Dag Wulsten

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic extracellular matrix (ECM) that contributes to tumor progression, therapeutic resistance, and poor patient survival. However, the relationship between in vivo imaging-derived mechanical properties, ex vivo tissue biomechanics, ECM architecture, and cellularity remains incompletely understood. Here, we combined pre-operative in vivo clinical magnetic resonance elastography (MRE) with ex vivo biomechanical testing of fresh human PDAC tissue and histopathological analyses. Nine patients undergoing pancreatic resection were prospectively enrolled. Quantitative MRE was performed pre-operatively to assess tissue stiffness through shear wave speed (c) and relative viscosity or fluidity through the loss angle (φ). Fresh tumor and adjacent non-malignant tissue biopsies were subsequently analyzed ex vivo by unconfined uniaxial compression testing to determine elastic moduli and stress relaxation halftime. Histological analyses quantified collagen-rich fibrous tissue area, cell nuclei density, and nuclear morphology. Tumor tissue exhibited significantly increased stiffness and collagen fraction compared with adjacent non-malignant tissue, together with reduced cellularity, smaller nuclear area and more elongated nuclei. Ex vivo stiffness positively correlated with collagen content and negatively correlated with patient survival. Reduced stress relaxation halftime, indicative of increased tissue viscosity, was associated with lower cellularity and elongated nuclei. Importantly, pre-operative MRE parameters of the intact surrounding environment correlated significantly with ex vivo tumor mechanics, cellular organization, and survival. Specifically, a softer and less viscous surrounding environment was associated with stiffer and more viscous tumors, with lower cellularity and elongated nuclei, and poorer prognosis. These findings demonstrate that MRE-derived mechanical biomarkers reflect underlying ECM remodeling and tumor mechanobiology in PDAC. Integrating in vivo imaging with ex vivo tissue mechanics and histopathology may improve non-invasive disease characterization and support biomechanically-informed therapeutic strategies.

Biological bioprostheses such as grafts, patches, and heart valves are often derived from biological tissue like the pericardium. These bioprostheses can be of xenogenic, allogeneic, or autologous origin. Irrespective of their origin, all types are pre-treated via crosslinking to render the tissue non-antigenic and mechanically strong or to minimize degradation. The most widely used crosslinking agent is glutaraldehyde. However, glutaraldehyde-treated tissue is prone to calcification, inflammatory degradation, and mechanical injury, and it is incapable of matrix regeneration, leading to structural degeneration over time. In this work, we are investigating an alternative crosslinking method for an intraoperative application. The treated tissue‘s crosslinking degree was evaluated by differential scanning calorimetry. To confirm the findings, a collagenase assay was conducted. Uniaxial tensile testing was used to assess the tissue’s mechanical properties. To support the findings, the treated tissue was visualized using two-photon microscopy. Additionally, fourier transform infrared spectroscopy was performed to study the overall protein secondary structure. Finally, a crosslinking procedure was identified for intraoperative processing. The samples showed a significant increase in thermal and enzymatic stability after treatment compared to the control, with a difference of up to 22.2 °C and 100%, respectively. Also, the tissue showed similar biomechanics to glutaraldehyde-treated tissue, showing greater extensibility, a higher failure strain, and a lower ultimate tensile strength than the control. The significant difference in the structure band ratio after treatment is proof of the introduction of additional crosslinks compared to the untreated control with regard to differences in the amide-I region. The microscopic images support these findings, showing an alteration of the fiber orientation after treatment. For collagen-based biomaterials, such as pericardial tissue, the novel phenolic crosslinking agent proved to be an equivalent alternative to glutaraldehyde regarding tissue characteristics. Although long-term studies must be performed to investigate superiority in terms of longevity and calcification, our novel crosslinking agent can be applied in concentrations of 1.5% or 2.0% for the treatment of biomaterials.

Bite force measuring devices that are generally suitable for edentulous patients or patients undergoing mandibular reconstruction are missing. This study assesses the validity of a new bite force measuring device (prototype of loadpad^®, novel GmbH) and evaluates its feasibility in patients after segmental mandibular resection. Accuracy and reproducibility were analyzed with two different protocols using a universal testing machine (Z010 AllroundLine, Zwick/Roell, Ulm, Germany). Four groups were tested to evaluate the impact of silicone layers around the sensor: no silicone (“pure”), 2.0 mm soft silicone (“2-soft”), 7.0 mm soft silicone (“7-soft”) and 2.0 mm hard silicone (“2-hard”). Thereafter, the device was tested in 10 patients prospectively who underwent mandibular reconstruction using a fibula free flap. Average relative deviations of the measured force in relation to the applied load reached 0.77% (“7-soft”) to 5.28% (“2-hard”). Repeated measurements in “2-soft” revealed a mean relative deviation of 2.5% until an applied load of 600 N. Maximum bite force decreased postoperatively by 51.8% to a maximum mean bite force of 131.5 N. The novel device guarantees a high accuracy and degree of reproducibility. Furthermore, it offers new opportunities to quantify perioperative oral function after reconstructive surgery of the mandible also in edentulous patients.

In fractures of the mandible, osteosynthesis with titanium plates is considered the gold standard. Titanium is an established and reliable material, its main disadvantages being metal artefacts and the need for removal in case of osteosynthesis complications. Magnesium, as a resorbable material with an elastic modulus close to cortical bone, offers a resorbable alternative osteosynthesis material, yet mechanical studies in mandible fracture fixation are still missing. The hypothesis of this study was that magnesium miniplates show no significant difference in the mechanical integrity provided for fracture fixation in mandible fractures under load-sharing indications. In a non-inferiority test, a continuous load was applied to a sheep mandible fracture model with osteosynthesis using either titanium miniplates of 1.0 mm thickness (Ti1.0), magnesium plates of 1.75 mm (Mg1.75), or magnesium plates of 1.5 mm thickness (Mg1.5). No significant difference (p > 0.05) was found in the peak force at failure, stiffness, or force at vertical displacement of 1.0 mm between Mg1.75, Mg1.5, and Ti1.0. This study shows the non-inferiority of WE43 magnesium miniplates compared to the clinical gold standard titanium miniplates.

Resumo: Objetivo Este estudo avaliou diferenças entre parafusos com rosca total ou parcial na resistência à compressão interfragmentar inicial. Nossa hipótese era de que haveria maior perda de resistência à compressão inicial com o parafuso de rosca parcial. Métodos Uma linha de fratura oblíqua de 45 graus foi criada em amostras de osso artificial. O primeiro grupo (TOTAL, n = 6) foi fixado com um parafuso de 3,5 mm de rosca total, enquanto o segundo grupo (PARCIAL, n = 6) usou um parafuso de 3,5 mm de rosca parcial. Avaliamos a rigidez à torção em ambas as direções de rotação. Os grupos foram comparados com base nos seguintes parâmetros biomecânicos: momento de rigidez-ângulo, momento de rigidez-tempo, momento de torção máxima (carga de falha) e força de compressão calibrada com base na medida do sensor de pressão. Resultados Depois da perda de uma amostra PARCIAL, não foram observadas diferenças estatisticamente significativas na força de compressão calibrada entre os 2 grupos [mediana (intervalo interquartil)]: TOTAL: 112,6 (10,5) N e PARCIAL: 106,9 (7,1) N, com p = 0,8 segundo o teste U de Mann-Whitney). Além disso, após a exclusão de 3 amostras para testes mecânicos (TOTAL, n = 5, PARCIAL, n = 4), não foram observadas diferenças estatisticamente significativas entre os construtos TOTAL e PARCIAL quanto ao momento de rigidez-ângulo, momento de rigidez-tempo ou momento de torção máxima (carga de falha). Conclusão Não há diferença aparente na força de compressão inicial (força de compressão ou rigidez do construto ou carga de falha) com o uso de parafusos de rosca total ou parcial neste modelo biomecânico em osso artificial de alta densidade. Parafusos de rosca total podem, portanto, ser mais úteis no tratamento de fraturas diafisárias. Mais pesquisas são necessárias sobre o impacto em modelos ósseos osteoporóticos ou metafisários de menor densidade e avaliação do significado clínico.

In recent years, an increase in periprosthetic femur fractures has become apparent due to the increased number of hip replacements. In the case of Vancouver type B1 fractures, locking plate systems offer safe procedures. This study compared the distal lateral femur plate (LOQTEQ^®, aap Implantate AG) with a standard L.I.S.S. LCP^® (DePuy Synthes) regarding their biomechanical properties in fixation of periprosthetic femur fractures after hip arthroplasty. We hypothesized that the new LOQTEQ system has superior stability and durability in comparison. Eighteen artificial left femurs were randomized in two groups (Group A: LOQTEQ^®; Group B: L.I.S.S. LCP^®) and tested until failure. Failure was defined as 10° varus deformity and catastrophic implant failure (loosening, breakage, progressive bending). Axial stiffness, loads of failure, cycles of failure, modes of failure were recorded. The axial stiffness in Group A with 73.4 N/mm (SD +/− 3.0) was significantly higher (p = 0.001) than in Group B (40.7 N/mm (SD +/− 2.8)). Group A resists more cycles than Group B until 10° varus deformity. Catastrophic failure mode was plate breakage in Group A and bending in Group B. In conclusion, LOQTEQ^® provides higher primary stability and tends to have higher durability.

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1^mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1/2 phosphorylation in females vs. males, demonstrating a greater activation of TGFβ signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches.

Bioactive coatings have the potential to improve the bony integration of mechanically loaded orthopedic ceramic implants. Using the concept of mimicking the natural bone surface, four different coatings of varying thickness on a zirconia toughened alumina (ZTA) ceramic implant were investigated regarding their osseointegration in a drill-hole model in sheep. The hypothesis that a bioactive coating of ZTA ceramics would facilitate cancellous bone integration was investigated. The bioactive coatings consisted of either a layer of covalently bound multi phosphonate molecules (chemical modification = CM), a nano hydoxyapatite coating (HA), or two different bioactive glass (BG) coatings in micrometer thickness, forming a hydroxyl-carbonate apatite layer on the implant surface in vivo (dip-coated 45S5 = DipBG; sol-gel 70S30C = SGBG). Coated surfaces were characterized by scanning electron microscopy and X-ray photoelectron spectroscopy. After 12 weeks, osseointegration was evaluated via mechanical push-out testing and histology. HA enhanced the maximum push-out force (HA: mean 3573.85 ± 1119.91 N; SGBG: mean 1691.57 ± 986.76 N; p = 0.046), adhesive shear strength (HA: mean 9.82 ± 2.89 MPA; SGBG: mean 4.57 ± 2.65 MPA; p = 0.025), and energy release rate (HA: mean 3821.95 ± 1474.13 J/mm²; SGBG: mean 1558.47 ± 923.47 J/mm²; p = 0.032) compared to SGBG. The implant-bone interfacial stiffness increased by CM compared to SGBG coating (CM: mean 6258.06 ± 603.80 N/mm; SGBG: mean 3565.57 ± 1705.31 n/mm; p = 0.038). Reduced mechanical osseointegration of SGBG coated implants could be explained histologically by a foreign body reaction surrounding the implants.

To compare the mechanical strength of antegrade versus retrograde lag screw fixation of anterior column acetabular fractures.