Origami-Inspired Conductive Paper-Based Folded Pressure Sensor with Interconnection Scaling at the Crease for Novel Wearable Applications.

Drawing inspiration from origami structures, a pressure sensor was developed with unique interconnection scaling at its creases crafted on a conductive paper substrate, paving the way for advanced wearable technology. Two screen-printed conductive paper substrates were combined face-to-face, and specific folds were introduced to optimize the sensor structure. The Electrical Contact Resistance (ECR) was systematically analyzed across different fold numbers and crease gaps, revealing a notable trade-off: while increasing the number of folds expanded the sensing area, it also influenced the ECR, reaching a performance plateau. Strategic modifications in the sensor's design, including refining interconnections at the crease, enhanced its sensitivity and stability, culminating in a remarkable sensitivity of 3.75 kPa-1 at subtle pressure levels (0-0.05 kPa). This sensor's real-world applications proved to be transformative, from detecting bruxism and aiding in neck posture correction to remotely sensing trigger finger locking phenomena, highlighting its potential as a pivotal tool in upcoming medical diagnostics and treatments.

Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex.

OBJECTIVES: Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures. METHODS: A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion. RESULTS: We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis. CONCLUSION: These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.Cite this article: K. Nathan, L. Y. Lu, T. Lin, J. Pajarinen, E. Jämsen, J-F. Huang, M. Romero-Lopez, M. Maruyama, Y. Kohno, Z. Yao, S. B. Goodman. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res 2019;8:481-488. DOI: 10.1302/2046-3758.810.BJR-2018-0231.R2.

Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro.

Cell therapy using bone marrow concentrate (BMC) or purified and expanded mesenchymal stem cells (MSCs) has been shown to have a promising osteogenic capacity. However, few studies have directly compared their relative osteogenic ability. The aim of this study was to compare the osteogenic ability of BMC isolated by density gradient centrifugation with bone marrow-derived MSCs in vitro using the cells of 3-month-old Sprague-Dawley rats. The isolated cells were seeded onto 24-well plates (1 × 105 cells/well) and cultured in control growth media, osteogenic media with dexamethasone, or media without dexamethasone (which simulated the in vivo tissue environment). Alkaline phosphatase activity at week 2, osteocalcin using quantitative real-time polymerase chain reaction at week 4, and Alizarin red staining at week 4 were evaluated. In the osteogenic media with dexamethasone, BMC showed equivalent (osteocalcin) or even greater (Alizarin red staining) osteogenic ability compared to MSCs, suggesting that cross-talk among various cells in the BMC leads to greater osteogenesis. Furthermore, in the osteogenic media without dexamethasone, BMC showed equivalent (osteocalcin) or a trend for greater (Alizarin red staining) bone formation than MSCs alone. Our results suggest that BMC has at least comparable bone regeneration potential to MSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2500-2506, 2019.

Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages.

IMPACT STATEMENT: Pathogen-associated molecular patterns, damage-associated molecular patterns, and other noxious stimuli activate macrophages to induce the proinflammatory responses. Modulation of inflammatory macrophages (M1) into an anti-inflammatory tissue repair macrophage (M2) phenotype at the appropriate time optimizes bone remodeling and regeneration. Simulating the proinflammatory stimuli by using preconditioned mesenchymal stem cells (MSCs) at an earlier stage, and alleviate the inflammation by using IL4-secreting MSCs at a later stage could further optimize bone regeneration in chronic inflammatory conditions, including periprosthetic osteolysis.

Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.

Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen-associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-γ plus TNF-α restimulation-induced iNOS expression as a model of MSC activation, because IFN-γ and TNF-α play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-α, IL-1ß, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.

NFκB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles.

Total joint replacement is a highly effective treatment for patients with end-stage arthritis. Proinflammatory macrophages (M1) mediate wear particle-associated inflammation and bone loss. Anti-inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)-based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of (1) unmodified MSCs, (2) MSCs preconditioned by NFκB stimulating ligands [lipopolysaccharide (LPS) plus TNFα], and (3) genetically modified MSCs that secrete IL-4 as a response to NFκB activation (NFκB-IL4) was compared in a macrophage/MSC co-culture system. Sterile or LPS-contaminated ultra-high molecular weight polyethylene particles were used to induce the proinflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFα, IL1ß, and iNOS), while NFκB-IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg 1 and CD206 high). The IL4 secretion by NFκB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naïve MSCs was negligible when compared with NFκB-IL4 MSC. Our findings indicated that NFκB-IL4 MSCs have the "on-demand" immunomodulatory ability to mitigate wear particle-associated inflammation with minimal adverse effects. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2744-2752, 2018.

Transplanted interleukin-4--secreting mesenchymal stromal cells show extended survival and increased bone mineral density in the murine femur.

BACKGROUND: Mesenchymal stromal cell (MSC)-based therapy has great potential to modulate chronic inflammation and enhance tissue regeneration. Crosstalk between MSC-lineage cells and polarized macrophages is critical for bone formation and remodeling in inflammatory bone diseases. However, the translational application of this interaction is limited by the short-term viability of MSCs after cell transplantation. METHODS: Three types of genetically modified (GM) MSCs were created: (1) luciferase-expressing reporter MSCs; (2) MSCs that secrete interleukin (IL)-4 either constitutively; and (3) MSCs that secrete IL-4 as a response to nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) activation. Cells were injected into the murine distal femoral bone marrow cavity. MSC viability and bone formation were examined in vivo. Cytokine secretion was determined in a femoral explant organ culture model. RESULTS: The reporter MSCs survived up to 4 weeks post-implantation. No difference in the number of viable cells was found between high (2.5 × 106) and low (0.5 × 106) cell-injected groups. Injection of 2.5 × 106 reporter MSCs increased local bone mineral density at 4 weeks post-implantation. Injection of 0.5 × 106 constitutive IL-4 or NFκB-sensing IL-4-secreting MSCs increased bone mineral density at 2 weeks post-implantation. In the femoral explant organ culture model, LPS treatment induced IL-4 secretion in the NFκB-sensing IL-4-secreting MSC group and IL-10 secretion in all the femur samples. No significant differences in tumor necrosis factor (TNF)α and IL-1ß secretion were observed between the MSC-transplanted and control groups in the explant culture. DISCUSSION: Transplanted GM MSCs demonstrated prolonged cell viability when transplanted to a compatible niche within the bone marrow cavity. GM IL-4-secreting MSCs may have great potential to enhance bone regeneration in disorders associated with chronic inflammation.

On the size evolution of monolayer-protected gold clusters during ligand place-exchange reactions: the effect of solvents.

Ligand place-exchange (LPE) reactions are extensively applied for the post-functionalization of monolayer-protected gold clusters (MPCs) by using excessive incoming ligands to displace initial ones. However, the modified MPCs are often enlarged or degraded; this results in ill-defined size-dependent properties. The growth of MPCs essentially involves an unprotected surface that is subsequently has gold atoms added or is fused with other gold cores owing to collision. Reported herein is a guideline for the selection of solvents to suppress unwanted MPC growth. Favorable solvents are those with significant affinity to gold or with low solubility for desorbed ligands because these properties retard LPE reactions and minimize the time available for unprotected gold cores. This finding provides a general and convenient approach to regulate the size of functionalized MPCs.