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.

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.

Obesity-mediated regulation of cardiac protein acetylation: parallel analysis of total and acetylated proteins via TMT-tagged mass spectrometry.

Lysine residues undergo diverse and reversible post-translational modifications (PTMs). Lysine acetylation has traditionally been studied in the epigenetic regulation of nucleosomal histones that provides an important mechanism for regulating gene expression. Histone acetylation plays a key role in cardiac remodeling and function. However, recent studies have shown that thousands of proteins can be acetylated at multiple acetylation sites, suggesting the acetylome rivals the kinome as a PTM. Based on this, we examined the impact of obesity on protein lysine acetylation in the left ventricle (LV) of male c57BL/6J mice. We reported that obesity significantly increased heart enlargement and fibrosis. Moreover, immunoblot analysis demonstrated that lysine acetylation was markedly altered with obesity and that this phenomenon was cardiac tissue specific. Mass spectral analysis identified 2515 proteins, of which 65 were significantly impacted by obesity. Ingenuity Pathway Analysis® (IPA) further demonstrated that these proteins were involved in metabolic dysfunction and cardiac remodeling. In addition to total protein, 189 proteins were acetylated, 14 of which were significantly impacted by obesity. IPA identified the Cardiovascular Disease Pathway as significantly regulated by obesity. This network included aconitate hydratase 2 (ACO2), and dihydrolipoyl dehydrogenase (DLD), in which acetylation was significantly increased by obesity. These proteins are known to regulate cardiac function yet, the impact for ACO2 and DLD acetylation remains unclear. Combined, these findings suggest a critical role for cardiac acetylation in obesity-mediated remodeling; this has the potential to elucidate novel targets that regulate cardiac pathology.