To unravel the diffusion mechanisms of percutaneous drug delivery, suitable numerical analysis of stratum corneum structure is essential. In this research paper, we accounted for the permeable envelope layer in the brick-and-mortar finite element models of human stratum corneum. Both penetration and desorption experiments for tritiated water were simulated by transient finite element analysis. Rivet-shaped corneodesmosomes were included in the brick and mortar model. Results showed that cornified lipid permeability (Penv) is a determinant in desorption of the solute, while lipid transverse diffusion coefficient (Dlip-trans) is prominent during penetration. These two major unknowns (Penv and Dlip-trans) were obtained by extensive fitting of the finite element model to the experimental water data. Penv and Dlip-trans were determined to be 1×10-2 cm/s and 5.7×10-10 cm2/s, respectively.

This work expands the recently developed compartmental model for skin transport to model variable diffusion and/or partition coefficients, and the presence of slow equilibration/slow binding kinetics within stratum corneum. The model was validated by comparing it with the diffusion model which was solved numerically using the finite element method. It was found that the new compartmental model predictions agreed well with that of the diffusion model, providing a sufficient number of compartments was used. The compartmental model was applied to two previously published experimental data sets: water penetration and desorption data and the finite dose dermal penetration of testosterone. Significant improvement of the fitting quality for all these data sets was achieved using the compartmental model.

In this work, we developed a number of generalised skin diffusion based pharmacokinetic models to relate published in vivo urinary excretion data to matching experimentally generated in vitro human skin permeation test (IVPT) data for a series of topically applied salicylate esters. A simplified linear in vivo model was found to inadequately describe the time course of urinary excretion over the entire sampling period. We represented the skin barrier as both a one layer (stratum corneum) and a two-layer (stratum corneum with viable epidermis) diffusion model and convoluted their Laplace solutions with that for a single exponential disposition phase to describe the urinary excretion profiles in the Laplace domain. We also derived asymptotic approximations for the model and estimated the conditions under which they could be used. We then sought to develop in vitro - in vivo relationships (IVIVR) for topically applied methyl, ethyl and glycol salicylates using our experimental IVPT data and the literature urinary excretion data. Good linear IVIVRs for ethyl and glycol salicylates were obtained, but the IVIVR for methyl salicylate was poor, perhaps because of topical stimulation of local skin blood flow by methyl salicylate. The ratio of the hydrated to dehydrated skin permeation for all salicylate esters was the same in both the IVPT and in vivo studies. A diffusion based one compartment pharmacokinetic model was also developed to describe the urinary excretion of solutes after removal of topical products and to compare the methyl salicylate skin permeation for five different body sites. The work presented here is consistent with the development of skin IVIVRs, but suggests that different skin conditions, application sites and local skin effects may affect model predictions.

Polymeric drug delivery systems can improve patient compliance, decrease toxicity and prolong therapeutic effects for a wide range of therapeutic treatments, by controlling drug release. Polymer delivery system development can be facilitated by mathematical models. We present here a new compartmental model that will be more familiar to pharmaceutical professionals and equally as effective as common diffusion equation-based models. The compartmental model considers both polymer degradation and drug diffusion to predict drug release. The model is adapted into three different geometries for different polymer delivery scenarios: membranes, fibres and particles. Model parameters are derived in terms of diffusion coefficients. Polymer-drug binding interactions and distributions of fibre/particle diameters are incorporated to the model. The model is validated by comparison to common diffusion equation-based solutions and fitting to experimental data. It is shown how the model for drug release can be incorporated into existing distribution models to predict plasma concentrations of an in vivo administration. A user-friendly Python implementation of the model is available on Github, at https://github.com/spirt-t/compartments_model.

Background Peripheral venous cannulation is one of the most common procedures in medicine. It is associated with noticeable pain and apprehension, although in most cases it is performed without any anesthesia due to lack of a painless, cost-effective option, which would provide rapid local anesthesia with subsequent significant reduction in the experienced pain. We conducted an open-label placebo-controlled clinical trial to evaluate the efficacy and safety of a 2% lidocaine injection using the commercially available microneedle device MinronJet600 (NanoPass Technologies Ltd, Israel) to achieve rapid local anesthesia prior to peripheral venous cannulation. Methods One hundred and two subjects were randomly allocated into two groups. In the first group, 100μL of lidocaine hydrochloride (2%) was injected intradermally to subjects using the MicronJet600 device in the left arm (MJ-Lido) and 100μL of saline was injected intradermally using the device in the right arm (MJ-Saline). In the second group, 100μL of lidocaine hydrochloride (2%) was injected using the MicronJet600 device into the left arm (MJ-Lido), with no injection into the right arm of subjects (No pretreatment). In both groups the intradermal injection was performed at the cannulation site prior to insertion of a 18G cannula into a median cubital vein in both arms. As a primary variable, a score of cannulation-induced pain was indicated by subjects using a 100-point visual analog scale immediately after cannulation. As a secondary variable, subjects in Group 2 also indicated their preference to receive the anaesthetic injection with MicronJet600 in the future by using the 5-point Likert scale. Also, as a secondary variable, the duration of skin numbness after lidocaine injection was indicated by performing a superficial pin-prick with a 27G needle at 15, 30 and 45 minutes, at distances of 1, 2 and 3 centimeters from the injection site. Results A significant pain reduction (11.0-fold) was achieved due to the lidocaine injection compared to the cannulation without any pretreatment (p< 0.005). After the lidocaine injection the anesthesia was effective up to 2 centimeters from the injection site and remained for up to 30 minutes. Eighty percent of subjects from the second group preferred cannulation after the lidocaine injection over cannulation without any pretreatment. No significant side effects were identified. Conclusion Intradermal injection of anaesthetic with Micronjet600 was found to be a safe and effective option for providing rapid local anesthesia for peripheral intravenous cannulation. Trial regiatration The clinical trial was registered, before the patient enrollment began, in the Research Registry publicly accessible database (registration identifier: researchregistry4662). Also, the trial was registered in ClinicalTrials.gov (registration identifier: NCT05108714) after its completion.

The skin concentration of a substance after a topical application or exposure determines both local treatment outcomes and the dermal toxicity assessment of various products. However, quantifying the time course of those concentrations at skin effect sites, such as the viable epidermal, superficial dermis and appendages in humans is especially problematic in vivo, making physiologically based mathematical modelling an essential tool to meet this need. This work further develops our published physiologically based pharmacokinetic and COMSOL based dermal transport modelling by considering the impact of the superficial subpapillary dermal plexus, which we represent as two well stirred compartments. The work also studied the impact on dermal concentrations of subpapillary plexus size, depth, blood velocity and density of subpapillary plexus vessels. Sensitivity analyses are used to define the most important transport determinants of skin concentrations after topical application of a substance, with previously published results used to validate the resulting analyses. This resulting model describes the available experimental data better than previous models, especially at deeper dermal depths.

Viable skin drug transport is an important concept to consider as it can have a significant impact on the local concentration of a drug. The concentration becomes even more critical for toxicological issues when implementing different permeability enhancement techniques. For this reason, it is important to develop models that can predict drug transport in the viable skin. This paper expands upon previous capillary modeling by representing the convective transport of a solute that has permeated into the capillary loops. As a result, convective transport caused the concentration profile to plateau within the deeper dermal layers, effectively matching the trend of previous experimental data. Furthermore, the new model also has a significantly quicker transient profile as the time required to reach steady-state is five-fold faster than predicted in previous homogenous models.

Increasing emphasis is being placed on using in vitro permeation test (IVPT) results for topical products as a surrogate for their in vivo behaviour. This study sought to relate in vivo plasma concentration - time pharmacokinetic (PK) profiles after topical application of drug products to IVPT findings with mechanistic diffusion and compartment models that are now widely used to describe permeation of solutes across the main skin transport barrier, the stratum corneum. Novel in vivo forms of the diffusion and compartment-in-series models were developed by combining their IVPT model forms with appropriate in vivo disposition functions. Available in vivo and IVPT data were then used with the models in data analyses, including the estimation of prediction intervals for in vivo plasma concentrations derived from IVPT data. The resulting predicted in vivo plasma concentration - time profiles for the full models corresponded closely with the observed results for both nitroglycerin and rivastigmine at all times. In contrast, reduced forms of these in vivo models led to discrepancies between model predictions and observed results at early times. A two-stage deconvolution procedure was also used to estimate the in vivo cumulative amount absorbed and shown to be linearly related to that from IVPT, with an acceptable prediction error. External predictability was also shown using a separate set of in vitro and in vivo data for different nitroglycerin patches. This work suggests that mechanistic and physiologically based pharmacokinetic models can be used to predict in vivo behaviour from IVPT data for topical products.

Recent advances in cell transplantation technologies have shown that polymeric fibrous tissue-engineered scaffolds provide a suitable physical environment, including the structural support, for cell delivery and effectively mimic the transplanted cells' extracellular matrix. Our study investigates the structure, composition and properties of three most commonly used polyester-based biopolymer materials blended with poly(epsilon-caprolactone) (PCL) at 2:1 (wt.%) ratio, namely, poly(glycerol sebacate) (PGS)/PCL, polylactic-co-glycolic acid (PLGA)/PCL, poly-l-lactide (PLLA)/PCL and pure PCL as carrier vehicles for retinal progenitor cell (RPC) attachment and RPC proliferation. The physicochemical properties of PGS/PCL, PLLA/PCL, PLGA/PCL and pure PCL fibrous scaffolds, fabricated under the identical electrospinning conditions, were analysed employing scanning electron microscopy, contact angle analysis, Raman spectroscopy, electrical and ionic conductivity measurements, and supplemented by an in-vitro RPC adhesion and proliferation studies. Our findings have shown that PGS/PCL scaffolds promote RPC attachment and RPC proliferation more favourably compared to other polymeric blends and pure PCL, owing to a combination of advantageous surface and bulk properties, overall demonstrating a potential for PGS/PCL blend to become a suitable vehicle for RPC delivery in a possible future clinical therapy for the treatment of retinal degenerative disorders.

The development of nanotheranostics represents one of the most dynamic technological frontiers in the treatment of different pathological conditions. With the goal in mind to generate nanocarriers with both therapeutic and diagnostic properties, current research aims at implementing these technologies with multiple functions, including targeting, multimodal imaging, and synergistic therapies. The working mechanism of some nanotheranostics relies on physical, chemical, and biological triggers allowing for the activation of the therapeutic and/or the diagnostic properties only at the diseased site. In this review, we explored new advances in the development of smart nanotheranostics responsive to pathological stimuli, including altered pH, oxidative stress, enzymatic expression, and reactive biological molecules with a deep focus on the material used in the field to generate the particles in the context of the analyzed disease.

INTRODUCTION:In the past, mathematical modeling of the transport of transdermal drugs has been primarily focused on the stratum corneum. However, the development of pharmaceutical technologies, such as chemical enhancers, iontophoresis, and microneedles, has led to two outcomes; an increase in permeability in the stratum corneum or the ability to negate the layer entirely. As a result, these outcomes have made the transport of a solute in the viable skin far more critical when studying transdermal drug delivery.AREAS COVERED:The review will explicitly show the various attempts to model drug transport within the viable skin. Furthermore, a brief review will be conducted on the different models that explain stratum corneum transport, microneedle dynamics and estimation of the diffusion coefficient.EXPERT OPINION:Future development of mathematical models requires the focus to be changed from traditional diffusion-based tissue models to more sophisticated three-dimensional models that incorporate the physiology of the skin.

BACKGROUND:Glaucoma, a characteristic type of optic nerve degeneration in the posterior pole of the eye, is a common cause of irreversible vision loss and the second leading cause of blindness worldwide. As an optic neuropathy, glaucoma is identified by increasing degeneration of retinal ganglion cells (RGCs), with consequential vision loss. Current treatments only postpone the development of retinal degeneration, and there are as yet no treatments available for this disability. Recent studies have shown that replacing lost or damaged RGCs with healthy RGCs or RGC precursors, supported by appropriately designed bio-material scaffolds, could facilitate the development and enhancement of connections to ganglion cells and optic nerve axons. The consequence may be an improved retinal regeneration. This technique could also offer the possibility for retinal regeneration in treating other forms of optic nerve ailments through RGC replacement.METHODS:In this brief review, we describe the innovations and recent developments in retinal regenerative medicine such as retinal organoids and gene therapy which are specific to glaucoma treatment and focus on the selection of appropriate bio-engineering principles, biomaterials and cell therapies that are presently employed in this growing research area.RESULTS:Identification of optimal sources of cells, improving cell survival, functional integration upon transplantation, and developing techniques to deliver cells into the retinal space without provoking immune responses are the main challenges in retinal cell replacement therapies.CONCLUSION:The restoration of visual function in glaucoma patients by the RGC replacement therapies requires appropriate protocols and biotechnology methods. Tissue-engineered scaffolds, the generation of retinal organoids, and gene therapy may help to overcome some of the challenges in the generation of clinically safe RGCs.

This study aims to investigate the comparative study of calcium phosphate coatings for flexible intramedullary nails (FINs) used to lengthen long tubular bones. The presence of a calcium phosphate coating deposited by micro-arc oxidation (MAO) or a composite coating based on a co-polymer of vinylidene fluoride with tetrafluoroethylene (VDF-TeFE) and hydroxyapatite (HA) on the surface of the FIN significantly enhanced the regeneration of bone in the area of osteotomy during limb lengthening by combined osteosynthesis. The investigation of the physico-chemical properties of the FIN coated with calcium phosphate via MAO demonstrated that the improved bone tissue formation resulted from favourable conditions for adhesion, proliferation and differentiation of multipotent stem cells into osteoblasts on the coating surface. The composite coatings only stimulated the formation of bone tissue in vivo, primarily because of the piezoelectric properties of the VDF-TeFE co-polymer.

Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.

A comparative study of flexible intramedullary nails (FIN) used for lengthening of long tubular bones in children is presented. It has been found that the presence of calcium phosphate coating obtained by micro-arc oxidation or a composite coating based on a copolymer of vinylidene fluoride with tetrafluoroethylene and hydroxyapatite on the surface of FIN significantly enhances the formation of bone regenerate in the area of osteotomy during limb lengthening by combined osteosynthesis. The investigation of physico-chemical properties of FIN with calcium phosphate coating obtained by micro-arc oxidation demonstrated that improved bone tissue formation is due to favourable conditions for adhesion, proliferation, and differentiation of MMSCs into osteoblasts on the coating surface. Composite coatings stimulated the formation of bone tissue only in vivo, mainly due to the piezoelectric properties of the copolymer of vinylidene fluoride with tetrafluoroethylene.

The stratum corneum is the main barrier to transdermal drug delivery which has previously resulted in mathematical modelling of solute transport in the skin being primarily directed at this skin layer. However, for topical treatment and skin toxicity studies, the concentration in the epidermis and dermis is important and needs to be modelled mathematically. Hitherto, mathematical models for viable skin layers typically simplified the clearance of solute by blood, either assuming sink condition at the top of the skin capillary loops or assuming a distributed clearance in the dermis. This paper is an attempt to develop a physiologically based mathematical model of drug transport in the viable skin. It incorporates explicit modelling of the capillary loops within the dermis and employs COMSOL Multiphysics® software to model the transport in three dimensions. Previously derived simplified models were compared to the results from this new numerical model. The results of this comparison showed that the simplified model reasonably described the average concentration in the viable skin layers when parameters of the models were chosen appropriately. When the recruitment of the capillary loops in the dermis was full and the top of capillary loops was at a depth of 100μm, the effective depth to place a sink condition in the simpler models was found to be at 150μm. However, when there was only partial recruitment of the capillaries, the effective depth increased to 180μm. The presented modelling is also essential for determining a transdermal flux when the stratum corneum barrier is compromised by such methods as microporation, application of chemical enhancers or microneedles.

Nitrogen-doped thin titanium dioxide films formed by the reactive magnetron sputtering method on the surface of PLLA electrospun microfibers scaffold were investigated. It was shown that the chemical composition of the films is shifting from titanium dioxide (TiO2) composites saturated with C–NH, C=N, N–C=N and HN–C=O compounds to solid solutions of titanium oxides (TixOy) and titanium oxynitrides (TiOxNy) with the increased time of the treatment. An empirical model describing changes in the chemical composition of the surface due to the treatment was proposed. It was shown that the modification of the PLLA microfibers scaffolds surface improves cell-scaffold and cell–cell interactions with the highest number of viable adherent cells observed on the scaffold treated for 4 min.

In this study, drug flux through microporated skin was modeled using detailed numerical solution of the diffusion equation. The results of the modeling were compared to previously published simplified and easy to use analytical equations. Limitations and accuracy of these equations were investigated. Appropriate modifications of the equations were identified to expand them to wider practical applications when pore shape is not circular. Numerical simulations have shown a good accuracy of the new simple equations when these are used within their limits of application.

The article describes fabrication and properties of composite fibrous scaffolds obtained by electrospinning of the solution of poly({\epsilon}-caprolactone) and arginine in common solvent. The influence of arginine content on structure, mechanical, surface and biological properties of the scaffolds was investigated. It was found that with an increase of arginine concentration diameter of the scaffold fibers was reduced, which was accompanied by an increase of scaffold strength and Young modulus. It was demonstrated that porosity and water contact angle of the scaffold are independent from arginine content. The best cell adhesion and viability was shown on scaffolds with arginine concentration from 0.5 to 1 % wt.

In recent years, flooding has caused disruptions to road management by significantly increasing rehabilitation costs. To date, there is very limited literature addressing the rapid deterioration of pavements immediately after a flooding event. This paper presents a state-of-the-art review of the literature on assessment and modeling deterioration of flood-affected pavements. Twenty peer-reviewed journal articles and conference papers and nine published reports are reviewed. Very few studies have attempted to incorporate flooding events on pavement condition. The critical review of the literature discusses the contributions and limitations in the assessment of flood-affected pavements to date. It also discusses the research conducted on the development of new deterioration models specifically for flood-affected pavements and the importance of developing such models for the road management system. Because there is no deterioration models for rutting and roughness of flood-affected pavements, this paper also presents two mechanistic-empirical deterministic based models for deterioration of rutting and roughness of flood-affected pavements. These models are sufficient to be used by other road agencies after calibrating for local road conditions. The outcomes of this paper will guide future research and help to understand the impact of flooding events on rapid deterioration of pavements. The newly developed deterioration models will help road agencies make effective decisions for the rehabilitation and management of flood-affected pavements.