bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACCURACY EVALUATION OF AUTOMATIC SEGMENTATION IN BIOMEDICAL IMAGES: 3D SPATIAL MAPPING OF SEGMENTATION ERRORS
Authors: Grammens J. , Pereira L. F.A. , Danckaers F. , Vanlommel J. , Van Haver A. , Verdonk P. , Sijbers J. 
Published: January 2024

Currently implemented accuracy metrics in open-source libraries for segmentation by supervised machine learning are typically one-dimensional scores [1]. While extremely relevant to evaluate applicability in clinics, anatomical location of segmentation errors is often neglected.This study aims to include the three-dimensional (3D) spatial information in the development of a novel framework for segmentation accuracy evaluation and comparison between different methods.Predicted and ground truth (manually segmented) segmentation masks are meshed into 3D surfaces. A template mesh of the same anatomical structure is then registered to all ground truth 3D surfaces. This ensures all surface points on the ground truth meshes to be in the same anatomically homologous order. Next, point-wise surface deviations between the registered ground truth mesh and the meshed segmentation prediction are calculated and allow for color plotting of point-wise descriptive statistics. Statistical parametric mapping includes point-wise false discovery rate (FDR) adjusted p-values (also referred to as q-values).The framework reads volumetric image data containing the segmentation masks of both ground truth and segmentation prediction. 3D color plots containing descriptive statistics (mean absolute value, maximal value,…) on point-wise segmentation errors are rendered. As an example, we compared segmentation results of nnUNet [2], UNet++ [3] and UNETR [4] by visualizing the mean absolute error (surface deviation from ground truth) as a color plot on the 3D model of bone and cartilage of the mean distal femur.A novel framework to evaluate segmentation accuracy is presented. Output includes anatomical information on the segmentation errors, as well as point-wise comparative statistics on different segmentation algorithms. Clearly, this allows for a better informed decision-making process when selecting the best algorithm for a specific clinical application.
ACCELERATIONS RECORDED BY LOW-FREQUENCY WEARABLE SENSORS AS EFFECTIVE DISCRIMINATORS OF KNEE AND HIP OSTEOARTHRITIS
Authors: Ghaffari A. , Clasen P.D. , Boel R.V. , Kappel A. , Jakobsen T. , Kold S. , Rahbek O. 
Published: January 2024

Wearable inertial sensors can detect abnormal gait associated with knee or hip osteoarthritis (OA). However, few studies have compared sensor-derived gait parameters between patients with hip and knee OA or evaluated the efficacy of sensors suitable for remote monitoring in distinguishing between the two. Hence, our study seeks to examine the differences in accelerations captured by low-frequency wearable sensors in patients with knee and hip OA and classify their gait patterns.We included patients with unilateral hip and knee OA. Gait analysis was conducted using an accelerometer ipsilateral with the affected joint on the lateral distal thighs. Statistical parametric mapping (SPM) was used to compare acceleration signals. The k-Nearest Neighbor (k-NN) algorithm was trained on 80% of the signals' Fourier coefficients and validated on the remaining 20% using 10-fold cross-validation to classify the gait patterns into hip and knee OA.We included 42 hip OA patients (19 females, age 70 [63–78], BMI of 28.3 [24.8–30.9]) and 59 knee OA patients (31 females, age 68 [62–74], BMI of 29.7 [26.3–32.6]). The SPM results indicated that one cluster (12–20%) along the vertical axis had accelerations exceeding the critical threshold of 2.956 (p=0.024). For the anteroposterior axis, three clusters were observed exceeding the threshold of 3.031 at 5–19% (p = 0.0001), 39–54% (p=0.00005), and 88–96% (p = 0.01). Regarding the mediolateral axis, four clusters were identified exceeding the threshold of 2.875 at 0–9% (p = 0.02), 14–20% (p=0.04), 28–68% (p < 0.00001), and 84–100% (p = 0.004). The k-NN model achieved an AUC of 0.79, an accuracy of 80%, and a precision of 85%.In conclusion, the Fourier coefficients of the signals recorded by wearable sensors can effectively discriminate the gait patterns of knee and hip OA. In addition, the most remarkable differences in the time domain were observed along the mediolateral axis.
MAGNETICALLY ASSISTED NANOPLATFORMS FOR REMOTE-CONTROLLED THERAPIES: TARGETING AND SWITCHING MACROPHAGE FUNCTIONS
Authors: Rodrigues M.T. , Almeida A.F. , Miranda M.S. , Vinhas A. , Gonçalves A. I. , Gomes M.E. 
Published: January 2024

Chronic inflammatory events have been associated to almost every chronic disease, including cardiovascular-, neurodegenerative- and autoimmune- diseases, cancer, and host-implant rejection. Given the toll of chronic inflammation in healthcare and socioeconomical costs developing strategies to resolve and control chronic states of inflammation remain a priority for the significant benefit of patients.Macrophages (Mφ) hold a central role both in the initiation and resolution of inflammatory events, assuming different functional profiles. The outstanding features of Mφ counting with the easy access to tissues, and the extended networking make Mφ excellent candidates for precision therapy. Moreover, sophisticated macrophage-oriented systems could offer innovative immune-regulatory alternatives to effectively regulate chronic environments that traditional pharmacological agents cannot provide.We propose magnetically assisted systems for balancing Mφ functions at the injury site. This platform combines polymers, inflammatory miRNA antagonists and magnetically responsive nanoparticles to stimulate Mφ functions towards pro-regenerative phenotypes. Strategies with magnetically assisted systems include contactless presentation of immune-modulatory molecules, cell internalization of regulatory agents for functional programming via magnetofection, and multiple payload delivery and release.Overall, Mφ-oriented systems stimulated pro-regenerative functions of Mφ supporting magnetically assisted theranostic nanoplatforms for precision therapies, envisioning safer and more effective control over the distribution of sensitive nanotherapeutics for the treatments of chronical inflammatory conditions.Acknowledgements: ERC CoG MagTendon No.772817; FCT Doctoral Grant SFRD/BD/144816/2019, and TERMRES Hub (Norte-01-0145-FEDER-022190).
3D POROUS COMPOSITE SCAFFOLDS WITH HIGH CALCIUM PHOSPHATE CONTENT AND ADDITION OF INORGANIC IONS FOR BONE REGENERATION APPLICATIONS
Authors: Nikody M. , Li J. , Koper D. , Balmayor E.R. , Habibovic P. , Moroni L. 
Published: January 2024

Critical-sized bone defects remain challenging in the clinical setting. Autologous bone grafting remains preferred by clinicians. However, the use of autologous tissue is associated with donor-site morbidity and limited accessibility to the graft tissue. Advances in the development of synthetic bone substitutes focus on improving their osteoinductive properties. Whereas osteoinductivity has been demonstrated with ceramics, it is still a challenge in case of polymeric composites. One of the approaches to improve the regenerative properties of biomaterials, without changing their synthetic character, is the addition of inorganic ions with known osteogenic and angiogenic properties. We have previously reported that the use of a bioactive composite with high ceramic content composed of poly(ethyleneoxide terephthalate)/poly(butylene terephthalate) (1000PEOT70PBT30, PolyActive, PA) and 50% beta-tricalcium phosphate (β-TCP) with the addition of zinc in a form of a coating of the TCP particles can enhance the osteogenic differentiation of human mesenchymal stromal cells (hMSCs) (3). To further support the regenerative properties of these scaffolds, inorganic ions with known angiogenic properties, copper or cobalt, were added to the coating solution.β-TCP particles were immersed in a zinc and copper or zinc and cobalt solution with a concentration of 15 or 45 mM. 3D porous scaffolds composed of 1000PEOT70PBT30 and pure or coated β-TCP were additively manufactured by 3D fibre deposition. The osteogenic and angiogenic properties of the fabricated scaffolds were tested in vitro through culture with hMSCs and human umbilical vein endothelial cells, respectively. The materials were further evaluated through ectopic implantation in an in vivo mini-pig model. The early expression of relevant osteogenic gene markers (collagen-1, osteocalcin) of hMSCs was upregulated in the presence of lower concentration of inorganic ions. Further analysis will focus on the evaluation of ectopic bone formation and vascularisation of these scaffolds after implantation in a mini-pig ectopic intramuscular model.
MULTISCALE ASSESSMENT OF ACHILLES TENDON MECHANICS AND MECHANOBIOLOGY
Authors: Isaksson H. , Pierantoni M. , Barreto I.S. , Hammerman M. , Eliasson P. 
Published: January 2024

Achilles tendon mechanical properties depend on a complex hierarchical design, with collagen being the smallest load-bearing unit. At the nanoscale, collagen molecules are organized into fibrils, which at the microscale are assembled into fibers, followed by larger structures such as sub-tendons or fascicles. Degree of in vivo loading affects the collagen content, and organization and consequently the tissue's mechanical response. We aim to unravel how composition, structural organization, and mechanical response are affected by degree of in vivo loading at each length scale. The presentation will outline the results to date about to the use of high-resolution synchrotron-based tissue characterisation methods on several length scales in combination with in situ mechanical tests. We use a rat model, where the tendons are subjected to varying loading in vivo. To characterize the tissue microstructure, phase-contrast enhanced synchrotron micro-tomography is performed. The 3D fiber organization in fully loaded tendons is highly aligned, whereas the fibers in unloaded tendons are significantly more heterogeneously arranged and crimped. To characterize the collagen fibril response, Small Angle X-ray Scattering is performed. Two types of fibril organizations are found; a single population oriented towards the main load direction and two fibril subpopulations with clearly distinct orientations. Scattering during loading showed that the fibrils in unloaded tendons did not strain as much in fully loaded. In situ loading concurrently with high resolution synchrotron experiments show the complex tendon response to in situ load and its relation to in vivo loading and tendon hierarchical structure. Unloading seems to alter the organization of the fibrils and fibers, e.g. increased crimping and more pronounced sub-tendon twists.Acknowledgements: Funding from Knut and Alice Wallenberg Foundation and European Research Council (101002516). Paul Scherrer Institut, Switzerland for beamtime at cSAXS and TOMCAT.
CHONDROCYTE-SPECIFIC KNOCKOUT OF PIEZO ION CHANNELS PROTECTS AGAINST POST-TRAUMATIC OSTEOARTHRITIS
Authors: Ely E.V. , Collins K.H. , Lenz K. , Paradi S. , Liedtke W. , Chen Y. , Guilak F. 
Published: January 2024

Osteoarthritis (OA) is the leading cause of pain and disability worldwide and is characterized by the degenerative changes of articular cartilage. Joint loading is required for cartilage maintenance; however, hyper-physiologic loading is a risk factor for OA. Mechanosensitive ion channels Piezo1 and Piezo2 synergistically transduce hyper-physiologic compression of chondrocytes, leading to chondrocyte death and onset of OA. This injury response is inhibited by Piezo channel loss of function, however the mechanistic role of Piezo channels in vivo is unknown. We examined the hypothesis that deletion of Piezo in chondrocytes will protect mice from joint damage and pain-related behaviors following a surgical destabilization of the medial meniscus (DMM), investigating a key mechanistic and mechanobiological role of these channels in the pathogenesis of OA.Aggrecan-Cre Piezo1 and Piezo1/2 knockout mice ((Agc)1-CREERT2;Piezo1fl/flPiezo2fl/fl) were generated and given a 5-day Tamoxifen regimen at 12-weeks of age (n=6–12/group/sex). Cre-negative mice served as controls. At 16-weeks, mice received DMM surgery on the left knee. 12-weeks following DMM prior to sacrifice, activity and hyperalgesia were measured using spontaneous running wheels and a small animal algometer. Structural changes in bone, cartilage, and synovium were characterized using microCT, histology, and Modified Mankin Score criteria.Knockout of Piezo1/2 channels was chondroprotective in both sexes following DMM surgery as demonstrated by reduced Modified Mankin Score compared to control animals. Piezo1 KO was chondroprotective in only female mice, indicating a sexually dimorphic response. Piezo1 and Piezo1/2 KO was protective against pain in male mice, while females displayed no differences compared to controls. No changes were observed in bone morphology.Chondrocyte-specific Piezo1/2 knockout protects the knee joint from structural damage, hyperalgesia and functional deficits in a surgical model of PTOA in male and female mice, illustrating the importance of Piezo channels in response to injury in vivo. Future work aims to interrogate potential sexually dimorphic responses to cartilage damage and investigating Piezo2 KO mice.
RAPAMYCIN HAS A LIMITED EFFECT ON TENDON HEALING IN A RODENT MODEL
Authors: Marr N. , Zamboulis D.E. , Beaumont R.E. , Tatarczyk Z.J. , Meeson R. , Thorpe C.T. 
Published: January 2024

Tendon injuries occur frequently in athletes and the general population, with inferior healing leading to deposition of fibrotic scar tissue. New treatments are essential to limit fibrosis and enable tendon regeneration post-injury. In this study, we tested the hypothesis that rapamycin improves tendon repair and limits fibrosis by inhibiting the mTOR pathway.The left hindlimb of female adult Wistar rats was injured by needle puncture and animals were either given daily injections of rapamycin (2mg/kg) or vehicle. Animals were euthanized 1 week or 3 weeks post-injury (n=6/group). Left and right Achilles tendons were harvested, with the right limbs acting as controls. Tendon sections were stained with haematoxylin & eosin, and scored by 2 blinded scorers, assessing alterations in cellularity, cell morphology, vascularity, extracellular matrix (ECM) organization and peritendinous fibrosis. Immunohistochemistry was performed for the tendon pan-vascular marker CD146 and the autophagy marker LC3.Injury resulted in significantly altered ECM organization, cell morphology and cellularity in both rapamycin and vehicle-treated groups, but no alterations in vascularity compared to uninjured tendons. Rapamycin had a limited effect on tendon repair, with a significant reduction in peritendinous fibrosis 3 weeks after injury (p=0.028) but no change in cell morphology, cellularity or ECM organization compared to vehicle treated tendons at either 1 week or 3 weeks post injury. CD146 labelling was increased at the site of injury, but there was no apparent difference in CD146 or LC3 labelling in rapamycin and vehicle treated tendons.The decrease in peritendinous fibrosis post-injury observed in rapamycin treated tendons indicates rapamycin as a potential therapy for tendon adhesions. However, the lack of improvement of other morphological parameters in response to rapamycin treatment indicates that rapamycin is not an effective therapy for injuries to the tendon core.Acknowledgements: This study was funded by Versus Arthritis (22607)
POLARIZED MACROPHAGE-DERIVED EXTRACELLULAR VESICLES AS POTENTIAL MEDIATORS OF TENDON REPAIR
Authors: Graça A.L. , Rodrigues M.T. , Domingues R.M.A. , Gomes M.E. , Gomez-Florit M. 
Published: January 2024

Macrophages play a critical role in innate immunity by promoting or inhibiting tissue inflammation and repair. Classically, macrophages can differentiate into either pro-inflammatory (M1) or pro-reparative (M2) phenotypes in response to various stimuli. Therefore, this study aimed to address how extracellular vesicles (EVs) derived from polarized macrophages can affect the inflammatory response of tendon cells.For that purpose, human THP-1 cells were stimulated with lipopolysaccharide (LPS), and interleukins -4 and -13 (IL- 4, IL-13), to induce macrophages polarization into M1, M2, and hybrid M1/M2 phenotypes. Subsequently, the EVs were isolated from the culture medium by ultracentrifugation. The impact of these nanovesicles on the inflammation and injury scenarios of human tendon-derived cells (hTDCs), which had previously been stimulated with interleukin- 1 beta (IL-1ß) to mimic an inflammatory scenario, was assessed.We were able to isolate three different nanovesicles populations, showing the typical shape, size and surface markers of EVs. By extensively analyzing the proteomic expression profiles of M1, M2, and M1/M2, distinct proteins that were upregulated in each type of macrophage-derived EVs were identified. Notably, most of the detected pro- inflammatory cytokines and chemokines had higher expression levels in M1-derived EVs and were mostly absent in M2-derived EVs. Hence, by acting as a biological cue, we observed that M2 macrophage-derived EVs increased the expression of the tendon-related marker tenomodulin (TNMD) and tended to reduce the presence of pro-inflammatory markers in hTDCs. Overall, these preliminary results show that EVs derived from polarized macrophages might be a potential tool to modulate the immune system responses becoming a valuable asset in the tendon repair and regeneration fields worthy to be further explored.
SOURCE OF MESENCHYMAL STEM CELLS IS VITAL FOR BONE-REGENERATIVE APPLICATIONS
Authors: Mohamed-Ahmed S. , Yassin M.A. , Rashad A. , Lie S.A. , Suliman S. , Espedal H. , Idris S.B. , Finne-Wistrand A. , Mustafa K. , Vindenes H. , Fristad I. 
Published: January 2024

Mesenchymal stem cells (MSC) have been used for bone regenerative applications as an alternative approach to bone grafting. Selecting the appropriate source of MSC is vital for the success of this therapeutic approach. MSC can be obtained from various tissues, but the most used sources of MSC are Bone marrow (BMSC), followed by adipose tissue (ASC). A donor-matched comparison of these two sources of MSC ensures robust and reliable results.Despite the similarities in morphology and immunophenotype of donor-matched ASC and BMSC, differences existed in their proliferation and in vitro differentiation potential, particularly osteogenic differentiation that was superior for BMSC, compared to ASC. However, these differences were substantially influenced by donor variations. In vivo, although the upregulated expression of osteogenesis-related genes in both ASC and BMSC, more bone was regenerated in the calvarial defects treated with BMSC compared to ASC, especially during the initial period of healing. According to these findings, compared to ASC, BMSC may result in faster regeneration and healing, when used for bone regenerative applications.
PHASE SEPARATION AND PARTICULATE LEACHING INTEGRATED 3D PRINTING OF POROUS SCAFFOLDS FOR BONE TISSUE ENGINEERING APPLICATIONS
Authors: Aydin M. S. 
Published: January 2024

Conventional 3D printing by itself is incapable of creating pores on a micro scale within deposited filaments throughout 3D scaffolds. These pores and hence larger surface areas are needed for cells to be adhered, proliferated, and differentiated. The aim of this work was to fabricate 3D polycaprolactone (PCL) scaffolds with internal multiscale porosity by using two different 3D printing techniques (ink/pellet of polymer-salt composite in low/high temperature printing) combined with salt leaching to improve cell adhesion, and cell proliferation besides to change degradation rate of PCL scaffolds:1. Non-solvent phase separation integrated 3D printing of polymer-salt inks with various salt content (i.e., low temperature ink-based printing, LT).2. FDM printing of composite polymer-salt pellets which will be obtained by casting and evaporating of prepared ink (i.e., high temperature composite-pellet-based printing, HT).Further, the two approaches were followed by post salt leaching. Stem cells were able to attach on the surface and grow up to 14 days based on increasing cellular activities.
TRIAZINE-TRIONE BASED COMPOSITE MATERIALS FOR POTENTIAL BONE TISSUE ENGINEERING
Authors: Johansen Å. , Lin J. , Yamada S. , Yassin M. A. , Hutchinson D. , Malkoch M. , Mustafa K. 
Published: January 2024

Several synthetic polymers have been widely investigated for their use in bone tissue engineering applications, but the ideal material is yet to be engineered. Triazine-trione (TATO) based materials and their derivatives are novel in the field of biomedical engineering but have started to draw interest. Different designs of the TATO monomers and introduction of different chemical linkages and end-groups widens the scope of the materials due to a range of mechanical properties.The aim of our work is to investigate novel TATO based materials, with or without hydroxyapatite filler, for their potential in bone tissue engineering constructs. Initially the biocompatibility of the materials was tested, indirectly and directly, according to ISO standards. Following this the osteoconductive properties were investigated with primary osteoblasts and an osteoblastic cell line. Bone marrow derived mesenchymal stem cells were used to evaluate the osteogenic differentiation and consequently the materials potential in bone tissue engineering applications.
MESENDODERM PROGENITOR CELLS DERIVED FROM PLURIPOTENT STEM CELLS FOR DISC REGENERATION: A PRELIMINARY STUDY IN AN OVINE MODEL
Authors: Cicione C. , Tilotta V. , Giacomo G. Di , Ambrosio L. , Russo F. , Papalia R. , Vadalà G. , Denaro V. 
Published: January 2024

Low back pain (LBP) is a worldwide leading cause of disability. Treatment of intervertebral disc (IVD) with stem cells has been used on degenerate discs (IDD), cause of around 40% of LBP cases. Despite pain reduction, clinical studies' follow-up have not shown a structural IVD improvement. A valid alternative may be the use of notocordal cells (NC) or their precursors. Mesendoderm progenitor cells (MEPC) have the ability to replicate and differentiate toward NC. In this preliminary study we evaluated in a preclinical IDD model the viability and NC differentiation of MEPC derived from induced pluripotent stem cells (iPSC).MEPC derived from iPSC were developed during the iPSpine project (# 825925), thawed, plated for 24h on laminin and labeled with PKH26.Two adult sheep were subjected to nucleotomy of five lumbar discs for the induction of IDD. After 5 weeks, 3 degenerated discs were treated with MEPC at 3 different doses (low, medium and high). One sheep was sacrificed after 7 days and one after 30 days. Clinical parameters were collected to evaluate the safety of treatment. Discs were analysed using histological techniques. Survival (PKH26), proliferation (PCNA), notocordal cell differentiation (Brachyury, Cytokeratin 8/18/19, Sox9, Foxa2) and endodermal differentiation (Sox17) were evaluated.At 7 days from treatment, both sheep lost about 20% of body weight. Only in discs treated with the highest dose PKH26 stained cells were alive up to 30 days. These cells turn out to be: proliferating (PCNA); positive for Brachyury, cytokeratin 8/18/19 and Foxa2; positive for SOX17 in a small percentage.This preliminary study shows that MEPC, derived from iPSC and injected into ovine discs degenerated by nucleotomy, are able to survive up to 30 days and differentiate within the disc predominantly towards the notocordal phenotype.