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Abstract Background Evidence on how to improve daily physical activity (PA) levels following total knee arthroplasty (TKA) or medial uni-compartmental knee arthroplasty (mUKA) by motivational feedback is lacking. Moreover, it is unknown whether a focus on increased PA after discharge from the hospital improves rehabilitation, physical function, and quality of life. The aim of this randomized controlled trial (RCT) nested in a prospective cohort is (a) to investigate whether PA, physical function, and quality of life following knee replacement can be increased using an activity monitoring device including motivational feedback via a patient app in comparison with activity monitoring without feedback (care-as-usual), and (b) to investigate the potential predictive value of PA level prior to knee replacement for the length of stay, return to work, and quality of life. Methods The study is designed as a multicenter, parallel-group, superiority RCT with balanced randomization (1:1) and blinded outcome assessments. One hundred and fifty patients scheduled for knee replacement (TKA or mUKA) will be recruited through Odense University Hospital, Denmark, Vejle Hospital, Denmark and Herlev/Gentofte Sygehus, Denmark. Patients will be randomized to either 12 weeks of activity monitoring and motivational feedback via a patient app by gamification or 'care-as-usual,' including activity monitoring without motivational feedback. The primary outcome is the between-group change score from baseline to 12-week follow-up of cumulative daily accelerometer counts, which is a valid proxy for average objectively assessed daily PA. Discussion Improving PA through motivational feedback following knee replacement surgery might improve post-surgical function, health-related quality of life, and participation in everyday life. Trial registration ClinicalTrials.gov, ID: NCT06005623. Registered on 2023–08-22. Trial status Recruiting.

Abstract The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devise a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies.

Abstract Bone infections are still a major problem in surgery. To avoid severe side effects of systemically administered antibiotics, local antibiotic therapy is increasingly being considered. Using a pressure-based method developed in our group, microporous β-TCP ceramics, which had previously been characterized, were loaded with 2% w/v alginate containing 50 mg/mL clindamycin and 10 µg/mL rhBMP-2. Release experiments were then carried out over 28 days with changes of liquid at defined times (1, 2, 3, 6, 9, 14, 21 and 28d). The released concentrations of clindamycin were determined by HPLC and those of rhBMP-2 by ELISA. Continuous release (anomalous transport) of clindamycin and uniform release (Fick’s diffusion) of BMP-2 were determined. The composites were biocompatible (live/dead, WST-I and LDH) and the released concentrations were all antimicrobially active against Staph. aureus. The results were very promising and clindamycin was detected in concentrations above the MIC as well as a constant rhBMP-2 release over the entire study period. Biocompatibility was also not impaired by either the antibiotic or the BMP-2. This promising approach can therefore be seen as an alternative to the common treatment with PMMA chains containing gentamycin, as the new composite is completely biodegradable and no second operation is necessary for removal or replacement. Graphical Abstract

Abstract Background To evaluate T1ρ relaxation mapping in patients with symptomatic talar osteochondral lesions (OLT) and healthy controls (HC) at rest, with axial loading and traction. Methods Participants underwent 3-T ankle magnetic resonance imaging at rest and with 500 N loading and 120 N traction, without axial traction for a subcohort of 17/29 HC. We used a fast low-angle shot sequence with variable spin-lock intervals for monoexponential T1ρ fitting. Cartilage was manually segmented to extract T1ρ values. Results We studied 29 OLT patients (age 31.7 ± 7.5 years, 15 females, body mass index [BMI] 25.0 ± 3.4 kg/m2) and 29 HC (age 25.2 ± 4.3 years, 17 females, BMI 22.5 ± 2.3 kg/m2. T1ρ values of OLT (50.4 ± 3.4 ms) were higher than those of intact cartilage regions of OLT patients (47.2 ± 3.4 ms; p = 0.003) and matched HC cartilage (48.1 ± 3.3 ms; p = 0.030). Axial loading and traction induced significant T1ρ changes in the intact cartilage regions of patients (loading, mean difference -1.1 ms; traction, mean difference 1.4 ms; p = 0.030 for both) and matched HC cartilage (-2.2 ms, p = 0.003; 2.3 ms, p = 0.030; respectively), but not in the OLT itself (-1.3 ms; p = 0.150; +1.9 ms; p = 0.150; respectively). Conclusion Increased T1ρ values may serve as a biomarker of cartilage degeneration in OLT. The absence of load- and traction-induced T1ρ changes in OLT compared to intact cartilage suggests that T1ρ may reflect altered biomechanical properties of hyaline cartilage. Trial registration DRKS, DRKS00024010. Registered 11 January 2021, https://drks.de/search/de/trial/DRKS00024010 . Relevance statement T1ρ mapping has the potential to evaluate compositional and biomechanical properties of the talar cartilage and may improve therapeutic decision-making in patients with osteochondral lesions. Key Points T1ρ values in osteochondral lesions increased compared to intact cartilage. Significant load- and traction-induced T1ρ changes were observed in visually intact regions and in healthy controls but not in osteochondral lesions. T1ρ may serve as an imaging biomarker for biomechanical properties of cartilage. Graphical Abstract

Abstract Background Antibiotic-containing carrier systems are one option that offers the advantage of releasing active ingredients over a longer period of time. In vitro sustained drug release from a carrier system consisting of microporous β-TCP ceramic and alginate has been reported in previous works. Alginate dialdehyde (ADA) gelatin gel showed both better mechanical properties when loaded into a β-TCP ceramic and higher biodegradability than pure alginate. Methods Dual release of daptomycin and BMP-2 was measured on days 1, 2, 3, 6, 9, 14, 21, and 28 by HPLC and ELISA. After release, the microbial efficacy of the daptomycin was verified and the biocompatibility of the composite was tested in cell culture. Results Daptomycin and the model compound FITC protein A (n = 30) were released from the composite over 28 days. A Daptomycin release above the minimum inhibitory concentration (MIC) by day 9 and a burst release of 71.7 ± 5.9% were observed in the loaded ceramics. Low concentrations of BMP-2 were released from the loaded ceramics over 28 days.

Abstract Background There has long been discussion regarding the impact of medial malleolar osteotomies (MMO) as an adjunctive treatment for osteochondral lesions of the talus (OCLT). MMO may improve the visibility and accessibility of the talus, but they also pose a risk of periprocedural morbidity. There is a lack of research about the prevalence and consequences of MMO in the surgical treatment of OCLT. Methods This study retrospectively evaluated data from the German Cartilage Register (KnorpelRegister DGOU) from its implementation in 2015 to December 2020. The impact of MMO on patient-reported outcome measures (PROMs) was investigated. Wherever possible, subgroups were built and matched using a propensity score which matched a group undergoing OCLT without MMO. Matching included age, sex, weight, localization of the OCLT, the international cartilage repair society (ICRS) grading, surgical procedure and preoperative symptoms using the Foot and Ankle Ability Measure (FAAM) and the Activities of Daily Living Subscale (ADL). Results The prevalence of MMO in the operative treatment of OCLT was 15.9%. Most of the osteotomies were performed in OCL of the medial talar dome (76.8%) and in more serious lesions with an ICRS grade of III (29.1%) and IV (61.4%). More than half of the osteotomies (55.6%) were performed during revision surgery. A matched pair analysis of n = 44 patients who underwent AMIC® via arthrotomy and MMO vs. arthrotomy alone showed no significant differences in patient-reported outcome measures (PROMs, i.e. FAAM-ADL, and FAOS) at 6,12 and 24 months. Conclusions MMO are mostly used in the treatment of severe (≥ ICRS grade 3) OCL of the medial talar dome and in revision surgery. Functional and patient-reported outcome measures are not significantly affected by MMO compared to arthrotomy alone. Trial registration The German Cartilage Register (KnorpelRegister DGOU) was initially registered at the German Clinical Trials Register ( https://www.drks.de , register number DRKS00005617, Date of registration 03.01.2014) and was later expanded by the ankle module.

Purpose: The fixation method of distal, extra-articular femur fractures is a controversially discussed. To ensure better stability itself, earlier mobilization and to prevent blood loss – all these are justifications for addressing the femur via reamed intramedullary nailing (RIMN). Anatomical reposition of multifragmentary fractures followed by increased risks of non-union are compelling reasons against it. The purpose of this study was to systematically review the literature for rates of non-union and wound infection, as well as blood loss and time of surgery. Methods: According to the PRISMA guidelines we conducted this systematic review by searching the Cochrane, PubMed, Ovid, MedLine, and Embase databases. Inclusion criteria were the modified Coleman methodology score (mCMS) >60, age >18 years, and extra-articular fractures of the distal femur. Biomechanical and animal studies were excluded. By referring to title and abstract relevant articles were reviewed independently. In the consecutive meta-analysis, we compared 9 studies and 639 patients. Results: There is no statistically significant difference comparing superficial wound infections when RIMN was performed (OR = 0.50; 95% CI: 0.18 – 1.42; P = 0.19) as well as in deep wound infections (OR = 0.74; 95% CI: 0.19–2.81; P = 0.62). However, these results were not significant. We also calculated for potential differences in the rate of non-unions depending on the surgical treatment applied. Data of 556 patients revealed an overall number of 43 non-unions. There was no significant difference in rate of non-unions between both groups (OR = 0.97; 95% CI: 0.51–1.85; P = 0.92). Conclusion: No statistical difference was found in our study among RIMN and plate fixation in the treatment of distal femoral fractures with regard to the incidence of non-union and wound infections. Therefore, the indication for RIMN or plating should be made individually and based on the surgeon’s experience.

IntroductionIntervertebral disk degeneration is a growing problem in our society. The degeneration of the intervertebral disk leads to back pain and in some cases to a herniated disk. Advanced disk degeneration can be treated surgically with either a vertebral body fusion or a disk prosthesis. Vertebral body fusion is currently considered the gold standard of surgical therapy and is clearly superior to disk prosthesis based on the number of cases. The aim of this work was the 3D printing of Gyroid structures and the determination of their mechanical properties in a biomechanical feasibility study for possible use as an intervertebral disc prosthesis.Material and methodsCreo Parametric 6.0.6.0 was used to create models with various Gyroid properties. These were printed with the Original Prusa i3 MK3s+. Different flexible filaments (TPU FlexHard and TPU FlexMed, extrudr, Lauterach, Austria) were used to investigate the effects of the filament on the printing results and mechanical properties of the models. Characterization was carried out by means of microscopy and tension/compression testing on the universal testing machine.ResultsThe 3D prints with the FlexHard and FlexMid filament went without any problems. No printing errors were detected in the microscopy. The mechanical confined compression test resulted in force-deformation curves of the individual printed models. This showed that changing the Gyroid properties (increasing the wall thickness or density of the Gyroid) leads to changes in the force-deformation curves and thus to the mechanical properties.ConlcusionThe flexible filaments used in this work showed good print quality after the printing parameters were adjusted. The mechanical properties of the discs were also promising. The parameters Gyroid volume, wall thickness of the Gyroid and the outer wall played a decisive role for both FlexMed and FlexHard. All in all, the Gyroid structured discs (Ø 50 mm) made of TPU represent a promising approach with regard to intervertebral disc replacement. We would like to continue to pursue this approach in the future.

Background and purpose: Mortality after major lower extremity amputations is high and may depend on amputation level. We aimed to examine the mortality risk in the first year after major lower extremity amputation divided into transtibial and transfemoral amputations. Methods: This observational cohort study used data from the Danish Nationwide Health registers. 11,205 first-time major lower extremity amputations were included from January 1, 2010, to December 31, 2021, comprising 3,921 transtibial amputations and 7,284 transfemoral amputations. Results: The 30-day mortality after transtibial amputation was overall 11%, 95% confidence interval (CI) 10–12 (440/3,921) during the study period, but declined from 10%, CI 7–13 (37/381) in 2010 to 7%, CI 4–11 (15/220) in 2021. The 1-year mortality was 29% overall, CI 28–30 (1,140 /3,921), with a decline from 31%, CI 21–36 (117/381) to 20%, CI 15–26 (45/220) during the study period. For initial transfemoral amputation, the 30-day mortality was overall 23%, CI 22–23 (1,673/7,284) and declined from 27%, CI 23–31 (138/509) to 22%, CI 19–25 (148/683) during the study period. The 1-year mortality was 48% overall, CI 46–49 (3,466/7,284) and declined from 55%, CI 50–59 (279/509) to 46%, CI 42–50 (315/638). Conclusion: The mortality after major lower extremity amputation declined in the 12-year study period; however, the 1-year mortality remained high after both transtibial and transfemoral amputations (20% and 46% in 2021). Hence, major lower extremity amputation patients constitute one of the most fragile orthopedic patient groups, emphasizing an increased need for attention in the pre-, peri-, and postoperative setting.

The core/shell 3D printing process using CPC and alginate is intended to create biodegradable scaffolds that have a similar stability to bone tissue and also offer sufficient and continuous antibiotic release. In this way, a patient-specific and patient-friendly process will be established, which should optimally support the human organism in its regeneration. To generate the best possible strength values, the printed scaffolds underwent various post-treatments and were then tested in a material test. The test methods included self-setting, storage in a drying cabinet with a water-saturated atmosphere at 37°C, followed by incubation in PBS, freeze-drying, and coating the samples with alginate. Additionally, a degradation test at pH 7.4 and pH 5 was carried out to test stability under in vitro conditions. It was shown that the untreated and freeze-dried samples failed at a maximum load of 30–700 N, while the remaining scaffolds could withstand a load of at least 2,000 N. At this failure load, most of the test series showed an average deformation of 43.95%. All samples, therefore, remained below the strength of cancellous bone. However, based on a 20% load after surgery, the coated scaffolds represented the best possible alternative, with a Young’s modulus of around 1.71 MPa. We were able to demonstrate that self-setting occurs in core-shell printed CPC/alginate scaffolds after only 1 day, and that mass production is possible. By coating with alginate, the compressive strength could be increased without the need for additional post-treatment. The mechanical strength was sufficient to be available as a scaffold for bone regeneration and additionally as a drug delivery device for future applications and experiments.

Goal: We introduce an in-vivo validated finite element (FE) simulation approach for predicting individual knee joint kinematics. Our vision is to improve clinicians' understanding of the complex individual anatomy and potential pathologies to improve treatment and restore physiological joint kinematics. Methods: Our 3D FE modeling approach for individual human knee joints is based on segmentation of anatomical structures extracted from routine static magnetic resonance (MR) images. We validate the predictive abilities of our model using static MR images of the knees of eleven healthy volunteers in dedicated knee poses, which are achieved using a customized MR-compatible pneumatic loading device. Results: Our FE simulations reach an average translational accuracy of 2 mm and an average angular accuracy of 1$^\circ$ compared to the reference knee pose. Conclusions: Reaching high accuracy, our individual FE model can be used in the decision-making process to restore knee joint stability and functionality after various knee injuries.

Abstract Background Patellar fractures have a comparatively low incidence compared to all fracture frequencies of the musculoskeletal system. However, surgical management is crucial to prevent postoperative complications that affect the knee joint. The purpose of the present study was to evaluate the incidence of postoperative complications and onset of postoperative osteoarthritis related to the chosen technique of patellar fracture management. Methods In a retrospective cohort study consecutive managed, isolated patella fractures were reviewed for demographic data, trauma mechanism, patella fracture type, fixation technique and postoperative complications. The results were documented radiographically and clinically and analysed statistically. The reporting followed the STROBE guidelines. Results A total of 112 patients were eligible for data evaluation. Surgical management of comminuted patellar fractures with small fragment screws showed significant fewer postoperative complications compared to other fixation techniques (8%, p

The aim of the study was to compare conventional sintering with additive manufacturing techniques for β-TCP bioceramics, focusing on mechanical properties and biocompatibility. A “critical” bone defect requires surgical intervention beyond simple stabilization. Autologous bone grafting is the gold standard treatment for such defects, but it has its limitations. Alloplastic bone grafting with synthetic materials is becoming increasingly popular. The use of bone graft substitutes has increased significantly, and current research has focused on optimizing these substitutes, whereas this study compares two existing manufacturing techniques and the resulting β-TCP implants. The 3D printed β-TCP hybrid structure implant was fabricated from two components, a column structure and a freeze foam, which were sintered together. The conventionally fabricated ceramics were fabricated by casting. Both scaffolds were characterized for porosity, mechanical properties, and biocompatibility. The hybrid structure had an overall porosity of 74.4 ± 0.5%. The microporous β-TCP implants had a porosity of 43.5 ± 2.4%, while the macroporous β-TCP implants had a porosity of 61.81%. Mechanical testing revealed that the hybrid structure had a compressive strength of 10.4 ± 6 MPa, which was significantly lower than the microporous β-TCP implants with 32.9 ± 8.7 MPa. Biocompatibility evaluations showed a steady increase in cell proliferation over time for all the β-TCP implants, with minimal cytotoxicity. This study provides a valuable insight into the potential of additive manufacturing for β-TCP bioceramics in the treatment of bone defects.

Three parameters are important to characterize a circadian and in general any biological clock: period, phase and amplitude. While circadian periods have been shown to correlate with entrainment phases, and clock amplitude influences the phase response of an oscillator to pulse-like zeitgeber signals, the co-modulations of amplitude and periods, which we term twist, have not been studied in detail. In this paper we define two concepts: parametric twist refers to amplitude-period correlations arising in ensembles of self-sustained, limit cycle clocks in the absence of external inputs, and phase space twist refers to the co-modulation of an individual clock’s amplitude and period in response to external zeitgebers. Our findings show that twist influences the interaction of oscillators with the environment, facilitating entrainment, speeding upfastening recovery to pulse-like perturbations or modifying the response of an individual clock to coupling. This theoretical framework might be applied to understand the emerging properties of other oscillating systems.

Three parameters are important to characterize a circadian and in general any biological clock: period, phase and amplitude. While circadian periods have been shown to correlate with entrainment phases, and clock amplitude influences the phase response of an oscillator to pulse-like zeitgeber signals, the co-modulations of amplitude and periods, which we term twist, have not been studied in detail. In this paper we define two concepts: parametric twist refers to amplitude-period correlations arising in ensembles of self-sustained, limit cycle clocks in the absence of external inputs, and phase space twist refers to the co-modulation of an individual clock’s amplitude and period in response to external zeitgebers. Our findings show that twist influences the interaction of oscillators with the environment, facilitating entrainment, speeding upfastening recovery to pulse-like perturbations or modifying the response of an individual clock to coupling. This theoretical framework might be applied to understand the emerging properties of other oscillating systems.