bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE EFFECT OF IMMEDIATE AND DELAYED MECHANICAL STIMULATION ON SECONDARY BONE HEALING
Authors: Barcik J. , Ernst M. , Buchholz T. , Constant C. , Mys K. , Epari D. , Zeiter S. , Gueorguiev B. , Windolf M. 
Published: January 2024

Secondary bone healing is impacted by the extent of interfragmentary motion at the fracture site. It provides mechanical stimulus that is required for the formation of fracture callus. In clinical settings, interfragmentary motion is induced by physiological loading of the broken bone – for example, by weight-bearing. However, there is no consensus about when mechanical stimuli should be applied to achieve fast and robust healing response. Therefore, this study aims to identify the effect of the immediate and delayed application of mechanical stimuli on secondary bone healing.A partial tibial osteotomy was created in twelve Swiss White Alpine sheep and stabilized using an active external fixator that induced well-controlled interfragmentary motion in form of a strain gradient. Animals were randomly assigned into two groups which mimicked early (immediate group) and late (delayed group) weight-bearing. The immediate group received daily stimulation (1000 cycles/day) from the first day post-op and the delayed group from the 22nd day post-op. Healing progression was evaluated by measurements of the stiffness of the repair tissue during mechanical stimulation and by quantifying callus area on weekly radiographs. At the end of the five weeks period, callus volume was measured on the post-mortem high-resolution computer tomography (HRCT) scan.Stiffness of the repair tissue (p<0.05) and callus progression (p<0.01) on weekly radiographs were significantly larger for the immediate group compared to the delayed group. The callus volume measured on the HRCT was nearly 3.2 times larger for the immediate group than for the delayed group (p<0.01).This study demonstrates that the absence of immediate mechanical stimuli delays callus formation, and that mechanical stimulation already applied in the early post-op phase promotes bone healing.
SCOPING REVIEW OF ROTATIONAL GUIDED GROWTH IN THE GROWING BONE
Authors: Halloum A. , Kold S. , Rölfing J.D. , Abood A.A. , Rahbek O. 
Published: January 2024

The aim of this scoping review is to understand the extent and type of evidence in relation to the use of guided growth for correcting rotational deformities of long bones. Guided growth is routinely used to correct angular deformities in long bones in children. It has also been proven to be a viable method to correct rotational deformities, but the concept is not yet fully examined. Databases searched include Medline, Embase, Cochrane Library, Web of Science and Google Scholar.All identified citations were uploaded into Rayyan.ai and screened by at least two reviewers. The search resulted in 3569 hits. 14 studies were included: 1 review, 3 clinical trials and 10 pre-clinical trials. Clinical trials: a total of 21 children (32 femurs and 5 tibiae) were included. Surgical methods were 2 canulated screws connected by cable, PediPlates obliquely oriented, and separated Hinge Plates connected by FiberTape. Rotation was achieved in all but 1 child. Adverse effects reported include limb length discrepancy (LLD), knee stiffness and rebound of rotation after removal of tethers. 2 pre-clinical studies were ex-vivo studies, 1 using 8-plates on Sawbones and 1 using a novel z-shaped plates on human cadaver femurs. There were 5 lapine studies (2 using femoral plates, 2 using tibial plates and 1 using an external device on tibia), 1 ovine (external device on tibia), 1 bovine (screws and cable on metacarp) and a case-report on a dog that had an external device spanning from femur to tibia. Rotation was achieved in all studies. Adverse effects reported include implant extrusions, LLD, articular deformities, joint stiffness and rebound. All included studies conclude that guided growth is a viable treatment for rotational deformities of long bones, but there is great variation in models and surgical methods used, and in reported adverse effects.
THERMALLY DISINFECTED HUMAN FEMORAL HEAD AS SCAFFOLD FOR OSTEOINDUCTIVE SUBSTANCES
Authors: Tashmetov E. , Saginova D. , Kamyshanskiy Y. , Saginov A. , Koshanova A. 
Published: January 2024

Various approaches have been implemented to enhance bone regeneration, including the utilization of autologous platelet-rich plasma and bone morphogenetic protein-2. The objective of this study was to evaluate the impact of Marburg Bone Bank-derived bone grafts in conjunction with platelet-rich plasma (PRP), recombinant human bone morphogenetic protein-2 (rhBMP-2), and zoledronic acid (ZA) on osteogenesis within rabbit bone defects.MethodologyBone defects (5mm in diameter) were created in the femurs of 96 male rabbits. The animals were allocated into five groups: (1) bone graft + PRP (BG + PRP), (2) bone graft + 5μg rhBMP-2 (BG + rhBMP-2), (3) bone graft + 5μg ZA (BG + ZA), (4) bone graft + 10μg rhBMP-2 + 5μg ZA (BG + rhBMP-2 + ZA), and (5) bone graft (BG). Marburg Bone Bank-processed human femoral head allografts were utilized for bone grafting. The rabbits were euthanized at 14-, 30-, and 60-days post-surgery, and their femurs underwent histopathological and histomorphometric assessments.ResultsHistomorphometric analysis revealed significantly enhanced de novo osteogenesis within the bone allografts in the BG + PRP and BG + rhBMP-2 groups compared to the BG, BG + ZA, and BG + rhBMP-2 + ZA groups at 14 and 30 days (p < 0.05). However, on day 60, the BG + rhBMP-2 group exhibited elevated osteoclastic activity (early resorption). The local co-administration of ZA with thermally treated grafts impeded both bone graft resorption and new bone formation within the bone defect across all time points. The addition of ZA to BG + rhBMP-2 resulted in diminished osteogenic activity compared to the BG + rhBMP-2 group (p < 0.000).ConclusionThe study findings indicated that the combination of PRP and rhBMP-2 with Marburg bone grafts facilitates early-stage osteogenesis in bone defect healing. Incorporating ZA into the thermally treated bone graft hinders both graft resorption and de novo bone formation.
LEVERAGING THE HEDGEHOG SIGNALLING PATHWAY TO IMPROVE TENDON-TO-BONE INTEGRATION
Authors: Kamalitdinov T. , Fujino K. , Jiang X. , Madi R. , Marcelin J. , Kuntz A. , Dyment N. 
Published: January 2024

Despite extensive research aimed at improving surgical outcomes of enthesis injuries, re-tears remain a common problem, as the repairs often lead to fibrovascular scar as opposed to a zonal enthesis. Zonal enthesis formation involves anchoring collagen fibers, synthesizing proteoglycan-rich fibrocartilage, and mineralizing this fibrocartilage [1]. During development, the hedgehog signaling pathway promotes the formation and maturation of fibrocartilage within the zonal tendon-to-bone enthesis [1-4]. However, whether this pathway has a similar role in adult zonal tendon-to-bone repair is not known. Therefore, we developed a murine anterior cruciate ligament (ACL) reconstruction model [5] to better understand the zonal tendon-to-bone repair process and perturb key developmental regulators to determine the extent to which they can promote successful repair in the adult. In doing so, we activated the hedgehog signaling pathway both genetically using transgenic mice and pharmacologically via agonist injections. We demonstrated that both treatments improved the formation of zonal attachments and tunnel integration strength [6]. These improved outcomes were due in part to hedgehog signaling's positive role in proliferation of the bone marrow stromal cell (bMSC) progenitor pool and subsequent fibrocartilage production of bMSC progeny cells that form the attachments. These results suggest that, similar to growth and development, hedgehog signaling promotes the production and maturation of fibrocartilage during tendon-to-bone integration in adults. Lastly, we developed localized drug delivery systems to further improve the treatment of these debilitating injuries in future translational studies.Acknowledgements: This work was supported by NIH R01AR076381, R21AR078429, R00AR067283, F31AR079840, T32AR007132, and P30AR069619, in addition to the McCabe Fund Pilot Award at the University of Pennsylvania.
THE METABOLIC ROLE OF IL-4 AND IL-10 IN INTERVERTEBRAL DISC DEGENERATION
Authors: Bermudez-Lekerika P. , Tseranidou S. , Kanelis E. , Crump K.B. , Le Maitre C. , Wuertz-Kozak K. , Alexopoulos L.G. , Noailly J. , Gantenbein B. 
Published: January 2024

Intervertebral disc (IVD) degeneration is a pathological process often associated with chronic back pain and considered a leading cause of disability worldwide1. During degeneration, progressive structural and biochemical changes occur, leading to blood vessel and nerve ingrowth and promoting discogenic pain2. In the last decades, several cytokines have been applied to IVD cells in vitro to investigate the degenerative cascade. Particularly, IL-10 and IL-4 have been predicted as important anabolic factors in the IVD according to a regulatory network model based in silico approach3. Thus, we aim to investigate the potential presence and anabolic effect of IL-10 and IL-4 in human NP cells (in vitro) and explants (ex vivo) under hypoxia (5% O2) after a catabolic induction.Primary human NP cells were expanded, encapsulated in 1.2% alginate beads (4 × 106 cells/ml) and cultured for two weeks in 3D for phenotype recovery while human NP explants were cultured for five days. Afterwards, both alginate and explant cultures were i) cultured for two days and subsequently treated with 10 ng/ml IL-10 or IL-4 (single treatments) or ii) stimulated with 0.1 ng/ml IL-1β for two days and subsequently treated with 10 ng/ml IL-10 or IL-4 (combined treatments).The presence of IL-4 receptor, IL-4 and IL-10 was confirmed in human intact NP tissue (Fig 1). Additionally, IL-4 single and combined treatments induced a significant increase of proinflammatory protein secretion in vitro (Fig. 2A-C) and ex vivo (Fig. 2D and E). In contrast, no significant differences were observed in the secretome between IL-10 single and combined treatments compared to control group.Overall, IL-4 containing treatments promote human NP cell and explant catabolism in contrast to previously reported IL-4 anti-inflammatory performance4. Thus, a possible pleiotropic effect of IL-4 could occur depending on the IVD culture and environmental condition.Acknowledgements: This project was supported by the Marie Skłodowska Curie International Training Network “disc4all” under the grant agreement #955735.For any figures and tables, please contact the authors directly.
IMPACT OF MINCING TECHNIQUES ON CHONDROCYTE VIABILITY IN BOVINE ARTICULAR CARTILAGE: A COMPARATIVE STUDY BETWEEN COMMERCIALLY AVAILABLE SHAVERS AND SCALPEL MINCING
Authors: Bauer C. , Moser L. , Otahal A. , Kern D. , Dammerer D. , Zantop T. , Nehrer S. 
Published: January 2024

Mincing cartilage with commercially available shavers is increasingly used for treating focal cartilage defects. This study aimed to compare the impact of mincing bovine articular cartilage using different shaver blades on chondrocyte viability.Bovine articular cartilage was harvested using a scalpel or three different shaver blades (2.5 mm, 3.5 mm, or 4.2 mm) from a commercially available shaver. The cartilage obtained with a scalpel was minced into fragments smaller than 1 mm3. All four conditions were cultivated in a culture medium for seven days. After Day 1 and Day 7, metabolic activity, RNA isolation, and gene expression of anabolic (COL2A1, ACAN) and catabolic genes (MMP1, MMP13), Live/Dead staining and visualization using confocal microscopy, and flow cytometric characterization of minced cartilage chondrocytes were measured.The study found that mincing cartilage with shavers significantly reduced metabolic activity after one and seven days compared to scalpel mincing (p<0.001). Gene expression of anabolic genes was reduced, while catabolic genes were increased after day 7 in all shaver conditions. The MMP13/COL2A1 ratio was also increased in all shaver conditions. Confocal microscopy revealed a thin line of dead cells at the lesion site with viable cells below for the scalpel mincing and a higher number of dead cells diffusely distributed in the shaver conditions. After seven days, there was a significant decrease in viable cells in the shaver conditions compared to scalpel mincing (p<0.05). Flow cytometric characterization revealed fewer intact cells and proportionally more dead cells in all shaver conditions compared to the scalpel mincing.Mincing bovine articular cartilage with commercially available shavers reduces the viability of chondrocytes compared to scalpel mincing. This indicates that mincing cartilage with a shaver should be considered a matrix rather than a cell therapy. Further experimental and clinical studies are required to standardize the mincing process with a shaver.Acknowledgements: This study received unrestricted funding from KARL STORZ SE & Co. KG.
PSYCHOLOGICAL AND CLINICAL ISSUES IN OCTOGENARIAN AND NONAGENARIAN PATIENTS ADDRESSING ELECTIVE TOTAL HIP ARTHROPLASTY
Authors: Camera A. , Biggi S. , Capuzzo A. , Cattaneo G. , Tedino R. , Bolognesi G. 
Published: January 2024

Elective orthopaedic procedures, and particularly total hip arthroplasty (THA), in octogenarians and nonagenarians patients are burdened of several implications. Besides the comorbidities and the anesthesiological issues, legal and ethical implications are present. Some literature data show the clinical improvement of THA in elderly patient but the psychological aspects are not yet evaluated. Aim of this study is to evaluate the clinical aspects and the psychological impact in daily living in octogenarians and nonagenarians patients addressing THA.We conducted a retrospective evaluation of 81 THA in 81 patients of age more than 85 years with a minimum follow-up of 6 months. Clinical aspects were evaluated using the Hip disability and Osteoarthritis Outcome Score (HOOS). The psychological issues were evaluated with the Short Form 12 (SF-12) using both the Physical Component Summary (PCS) and the Mental Component Summary (MCS). From the starter cohort of 81 patients, 8 patients were died for causes unrelated to surgery, 13 were lost to follow-up, 1 patient was revised for periprosthetic fracture; 59 patients composed the final cohort. Mean HOOS rased from 18,07 ± 17,81 to 92,36 ± 5,74 with statistically significant distribution both in the global score than in all of the different subscales. The PCS raised from 26,81 ± 10,81 to 51,86 ± 4,45 and The MCS raised from 34,84 ± 10,81 to 56,70 ± 5,04, but none of them showed a statistically significant distribution. THA in octogenarians and nonagenarians patients could be a safe procedure with positive results for clinical and psychological aspects.
EXTRACELLULAR VESICLE-FUNCTIONALIZED FIBRINOGEN AND MAGNESIUM SCAFFOLDS TO PROMOTE BONE REGENERATION
Authors: Cardona-Timoner M. , Bessa-Gonçalves M. , Nogueira F. , Barbosa M.S. , Santos S.G. 
Published: January 2024

Bone defects and fractures, caused by injury, trauma or tumour resection require hospital treatment and temporary loss of mobility, representing an important burden for societies and health systems worldwide. Autografts are the gold standard for promoting new bone formation, but these may provide insufficient material and lead to donor site morbidity and pain. We previously showed that Fibrinogen (Fg) scaffolds promote bone regeneration in vivo (1), and that modifying them with 10mM of Magnesium (Mg) ions modulates macrophage response in vitro and in vivo (2). Also, we showed that Extracellular Vesicles (EV) secreted by Dendritic Cells (DC) recruit Mesenchymal Stem/Stromal Cells (MSC)(3).Herein, we aim to functionalize FgMg scaffolds with DC-EV, to promote recruitment and osteogenic differentiation of MSC.Scaffolds were produced by freeze-drying (2). Ethical permission was sought for all studies. Primary human peripheral blood monocyte-derived DC were cultured, their secreted EV were isolated by differential (ultra)-centrifugation and characterised by transmission electron microscopy and nanoparticle tracking analysis (3). Bone marrow MSC were used to determine the impact of EV-functionalized scaffolds through migration assays and their osteogenic differentiation was assessed by Alizarin Red staining.Fg and FgMg scaffolds functionalized with EV were characterized. Fg and FgMg scaffolds functionalized with DC-secreted EV were more efficient at recruiting MSC than scaffolds alone. MSC cultured on FgMg scaffolds showed significantly increased calcium deposits, in comparison with those cultured on Fg scaffolds.Fg scaffold modification by Mg promotes MSC osteogenic differentiation, while their functionalization with DC-secreted EV acts to promote MSC recruitment. This renders the FgMg-EV functionalized scaffolds an attractive material to promote new bone formation.Acknowledgments: Work funded by Orthoregeneration Network (ON Pilot Grant Spine 2021, EVS4Fusion). MCT supported by ERASMUS+ program.
TENDON HEALTH AND DISEASE: EXPLORING THE INTERFASCICULAR NICHE
Authors: Screen H.R.C. 
Published: January 2024

Tendon injury is debilitating and recalcitrant. With limited knowledge of disease aitiology we have are lacking in effective treatments for this prevalent musculoskeletal complaint.This presentation will outline our findings over the past few years in which we have demonstrated the importance of the interfascicular matrix (IFM) niche in maintaining healthy tendon function and driving disease progression1,2. It will also continue to describe our progress in developing both in vivo and in vitro models to interrogate disease progression.We have developed and validated a rat Achilles tendon overload model, in order to explore the impact of loading on IFM and fascicle structure, and the resulting cell response. Data highlights that structural disruption and inflammatory response both initiate in the IFM region, and can be seen in the absence of demonstrable changes to animal gait, indicating a sub-injury response in the tendon which we hypothesis may drive increased matrix turnover and repair3.We are now looking to interrogate the pathways driving this inflammatory behaviour in an organ-chip model, exploring the interplay between IFM cells and cells within fascicles. We have demonstrated phenotypic distinction of cells from the two niche environments, localized the progenitor phenotype to the IFM region and demonstrated significant mechanosensitivity in the IFM cell population4. We are currently building appropriate niche environments to maintain cell phenotype in our in vitro models, to explore the metabolic changes associated with disease progression.Acknowledgements: This body of work has received funding from: BBSRC (BB/K008412 /1); Versus Arthritis (project grant 20262); Horserace Betting Levy Board (T5); Dunhill Medical Charity (project grant RPGF1802\23); MRC (MR/T015462/1).
THE RELATIONSHIP BETWEEN MICROSTRUCTURE AND MECHANICAL RESPONSE IN THE HUMAN MENISCUS
Authors: Pierantoni M. , Dejea H. , Geomini L. , Abrahamsson M. , Gstöhl S. , Schlepütz C.M. , Englund M. , Isaksson H. 
Published: January 2024

To characterize the microstructural organization of collagen fibers in human medial menisci and the response to mechanical loading in relation to age. We combine high resolution imaging with mechanical compression to visualize the altered response of the tissue at the microscale. Menisci distribute the load in the knee and are predominantly composed of water and specifically hierarchically arranged collagen fibers. Structural and compositional changes are known to occur in the meniscus during aging and development of osteoarthritis. However, how microstructural changes due to degeneration affect mechanical performance is still largely unknown [1].Fresh frozen 4 mm Ø plugs of human medial menisci (n=15, men, 20-85 years) with no macroscopic damage nor known diseases from the MENIX biobank at Skåne University Hospital were imaged by phase contrast synchrotron tomography at the TOMCAT beamline (Paul Scherrer Institute, CH). A rheometer was implemented into the beamline to perform in-situ stress relaxation (2 steps 15% and 30% strain) during imaging (21 keV, 2.75μm pixel size). 40s scans were acquired before and after loading, while 14 fast tomographs (5s acquisitions) were taken during relaxation. The fiber 3D orientations and structural changes during loading were determined using a structure tensor approach (adapting a script from [1]). The 3D collagen fiber orientation in menisci revealed alternating layers of fibers. Two main areas are shown: surfaces and bulk. The surface layers are a mesh of randomly oriented fibers. Within the bulk 2-3 layers of fibers are visible that alternate about 30° to each other. Structural degeneration with age is visible and is currently being quantified. During stress-relaxation all menisci show a similar behavior, with samples from older donors being characterized by larger standard deviation Furthermore, the behavior of the different layers of fibers is tracked during relaxation showing how fibers with different orientation respond to the applied loading.Acknowledgments: We thank PSI for the beamtime at the TOMCAT beamline X02DA, and funding from Swedish Research Council (2019-00953), under the frame of ERA PerMed, and the Novo Nordisk Foundation through MathKOA (NNF21OC0065373).
RECENT ADVANCES IN GUIDED BONE GROWTH FOR DEFORMITY CORRECTION
Authors: Rahbek O. , Halloum A. , Rolfing J. , Kold S. , Abood A. 
Published: January 2024

The concept of guided growth was proposed by Andry in 1741. In the last decades the concept has been widely used as implants has been introduced that can modulate the growth of the bone and pediatric longitudinal and angular deformities is widely treated by this technique. However, there is there is a huge variation in techniques and implants used and high-quality clinical trials is still lacking. Recently implants correcting rotational bony deformities have been proposed and clinical case series have been published.The current status of guided growth will be presented in this narrative review and preliminary experiences with rotational guided growth will be shared. Is guided growth to be considered a safe treatment at this time point?