A theoretical compartment model for antigen kinetics in the skin

Abstract

The skin is a promising location for vaccination with its abundant population of antigen capturing and presenting cells. The development of new techniques, such as the use of microneedles, can facilitate the delivery of vaccines into the skin. In recent years, many different types of microneedle arrays have been designed. However, their geometry and arrangement within an array may be optimized to trigger sufficient antigen presenting cells. A computational model can support the rational design of microneedle arrays. Therefore, the aim of the current study was to describe the distribution and kinetics of a delivered antigen within the skin using a theoretical compartment model, which included binding of antigens to receptors and their uptake by cells, and to determine which parameters should be measured to validate the model for a specific application. Multiple simulations were performed using a high and low antigen delivery dose and a range of values for the rate constants. The results indicated that the cells were highly saturated when a high dose was applied, while for a low dose saturation was only reached in 5% of the simulations. This was caused by the difference in the ratio between the administered dose and the available binding sites and suggests the dose should be adapted to the number of cells and receptors for a specific compound. The sensitivity analysis of the model parameters confirmed that the initial dose and receptor concentrations were indeed the two parameters that had the largest influence on the variance in antigen concentrations within the cells and circulation at equilibrium. Hence, these parameters are important to be measured in vivo. The presented pharmacokinetics model can be used in future computational models to predict the influence of microneedle array geometry to optimize their design.

Extended delivery of vaccines to the skin improves immune responses

“…In contrast, MN patches are dry formulations that slowly hydrate, form a viscous gel of sugars and polymers and eventually clear from skin, thereby lengthening antigen presentation [17,50]. The clearance rate of vaccine from the skin has been shown previously to depend on the antigen and formulation used, as well as the uptake and migration of APCs in the skin [17,18,[51][52][53].…”

Predicting the optimal geometry of microneedles and their array for dermal vaccination using a computational model

“…For each specific situation, the relevant kinetic parameters, number of receptors and dose should be determined. In our previous study, we showed that from these parameters the number of receptors and dose had the largest influence on the output of the model (Römgens et al 2016). In the current study, the model was used to provide an insight into the efficiency of dermal cells.…”

“…Our previous study revealed that the rate constants had little effect on the output of the model and can therefore be taken from general values from the literature (Römgens et al 2016). The initial receptor concentration was estimated from the cell density (6.2 × 10 4 cells/mm 3 for the dermis, 1.3 × 10 6 cells/mm 3 for the epidermis) and the number of receptors per cell (1 × 10 5 ) for both the epidermis and dermis (Avraméas et al 1996;McLellan et al 1998;Szolnoky et al 2001;Mulholland et al 2006;Römgens et al 2016). The diffusion coefficient in both these layers was based on measurements with 40 kDa dextran (Römgens et al 2015).…”

“…In addition to internalization, antigens can be taken up into the blood and lymph capillaries located in the dermis and deeper tissue layers. This process of antigen release, diffusion, and internalization by the cells can be described by a set of partial differential equations (1)- (6) (Römgens et al 2016):…”

“…This model was designed to predict the spatial-temporal diffusion of antigens released from a coated microneedle, and includes skin kinetics, as described in our previously developed compartment model (Römgens et al 2016). The efficiency of the design was determined by means of the number of antigen presenting cells that were activated.…”