bluuebunny/crossref_metadata_2025_split huggingface dataset:
POST-PRINTING CHONDROGENIC DIFFERENTIATION OF STEM CELL SPHEROID CONSTRUCTS FOR CARTILAGE TISSUE ENGINEERING
Authors: Decarli M.C. , Seijas-Gamardo A. , Morgan F.L.C. , Wieringa P. , Baker M.B. , Silva J.V.L , Moraes A.M. , Lorenzo M. , Mota C. 
Published: January 2024

Cartilage lesions often undergo irreversible progression due to low self-repair capability of this tissue. Tissue engineered approaches based in extrusion bioprinting of constructs loaded with stem cell spheroids may offer valuable alternatives for the treatment of cartilage lesions. Human mesenchymal stromal cell (hMSC) spheroids can be chondrogenically differentiated faster and more efficiently than single cells. This approach allows obtaining larger tissues in a rapid, controlled and reproducible way. However, it is challenging to control tissue architecture, construct stability, and cell viability during maturation. In this study we aimed at the development of a reproducible bioprinting process followed by post-bioprinting chondrogenic differentiation procedure using large quantities of hMSC spheroids encapsulated in a xanthan gum-alginate hydrogel. Multi-layered constructs were bioprinted, ionically crosslinked, and chondrogenically differentiated for 28 days. The expression of glycosaminoglycan, collagen II and IV were observed. After 56 days in culture, the bioprinted constructs were still stable and show satisfactory cell metabolic activity with profuse extracellular matrix production. These results showed a promising procedure to obtain 3D cartilage-like constructs that could be potential use as stable chondral tissue implants for future therapies.Acknowledgments: The National Council for Scientific and Technological Development (CNPq, Brazil – Grants # 314 724/2021-4, 307 829/2018-9, 430 860/2018-8, 142 050/2018-0 and 465 656/2014-5), the Coordination for the Improvement of Higher Educational Personnel (CAPES, Brazil – PrInt 88 887.364849/2019-00 and PrInt 88 887.310405/2018-00), the Fund for Support to Teaching, Research and Extension from the University of Campinas (FAEPEX/UNICAMP, Brazil – Grants # 2921/18, 2324/21), and the European Union's Horizon 2020 JointPromise project – Precision manufacturing of microengineered complex joint implants, under grant agreement 874 837 are acknowledged for the financial support of this study.
PATHOGENETIC PATHWAYS AND POSSIBLE TREATMENT OPTIONS FOR NONUNION FRACTURES
Authors: van Griensven M. 
Published: January 2024

Bone regeneration is pivotal for the healing of fractures. In case this process is disturbed a non-union can occur. This can be induced by environmental factors such as smoking, overloading etc. Co-morbidities such as diabetes, osteoporosis etc. may be more intrinsic factors besides other disturbances in the process. Those pathways negatively influence the bone regeneration process. Several intrinsic signal transduction pathways (WNT, BMP etc.) can be affected. Furthermore, on the transcriptional level, important mRNA expression can be obstructed by deregulated miRNA levels. For instance, several miRNAs have been shown to be upregulated during osteoporotic fractures. They are detrimental for osteogenesis as they block bone formation and accelerate bone resorption. Modulating those miRNAs may revert the physiological homeostasis. Indeed, physiological fracture healing has a typical miRNA signature. Besides using molecular pathways for possible treatment of non-union fractures, providing osteogenic cells is another solution. In 5 clinical cases with non-union fractures with defects larger than 10 cm, successful administration of a 3D printed PCL-TCP scaffold with autologous bone marrow aspirate concentrate and a modulator of the pathogenetic pathway has been achieved. All patients recovered well and showed a complete union of their fractures within one year after start of the regenerative treatment.Thus, non-union fractures are a diverse entity. Nevertheless, there seem to be common pathogenetic disturbances. Those can be counteracted at several levels from molecular to cell. Compositions of those may be the best option for future therapies. They can also be used in a more personalized fashion in case more specific measurements such as miRNA signature and stem cell activity are applied.
THE CORRELATION BETWEEN ELECTRICAL IMPEDANCE AND CALLUS QUALITY: AN IN VIVO STUDY OF TIBIAL FRACTURES IN RABBITS
Authors: Frost M.W. , Tirta M. , Rahbek O. , Rytoft L.A. , Ding M. , Shen M. , Duch K. , Kold S. 
Published: January 2024

Healing after bone fracture is assessed by frequent radiographs, which expose patients to radiation and lacks behind biological healing. This study aimed to investigate whether the electrical impedance using electrical impedance spectroscopy correlated to quantitative scores of bone healing obtained from micro-CT and mechanical bending test.Eighteen rabbits were subjected to tibial fracture that was stabilized with external fixator. Two electrodes were positioned, one electrode placed within the medullary cavity and the other on the lateral cortex, both three millimeters from the fracture site. Impedance was measured daily across the fracture site at a frequency range of 5 Hz to 1 MHz. The animals were divided into three groups with different follow-up time: 1, 3 and 6 weeks for micro-CT (Bone volume/tissue volume (BV/TV, %)) and mechanical testing (maximum stress (MPa), failure energy (kJ/cm3), young modulus (Mpa)).There was a statistically significant correlation between last measured impedance at 5 Hz frequency immediately prior to euthanasia and BV/TV of callus (−0.68, 95%CI: (−0.87; −0.31)). Considering the mechanical testing with three-point bending, no significant correlation was found between last measured impedance at 5 Hz frequency immediately prior to euthanasia and maximum stress (−0.35, 95%CI: (−0.70; 0.14)), failure energy (−0.23, 95%CI: (−0.63; 0.26)), or young modulus (−0.28, 95%CI: (−0.66; 0.22)).The significant negative correlation between impedance and BV/TV might indicate that impedances correlate with the relative bone volume in the callus site. The lack of correlation between impedance and mechanical parameters when at the same time observing a correlation between impedance and days since operation (0-42 days), might indicate that the impedance can measure biological changes at an earlier time point than rough mechanical testing.
SAFE USE OF INTRAOPERATIVE TOURNIQUET: DOES ORTHOPAEDIC PRACTICE NEED GUIDANCE TO PREVENT RARE COMPLICATIONS?
Authors: Elbahi A. , Wasim M. , Yusuf K. , Thilagarajah M. 
Published: January 2024

Tourniquet is a commonly used tool in orthopaedic practice. Incidence of complications is low but if any develops, it is devastating. Transient nerve damage, ischemia or skin burns are the possible tourniquet related complications. There is big variation in practice regarding the limb occlusion pressure.51 procedures in 50 patients were reviewed retrospectively in our district general hospital. We looked at quality of documentation guided by the BOAST standard (The Safe Use of Intraoperative Tourniquets, published in October 2021). Limb occlusion pressure and ischemic time were analysed. Intra-operative and post-operative notes were reviewed to assess quality of documentation and post-operative complications.Although limb occlusion pressure was above the recommended range in more than 75% of cases, there were no significant complications observed. Two cases only developed transient neuropraxia in common peroneal nerve and median nerve following tibial plateau ORIF and trapeziectomy simultaneously. Tibial ORIF fixation case had prolonged ischemic time (more than 120 minutes) and the limb occlusion pressure for the hand case was above the recommended range. Both have recovered within few days with no long-term consequences. Minimum documentation threshold was not met with regarding tourniquet site condition, method of skin isolation and padding, and exsanguination method.This relatively new standard with no previous similar guidance needs time until it is followed by the health care professionals especially when there is no high incidence of complications related to the use of the tourniquet. However, it is crucial to increase the theatre staff awareness of such standards. This will prevent devastating complications specifically in vulnerable patients. Adjustments to theatre checklist have been suggested to improved documentation. Additionally, local teaching sessions will be delivered to theatre personnel aiming at improving our compliance to this standard.
THE INDUCED MEMBRANE TECHNIQUE IMPROVES THE HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH A POST-TRAUMATIC LONG BONE NONUNION
Authors: der Broeck L.V. , Geurts J. , Qiu S. , Poeze M. , Blokhuis T.J. 
Published: January 2024

The optimal treatment strategy for post-traumatic long bone non-unions is subject of an ongoing discussion. At the Maastricht University Medical Center (MUMC+) the induced membrane technique is used to treat post-traumatic long bone non-unions. This technique uses a multimodal treatment algorithm involving bone marrow aspirate concentrate (BMAC), the reamer-irrigator-aspirator (RIA) and P-15 bioactive peptide (iFactor, Cerapedics). Bioactive glass (S53P4 BAG, Bonalive) is added when infection is suspected. This study aims to objectify the effect of this treatment algorithm on the health-related quality of life (HRQoL) of patients with post-traumatic long bone non-unions. We hypothesized that HRQoL would improve after treatment.From January 2020 to March 2023, consecutive patients who were referred to a multidisciplinary (trauma, orthopaedic and plastic surgery) non-union clinic at the MUMC+, The Netherlands, were evaluated using the Non-Union Scoring System (NUSS). The EQ-5D-5L questionnaire and the Lower Extremity Functional Scale (LEFS) were employed to obtain HRQoL outcomes both prior to and subsequent to surgery, with a follow-up at 6, 18 and 35 weeks.Seventy-six patients were assessed at baseline (T0), with a mean NUSS of 40 (± 13 SD). Thirty-eight patients had their first follow-up, six weeks after surgery (T1). Thirty-one patients had a second follow-up at 18 weeks (T2), and twenty patients had the third follow-up at 35 weeks (T3). The EQ-5D index mean at baseline was 0.480, followed by an index of 0.618 at T1, 0.636 at T2, and 0.702 at T3. A significant difference was found in the HRQoL score between T0 and T1, as well as T2 and T3 (p<0.001; p=0.011). The mean LEFS significantly increased from 26 before intervention to 34, 39, and 43 after treatment (p<0.001; p=0.033; p=0.016).This study demonstrated a significant improvement in the health-related quality of life of patients with post-traumatic long bone non-unions after the standardized treatment algorithm following the induced membrane technique.
NEW-GENERATION SUPERIOR SINGLE PLATING VERSUS LOW-PROFILE DUAL MINI-FRAGMENT PLATING OF DIAPHYSEAL CLAVICLE FRACTURES: A BIOMECHANICAL STUDY
Authors: Pastor T. , Zderic I. , Berk T. , Souleiman F. , Vögelin E. , Beeres F.J.P. , Gueorguiev B. , Pastor T. 
Published: January 2024

Recently, a new generation of superior clavicle plates was developed featuring the variable-angle locking technology for enhanced screw positioning and optimized plate-to-bone fit design. On the other hand, mini-fragment plates used in dual plating mode have demonstrated promising clinical results. However, these two bone-implant constructs have not been investigated biomechanically in a human cadaveric model. Therefore, the aim of the current study was to compare the biomechanical competence of single superior plating using the new generation plate versus dual plating with low-profile mini-fragment plates.Sixteen paired human cadaveric clavicles were assigned pairwise to two groups for instrumentation with either a 2.7 mm Variable Angle Locking Compression Plate placed superiorly (Group 1), or with one 2.5 mm anterior plate combined with one 2.0 mm superior matrix mandible plate (Group 2). An unstable clavicle shaft fracture AO/OTA15.2C was simulated by means of a 5 mm osteotomy gap. All specimens were cyclically tested to failure under craniocaudal cantilever bending, superimposed with bidirectional torsion around the shaft axis and monitored via motion tracking.Initial stiffness was significantly higher in Group 2 (9.28±4.40 N/mm) compared to Group 1 (3.68±1.08 N/mm), p=0.003. The amplitudes of interfragmentary motions in terms of craniocaudal and shear displacement, fracture gap opening and torsion were significantly bigger over the course of 12500 cycles in Group 1 compared to Group 2; p≤0.038. Cycles to 2 mm shear displacement were significantly lower in Group 1 (22792±4346) compared to Group 2 (27437±1877), p=0.047.From a biomechanical perspective, low-profile 2.5/2.0 dual plates demonstrated significantly higher initial stiffness, less interfragmentary movements, and higher resistance to failure compared to 2.7 single superior variable-angle locking plates and can therefore be considered as a useful alternative for diaphyseal clavicle fracture fixation especially in unstable fracture configurations.
THE KNEE-HIP-SPINE TRILEMMA IN PATIENTS WITH SEVERE CONGENITAL DYSPLASIA OF THE HIP UNDERGOING TOTAL HIP ARTHROPLASTY: 77 HIPS FOLLOWED UP FOR A MINIMUM OF FIVE YEARS
Authors: García-Rey E. , Gómez-Barrena E. 
Published: January 2024

Pelvic bone defect in patients with severe congenital dysplasia of the hip (CDH) lead to abnormalities in lumbar spine and lower limb alignment that can determine total hip arthroplasty (THA) patients' outcome. These variables may be different in uni- or bilateral CDH.We compared the clinical outcome and the spinopelvic and lower limb radiological changes over time in patients undergoing THA due to uni- or bilateral CHD at a minimum follow-up of five years.Sixty-four patients (77 hips) undergoing THA due to severe CDH between 2006 and 2015 were analyzed: Group 1 consisted of 51 patients with unilateral CDH, and group 2, 113 patients (26 hips) with bilateral CDH. There were 32 females in group 1 and 18 in group 2 (p=0.6). The mean age was 41.6 years in group 1 and 53.6 in group 2 (p<0.001). We compared the hip, spine and knee clinical outcomes. The radiological analysis included the postoperative hip reconstruction, and the evolution of the coronal and sagittal spinopelvic parameters assessing the pelvic obliquity (PO) and the sacro-femoro-pubic (SFP) angles, and the knee mechanical axis evaluating the tibio-femoral angle (TFA).At latest follow-up, the mean Harris Hip Score was 88.6 in group 1 and 90.7 in group 2 (p=0.025). Postoperative leg length discrepancy of more than 5 mm was more frequent in group 1 (p=0.028). Postoperative lumbar back pain was reported in 23.4% of the cases and knee pain in 20.8%, however, there were no differences between groups. One supracondylar femoral osteotomy and one total knee arthroplasty were required. The radiological reconstruction of the hip was similar in both groups. The PO angle improved more in group 1 (p=0.01) from the preoperative to 6-weeks postoperative and was constant at 5 years. The SFP angle improved in both groups but there were no differences between groups (p=0.5). 30 patients in group 1 showed a TFA less than 10º and 17 in group 2 (p=0.7).Although the clinical outcome was better in terms of hip function in patients with bilateral CDH than those with unilateral CDH, the improvement in low back and knee pain was similar. Patients with unilateral dysplasia showed a better correction of the PO after THA. All spinopelvic and knee alignment parameters were corrected and maintained over time in most cases five years after THA.
ADVANCED BIOREACTOR STUDIES OF REGION-SPECIFIC RESPONSE IN THE INTERVERTEBRAL DISC TO COMPRESSION, FLEXION/EXTENSION, AND TORSION
Authors: Šećerović A. , Ristaniemi A. , Crivelli F. , Heub S. , Weder G. , Ferguson S.J. , Ledroit D. , Grad S. 
Published: January 2024

Intervertebral disc (IVD) degeneration is inadequately understood due to the lack of in vitro systems that fully mimic the mechanical and biological complexity of this organ. We have recently made an advancement by developing a bioreactor able to simulate physiological, multiaxial IVD loading and maintain the biological environment in ex vivo IVD models [1].To validate this new bioreactor system, we simulated natural spine movement by loading 12 bovine IVDs under a combination of static compression (0.1 MPa), cyclic flexion/extension (±3˚, ±6˚ or 0-6˚) and cyclic torsion (±2˚, ±4˚ or 0-4˚) for more than 10’000 (0.2 Hz) or 100’000 (1 Hz) cycles over 14 days. A higher number of cycles increased the release of glycosaminoglycans and nitric oxide, as an inflammation marker, whereas fewer cycles maintained these two factors at physiological levels. All applied protocols upregulated the expression of MMP13 in the outermost annulus fibrosus (AF), indicating a collagen degradation response. This was supported by fissures observed in the AF after a longer loading duration. Increasing loading cycles induced high cell death in the nucleus pulposus and inner AF, while with fewer cycles, high cell viability was maintained in all IVD regions, irrespective of the magnitude of rotation.Less frequent multiaxial loading maintains IVD homeostasis while more frequent loading initiates an IVD degenerative profile. Specifically, the morphological and molecular changes were localized in the AF, which can be associated with combined flexion/extension and torsion. More loading cycles induced region-specific cell death and a higher release of extracellular matrix molecules from the innermost IVD regions, likely associated with longer exposure to static compression. Altogether, we demonstrated the advantages of the multiaxial bioreactor to study region-specific response in the IVD, which will allow a more profound investigation of IVD degeneration under different combinations of motions.
A NEW TISSUE-ENGINEERED PRODUCT INDICATED FOR BONE RECONSTRUCTION: PROOF OF CONCEPT
Authors: Mbuku R.B. , Sanchez C. , Evrard R. , Englebert A. , Manon J. , Henriet V. , Nolens G. , Duy K.T. , Schubert T. , Henrotin Y. , Cornu O. 
Published: January 2024

To design slow resorption patient-specific bone graft whose properties of bone regeneration are increased by its geometry and composition and to assess it in in-vitro and in-vivo models.A graft composed by hydroxyapatite (HA) and β-TCP was designed as a cylinder with 3D gyroid porosities and 7 mm medullary space based on swine's anatomy. It was produced using a stereolithography 3D-printing machine (V6000, Prodways).Sterile bone grafts impregnated with or without a 10µg/mL porcine BMP-2 (pBMP-2) solution were implanted into porcine femurs in a bone loss model. Bone defect was bi-weekly evaluated by X-ray during 3 months. After sacrifice, microscanner and non-decalcified histology analysis were conducted on biopsies.Finally, osteoblasts were cultured inside the bone graft or in monolayer underneath the bone graft. Cell viability, proliferation, and gene expression were assessed after 7 and 14 days of cell culture (n=3 patients).3D scaffolds were successfully manufactured with a composition of 80% HA and 20% β-TCP ±5% with indentation compressive strength of 4.14 MPa and bending strength of 11.8MPa.In vivo study showed that bone regeneration was highly improved in presence of pBMP-2. Micro-CT shows a filling of the gyroid sinuses of the implant (Figure 1).In vitro, the presence of BMP2 did not influence the viability of the osteoblasts and the mortality remained below 3%. After 7 days, the presence of BMP2 in the scaffold significantly increased by 85 and 65% the COL1A1 expression and by 8 and 33-fold the TNAP expression by osteoblasts in the monolayer or in the scaffold, respectively. This BMP2 effect was transient in monolayer and did not modify gene expression at day 14.BMP2-impregnated bone graft is a promising patient-personalized 3D-printed solution for bone defect regeneration, by promoting neighboring host cells recruitment and solid new bone formation.For any figures and tables, please contact the authors directly.
BONE TISSUE REGENERATION INDUCED BY LOCAL DELIVERY OF BONE MORPHOGENETIC PROTEIN 2 FROM PRO-ANGIOGENIC NEAR-INFRARED-RESPONSIVE HYDROGELS
Authors: Escudero-Duch C. , Serrano-Yamba R. , Sánchez-Casanova S. , Falguera-Uceda M. , Yus C. , Lerma-Juárez M.A. , Arruebo M. , Vilaboa N. 
Published: January 2024

In this work, we combined tissue engineering and gene therapy technologies to develop a therapeutic platform for bone regeneration. We have developed photothermal fibrin-based hydrogels that incorporate degradable CuS nanoparticles (CuSNP) which transduce incident near-infrared (NIR) light into heat. A heat-activated and rapamycin-dependent transgene expression system was incorporated into mesenchymal stem cells to conditionally control the production of bone morphogenetic protein 2 (BMP-2). Genetically engineered cells were entrapped in the photothermal hydrogels. In the presence of rapamycin, photoinduced mild hyperthermia induced the release of BMP-2 from the NIR responsive cell constructs. Transcriptome analysis of BMP-2 expressing cells showed a signature of induced genes related to stem cell proliferation and angiogenesis. We next generated 4 mm diameter calvarial defects in the left parietal bone of immunocompetent mice. The defects were filled with NIR-responsive hydrogels entrapping cells that expressed BMP-2 under the control of the gene circuit. After one and eight days, rapamycin was administered intraperitoneally followed by irradiation with an NIR laser. Ten weeks after implantation, the animals were euthanized and samples from the bone defect zone were processed for histological analysis using Masson's trichrome staining and for immunohistochemistry analyses using specific CD31 and CD105 antibodies. Samples from mice that were only administered rapamycin or vehicle or that were only NIR-irradiated showed the persistence of fibrous tissue bridging the defect. In animals that were treated with rapamycin, NIR irradiation of implants resulted in the formation of new mineralized tissue with a high degree of vascularization, thus indicating the therapeutic potential of the approach.Acknowledgements: This research was supported by grants RTI2018-095159-B-I00 and PID2021-126325OB-I00 (MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe”), by grant P2022/BMD- 7406 (Regional Government of Madrid). M.A.L-J. is the recipient of predoctoral fellowship PRE2019-090430 (MCIN/AEI/10.13039/501100011033).