Mechanical damage in porcine dermis: Micro-mechanical model and experimental characterization.

Skin is subjected to extreme mechanical loading during needle insertion and drug delivery to the subcutaneous space. There is a rich literature on the characterization of porcine skin biomechanics as the preeminent animal model for human skin, but the emphasis has been on the elastic response and specific anatomical locations such as the dorsal and the ventral regions. During drug delivery, however, energy dissipation in the form of damage, softening, and fracture, is expected. Similarly, reports on experimental characterization are complemented by modeling efforts, but with similar gaps in microstructure-driven modeling of dissipative mechanisms. Here we contribute to the bridging of these gaps by testing porcine skin from belly and breast regions, in two different orientation with respect to anatomical axes, and to progressively higher stretches in order to show damage accumulation and stiffness degradation. We complement the mechanical test with imaging of the collagen structure and a micro-mechanics modeling framework. We found that skin from the belly is stiffer with respect to the breast region when comparing the calf stiffness of the J-shaped stress-stretch response observed in most collagenous tissues. No significant direction dependent properties were found in either anatomical location. Both locations showed energy dissipation due to damage, evident though a softening of the stress-stretch response. The microstructure model was able to capture the elastic and damage progression with a small set of parameters, some of which were determined directly from imaging. We anticipate that data and model fits can help in predictive simulations for device design in situations where skin is subject to supra-physiological deformation such as in subcutaneous drug delivery.

Damage and Fracture Mechanics of Porcine Subcutaneous Tissue Under Tensile Loading.

Subcutaneous injection, which is a preferred delivery method for many drugs, causes deformation, damage, and fracture of the subcutaneous tissue. Yet, experimental data and constitutive modeling of these dissipation mechanisms in subcutaneous tissue remain limited. Here we show that subcutaneous tissue from the belly and breast anatomical regions in the swine show nonlinear stress-strain response with the characteristic J-shaped behavior of collagenous tissue. Additionally, subcutaneous tissue experiences damage, defined as a decrease in the strain energy capacity, as a function of the previously experienced maximum deformation. The elastic and damage response of the tissue are accurately described by a microstructure-driven constitutive model that relies on the convolution of a neo-Hookean material of individual fibers with a fiber orientation distribution and a fiber recruitment distribution. The model fit revealed that subcutaneous tissue can be treated as initially isotropic, and that changes in the fiber recruitment distribution with loading are enough to explain the dissipation of energy due to damage. When tested until failure, subcutaneous tissue that has undergone damage fails at the same peak stress as virgin samples, but at a much larger stretch, overall increasing the tissue toughness. Together with a finite element implementation, these data and constitutive model may enable improved drug delivery strategies and other applications for which subcutaneous tissue biomechanics are relevant.

Anisotropic damage model for collagenous tissues and its application to model fracture and needle insertion mechanics.

The analysis of tissue mechanics in biomedical applications demands nonlinear constitutive models able to capture the energy dissipation mechanisms, such as damage, that occur during tissue deformation. Furthermore, implementation of sophisticated material models in finite element models is essential to improve medical devices and diagnostic tools. Building on previous work toward microstructure-driven models of collagenous tissue, here we show a constitutive model based on fiber orientation and waviness distributions for skin that captures not only the anisotropic strain-stiffening response of this and other collagen-based tissues, but, additionally, accounts for tissue damage directly as a function of changes in the microstructure, in particular changes in the fiber waviness distribution. The implementation of this nonlinear constitutive model as a user subroutine in the popular finite element package Abaqus enables large-scale finite element simulations for biomedical applications. We showcase the performance of the model in fracture simulations during pure shear tests, as well as simulations of needle insertion into skin relevant to auto-injector design.

The biomechanics of autoinjector-skin interactions during dynamic needle insertion.

Autoinjector devices are rapidly becoming the preferred method of drug delivery for a wide array of pharmaceuticals such as monoclonal antibodies. Yet, our understanding of injection biomechanics is limited, but is crucially important to create autoinjectors that lead to the least amount of pain, penetrate the skin to a desired depth, produce small lesions that minimize back flow of drug, and operate robustly even given the variability in the skin mechanics among individuals. We propose a finite element model of needle insertion coupled to the dynamic model of an autoinjector. The finite element model is embedded with a cohesive zone plane to capture crack initiation and propagation within an energy-based fracture mechanics framework. The cohesive zone model is supported by experimental observations of a mode I crack during the needle insertion into the soft tissue. Model calibration against force curves from needle insertion experiments leads to estimated material and fracture properties that match values reported in independent experiments from the literature. With the calibrated model we explore the effect of change in the material properties and device parameters on the insertion dynamics. One of the most interesting findings is that pre-compression of skin from the autoinjector base plate can regulate the stress field near the skin surface and add strain energy that is available for crack formation.

Data-driven Modeling of the Mechanical Behavior of Anisotropic Soft Biological Tissue.

Closed-form constitutive models are the standard to describe soft tissue mechanical behavior. However, inherent pitfalls of an explicit functional form include poor fits to the data, non-uniqueness of fit, and sensitivity to parameters. Here we design deep neural networks (DNN) that satisfy desirable physics constraints in order to replace expert models of tissue mechanics. To guarantee stress-objectivity, the DNN takes strain (pseudo)-invariants as inputs, and outputs the strain energy and its derivatives. Polyconvexity of strain energy is enforced through the loss function. Direct prediction of both energy and derivative functions enables the computation of the elasticity tensor needed for a finite element implementation. We showcase the DNN ability to learn the anisotropic mechanical behavior of porcine and murine skin from biaxial test data. A multi-fidelity scheme that combines high fidelity experimental data with a low fidelity analytical approximation yields the best performance. Finite element simulations of tissue expansion with the DNN model illustrate the potential of this method to impact medical device design for skin therapeutics. We expect that the open data and software from this work will broaden the use of data-driven constitutive models of tissue mechanics.

Linking microvascular collapse to tissue hypoxia in a multiscale model of pressure ulcer initiation.

Pressure ulcers are devastating injuries that disproportionately affect the older adult population. The initiating factor of pressure ulcers is local ischemia, or lack of perfusion at the microvascular level, following tissue compression against bony prominences. In turn, lack of blood flow leads to a drop in oxygen concentration, i.e, hypoxia, that ultimately leads to cell death, tissue necrosis, and disruption of tissue continuity. Despite our qualitative understanding of the initiating mechanisms of pressure ulcers, we are lacking quantitative knowledge of the relationship between applied pressure, skin mechanical properties as well as structure, and tissue hypoxia. This gap in our understanding is, at least in part, due to the limitations of current imaging technologies that cannot simultaneously image the microvascular architecture, while quantifying tissue deformation. We overcome this limitation in our work by combining realistic microvascular geometries with appropriate mechanical constitutive models into a microscale finite element model of the skin. By solving boundary value problems on a representative volume element via the finite element method, we can predict blood volume fractions in response to physiological skin loading conditions (i.e., shear and compression). We then use blood volume fraction as a homogenized variable to couple tissue-level skin mechanics to an oxygen diffusion model. With our model, we find that moderate levels of pressure applied to the outer skin surface lead to oxygen concentration contours indicative of tissue hypoxia. For instance, we show that applying a pressure of 60 kPa at the skin surface leads to a decrease in oxygen partial pressure from a physiological value of 65 mmHg to a hypoxic level of 31 mmHg. Additionally, we explore the sensitivity of local oxygen concentration to skin thickness and tissue stiffness, two age-related skin parameters. We find that, for a given pressure, oxygen concentration decreases with decreasing skin thickness and skin stiffness. Future work will include rigorous calibration and validation of this model, which may render our work an important tool toward developing better prevention and treatment tools for pressure ulcers specifically targeted toward the older adult patient population.