Poroelastic Characterization and Modeling of Subcutaneous Tissue Under Confined Compression.

Subcutaneous tissue mechanics are important for drug delivery. Yet, even though this material is poroelastic, its mechanical characterization has focused on its hyperelastic response. Moreover, advancement in subcutaneous drug delivery requires effective tissue mimics such as hydrogels for which similar gaps of poroelastic data exist. Porcine subcutaneous samples and gelatin hydrogels were tested under confined compression at physiological conditions and strain rates of 0.01%/s in 5% strain steps with 2600 s of stress relaxation between loading steps. Force-time data were used in an inverse finite element approach to obtain material parameters. Tissues and gels were modeled as porous neo-Hookean materials with properties specified via shear modulus, effective solid volume fraction, initial hydraulic permeability, permeability exponent, and normalized viscous relaxation moduli. The constitutive model was implemented into an isogeometric analysis (IGA) framework to study subcutaneous injection. Subcutaneous tissue exhibited an initial spike in stress due to compression of the solid and fluid pressure buildup, with rapid relaxation explained by fluid drainage, and longer time-scale relaxation explained by viscous dissipation. The inferred parameters aligned with the ranges reported in the literature. Hydraulic permeability, the most important parameter for drug delivery, was in the range k 0 ∈ [ 0.142 , 0.203 ] mm 4 /(N s). With these parameters, IGA simulations showed peak stresses due to a 1-mL injection to reach 48.8 kPa at the site of injection, decaying after drug volume disperses into the tissue. The poro-hyper-viscoelastic neo-Hookean model captures the confined compression response of subcutaneous tissue and gelatin hydrogels. IGA implementation enables predictive simulations of drug delivery.

Computational modeling of the effect of skin pinch and stretch on subcutaneous injection of monoclonal antibodies using autoinjector devices.

Subcutaneous injection of monoclonal antibodies (mAbs) has experienced unprecedented growth in the pharmaceutical industry due to its benefits in patient compliance and cost-effectiveness. However, the impact of different injection techniques and autoinjector devices on the drug's transport and uptake is poorly understood. Here, we develop a biphasic large-deformation chemomechanical model that accounts for the components of the extracellular matrix that govern solid deformation and fluid flow within the subcutaneous tissue: interstitial fluid, collagen fibers and negatively charged proteoglycan aggregates. We use this model to build a high-fidelity representation of a virtual patient performing a subcutaneous injection of mAbs. We analyze the impact of the pinch and stretch methods on the injection dynamics and the use of different handheld autoinjector devices. The results suggest that autoinjector base plates with a larger device-skin contact area cause significantly lower tissue mechanical stress, fluid pressure and fluid velocity during the injection process. Our simulations indicate that the stretch technique presents a higher risk of intramuscular injection for autoinjectors with a relatively long needle insertion depth.

MPET2: a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection.

Subcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests.

Modeling large-volume subcutaneous injection of monoclonal antibodies with anisotropic porohyperelastic models and data-driven tissue layer geometries.

Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has become one of the fastest-growing fields in the pharmaceutical industry. The transport and mechanical processes behind large volume injections are poorly understood. Here, we leverage a large-deformation poroelastic model to study high-dose, high-speed subcutaneous injection. We account for the anisotropy of subcutaneous tissue using of a fibril-reinforced porohyperelastic model. We also incorporate the multi-layer structure of the skin tissue, generating data-driven geometrical models of the tissue layers using histological data. We analyze the impact of handheld autoinjectors on the injection dynamics for different patient forces. Our simulations show the importance of considering the large deformation approach to model large injection volumes. This work opens opportunities to better understand the mechanics and transport processes that occur in large-volume subcutaneous injections of mAbs.

Mixed-dimensional multi-scale poroelastic modeling of adipose tissue for subcutaneous injection.

Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has gained increasing interest in the pharmaceutical industry. The transport, distribution and absorption of mAbs in the skin after injection are not yet well-understood. Experiments have shown that fibrous septa form preferential channels for fluid flow in the tissue. The majority of mAbs can only be absorbed through lymphatics which follow closely the septa network. Therefore, studying drug transport in the septa network is vital to the understanding of drug absorption. In this work, we present a mixed-dimensional multi-scale (MDMS) poroelastic model of adipose tissue for subcutaneous injection. More specifically, we model the fibrous septa as reduced-dimensional microscale interfaces embedded in the macroscale tissue matrix. The model is first verified by comparing numerical results against the full-dimensional model where fibrous septa are resolved using fine meshes. Then, we apply the MDMS model to study subcutaneous injection. It is found that the permeability ratio between the septa and matrix, volume capacity of the septa network, and concentration-dependent drug viscosity are important factors affecting the amount of drug entering the septa network which are paths to lymphatics. Our results show that septa play a critical role in the transport of mAbs in the subcutaneous tissue, and this role was previously overlooked.

On the importance of tunica intima in the aging aorta: a three-layered in silico model for computing wall stresses in abdominal aortic aneurysms.

Layer-specific experimental data for human aortic tissue suggest that, in aged arteries and arteries with non-atherosclerotic intimal thickening, the innermost layer of the aorta increases significantly its stiffness and thickness, becoming load-bearing. However, there are very few computational studies of abdominal aortic aneurysms (AAAs) that take into account the mechanical contribution of the three layers that comprise the aneurysmal tissue. In this paper, a three-layered finite element model is proposed from the simplest uniaxial stress state to geometrically parametrized models of AAAs with different asymmetry values. Comparisons are made between a three-layered artery wall and a mono-layered intact artery, which represents the complex behavior of the aggregate adventitia-media-intima in a single layer with averaged mechanical properties. Likewise, the response of our idealized geometries is compared with similar experimental and numerical models. Finally, the mechanical contributions of adventitia, media and intima are analyzed for the three-layered aneurysms through the evaluation of the mean stress absorption percentage. Results show the relevance and necessity of considering the inclusion of tunica intima in multi-layered models of AAAs for getting accurate results in terms of peak wall stresses and displacements.