Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases.

Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis.

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

Platelet and endothelial cell responses under concurrent shear stress and tensile strain.

Thrombosis can lead to significant mortality and morbidity. Both platelets and vascular endothelial cells play significant roles in thrombosis. Platelets' response to blood flow-induced shear stress can vary greatly depending on shear stress magnitude, pattern and shear exposure time. Endothelial cells are also sensitive to the biomechanical environment. Endothelial cell activation and dysfunction can occur under low oscillatory shear stress and low tensile strain. Platelet and endothelial cell interaction can also be affected by mechanical conditions. The goal of this study was to investigate how blood flow-induced shear stress, vascular wall tensile strain, platelet-endothelial cell stress history, and platelet-endothelial cell interaction affect platelet thrombogenicity. Platelets and human coronary artery endothelial cells were pretreated with physiological and pathological shear stress and/or tensile strain separately. The pretreated cells were then put together and exposed to pulsatile shear stress and cyclic tensile strain simultaneously in a shearing-stretching device. Following treatment, platelet thrombin generation rate, platelet and endothelial cell activation, and platelet adhesion to endothelial cells was measured. The results demonstrated that shear stress pretreatment of endothelial cells and platelets caused a significant increase in platelet thrombin generation rate, cell surface phosphatidylserine expression, and adhesion to endothelial cells. Shear stress pretreatment of platelets and endothelial cells attenuated endothelial cell ICAM-1 expression under stenosis conditions, as well as vWF expression under recirculation conditions. These results indicate that platelets are sensitized by prior shearing, while in comparison, the interaction with shear stress-pretreated platelets may reduce endothelial cell sensitivity to pathological shear stress and tensile strain.

Tapinarof cream 1% once daily: Significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in the pivotal phase 3 ADORING trials.

BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P < .0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < .0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.

Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic relapsing–remitting disease with a multifactorial etiology involving epidermal barrier and immunologic dysfunction. Topical therapies form the mainstay of AD treatment, but options are limited by adverse effects and restrictions on application site, duration, and extent of use. Tapinarof (VTAMA; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis. AhR is a ligand-dependent transcription factor with wide-ranging roles, including regulation of homeostasis and immune response in skin cells. AhR expression and signaling are altered in many inflammatory skin diseases, and clinical trials with tapinarof have validated AhR as a therapeutic target capable of delivering significant efficacy. Tapinarof cream 1% once daily demonstrated efficacy versus vehicle in adults and adolescents with AD and is being investigated in the ADORING trials for the treatment of AD in adults and children down to 2 years of age. J Drugs Dermatol. 2024;23(2):23-28.  doi:10.36849/JDD.8026.

Exposure to Secondhand Smoke Extract Increases Cisplatin Resistance in Head and Neck Cancer Cells.

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers' saliva and treated with cisplatin (0.01-100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells' capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial.

BACKGROUND: Tapinarof cream 1% once daily, an aryl hydrocarbon receptor-modulating agent, was significantly more efficacious than vehicle and well tolerated in two 12-week phase 3 trials in adults with mild to severe plaque psoriasis. OBJECTIVE: To assess long-term safety, efficacy, remittive effect, durability of response, and tolerability of tapinarof. METHODS: Patients completing the 12-week trials were eligible for 40-weeks' open-label treatment and 4-weeks' follow-up. Treatment was based on the Physician Global Assessment (PGA) score. Patients entering with PGA≥1 received tapinarof until PGA = 0. Patients with PGA = 0 discontinued tapinarof and were monitored for remittive effect. Patients with PGA≥2 were re-treated until PGA = 0. RESULTS: Overall, 91.6% (n = 763) of eligible patients enrolled; 40.9% of patients achieved complete disease clearance (PGA = 0), and 58.2% entering with PGA≥2 achieved PGA = 0 or 1. Mean duration of off therapy remittive effect for patients achieving PGA = 0 was 130.1 days. No new safety signals were observed. Most frequent adverse events were folliculitis (22.7%), contact dermatitis (5.5%), and upper respiratory tract infection (4.7%). LIMITATIONS: Open-label; no control; may not be generalizable to all forms of psoriasis; remittive effect/response rate potentially underestimated. CONCLUSIONS: Efficacy improved beyond the 12-week trials, with a 40.9% complete disease clearance rate, ∼4-month off therapy remittive effect, durability on therapy, and consistent safety.

An in situ inferior vena cava ligation-stenosis model to study thrombin generation rates with flow.

BACKGROUND: Blood flow-induced shear stress affects platelet participation in coagulation and thrombin generation. We aimed to develop an in vivo model to characterize thrombin generation rates under flow. METHODS: An in situ inferior vena cava (IVC) ligation-stenosis model was established using C57BL/6 mice. Wild type C57BL/6 mice were fed normal chow diet for two weeks before experiments. On the day of experiments, mice were anesthetized, followed by an incision through the abdominal skin to expose the IVC, which was then ligated (followed by reperfusion through a stenosis for up to 2 h). IVC blood flow rate was monitored using a Transonic ultrasound flow meter. In sham animals, the IVC was exposed following the same procedure, but no ligation was applied. Thrombin generation following IVC ligation was estimated by measuring mouse plasma prothrombin fragment 1-2 concentration. Mouse plasma factor Va concentration was measured using phospholipids and a modified prothrombinase assay. Blood vessel histomorphology, vascular wall ICAM-1, von Willebrand Factor, tissue factor, and PECAM-1 expression were measured using immunofluorescence microscopy. RESULTS: IVC blood flow rate increased immediately following ligation and stenosis formation. Sizable clots formed in mouse IVC following ligation and stenosis formation. Both plasma factor Va and prothrombin fragment 1-2 concentration reduced significantly following IVC ligation/stenosis, while no changes were observed with ICAM-1, von Willebrand Factor, tissue factor and PECAM-1 expression. CONCLUSION: Clot formation was successful. However, the prothrombin-thrombin conversion rate constant in vivo cannot be determined as local thrombin and FVa concentration (at the injury site) cannot be accurately measured. Modification to the animal model is needed to further the investigation.

Dermal Safety of Tapinarof Cream 1%: Results From 4 Phase 1 Trials.

BACKGROUND: Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a novel, non-steroidal, topical, aryl hydrocarbon receptor agonist, FDA approved for psoriasis treatment and under investigation for atopic dermatitis treatment as a 1% cream formulation for once-daily (QD) application. OBJECTIVE: Evaluate cumulative skin irritation, sensitization, and photoallergic and phototoxic potential of tapinarof cream 1% across a range of dosing frequencies and conditions. METHODS: We conducted 4 randomized, controlled, phase 1 trials of topical tapinarof cream 1% vs vehicle or other appropriate controls in healthy adults. Cumulative skin irritation was assessed following QD application for 21 days under fully occlusive patch conditions. Contact sensitization, photoallergenicity, and phototoxicity were assessed under semi-occlusive patch conditions. The contact sensitization and photoallergenicity trials used an induction phase of repeated applications followed by a 2-week rest period and a 1-time challenge, with rechallenge if responses indicated sensitization/photosensitization; the phototoxicity trial comprised a single application. Ultraviolet A and B irradiation was used to assess photoallergenicity/toxicity. RESULTS: 376 participants were randomized across the 4 trials. In the cumulative irritation trial, tapinarof cream 1% QD was classified as having a slight potential for very mild cumulative irritation under the exaggerated test conditions of repeated dosing for 21 days. There was no evidence of sensitization, photosensitization, or phototoxicity. Tapinarof was well tolerated and there was a low discontinuation rate across all trials. CONCLUSIONS: Tapinarof cream 1% was well tolerated, non-sensitizing, non-phototoxic, and non-photoallergic, with no evidence of clinically meaningful cumulative skin irritation in 4 dermal safety trials in healthy adults. TRIAL REGISTRATION: IND 104601 J Drugs Dermatol. 2022;21(10):1084-1090. doi:10.36849/JDD.6627R1.

SARS-CoV-2 proteins regulate inflammatory, thrombotic and diabetic responses in human arterial fibroblasts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins. We hypothesized that after a short-term exposure to SARS-CoV-2 proteins, adventitial fibroblasts would have a higher expression of inflammatory, thrombotic and diabetic proteins, which would support a mechanism for altered vascular disease progression. After incubation, the expression of gC1qR, ICAM-1, tissue factor, RAGE and GLUT-4 was significantly up-regulated. In general, the extent of expression was different for each SARS-CoV-2 protein, suggesting that SARS-CoV-2 proteins interact with cells through different mechanisms. Thus, SARS-CoV-2 protein interaction with vascular cells may regulate vascular disease responses.

A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.

BACKGROUND: Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis. METHODS: In a phase 2b, double-blind, vehicle-controlled study, adults with plaque psoriasis were randomized to tapinarof cream 0.5% or 1% once or twice daily or vehicle once or twice daily for 12 weeks with 4-week follow-up. Efficacy outcomes included Physician Global Assessment (PGA) scores, change in PGA and total target lesion grading scores, and proportion of patients achieving ≥50%, ≥75%, and ≥90% reductions in the Psoriasis Area and Severity Index scores from baseline (PASI50, PASI75, and PASI90). RESULTS: At week 12, improvements were observed in all tapinarof groups vs vehicle in PGA response, change in PGA and total target lesion grading scores, PASI50 (71%-92% vs 10%-32%), PASI75 (46%-65% vs 5%-16%), and PASI90 (18%-40% vs 0%); all differences were statistically significant with tapinarof 1% once daily. Tapinarof responses were apparent from week 2, with significant efficacy at week 8 maintained through week 16. Most adverse events were mild or moderate. LIMITATIONS: The analyses reported require confirmation in larger prospective studies. CONCLUSIONS: Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.

BACKGROUND: Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment. METHODS: A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores. RESULTS: Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate. LIMITATIONS: Larger prospective studies are required to confirm the reported analyses. CONCLUSIONS: Tapinarof is a potential important advance in topical medicine development for AD.

Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor-modulating agent.

Tapinarof, a novel, first-in-class, small-molecule topical therapeutic aryl hydrocarbon receptor (AhR)-modulating agent, is in clinical development for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells and has critical roles in the regulation of skin homeostasis. Tapinarof-mediated AhR signaling underlies the mechanistic basis for the significant efficacy and acceptable tolerability observed in early-phase clinical trials of tapinarof cream in the treatment of psoriasis.

A comprehensive fluid-structure interaction model of the left coronary artery.

A fluid structure interaction model of a left anterior descending (LAD) coronary artery was developed, incorporating transient blood flow, cyclic bending motion of the artery, and myocardial contraction. The 3D geometry was constructed based on a patient's computed tomography angiography data. To simulate disease conditions, a plaque was placed within the LAD to create a 70% stenosis. The bending motion of the blood vessel was prescribed based on the LAD spatial information. The pressure induced by myocardial contraction was applied to the outside of the blood vessel wall. The fluid domain was solved using the Navier-Stokes equations. The arterial wall was defined as a nonlinear elastic, anisotropic, and incompressible material, and the mechanical behavior was described using the modified hyper-elastic Mooney-Rivlin model. The fluid (blood) and solid (vascular wall) domains were fully coupled. The simulation results demonstrated that besides vessel bending/stretching motion, myocardial contraction had a significant effect on local hemodynamics and vascular all stress/strain distribution. It not only transiently increased blood flow velocity and fluid wall shear stress, but also changed shear stress patterns. The presence of the plaque significantly reduced vascular wall tensile strain. Compared to the coronary artery models developed previously, the current model had improved physiological relevance.

Glycated albumin modifies platelet adhesion and aggregation responses.

A diabetic vasculature is detrimental to cardiovascular health through the actions of advanced glycation end products (AGEs) on endothelial cells and platelets. Platelets activated by AGEs agonize endothelial responses promoting cardiovascular disease (CVD) development. While it has been established that AGEs can alter platelet functions, little is known about the specific platelet pathways that AGEs modify. Therefore, we evaluated the effects of AGEs on specific salient platelet pathways related to CVDs and whether the effects that AGEs elicit are dependent on glycation extent. To accomplish our objective, platelets were incubated with reversibly or irreversibly glycated albumin. A time course for adhesion and aggregation agonist receptor expression was assessed. Optical platelet aggregometry was used to confirm the functional activity of platelets after AGE exposure. In general, platelets subjected to glycated albumin had a significantly enhanced adhesion and aggregation potential. Furthermore, we observed an enhancement in dense body secretion and intracellular calcium concentration. This was especially prevalent for platelets exposed to irreversibly glycated albumin. Additionally, functional aggregation correlated well with receptor expression, suggesting that AGE-induced altered receptor sensitivity translated to altered platelet functions. Our findings indicate that under diabetic vascular conditions platelets become more susceptible to activation and aggregation due to an overall enhanced receptor expression, which may act to promote CVD development.

Platelet activation, adhesion, inflammation, and aggregation potential are altered in the presence of electronic cigarette extracts of variable nicotine concentrations.

Tobacco smoke extracts prepared from both mainstream and sidestream smoking have been associated with heightened platelet activation, aggregation, adhesion, and inflammation. Conversely, it has been shown that pure nicotine inhibits similar platelet functions. In this work, we 1) evaluated the effects of e-cigarette extracts on platelet activities and 2) elucidated the differences between the nicotine-dependent and non-nicotine dependent (e.g. fine particulate matter or toxic compounds) effects of tobacco and e-cigarette products on platelet activities. To accomplish these goals, platelets from healthy volunteers (n = 50) were exposed to tobacco smoke extracts, e-cigarette vapor extracts, and pure nicotine and changes in platelet activation, adhesion, aggregation, and inflammation were evaluated, using optical aggregation, flow cytometry, and ELISA methods. Interestingly, the exposure of platelets to e-vapor extracts induced a significant up-regulation in the expression of the pro-inflammatory gC1qR and cC1qR and induced a marked increase in the deposition of C3b as compared with traditional tobacco smoke extracts. Similarly, platelet activation, as measured by a prothrombinase based assay, and platelet aggregation were also significantly enhanced after exposure to e-vapor extracts. Finally, platelet adhesion potential toward fibrinogen, von Willebrand factor, and other platelets was also enhanced after exposure to e-cigarette vapor extracts. In the presence of pure nicotine, platelet functions were observed to be inhibited, which further suggests that other constituents of tobacco smoke and electronic vapor can antagonize platelet functions, however, the presence of nicotine in extracts somewhat perpetuated the platelet functional changes in a dose-dependent manner.

A Shearing-Stretching Device That Can Apply Physiological Fluid Shear Stress and Cyclic Stretch Concurrently to Endothelial Cells.

Endothelial cell (EC) morphology and functions can be highly impacted by the mechanical stresses that the cells experience in vivo. In most areas in the vasculature, ECs are continuously exposed to unsteady blood flow-induced shear stress and vasodilation-contraction-induced tensile stress/strain simultaneously. Investigations on how ECs respond to combined shear stress and tensile strain will help us to better understand how an altered mechanical environment affects EC mechanotransduction, dysfunction, and associated cardiovascular disease development. In the present study, a programmable shearing and stretching device that can apply dynamic fluid shear stress and cyclic tensile strain simultaneously to cultured ECs was developed. Flow and stress/strain conditions in the device were simulated using a fluid structure interaction (FSI) model. To characterize the performance of this device and the effect of combined shear stress-tensile strain on EC morphology, human coronary artery ECs (HCAECs) were exposed to concurrent shear stress and cyclic tensile strain in the device. Changes in EC morphology were evaluated through cell elongation, cell alignment, and cell junctional actin accumulation. Results obtained from the numerical simulation indicated that in the "in-plane" area of the device, both fluid shear stress and biaxial tensile strain were uniform. Results obtained from the in vitro experiments demonstrated that shear stress, alone or combined with cyclic tensile strain, induced significant cell elongation. While biaxial tensile strain alone did not induce any appreciable change in EC elongation. Fluid shear stress and cyclic tensile strain had different effects on EC actin filament alignment and accumulation. By combining various fluid shear stress and cyclic tensile strain conditions, this device can provide a physiologically relevant mechanical environment to study EC responses to physiological and pathological mechanical stimulation.