient appointment. Discussion and Conclusion. Orthopaedic patients who use social media are more likely to be younger, research their condition prior to their appointment and undergo an average day's travel (120–180 miles) to see a physician. Up to 26% of all patients have seen or used a physician review site prior to their visit. Despite the increased social media usage, most orthopaedic patients still prefer telephone communication with their physicians. Overall, social networking and internet may be an effective way for surgeons to recruit a wider patient population. In an increasingly competitive market, surgeons with younger patient populations (Sports Medicine) will need to utilise social networking and the internet to capture new patient referrals