Subcutaneous Drug Delivery: A Review of the State-of-the-Art Modeling and Experimental Techniques.

Delivery of drug formulations through the subcutaneous route is a widely used modality for the treatment of several diseases, such as diabetes and auto-immune conditions. Subcutaneous injections are typically used to inject low-viscosity drugs in small doses. However, for new biologics, there is a need to deliver drugs of higher viscosity in large volumes. The response of subcutaneous tissue to such high-volume doses and higher viscosity injections is not well understood. Animal models have several drawbacks such as relevance to humans, lack of predictive power beyond the immediate population studied, cost, and ethical considerations. Therefore, a computational framework that can predict the tissue response to subcutaneous injections would be a valuable tool in the design and development of new devices. To model subcutaneous drug delivery accurately, one needs to consider: (a) the deformation and damage mechanics of skin layers due to needle penetration and (b) the coupled fluid flow and deformation of the hypodermis tissue due to drug delivery. The deformation of the skin is described by the anisotropic, hyper-elastic, and viscoelastic constitutive laws. The damage mechanics is modeled by using appropriate damage criteria and damage evolution laws in the modeling framework. The deformation of the subcutaneous space due to fluid flow is described by the poro-hyperelastic theory. The objective of this review is to provide a comprehensive overview of the methodologies used to model each of the above-mentioned aspects of subcutaneous drug delivery. We also present an overview of the experimental techniques used to obtain various model parameters.

Multiscale modeling of skin mechanical Behavior: Effect of dehydrating agent on Collagen's mechanical properties.

The dermis, second layer of human skin, is mainly responsible for mechanical response of the skin. The unique viscoelastic nature of this layer arises from the characteristic hierarchical structure of collagen at various length scales. The effect of topical formulation on skin's mechanical properties of great importance for several personal-care applications. Understanding the transport of an active ingredient across skin layer and its effects on the structure of collagen assembly is crucial for successful design of these applications. In this study, we report a multiscale modelling framework mimicking the skin's mechanical behavior. The framework captures the details from the nanoscale (tropocollagen) to microscale (fibers). At first, atomistic molecular dynamics simulations (MDS) of tropocollagen (TC) molecules of various lengths (∼100 nm) were performed to obtain the molecular modulus of TC. The stress-strain response data obtained from these simulations, were utilized in macroscopic models of fibrils and fibers. The modulus obtained from the mentioned framework was in good agreement with earlier reported experimental data. Further, we have utilized this framework to show the effect of dehydrating agent on skin's mechanical response. The hydration effect is utilized in many anti-ageing strategies to improve the overall mechanical property of skin. We showed that on incorporation of hydrating agent, the collagen structure changes significantly at molecular scale which effects the overall response of the skin at macroscopic scale. The reported multiscale framework can further be explored to gain insights into interlinked properties of collagen at much larger scales without extensive molecular simulations and detailed experiments.