bluuebunny/crossref_metadata_2025_split huggingface dataset:
DECIPHERING CELL–CELL INTERACTIONS OF HUMAN BONE MARROW MONONUCLEAR CELLS IN 3D CULTURE TO ENHANCE THE REGENERATIVE POTENTIAL OF BONE MARROW AUTOGRAFTS
Authors: Häusner S. , Horas K. , Blunk T. , Herrmann M. 
Published: January 2024

Autografts containing bone marrow (BM) are current gold standard in the treatment of critical size bone defects, delayed union and bone nonunion defects. Although reaching unprecedented healing rates in bone reconstruction, the mode of action and cell-cell interactions of bone marrow mononuclear cell (BM-MNC) populations have not yet been described. BM-MNCs consist of a heterogeneous mixture of hematopoetic and non-hematopoetic lineage fractions. Cell culture in a 3D environment is necessary to reflect on the complex mix of these adherend and non-adherend cells in a physiologically relevant context. Therefore, the main aim of this approach was to establish conditions for a stable 3D BM-MNC culture to assess cellular responses on fracture healing strategies.BM samples were obtained from residual material after surgery with positive ethical vote and informed consent of the patients. BM-MNCs were isolated by density gradient centrifugation, and cellular composition was determined by flow cytometry to obtain unbiased data sets on contained cell populations. Collagen from rat tail and human fibrin was used to facilitate a 3D culture environment for the BM-MNCs over a period of three days. Effects on cellular composition that could improve the regenerative potential of BM-MNCs within the BM autograft were assessed using flow cytometry. Cell-cell-interactions were visualized using confocal microscopy over a period of 24 hours. Cell localization and interaction partners were characterized using immunofluorescence labeled paraffin sectioning.Main BM-MNC populations like Monocytes, Macrophages, T cells and endothelial progenitor cells were determined and could be conserved in 3D culture over a period of three days. The 3D cultures will be further treated with already clinically available reagents that lead to effects even within a short-term exposure to stimulate angiogenic, osteogenic or immunomodulatory properties. These measures will help to ease the translation from “bench to bedside” into an intraoperative protocol in the end.
MAPPING THE SPATIAL AND TEMPORAL HETEROGENEITY OF MESENCHYMAL STROMAL CELLS WHEN USED AS A CELL THERAPY IN OSTEOCHONDRAL REPAIR
Authors: Seah M. , Birch M. , Moutsopoulos I. , Mohorianu I. , McCaskie A. 
Published: January 2024

Despite osteoarthritis (OA) representing a large burden for healthcare systems, there remains no effective intervention capable of regenerating the damaged cartilage in OA. Mesenchymal stromal cells (MSCs) are adult-derived, multipotent cells which are a candidate for musculoskeletal cell therapy. However, their precise mechanism of action remains poorly understood.The effects of an intra-articular injection of human bone-marrow derived MSCs into a knee osteochondral injury model were investigated in C57Bl/6 mice. The cell therapy was retrieved at different time points and single cell RNA sequencing was performed to elucidate the transcriptomic changes relevant to driving tissue repair. Mass cytometry was also used to study changes in the mouse immune cell populations during repair.Histological assessment reveals that MSC treatment is associated with improved tissue repair in C57Bl/6 mice. Single cell analysis of retrieved human MSCs showed spatial and temporal transcriptional heterogeneity between the repair tissue (in the epiphysis) and synovial tissue. A transcriptomic map has emerged of some of the distinct genes and pathways enriched in human MSCs isolated from different tissues following osteochondral injury. Several MSC subpopulations have been identified, including proliferative and reparative subpopulations at both 7 days and 28 days after injury. Supported by the mass cytometry results, the immunomodulatory role of MSCs was further emphasised, as MSC therapy was associated with the induction of increased numbers of regulatory T cells correlating with enhanced repair in the mouse knee.The transcriptomes of a retrieved MSC therapy were studied for the first time. An important barrier to the translation of MSC therapies is a lack of understanding of their heterogeneity, and the consequent lack of precision in its use. MSC subpopulations with different functional roles may be implicated in the different phases of tissue repair and this work offers further insights into repair process.
MINING OF BIOMECHANICAL AND GEOMETRY DATA OF INTERVERTEBRAL DISC FINITE ELEMENT SIMULATIONS
Authors: Muñoz-Moya E. , Ruiz C. , Piella G. , Noailly J. 
Published: January 2024

This study investigates the relationships between Intervertebral Disc (IVD) morphology and biomechanics using patient-specific (PS) finite element (FE) models and poromechanical simulations.169 3D lumbar IVD shapes from the European project MySpine (FP7-269909), spanning healthy to Pfirrmann grade 4 degeneration, were obtained from MRIs. A Bayesian Coherent Point Drift algorithm aligned meshes to a previously validated structural FE mesh of the IVD. After mesh quality analyses and Hausdorff distance measurements, mechanical simulations were performed: 8 and 16 hours of sleep and daytime, respectively, applying 0.11 and 0.54 MPa of pressure on the upper cartilage endplate (CEP). Simulation results were extracted from the anterior (ATZ) and posterior regions (PTZ) and the center of the nucleus pulposus (CNP). Data mining was performed using Linear Regression, Support Vector Machine, and eXtreme Gradient Boosting techniques. Mechanical variables of interest in DD, such as pore fluid velocity (FLVEL), water content, and swelling pressure, were examined. The morphological variables of the simulated discs were used as input features.Local morphological variables significantly impacted the local mechanical response. The local disc heights, respectively in the mid (mh), anterior (ah), and posterior (ph) regions, were key factors in general. Additionally, fluid transport, reflected by FLVEL, was greatly influenced (r2 0.69) by the shape of the upper and lower cartilage endplates (CEPs).This study suggests that disc morphology affects Mechanical variables of interest in DD. Attention should be paid to the antero-posterior distribution and local effects of disc heights. Surprisingly, the CEP morphology remotely affected the fluid transport in NP volumes around mid-height, and mechanobiological implications shall be explored. In conclusion, patient-specific IVD modeling has strong potential to unravel important correlations between IVD phenotypes and local tissue regulation.Acknowledgments: European Commission: Disc4All-MSCA-2020-ITN-ETN GA: 955735; O-Health-ERC-CoG-2021-101044828
GAIT ANALYSIS IN YOUR HAND: FEASIBILITY STUDY EVALUATING AN AI APPROACH TO GAIT ANALYSIS USING MONOCULAR VIDEO FROM MOBILE PHONES
Authors: Wendlandt R. , Volpert T. , Schroeter J. , Schulz A.P. , Paech A. 
Published: January 2024

Gait analysis is an indispensable tool for scientific assessment and treatment of individuals whose ability to walk is impaired. The high cost of installation and operation are a major limitation for wide-spread use in clinical routine.Advances in Artificial Intelligence (AI) could significantly reduce the required instrumentation. A mobile phone could be all equipment necessary for 3D gait analysis. MediaPipe Pose provided by Google Research is such a Machine Learning approach for human body tracking from monocular RGB video frames that is detecting 3D-landmarks of the human body.Aim of this study was to analyze the accuracy of gait phase detection based on the joint landmarks identified by the AI system.Motion data from 10 healthy volunteers walking on a treadmill with a fixed speed of 4.5km/h (Callis, Sprintex, Germany) was sampled with a mobile phone (iPhone SE 2nd Generation, Apple). The video was processed with Mediapipe Pose (Version 0.9.1.0) using custom python software. Gait phases (Initial Contact - IC and Toe Off - TO) were detected from the angular velocities of the lower legs. For the determination of ground truth, the movement was simultaneously recorded with the AS-200 System (LaiTronic GmbH, Innsbruck, Austria).The number of detected strides, the error in IC detection and stance phase duration was calculated.In total, 1692 strides were detected from the reference system during the trials from which the AI-system identified 679 strides. The absolute mean error (AME) in IC detection was 39.3 ± 36.6 ms while the AME for stance duration was 187.6 ± 140 ms.Landmark detection is a challenging task for the AI-system as can clearly be seen be the rate of only 40% detected strides. As mentioned by Fadillioglu et al., error in TO-detection is higher than in IC-detection.
MID-TERM SURVIVORSHIP AND OUTCOMES FOR HANDHELD ROBOTIC-ASSISTED UNICOMPARTMENTAL KNEE ARTHROPLASTY AND ITS LEARNING CURVE: A SINGLE-SURGEON STUDY OF 100 KNEES
Authors: Wong S.Y. W. , Grant S. 
Published: January 2024

Robotic assistance in knee arthroplasty has become increasingly popular due to improved accuracy of prosthetic implantation. However, literature on the mid-term outcomes is limited especially that of hand-held robotic-assisted devices. We present one of the longest follow-up series to date using this novel technology and discuss the learning curve for introducing robotic technology into our practice.The purpose of this single-surgeon study is to evaluate the survival, patient-reported outcomes and learning curve for handheld boundary-controlled robotic-assisted unicompartmental knee arthroplasties (HBRUKAs) at our hospital.This retrospective study evaluates 100 cases (94 Medial, 6 Lateral) performed by a single surgeon between October 2012 and July 2018. 52% were males, mean age was 64.5y (range 47.3y-85.2y) and mean BMI was 31.3 (range 21.8–43). Both inlay (40%) and onlay (60%) designs were implanted. Patients were followed up routinely at 1 and 5 years with Oxford Knee Scores (OKS) recorded. The learning curve was determined by tourniquet times.At a mean follow-up of 4.3 years (range 1.6y–7.3y), survivorship was 97%. There were three revisions: One case of aseptic loosening (1.5y), one case of deep-infection (3.8y) and one case of contralateral compartment osteoarthritis progression (5y). Mean 5-year OKS was 39.8. A 14.3% reduction in mean tourniquet times between the first 25 cases (105.5minutes) and subsequent cases (90.4minutes) was seen.This single-surgeon study showed good survivorship and patient-reported outcomes for HBRUKAs at our hospital. A learning curve of approximately 25 cases was shown, with significant decreases in tourniquet times with respect to increased surgeon experience.
THE EFFECT OF GEOMETRIES AND GRADIENT OF STRAIN-DEPENDENT SOLUTE DIFFUSIVITY ON THE METABOLIC TRANSPORT IN PATIENT-SPECIFIC INTERVERTEBRAL DISCS
Authors: Workineh Z.G. , Muñoz-Moya E. , Wills C.R. , Noailly J. 
Published: January 2024

Intervertebral discs (IVD) provide flexibility to the back and ensure functional distributions of the spinal loads. They are avascular, and internal diffusion-dependent metabolic transport is vital to supply nutrients to disc cells1, but interactions with personalized IVD shapes and mechanics remain poorly explored. Poromechanical finite element models of seven personalized lumbar IVD geometries, with mean heights ranging from 8 to 16 mm were coupled with a reactive oxygen, glucose and lactate transport model linked with tissue deformations and osmosis . In previous studies, reduced formulations of the divergence of the solute flux (∇ .J = ∇ . (D∇ C) = ∇ D. ∇ C +D∇ 2C) ignored the dependence of the diffusion on the deformation gradients, ∇ D. ∇C. We simulated this phenomenon to explore its significance in mechano-metabolic -transport couplings, in the different geometries, over 24h of simulated rest (8h) and physical activity (16h). ∇ D. ∇ C affected the daily variations of glucose concentrations in IVD thinner than 12 mm but with neglectable variation ranges, while not considering ∇ D. ∇ C in taller discs only slightly overestimated the glucose concentration. Most importantly, tall IVD had nearly 60% less glucose than thin IVD, with local drops below the concentration of 0.5 mM, considered to be critical for disc cells3, in the anterior nucleus pulposus. On the one hand, previous reduced formulations for mechanometabolic-transport models of the IVD seem acceptable, even for patient-specific modelling. On the other hand, tall IVD might suffer from unfortunate combinations of deformation-dependent solute diffusion and large diffusion distances, which may favor earlyAcknowledgements: Catalan Government and European Commission (2020 BP 00282; ERC-2021-CoG-O-Health-101044828)
APPLICATION OF EXTERNAL TORQUE ENHANCES THE DETECTION OF SUBTLE SYNDESMOTIC ANKLE INSTABILITY IN A WEIGHTBEARING CT
Authors: Huyghe M. , Peiffer M. , Cuigniez F. , Tampere T. , Ashkani-Esfahani S. , D'Hooghe P. , Audenaert E. , Burssens A. 
Published: January 2024

One-fourth of all ankle trauma involve injury to the syndesmotic ankle complex, which may lead to syndesmotic instability and/or posttraumatic ankle osteoarthritis in the long term if left untreated. The diagnosis of these injuries still poses a deceitful challenge, as MRI scans lack physiologic weightbearing and plain weightbearing radiographs are subject to beam rotation and lack 3D information. Weightbearing cone-beam CT (WBCT) overcomes these challenges by imaging both ankles during bipedal stance, but ongoingdebate remains whether these should be taken under weightbearing conditions and/or during application of external rotation stress. The aim of this study is study therefore to compare both conditions in the assessment of syndesmotic ankle injuries using WBCT imaging combined with 3D measurement techniques.In this retrospective study, 21 patients with an acute ankle injury were analyzed using a WBCT. Patients with confirmed syndesmotic ligament injury on MRI were included, while fracture associated syndesmotic injuries were excluded. WBCT imaging was performed in weightbearing and combined weightbearing-external rotation. In the latter, the patient was asked to internally rotate the shin until pain (VAS>8/10) or a maximal range of motion was encountered. 3D models were developed from the CT slices, whereafter. The following 3D measurements were calculated using a custom-made Matlab® script; Anterior tibiofibular distance (AFTD), Alpha angle, posterior Tibiofibular distance (PFTD) and Talar rotation (TR) in comparison to the contralateral non-injured ankle.The difference in neutral-stressed Alpha angle and AFTD were significant between patients with a syndesmotic ankle lesion and contralateral control (P=0.046 and P=0.039, respectively). There was no significant difference in neutral-stressed PFTD and TR angle.Combined weightbearing-external rotation during CT scanning revealed an increased AFTD in patients with syndesmotic ligament injuries. Based on this study, application of external rotation during WBCT scans could enhance the diagnostic accuracy of subtle syndesmotic instability.
3D QUANTITATIVE CHARACTERIZATION OF THE HUMAN MENISCAL VASCULAR NETWORK USING X-RAY MICRO-COMPUTED TOMOGRAPHY
Authors: Orellana F. , Grassi A. , Wahl P. , Nuss K. , Neels A. , Zaffagnini S. , Parrilli A. 
Published: January 2024

A comprehensive understanding of the self-repair abilities of menisci and their overall function in the knee joint requires three-dimensional information. However, previous investigations of the meniscal blood supply have been limited to two-dimensional imaging methods, which fail to accurately capture tissue complexity. In this study, micro-CT was used to analyse the 3D microvascular structure of the meniscus, providing a detailed visualization and precise quantification of the vascular network.A contrast agent (μAngiofil®) was injected directly into the femoral artery of cadaver legs to provide the proper contrast enhancement. First, the entire knee joint was analysed with micro-CT, then to increase the applicable resolution the lateral and medial menisci were excised and investigated with a maximum resolution of up to 4 μm. The resulting micro-CT datasets were analysed both qualitatively and quantitatively. Key parameters of the vascular network, such as vascular volume fraction, vessel radius, vessel length density, and tortuosity, were separately determined for the lateral and medial meniscus, and their four circumferential zones defined by Cooper.In accordance with previous literature, the quantitative micro-CT data confirm a decrease in vascular volume fraction along the meniscal zones. The highest concentration of blood vessels was measured in the meniscocapsular region 0, which is characterized by vascular segments with a significantly larger average radius. Furthermore, the highest vessel length density observed in zone 0 suggests a more rapid delivery of oxygen and nutrients compared to other regions. Vascular tortuosity was detected in all circumferential regions, indicating the occurrence of vascular remodelling in all tissue areas.In conclusion, micro-CT is a non-invasive imaging technique that allows for the visualization of the internal structure of an object in three dimensions. These advanced 3D vascular analyses have the potential to establish new surgical approaches that rely on the healing potential of specific areas of the meniscus.Acknowledgements: The authors acknowledge R. Hlushchuk, S. Halm, and O. Khoma from the University of Bern for their help with contrast agent perfusions.
A ROLE FOR PERFUSION-DELIVERED SHEAR FORCE IN THE PROMOTION OF TPSC EV PRODUCTION
Authors: Clerici M. , Ciardulli M.C. , Forsyth N.R. , Maffulli N. , Della Porta G. 
Published: January 2024

Tendon injuries are a common problem that can significantly impact an individual's quality of life. While traditional surgical methods have been used to address this issue, Extracellular Vesicles (EVs) have emerged as a promising approach to promote tendon repair and regeneration mechanisms, as they deliver specific biological signals to neighbouring cells. In this study, we extracted human Tendon Progenitor Stem cells (hTPSCs) from surgery explants and isolated their EVs from perfused and static media.hTPSCs were isolated from tendon surgery biopsy (Review Board prot./SCCE n.151, 29/10/2020) and cultured in both static and dynamic conditions, using a perfusion bioreactor (1ml/min). When cells reached 80% confluence, they were switched into a serum-free medium for 24 hours for EVs-production. Conditioned media was ultra-centrifuged for 90min (100000g). The recovered pellet was then characterized by size and concentration (Nanosight NS300), Zeta potential (Mastersizer S), morphology (SEM and TEM) and protein quantification.hTPSCs stemness and multipotency were confirmed through CD73, CD90, and CD105 expression and confirmation of quad-lineage (adipo-osteo-chondro-teno) differentiation. After 7 days, hTPSCs were ready for EVs-production. Ultracentrifugation revealed the presence of particles with a concentration of 7×107 particles/mL consistent across both cultures. Further characterization indicated that EVs collected from perfused conditions displayed an elevated vesicle mean size (mean 143±6.5 nm) in comparison to static conditions (mean 112±7.4 nm). Consistent with, but not in proportion with, the above protein content was measured at 20 ng/ml (dynamic) and 7 ng/mL (static) indicating a nearly 3-fold increase in concentration associated with a ~22% increase in particle size.Proposed data showed that sub-200 diameter vesicles were successfully collected from multipotent hTPSCs starvation, and the vesicle size and protein concentration were compatible with established EV literature; furthermore, dynamic culture conditions seemed more suitable for EVs-production. Further characterization will be required to better understand, EVs-compositions and their role in tendon regenerative events.
3D-PRINTED HYBRID SCAFFOLDS FOR CARTILAGE REGENERATION
Authors: Ferreira S.A. , Tallia F. , Heyraud A. , Walker S.A. , Salzlechner C. , Jones J.R. , Rankin S.M. 
Published: January 2024

For chondral damage in younger patients, surgical best practice is microfracture, which involves drilling into the bone to liberate the bone marrow. This leads to a mechanically inferior fibrocartilage formed over the defect as opposed to the desired hyaline cartilage that properly withstands joint loading. While some devices have been developed to aid microfracture and enable its use in larger defects, fibrocartilage is still produced and there is no clear clinical improvement over microfracture alone in the long term. Our goal is to develop 3D printed devices, which surgeons can implant with a minimally invasive technique. The scaffolds should match the functional properties of cartilage and expose endogenous marrow cells to suitable mechanobiological stimuli in-situ, in order to promote healing of articular cartilage lesions before they progress to osteoarthritis, and rapidly restore joint health and mobility. Importantly, scaffolds should direct a physiological host reaction, instead of a foreign body reaction, associated with chronic inflammation and fibrous capsule formation, negatively influencing the regenerative outcome.Our novel silica/polytetrahydrofuran/polycaprolactone hybrids were prepared by sol-gel synthesis and scaffolds were 3D printed by direct ink writing. 3D printed hybrid scaffolds with pore channels of ~250 µm mimic the compressive behaviour of cartilage. Our results show that these scaffolds support human bone marrow stem/stromal cell (hMSC) differentiation towards chondrogenesis in vitro under hypoxic conditions to produce markers integral to articular cartilage-like matrix evaluated by immunostaining and gene expression analysis. Macroscopic and microscopic evaluation of subcutaneously implanted scaffolds in mice showed that scaffolds caused a minimal resolving inflammatory response. Our findings show that 3D printed hybrid scaffolds have the potential to support cartilage regeneration.Acknowledgements: Authors acknowledge funding provided by EPSRC grant EP/N025059/1.