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Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffusive tumor-infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to tumor core was also found in human GBM. The levels of VEGF and VEGFR2 showed a spatial correlation with the extent of vascular abnormality spanning the tumor invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in invasion-associated vascular transition. As ANGPT2 was expressed only in a portion of the central tumor vessels, we developed a ligand-independent Tie2-activating antibody that can phosphorylate Tie2 in vivo. This agonistic Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition spatio-temporally associates with GBM invasion and may be controlled by Tie2 activation with a novel mechanism-of-action.

Purpose: We investigated the pharmacology of PMC-309 in ex vivo or in vivo characterization for the development of the preclinical study. Experimental procedures: Target selectivity: it was measured by SPR assay. Human VISTA expressing CHO k1 cells or CHO k1 mock cells were used in cell binding assay. Target cell analysis: human peripheral blood mononuclear cells (PBMC) containing lymphocyte and myeloid lineage cells were used for target cells analysis with flow cytometry. In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity (IRB #1041107-201703-BR-002-02) and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38 bearing human VISTA knock-in (KI) mice were employed for the assessment of anti-tumor activity of PMC-309. The tumor infiltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or flow cytometry (FACS) analysis. Statistics: All data were presented as the mean ± SEM and analyzed using one-way ANOVA followed by Dunnett’s multiple comparison tests in Graph pad prism®. ***p Summary of data: PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage that stimulates proinflammatory cytokine secretion of T cells. For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed in accompanied by a synergistic effect with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis. Conclusions: PMC-309 is a fully human anti-VISTA antibody that targets human VISTA specifically. PMC-309 enhanced both T cell activation and monocyte activation when monocytes were cultured with or without T cells by targeting VISTA. PMC-309 increased the number of T cell infiltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address highly medical unmet needs from patients with drug resistance to currently available IO treatment options. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Hyerim Han, Weon Sup Lee. PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5557.

Purpose: The delivery of drugs and immune cells into the tumor microenvironment is limited due to abnormal tumor vessel which is characterized as low oxygen concentration, low perfusion rate and leakage. It leads to diminish the efficacy radiation therapy. Traditional anti-angiogenesis strategies attempt to reduce the tumor vascular supply, but their success is restricted by insufficient efficacy or development of resistance. To solve the problem, we try to using PMC-403, which can normalize the abnormal condition of tumor vessel. Experimental procedures: Target selectivity: It was measured by Surface Plasmon Resonance (SPR) assay. Human TIE2 Cho-K1 cells or mouse TIE2 Cho-K1 cells were tested for species cross-reactive assay based on flow cytometry (FACS).In vitro studies: Human umbilical vein endothelial cells (HUVEC) were used for TIE2 signal pathway analysis with western blot assay and efficacy analysis with VEGF-induced vessel permeability assay.In vivo study: Glioblastoma model mice were employed for the assessment of tumor vessel normalizing activity of 1 mg/mouse PMC-403. CT26 colon cancer model mice were used to evaluate the anti-tumor efficacy of PMC403 (10 mg/kg) in combination with radiation therapy. Hypoxyprobe was used to measure the improvement of hypoxic conditions in tumor tissue. Summary of data: PMC-403 has a nanomolar range of affinity for both human or mouse TIE2 expressing cells. This contributed to dose-dependent ANG1-like TIE2 and FOXO1 phosphorylation and inhibited VEGF-induced vascular leakage, thereby contributing to ANG1-like vascular normalization. Moreover, similar to ANG-1, p-VEGFR2 and p-VE-Cadherin levels were significantly reduced by PMC-403, suggesting that PMC-403 can normalize blood vessels. In addition, PMC-403 stabilized abnormal tumor blood vessels in the glioblastoma mouse model and significantly reduced tumor growth and tumor hypoxia in the combination treatment (PMC-403 + radiation therapy) compared to radiation therapy alone, although the antitumor effect of PMC-403 alone was not effective in the same condition model. Conclusions: PMC-403, an anti-TIE2 monoclonal antibody, is a novel tumor vessel stabilizer. PMC-403 improved tumor microenvironment hypoxic condition that synergized with radiotherapy when it combined together for the anticancer therapy. These data strongly support the notion that PMC-403 can effectively treat tumors even with low doses of radiation by stabilizing tumor blood vessels. Citation Format: Eun-Ah Lee, Beom Yong Park, Nuri Kang, Cheon Ho Park, Weon Sup Lee. Tumor vessel normalization by a novel anti-TIE2 antibody PMC-403 enhances the effectiveness of radiation therapy on cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5970.

In this study, the fabrication process of a piezoelectric poly[(vinylidenefluoride-trifluoroethylene) [P(VDF-TrFE)] film was optimized to maximize its crystallinity and piezoelectric properties and to improve its thermal stability. The effect of purification of P(VDF-TrFE) solution dissolved in methyl ethyl ketone [MEK] and uniaxial stretching on the properties and performance of P(VDF-TrFE) film was studied. In the purification process, the solution was filtered with a syringe filter with 2.7 μm pores. X-ray diffraction measurements showed that the stretching and purification processes increased the crystallinity of the P(VDF-TrFE) films by approximately 16.2% and 2.2%, respectively. A high-temperature storage test showed that the unstretched P(VDF-TrFE) films lose most of their polarization after 1-h storage at 70 °C. The stretching process greatly increased the thermal stability of the films so that the purified and stretched P(VDF-TrFE) films exhibited a small variation within 6% in the piezoelectric strain constant (d33) for 96 h at 70 °C. Ultrasonic transducers (UTs) were also fabricated with the purified and stretched P(VDF-TrFE) films. The pulse-echo measurement showed that the sensitivity and bandwidth of the UTs increased by 4.5 dB and decreased by 24.3%, respectively, compared to UTs fabricated with the purified P(VDF-TrFE) film without stretching.

TME (tumor microenvironment) consists of blood & lymphatic vessels, stromal cells, and immune cells such as lymphocytes, macrophages, and antigen-presenting cells (APC). Cellular interactions among various immune cell types within TME regulate tumor growth, metastasis, and resistance to cancer therapy. V-domain Ig suppressor of T cell activation (VISTA) is a negative checkpoint regulator highly expressed on tumor-infiltrating myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs) and VISTA blockade could enhance antitumor immunity in TME. PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. Binding of PMC-309 on MDSC cells enhances the secretion of IFN-γ, TNF-α, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In in vivo study, PMC-309 suppressed tumor growth, which was further attenuated with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of tumor-infiltrating leukocytes (TIL) into TME. Patients who became resistant to anti-CTLA-4 and anti-PD(L)1 antibody showed increased expression of VISTA, suggesting that anti-VISTA therapeutics can help to treat the patients who do not respond well to other immuno-oncology drugs. We are developing PMC-309 as a next generation immuno-oncology (IO) agent, which can convert immunologically cold into hot tumors as a mono- or combo- therapy with other IO agent. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Sun Hyung Ha, Hye Rim Han, Nu Ri Kang, Beom Yong Park, Eun Ah Lee, Hyun Sun Park, Jin-San Yoo, Weon Sup Lee. PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1626.

Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor κB (NF-κB) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-κB in H9c2 cells overexpressing the urotensin II receptor (H9c2UT). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2UT cells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2UT cells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-κB signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3α/β were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2UT cells. Furthermore, UII-mediated cellular hypertrophy was inhibited by amlexanox, a selective GRK5 inhibitor, in H9c2UT cells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-κB and HDAC5 at least in part by ERK1/2 and GSK3α/β-independent pathways.

Objective: The delivery of drugs and immune cells into the tumor microenvironment is limited due to abnormal tumor vessel which is characterized as low oxygen concentration, low perfusion rate and leakage. It leads to diminish the efficacy of drugs and radiation therapy. Traditional anti-angiogenesis strategies attempt to reduce the tumor vascular supply, but their success is restricted by insufficient efficacy or development of resistance. To solve the problem, we try to using active vessel stabilizer, which can normalize the abnormal condition of tumor vessel. Background: Tie2 acts as cell-surface receptor for Ang1/Ang2 and regulates angiogenesis, endothelial cell survival, proliferation, migration, as well as maintenance of vascular quiescence. Especially, Ang1-Tie2 signaling pathway has been known to promote blood vessel maturation and stabilization. Methods: We have developed a series of novel human IgG monoclonal antibody that binds to human-TIE2 with a high affinity (Kd ~0.1 nM). The antibody binds to human TIE2 extracellular domain and activates its associated function in a ligand independent way. The mode of action was studied in vitro with human umbilical vein endothelial cells (HUVEC) and animal models. The vessel stabilization was investigated with laser induced choroidal neovascularization (CNV). The effect on tumor infiltrated lymphocyte was also studied in mouse colon cancer model. Results: Anti-Tie2 antibody increased human endothelial cell migration like Ang1 and inhibited VEGF-induced vascular leakage, contributing to vessel normalization. It binds to Tie2 in a ligand independent way and thus it can stabilize vessel as an agonist. Both p-VEGFR and p-VE-Cadherin levels are also significantly decreased on VEGF-induced VEGFR signaling pathway by anti-Tie2 antibody, suggesting that it can maintain cell to cell junction. The vessel stabilization effect was demonstrated in a mouse model of laser induced CNV. Moreover, in syngeneic CT26 mouse models, anti-Tie2 antibody showed anti-tumor effect in which it significantly reduced the tumor growth and synergistically when it combined with anti PD-1 antibody. The tumor infiltrating lymphocytes were increased in CT26 tumor, especially CD8+ T cells and MDSC when anti-Tie2 was administered. Conclusion: We developed active vessels stabilizer targeting Tie2, having an effect of vessel stabilization in a ligand independent way. It inhibited VEGF-induced vascular leakage through decrease of p-VEGFR and VE-cadherin. This active vessel stabilizer could help deliver drug and lymphocyte into the TME. The therapeutic efficacy of immune checkpoint inhibitors can be increased when it combined with this active vessel stabilizer. Thus, this active vessel stabilizer can change cold tumor into hot tumor. Citation Format: Eun-Ah Lee, Beomyong Park, Nu Ri Kang, Youngae Lee, Do-yun Kim, Sang Soon Byun, Jin Yong An, Cheon Ho Park, Weon Sup Lee, Joo Hyoung Lee. A novel anti-Tie2 antibody stabilizes vessel and increases tumor infiltrated lymphocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1483.

Lysophospholipase D (lysoPLD) is known to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). In this study, we examined the inhibitory effect of fish egg extracts, containing lipids, on bovine lysoPLD activity. Fish eggs extracts were tested for the inhibition of lysoPLD activity, and the inhibitory action was expressed as 50% inhibitory concentration (IC50). Among fish egg extracts of 20 fish species, the most potent inhibition was expressed by Hairtail egg extract (IC50, 0.07 ± 0.01 mg egg weight/mL), followed by extract of Spanish mackerel egg extract (0.11 ± 0.02 mg egg weight/mL) and extract of Pacific saury egg (0.48 ± 0.03 mg egg weight/mL). In ESI/MS analysis, major lysoPLD-inhibitory lipid components in egg extracts were identified to be species of LPC, LPA and fatty acid. From these results, it is suggested that the strong inhibition of lysoPLD activity by fish egg extracts might be ascribed to the presence of lysophospholipids. In a separate study, enzymatic oxidation using lipoxygenase or non-enzymatic oxidations such as HOCl oxidation or Cu2+-catalyzed oxidation enhanced the inhibitory activity to some extent, suggesting that the oxidation of polyunsaturated lysophospholipids might contribute to the increase of lysoPLD-inhibitory action. Taken together, it is suggested that fish eggs may contain potent lipid inhibitors of lysoPLD, and that the inhibitory action of lipid inhibitors was enhanced by oxidative process.

The arising critical implications of G-protein-coupled receptor kinase 2 and 5 (GRK2 and 5) in heart failure have been attracting attention and inhibitors of GRK2 and 5 were considered as a novel therapeutic strategy to prevent and treat heart failure disease. Despite this large therapeutic potential, to date few GRK2 inhibitors have been identified and GRK5 inhibitors in public have been unknown. In our efforts to discover a novel scaffold with potent GRK2 and GRK5 inhibitory activities, we found that a series of 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amines have been identified as a new class of GRK2 and 5 kinase inhibitor. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK2 and 5. This research highlight discusses the processing and findings of the recent study.

An experimental study was carried out on convective boiling heat transfer for mixtures of R11 and R113 flowing in a uniformly heated vertical tube by measuring the wall and bulk temperatures, and the results were compared with an existing correlation. A reduction of the average heat transfer coefficient for mixtures was verified for flow boiling. It was observed that two kinds of boiling behavior existed depending on mass flux. It was also found that the Chen's correlation was particularly successful for the case of high mass rate flow in which convective boiling prevailed. However in the case of low mass rate flow where nucleate boiling was dominant, the Chen's correlation was found to be inappropriate. Mass transfer resistance in the liquid film played a vital role for determining the heat transfer coefficient of refrigerant mixtures. It has been also found that the equilibrium assumption was hardly applicable to the convective boiling phenomena.

The violent oscillation of the bubble formed from the evaporated droplet at the superheat limit has been investigated analytically and numerically. In this study, we have formulated a general bubble dynamics model, which is suitable for the oscillating bubble in an incompressible liquid medium. One of distinct features of this model is that the velocity and temperature distribution of the gas inside the bubble are obtained by solving continuity and energy equations for the gas analytically. With uniform density and temperature distribution approximation, the calculated values of the far field pressure signal from the evolving bubble formed from the fully evaporated droplet are in good agreement with experimental results.

The arising critical implications of Rho kinase signaling in cardiovascular diseases have been attracting attention in the pharmacological potential of Rho kinase inhibitors. We identified a novel inhibitor of Rho kinase (2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine; DW 1865) and characterized its effects in biochemical, cellular, tissue and animal based assays. DW 1865 potently inhibited the kinase activity of both Rho kinase 1 and Rho kinase 2 in vitro, and behaved as an ATP-competitive inhibitor. Interestingly, DW1865 was 10 times more potent in inhibiting Rho kinase activities than fasudil as a selective Rho kinase inhibitor. The activity of DW1865 was shown to be highly selective for Rho kinase in the panel assay of 13 other kinases. In the isolated vascular tissue study, DW1865 exerted vasorelaxation in phenylephrine- or 5-hydroxytriptamine-induced contraction in a concentration-dependent manner manner. In spontaneously hypertensive rats, administration of DW1865 caused a significant and dose-related reduction in blood pressure. Furthermore, DW1865 blocked angiotensin II-induced stress fiber formation and cellular hypertrophy in rat heart-derived H9c2 cells. Taken together, these results suggest that DW1865 is a highly selective and potent Rho kinase inhibitor that will alleviate the pathophysiological actions of Rho kinase such as stress fiber formation, cellular hypertrophy, and hypertension.

Baicalein is a flavonoid (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran4-one) and an active principle in Scutellaria baicalensis. The present study was performed to investigate the mechanisms underlying the anti-fibrotic effects of baicalein with a focus on Rho kinase (ROCK) inhibition. The effect of baicalein on ROCK activity was analyzed using an immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The underlying mechanisms of baicalein were examined using angiotensin II-stimulated H9c2 cells. Rho kinase (ROCK1 and ROCK2) studies using IMAP-TR-FRET showed that baicalein possesses potent ROCK inhibitory activity with IC50 values of 6.55 and 2.82 µM, respectively. Pretreatment with baicalein (for 2 h) concentration-dependently decreased the angiotensin II-induced phosphorylation of myosin phosphatase (MYPT) and myosin light chain (MLC). Furthermore, baicalein also concentration-dependently suppressed actin stress fiber formation in angiotensin II-stimulated H9c2 cells. These results suggest that baicalein potently inhibits ROCK and that by so doing it modulates actin stress fiber formation. These anti-fibrotic effects of baicalein explain, at least in part, its pharmacology and mode of action.

Lysophosphatidylcholine (lysoPtdCho) is a component of oxidized low density lipoprotein, and is involved in the pathogenesis of atherosclerosis and inflammation. We studied the effects of lysoPtdCho on cytotoxicity, reactive oxygen species (ROS) production, activation of the extracellular signal-regulated kinase (ERK), mitogen-activated protein kinases and pro-inflammatory gene expression in RAW 264.7 murine macrophage cells. When cells were exposed to lysoPtdCho with various acyl chains in a culture medium containing 10% fetal bovine serum, only 1-linoleoyl (C18:2) lysoPtdCho showed a remarkable cytotoxicity, reaching the highest level at 24 h, and elicited ROS production, suggesting that oxidative stress might be implicated in the cytotoxicity of 1-linoleoyl (C18:2) lysoPtdCho. Presumably in support of this, antioxidants such as magnolol or trolox prevented 1-linoleoyl (C18:2) lysoPtdCho-induced cytotoxicity as well as ROS production, although only partially. Furthermore, the phosphorylation of ERK 1/2 and the expression of pro-inflammatory cytokines such as IL-1beta, CCL2 and CCL5 were augmented by 1-linoleoyl (C18:2) lysoPtdCho. Meanwhile, there was no structural importance of the acyl chain for the cytotoxic action of lysoPtdCho during 10 min incubation in serum-free media. Taken together, it is suggested that in a serum-containing medium, 1-linoleoyl (C18:2) lysoPtdCho can cause a significant cytotoxicity through ROS production, probably accompanied by activation of ERK and induction of related inflammatory cytokines, in RAW 264.7 cells.

Interaction of paraoxonase1 (PON1) with lysophospholipids was examined with respect to activity regulation and binding property. Paraoxonase activity of purified PON1 was partially inhibited by palmitoyl-lysophosphatidyl-glycerol (palmitoyl-lysoPG) and lysophosphatidylinositol (lysoPI), which had a stimulatory effect on arylesterase and diazoxonase activities. The selective inhibition of paraoxonase activity by palmitoyl-lysoPG, characterized by noncompetitiveness and charge interaction, was also observed with HDL- or dimyristoylphosphatidylcholine (DMPC)-bound PON1. Meanwhile, lysophosphatidylcholine (lysoPC) stimulated all three activities of purified PON1, although it stimulated DMPC-bound or HDL-bound PON1 to a lesser extent. The stimulatory action of lysophospholipids was observed around their CMC, suggesting that micelle formation of lysophospholpids might be involved in the stimulation of PON1 activity. Presumably in support of this, the tryptophan fluorescence intensity of PON1 was increased by lysophospholipids at concentrations required for the stimulation of PON1 activity. Separately, lysoPC stimulation was less remarkable for DMPC-bound PON1 than for either dimyristoylphosphatidylserine (DMPS)- or dimyristoylphosphatidylglycerol-bound PON1, suggesting a tight association between PON1 and DMPC. In support of this, the stimulatory role of apolipoprotein A-I was less prominent for DMPC-bound PON1 than for DMPS-bound PON1. Taken together, these data suggest that the inhibition of paraoxonase activity by lysoPG or lysoPI may be due to binding to a site distinct from the active center, whereas the stimulation by lysophospholipid may be ascribed to the micelle formation around the lipid-associable region of PON1.

To provide tactile feedback on flexible touch screens, transparent relaxor ferroelectric polymer film vibrators were designed and fabricated in this study. The film vibrator can be integrated underneath a transparent cover film or glass, and can also produce acoustic waves that cause a tactile sensation on human fingertips. Poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [P(VDF-TrFE-CTFE)] polymer was used as the relaxor ferroelectric polymer because it produces a large strain under applied electric fields, shows a fast response, and has excellent optical transparency. The natural frequency of this tactile-feedback touch screen was designed to be around 200–240 Hz, at which the haptic perception of human fingertips is the most sensitive; therefore, the resonance of the touch screen at its natural frequency provides maximum haptic sensation. A multilayered relaxor ferroelectric polymer film vibrator was also demonstrated to provide the same vibration power at reduced voltage. The flexible P(VDF-TrFE-CTFE) film vibrators developed in this study are expected to provide tactile sensation not only in large-area flat panel displays, but also in flexible displays and touch screens.