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Intramyocardial delivery of biomaterials is a promising concept for treating myocardial infarction. The delivered biomaterial provides mechanical support and attenuates wall thinning and elevated wall stress in the infarct region. This study aimed at developing a biventricular finite element model of an infarcted rat heart with a microstructural representation of an in situ biomaterial injectate, and a parametric investigation of the effect of the injectate stiffness on the cardiac mechanics. A three-dimensional subject-specific biventricular finite element model of a rat heart with left ventricular infarct and microstructurally dispersed biomaterial delivered 1 week after infarct induction was developed from ex vivo microcomputed tomography data. The volumetric mesh density varied between 303 mm -3 in the myocardium and 3852 mm -3 in the injectate region due to the microstructural intramyocardial dispersion. Parametric simulations were conducted with the injectate's elastic modulus varying from 4.1 to 405,900 kPa, and myocardial and injectate strains were recorded. With increasing injectate stiffness, the end-diastolic median myocardial fibre and cross-fibre strain decreased in magnitude from 3.6% to 1.1% and from -6.0% to -2.9%, respectively. At end-systole, the myocardial fibre and cross-fibre strain decreased in magnitude from -20.4% to -11.8% and from 6.5% to 4.6%, respectively. In the injectate, the maximum and minimum principal strains decreased in magnitude from 5.4% to 0.001% and from -5.4% to -0.001%, respectively, at end-diastole and from 38.5% to 0.06% and from -39.0% to -0.06%, respectively, at end-systole. With the microstructural injectate geometry, the developed subject-specific cardiac finite element model offers potential for extension to cellular injectates and in silico studies of mechanotransduction and therapeutic signalling in the infarcted heart with an infarct animal model extensively used in preclinical research., (© 2023 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Endovascular aortic repair (EVAR) is a challenging intervention whose long-term success strongly depends on the appropriate stent-graft (SG) selection and sizing. Most off-the-shelf SGs are straight and cylindrical. Especially in challenging vessel morphologies, the morphology of off-the-shelf SGs is not able to meet the patient-specific demands. Advanced manufacturing technologies facilitate the development of highly customized SGs. Customized SGs that have the same morphology as the luminal vessel surface could considerably improve the quality of the EVAR outcome with reduced likelihoods of EVAR related complications such as endoleaks type I and SG migration. In this contribution, we use an in silico EVAR methodology that approximates the deployed state of the elastically deformable SG in a hyperelastic, anisotropic vessel. The in silico EVAR results of off-the-shelf SGs and customized SGs are compared qualitatively and quantitatively in terms of mechanical and geometrical parameters such as stent stresses, contact tractions, SG fixation forces and the SG-vessel attachment. In a numerical proof of concept, eight different vessel morphologies, such as a conical vessel, a barrel shaped vessel and a curved vessel, are used to demonstrate the added value of customized SGs compared to off-the-shelf SGs. The numerical investigation has shown large benefits of the highly customized SGs compared to off-the-shelf SGs with respect to a better SG-vessel attachment and a considerable increase in SG fixation forces of up to 50% which indicate decreased likelihoods of EVAR related complications. Hence, this numerical proof of concept motivates further research and development of highly customized SGs for the use in challenging vessel morphologies., (© 2020 John Wiley & Sons, Ltd.)

The subendothelial matrix of the artery is a complex mechanical environment where endothelial cells respond to and affect changes upon the underlying substrate. Our recent work has demonstrated that endothelial cell strain heterogeneity increases on a more heterogeneous underlying subendothelial matrix, and these cells display increased focal adhesion presence on stiffer substrate areas. However, the impact of these grouped focal adhesions on endothelial cell strains has not been explored. Here, we use finite element modeling to investigate the effects of microscale stiffness heterogeneities and focal adhesion location and stiffness on endothelial cell strains. Shear stress applied to the apical cell layer demonstrated a minimal effect on cell strain values, while substrate stretch had a greater effect on cell strain in the cell-substrate model. The addition of focal adhesions into the computational model (cell-FA-substrate model) predicted a decrease and homogenization of the cell strains. For simulations including focal adhesions, stiffer and more distributed adhesions caused increased and more heterogeneous endothelial cell strains. Overall, our data indicate that cells may group focal adhesions to minimize and homogenize their basal strains., (© 2019 John Wiley & Sons, Ltd.)

Computational cardiac mechanical models, individualized to the patient, have the potential to elucidate the fundamentals of cardiac (patho-)physiology, enable non-invasive quantification of clinically significant metrics (eg, stiffness, active contraction, work), and anticipate the potential efficacy of therapeutic cardiovascular intervention. In a clinical setting, however, the available imaging resolution is often limited, which limits cardiac models to focus on the ventricles, without including the atria, valves, and proximal arteries and veins. In such models, the absence of surrounding structures needs to be accounted for by imposing realistic kinematic boundary conditions, which, for prognostic purposes, are preferably generic and thus non-image derived. Unfortunately, the literature on cardiac models shows no consistent approach to kinematically constrain the myocardium. The impact of different approaches (eg, fully constrained base, constrained epi-ring) on the predictive capacity of cardiac mechanical models has not been thoroughly studied. For that reason, this study first gives an overview of current approaches to kinematically constrain (bi) ventricular models. Next, we developed a patient-specific in silico biventricular model that compares well with literature and in vivo recorded strains. Alternative constraints were introduced to assess the influence of commonly used mechanical boundary conditions on both the predicted global functional behavior of the in-silico heart (cavity volumes, stroke volume, ejection fraction) and local strain distributions. Meaningful differences in global functioning were found between different kinematic anchoring strategies, which brought forward the importance of selecting appropriate boundary conditions for biventricular models that, in the near future, may inform clinical intervention. However, whilst statistically significant differences were also found in local strain distributions, these differences were minor and mostly confined to the region close to the applied boundary conditions., (© 2018 John Wiley & Sons, Ltd.)

Biomaterial injectates are promising as a therapy for myocardial infarction to inhibit the adverse ventricular remodeling. The current study explored interrelated effects of injectate volume and infarct size on treatment efficacy. A finite element model of a rat heart was utilized to represent ischemic infarcts of 10%, 20%, and 38% of left ventricular wall volume and polyethylene glycol hydrogel injectates of 25%, 50%, and 75% of the infarct volume. Ejection fraction was 49.7% in the healthy left ventricle and 44.9%, 46.4%, 47.4%, and 47.3% in the untreated 10% infarct and treated with 25%, 50%, and 75% injectate, respectively. Maximum end-systolic infarct fiber stress was 41.6, 53.4, 44.7, 44.0, and 45.3 kPa in the healthy heart, the untreated 10% infarct, and when treated with the three injectate volumes, respectively. Treating the 10% and 38% infarcts with the 25% injectate volume reduced the maximum end-systolic fiber stress by 16.3% and 34.7% and the associated strain by 30.2% and 9.8%, respectively. The results indicate the existence of a threshold for injectate volume above which efficacy does not further increase but may decrease. The efficacy of an injectate in reducing infarct stress and strain changes with infarct size. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Myocardial infarction is an increasing health problem worldwide. Because of an under-supply of blood, the cardiomyocytes in the affected region permanently lose their ability to contract. This in turn gradually weakens the overall heart function. A new therapeutic approach based on the injection of a gel into the infarcted area aims to support the healing and to inhibit adverse remodelling that can lead to heart failure. A computational model is the basis for obtaining a better understanding of the heart mechanics, in particular, how myocardial infarction and gel injections affect its pumping performance. A strain invariant-based stored energy function is proposed to account for the passive mechanical behaviour of the model, which also makes provision for active contraction. To incorporate injections an additive homogenization approach is introduced. The numerical framework is developed using an in-house code based on the element-free Galerkin method. The main focus of this contribution is to investigate the influence of gel injections on the mechanics of the left ventricle during the diastolic filling and systolic isovolumetric (isochoric) contraction phases. It is found that gel injections are able to reduce the elevated fibre stresses caused by an infarct., (Copyright © 2013 John Wiley & Sons, Ltd.)

Myocardial infarction therapies involving biomaterial injections have shown benefits in inhibiting progression towards heart failure. However, the underlying mechanisms remain unclear. A finite element model of the human left ventricle was developed from magnetic resonance images. An anteroapical infarct was represented at acute (AI) and fibrotic (FI) stage. Hydrogel injections in the infarct region were modelled with layered (L) and bulk (B) distribution. In the FI, injectates reduced end-systolic myofibre stresses from 291.6% to 117.6% (FI-L) and 115.3% (FI-B) of the healthy value, whereas all AI models exhibited sub-healthy stress levels (AI: 90.9%, AI-L: 20.9%, AI-B: 30.5%). Reduction in end-diastolic infarct stress were less pronounced for both FI (FI: 294.1%, FI-L: 176.5%, FI-B: 188.2%) and AI (AI: 94.1%, AI-L: 35.3%, AI-B: 41.2%). In the border zone, injectates reduced end-systolic fibre stress by 8-10% and strain from positive (AI) and zero (FI) to negative. Layered and bulk injectates increased ejection fraction by 7.4% and 8.4% in AI and 14.1% and 13.7% in FI. The layered injectate had a greater impact on infarct stress and strain at acute stage, whereas the bulk injectate exhibited greater benefits at FI stage. These findings were confirmed by our previous in vivo results., (Copyright © 2013 John Wiley & Sons, Ltd.)

Mice deficient in Hox11 are asplenic. As Hoxll can function as a transcription factor, we examined the spatial and temporal mRNA expression patterns of Hox11 and a candidate target gene, the Wilm's tumor gene Wt1, in the developing spleen. Hox11 mRNA first appears at approximately dE10.5 in the dorsal mesogastrium while Wt1 mRNA is expressed from dE11.5, approximately 24 hours after Hox11 mRNA first appears. Wt1 mRNA was significantly reduced in the spleen anlage of Hox11-null mice suggesting that Wt1 acts downstream of Hox11 in a transcriptional cascade. Additionally, Hox11 protein is able to transactivate the WT1 promoter in a Hox11-null fibroblast cell line. As Wt1-null embryos have recently been reported to be asplenic, these findings suggest that Wt1 and Hox11 may be components common to a genetic hierarchy that is required for spleen development.

Solagé is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Pulsed dye laser treatment of vascular malformations is moderately painful. Twenty-five percent lidocaine in 70% dimethyl sulfoxide-ethanol was used to achieve anesthesia in patients undergoing the procedure. Thirteen of 14 patients had some degree of anesthesia (average of 51%) ranging from 10% to 100%, with 8 of them experiencing good results (> 50% anesthesia). Diminishment of pain was assessed by comparison of laser therapy on lidocaine-treated versus untreated sites within the vascular malformation using verbal and visual analog scales. In vitro permeation demonstrated good absorption of lidocaine, peaking at one hour. Permeation of lidocaine was significantly greater then that observed from acid mantle cream or EMLA. Topical lidocaine at 25% concentration in dimethyl sulfoxide 70% was well tolerated and had no side effects except transient mild erythema.

Fourteen patients with various forms of psoriasis participated in a clinical study to characterize the pharmacokinetics of etretinate before, during, and after 6 months of therapy. A single 100 mg dose was initially given, followed 2 days later by approximately 170 days of multiple dosing with 25 mg one, two, three, or four times a day depending on the subject's response and tolerance. Blood samples were drawn for 48 hours after the initial dose, for 12 hours after dosing at monthly intervals, and for up to 8 months after administration of the last dose. Blood concentrations of etretinate were determined by a specific reverse-phase gradient elution HPLC assay. Blood concentrations after the first dose declined with an apparent t1/2 of approximately 7 hours, whereas those after the last dose declined with an apparent t1/2 of approximately 120 days. The lengthening of the t1/2 during chronic dosing appears to result from the cumulation of blood concentrations in the measurable range rather than from time-related alterations in drug kinetics. This is substantiated by the fact that etretinate blood concentration--time data for the entire course of therapy were fit by a nonlinear least-squares computer program designed to accommodate changes in the dosing regimen. A single polyexponential kinetic equation described the entire 6-month course of therapy as well as the 8-month washout without the need to invoke nonlinear kinetics. Although single-dose kinetic data for etretinate may not be good predictors of steady-state blood concentrations, etretinate appears to follow linear kinetics during these dosing regimens.