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1. Porous Scaffold-Hydrogel Composites Spatially Regulate 3D Cellular Mechanosensing

   https://doi.org/10.3389/fmedt.2022.884314  

   DiCerbo, Matthew ; Benmassaoud, Mohammed Mehdi ; Vega, Sebastián L. ( May 2022 , Frontiers in Medical Technology)

   Cells encapsulated in 3D hydrogels exhibit differences in cellular mechanosensing based on their ability to remodel their surrounding hydrogel environment. Although cells in tissue interfaces feature a range of mechanosensitive states, it is challenging to recreate this in 3D biomaterials. Human mesenchymal stem cells (MSCs) encapsulated in methacrylated gelatin (GelMe) hydrogels remodel their local hydrogel environment in a time-dependent manner, with a significant increase in cell volume and nuclear Yes-associated protein (YAP) localization between 3 and 5 days in culture. A finite element analysis model of compression showed spatial differences in hydrogel stress of compressed GelMe hydrogels, and MSC-laden GelMemore »hydrogels were compressed (0–50%) for 3 days to evaluate the role of spatial differences in hydrogel stress on 3D cellular mechanosensing. MSCs in the edge (high stress) were significantly larger, less round, and had increased nuclear YAP in comparison to MSCs in the center (low stress) of 25% compressed GelMe hydrogels. At 50% compression, GelMe hydrogels were under high stress throughout, and this resulted in a consistent increase in MSC volume and nuclear YAP across the entire hydrogel. To recreate heterogeneous mechanical signals present in tissue interfaces, porous polycaprolactone (PCL) scaffolds were perfused with an MSC-laden GelMe hydrogel solution. MSCs in different pore diameter (~280–430 μm) constructs showed an increased range in morphology and nuclear YAP with increasing pore size. Hydrogel stress influences MSC mechanosensing, and porous scaffold-hydrogel composites that expose MSCs to diverse mechanical signals are a unique biomaterial for studying and designing tissue interfaces.« less
2. Modulus of Fibrous Collagen at the Length Scale of a Cell

   https://doi.org/10.1007/s11340-018-00453-4  

   Proestaki, M. ; Ogren, A. ; Burkel, B. ; Notbohm, J. ( January 2019 , Experimental Mechanics)

   The extracellular matrix provides macroscale structural support to tissues as well as microscale mechanical cues, like stiffness, to the resident cells. As those cues modulate gene expression, proliferation, differentiation, and motility, quantifying the stiffness that cells sense is crucial to understanding cell behavior. Whereas the macroscopic modulus of a collagen network can be measured in uniform extension or shear, quantifying the local stiffness sensed by a cell remains a challenge due to the inhomogeneous and nonlinear nature of the fiber network at the scale of the cell. To address this challenge, we designed an experimental method to measure the modulusmore »of a network of collagen fibers at this scale. We used spherical particles of an active hydrogel (poly N-isopropylacrylamide) that contract when heated, thereby applying local forces to the collagen matrix and mimicking the contractile forces of a cell. After measuring the particles’ bulk modulus and contraction in networks of collagen fibers, we applied a nonlinear model for fibrous materials to compute the modulus of the local region surrounding each particle. We found the modulus at this length scale to be highly heterogeneous, with modulus varying by a factor of 3. In addition, at different values of applied strain, we observed both strain stiffening and strain softening, indicating nonlinearity of the collagen network. Thus, this experimental method quantifies local mechanical properties in a fibrous network at the scale of a cell, while also accounting for inherent nonlinearity.« less
3. Developing Bioactive-Nanograined Metals With Bacterial Biofilm Inhibition Properties For Orthopedic Devices

   Kelkar, Shaunak ; Saleh, Bahram ; Yusa, Fumie ; Suzuki, Yohei ; Komatsu, Takafumi ; Webster, Thomas ( January 2021 , Orthopaedic Research Society)

   INTRODUCTION: Orthopedic implants are important therapeutic devices for the management of a wide range of orthopedic conditions. However, bacterial infections of orthopedic implants remain a major problem, and not an uncommon one, leading to an increased rate of osteomyelitis, sepsis, implant failure and dysfunction, etc. Treating these infections is more challenging as the causative organism protects itself by the production of a biofilm over the implant’s surface (1). Infections start by the adhesion and colonization of pathogenic bacteria such as Staphylococcus aureus (SA), Staphylococcus epidermidis (SE), Escherichia coli (E. coli), Methicillin-Resistant Staphylococcus aureus (MRSA), and Multi-Drug Resistant Escherichia coli (MDRmore »E. coli) on the implant’s surfaces. Specifically, Staphylococcus comprises up to two-thirds of all pathogens involved in orthopedic implant infections (2). However, bacterial surface adhesion is a complex process influenced by several factors such as chemical composition, hydrophobicity, magnetization, surface charge, and surface roughness of the implant (3). Considering the intimate association between bacteria and the implant surface, we measured the effect of stainless-steel surface properties on bacterial surface attachment and subsequent formation of biofilms controlling above mentioned factors. METHODS: The prominent bacteria responsible for orthopedic implant infections (SA, SE, E. coli, MRSA, and MDR E. coli) were used in this study. We were able to control the grain size of medical grade 304 and 316L stainless steel without altering their chemical composition (grain size range= 20μm-200nm) (4). Grain size control affected the nano-topography of the material surfaces which was measured by an Atomic Force Microscope (AFM). Grain sizes, such as 0.2, 0.5, 1, 2, 3, 9, and 10 μm, were used both polished and non-polished. All the stainless-steel samples were cleaned by treating with acetone and ethanol under sonication. Triplicates of all polished and non-polished samples with different grain sizes were subjected to magnetization of DM, 0.1T, 0.5T, and 1T, before seeding them with the bacteria. Controls were used in the form of untreated samples. Bacterial were grown in Tryptic Soy Broth (TSB). An actively growing bacterial suspension was seeded onto the stainless-steel discs into 24-well micro-titer plates and kept for incubation. After 24 hours of incubation, the stainless-steel discs were washed with Phosphate Buffer Saline (PBS) to remove the plankton bacteria and allow the sessile bacteria in the biofilm to remain. The degree of development of the bacterial biofilms on the stainless-steel discs were measured using spectrophotometric analysis. For this, the bacterial biofilm was removed from the stainless steel by sonication. The formation of biofilms was also determined by performing a biofilm staining method using Safranin. RESULTS SECTION: AFM results revealed a slight decrease in roughness by decreasing the grain size of the material. Moreover, the samples were segregated into two categories of polished and non-polished samples, in which polishing decreased roughness significantly. After careful analysis we found out that polished surfaces showed a higher degree for biofilm formation in comparison to the non-polished ones. We also observed that bacteria showed a higher rate for biofilm formation for the demagnetized samples, whereas 0.5T magnetization showed the least amount of biofilm formation. After 0.5T, there was no significant change in the rate of biofilm formation on the stainless-steel samples. Altogether, stainless steel samples containing 0.5 μm and less grainsize, and magnetized with 0.5 tesla and stronger magnets demonstrated the least degree of biofilm formation. DISCUSSION: In summary, the results demonstrate that controlling the grain size of medical grade stainless steel can control and mitigate bacterial responses on, and thus possibly infections of, orthopedic implants or other implantable devices. The research was funded by Komatsuseiki Kosakusho Co., Ltd (KSJ: Japan) SIGNIFICANCE/CLINICAL RELEVANCE: Orthopedic implants that more than 70% of them are made of metals (i.e., stainless steel, titanium, and cobalt-chromium alloys) are failing through loosening and breakage due to their limited mechanical properties. On the other hand, the risk of infection for these implants and its financial burden on our society is undeniable. We have seen that our uniformly nanograined stainless steel shows improved mechanical properties (i.e., higher stiffness, hardness, fatigue) as compared to conventional stainless steel along with the reduction of biofilm formation on its surface. These promising results made us to peruse the development of nanograined titanium and cobalt-chromium alloys for resolving the complications of orthopedic implants.« less
4. A Model for Studying the Biomechanical Effects of Varying Ratios of Collagen Types I and III on Cardiomyocytes

   https://doi.org/https://doi.org/10.1007/s13239-020-00514-7  

   Roman, Brian ; Kumar, Shweta. A ; Allen, Shane C ; Delgado, Monica ; Moncayo, Sabastian ; Reyes, Andres M. ; Suggs, Laura J ; Chintalapalle, Ramana. ; Li, Chunqiang Q ; Joddar, Binata. ( June 2021 , Cardiovascular engineering and technology)

   null (Ed.)

   Purpose To develop a novel model composed solely of Col I and Col III with the lower and upper limits set to include the ratios of Col I and Col III at 3:1 and 9:1 in which the structural and mechanical behavior of the resident CM can be studied. Further, the progression of fibrosis due to change in ratios of Col I:Col III was tested. Methods Collagen gels with varying Col I:Col III ratios to represent a healthy (3:1) and diseased myocardial tissue were prepared by manually casting them in wells. Absorbance assay was performed to confirm the gelation ofmore »the gels. Rheometric analysis was performed on each of the collagen gels prepared to determine the varying stiffnesses and rheological parameters of the gels made with varying ratios of Col I:Col III. Second Harmonic Generation (SHG) was performed to observe the 3D characterization of the collagen samples. Scanning Electron microscopy was used for acquiring cross sectional images of the lyophilized collagen gels. AC16 CM (human) cell lines were cultured in the prepared gels to study cell morphology and behavior as a result of the varying collagen ratios. Cellular proliferation was studied by performing a Cell Trace Violet Assay and the applied force on each cell was measured by means of Finite Element Analysis (FEA) on CM from each sample. Results Second harmonic generation microscopy used to image Col I, displayed a decrease in acquired image intensity with an increase in the non-second harmonic Col III in 3:1 gels. SEM showed a fiber-rich structure in the 3:1 gels with well-distributed pores unlike the 9:1 gels or the 1:0 controls. Rheological analysis showed a decrease in substrate stiffness with an increase of Col III, in comparison with other cases. CM cultured within 3:1 gels exhibited an elongated rod-like morphology with an average end-to-end length of 86 ± 28.8 µm characteristic of healthy CM, accompanied by higher cell growth in comparison with other cases. Finite element analysis used to estimate the forces exerted on CM cultured in the 3:1 gels, showed that the forces were well dispersed, and not concentrated within the center of cells, in comparison with other cases. Conclusion This study model can be adopted to simulate various biomechanical environments in which cells crosstalk with the Collagen-matrix in diseased pathologies to generate insights on strategies for prevention of fibrosis.« less
5. Evaluating the Role of Breathing Guidance on Game-Based Interventions for Relaxation Training

   https://doi.org/10.3389/fdgth.2021.760268  

   Gummidela, Venkata Nitin ; Silva, Dennis R. ; Gutierrez-Osuna, Ricardo ( December 2021 , Frontiers in Digital Health)

   Working in a fast-paced environment can lead to shallow breathing, which can exacerbate stress and anxiety. To address this issue, this study aimed to develop micro-interventions that can promote deep breathing in the presence of stressors. First, we examined two types of breathing guides to help individuals learn deep breathing: providing their breathing rate as a biofeedback signal, and providing a pacing signal to which they can synchronize their breathing. Second, we examined the extent to which these two breathing guides can be integrated into a casual game, to increase enjoyment and skill transfer. We used a 2 × 2more »factorial design, with breathing guide (biofeedback vs. pacing) and gaming (game vs. no game) as independent factors. This led to four experimental groups: biofeedback alone, biofeedback integrated into a game, pacing alone, and pacing integrated into a game. In a first experiment, we evaluated the four experimental treatments in a laboratory setting, where 30 healthy participants completed a stressful task before and after performing one of the four treatments (or a control condition) while wearing a chest strap that measured their breathing rate. Two-way ANOVA of breathing rates, with treatment (5 groups) and time (pre-test, post-test) as independent factors shows a significant effect for time [ F (4, 50) = 18.49, p < 0.001, η t i m e 2 = 0 . 27 ] and treatment [ F (4, 50) = 2.54, p = 0.05, η 2 = 0.17], but no interaction effects. Post-hoc t-tests between pre and post-test breathing rates shows statistical significance for the game with biofeedback group [ t (5) = 5.94, p = 0.001, d = 2.68], but not for the other four groups, indicating that only game with biofeedback led to skill transfer at post-test. Further, two-way ANOVA of self-reported enjoyment scores on the four experimental treatments, with breathing guide and game as independent factors, found a main effect for game [ F ( 1 , 20 ) = 24 . 49 , p < 0 . 001 ,   η g a m e 2 = 0 . 55 ], indicating that the game-based interventions were more enjoyable than the non-game interventions. In a second experiment, conducted in an ambulatory setting, 36 healthy participants practiced one of the four experimental treatments as they saw fit over the course of a day. We found that the game-based interventions were practiced more often than the non-game interventions [ t (34) = 1.99, p = 0.027, d = 0.67]. However, we also found that participants in the game-based interventions could only achieve deep breathing 50% of the times, whereas participants in the non-game groups succeeded 85% of the times, which indicated that the former need adequate training time to be effective. Finally, participant feedback indicated that the non-game interventions were better at promoting in-the-moment relaxation, whereas the game-based interventions were more successful at promoting deep breathing during stressful tasks.« less