Towards microstructure-informed material models for human brain tissue.

Emerging evidence suggests that the mechanical behavior of the brain plays a critical role in development, disease, and aging. Recent studies have begun to characterize the mechanical behavior of gray and white matter tissue and to identify sets of material models that best reproduce the stress-strain behavior of different brain regions. Yet, these models are mainly phenomenological in nature, their parameters often lack clear physical interpretation, and they fail to correlate the mechanical behavior to the underlying microstructural composition. Here we make a first attempt towards identifying general relations between microstructure and mechanics with the ultimate goal to develop microstructurally motivated constitutive equations for human brain tissue. Using histological staining, we analyze the microstructure of brain specimens from different anatomical regions, the cortex, basal ganglia, corona radiata, and corpus callosum, and identify the regional stiffness and viscosity under multiple loading conditions, simple shear, compression, and tension. Strikingly, our study reveals a negative correlation between cell count and stiffness, a positive correlation between myelin content and stiffness, and a negative correlation between proteoglycan content and stiffness. Additionally, our analysis shows a positive correlation between lipid and proteoglycan content and viscosity. We demonstrate how understanding the microstructural origin of the macroscopic behavior of the brain can help us design microstructure-informed material models for human brain tissue that inherently capture regional heterogeneities. This study represents an important step towards using brain tissue stiffness and viscosity as early diagnostic markers for clinical conditions including chronic traumatic encephalopathy, Alzheimer's and Parkinson's disease, or multiple sclerosis. STATEMENT OF SIGNIFICANCE: The complex and heterogeneous mechanical properties of brain tissue play a critical role for brain function. To understand and predict how brain tissue properties vary in space and time, it will be key to link the mechanical behavior to the underlying microstructural composition. Here we use histological staining to quantify area fractions of microstructural components of mechanically tested specimens and evaluate their individual contributions to the nonlinear macroscopic mechanical response. We further propose a microstructure-informed material model for human brain tissue that inherently captures regional heterogeneities. The current work provides unprecedented insights into the biomechanics of human brain tissue, which are highly relevant to develop refined computational models for brain tissue behavior or to advance neural tissue engineering.

Functionalized solid lipid nanoparticles for transendothelial delivery.

The objectives of this study were to synthesize and characterize functionalized solid lipid nanoparticles (fSLN) to investigate their interaction with endothelial cell monolayers and to evaluate their transendothelial transport capabilities. fSLN bearing tetramethylrhodamine-isothiocyanate-labeled bovine serum albumin (TRITC-BSA) and Coumarin 6 were prepared using a single-step phase-inversion process that afforded concurrent surface modification with a variety of macromolecules such as polystyrene sulfonate (PSS), poly-L-lysine (PLL), heparin (Hep), polyacrylic acid (PAA), polyvinyl alcohol, and polyethylene glycol (PEG). TRITC-BSA/Coumarin 6 encapsulated in fSLN with composite surface functionality (PSS-PLL and PSS-PLL-Hep) were also investigated. Size and surface charge of fSLN were analyzed using dynamic light scattering and transmission electron microscopy. Transport across bovine aortic endothelial cell (BAEC) monolayers was assessed spectrophotometrically using a transwell assay, and fSLN localization at the level of the cell and permeable support was analyzed using fluorescence microscopy. fSLN with tunable size and surface functionality were successfully produced, and had significant effects on cell localization and transport. Specifically, fSLN with PSS-PLL-Hep composite surface functionalization was capable of translocating 53.2 +/- 8.7 mug of TRITC-BSA within 4 h, with fSLN-PEG, fSLN-PAA, and fSLN-PSS exhibiting near-complete apical, paracellular, and cytosolic localization, respectively. Coumarin 6 was released by fSLN as indicated by dye labeling of BAEC membranes. We have developed a rapid process for the production of fSLN bearing low- and high-molecular-weight payloads of varying physicochemical properties. These findings have impications for drug delivery and bioimaging applications, since due to tunable surface chemistry, fSLN internalization and/or translocation across intact endothelial cell monolayers is possible.

Selective differentiation of mammalian bone marrow stromal cells cultured on three-dimensional polymer foams.

Bone marrow stromal cells (BMSC) are pluripotent progenitor cells that can regenerate different skeletal tissues in response to environmental signals. In this study, we used highly porous, structurally stable three-dimensional polymer foams in conjunction with specific regulatory molecules to selectively differentiate mammalian BMSC into either cartilaginous or bone-like tissues. Bovine BMSC were expanded in monolayers and cultured on 5-mm-diameter, 2-mm-thick foams made of poly(lactic-co-glycolic acid) and poly(ethylene glycol). Constructs maintained their original size and shape for up to 4 weeks of culture and supported BMSC growth and production of extracellular matrix (ECM). By proper use of chondrogenic (dexamethasone, insulin, transforming growth factor-beta1) or osteogenic (dexamethasone, beta-glycerophosphate) medium supplements, we could control whether the generated ECM was cartilaginous (containing collagen type II and sulfated glycosaminoglycans) or bone-like (containing osteocalcin, osteonectin, and mineralized foci). After 4 weeks of cultivation, cartilaginous and bone-like ECM were uniformly distributed throughout the construct volume and respectively represented 34.2 +/- 9.3% and 12.6 +/- 3.2% of the total available area. BMSC culture on poly(lactic-co-glycolic acid)/poly(ethylene glycol) foams provides a three-dimensional model system to study the development of mesenchymal tissues in vitro and has potential applications in engineering autologous grafts for skeletal tissue repair.

Macroporous polymer foams by hydrocarbon templating.

Porous polymeric media (polymer foams) are utilized in a wide range of applications, such as thermal and mechanical insulators, solid supports for catalysis, and medical devices. A process for the production of polymer foams has been developed. This process, which is applicable to a wide range of polymers, uses a hydrocarbon particulate phase as a template for the precipitation of the polymer phase and subsequent pore formation. The use of a hydrocarbon template allows for enhanced control over pore structure, porosity, and other structural and bulk characteristics of the polymer foam. Polymer foams with densities as low as 120 mg/cc, porosity as high as 87%, and high surface areas (20 m(2)/g) have been produced. Foams of poly(l-lactic acid), a biodegradable polymer, produced by this process have been used to engineer a variety of different structures, including tissues with complex geometries such as in the likeness of a human nose.

Encapsulation and release of rhodium(II) citrate and its association complex with hydroxypropyl-beta-cyclodextrin from biodegradable polymer microspheres.

Rhodium(II) carboxylates and their derivatives constitute a promising class of second-generation transition metal compounds with anticancer properties. While most transition metal anticancer compounds chelate DNA and cause extensive chromosomal damage, rhodium(II) carboxylates act on the enzyme DNA polymerase alpha and hence cause minimal chromosomal damage. Rhodium(II) citrate, a recent member of the rhodium(II) carboxylate family is highly promising as an antitumor agent. However, due to its high water solubility, a high systemic dose is necessary to achieve efficacy. In this paper, we have explored the complexation of rhodium(II) citrate with hydroxypropyl-beta-cyclodextrin as a means to improve encapsulation and release kinetics from poly(dl-lactic-co-glycolic) acid (PLGA) and poly(anhydride) microspheres. We observed that complexation of rhodium(II) citrate with hydroxypropyl-beta-cyclodextrin significantly increased both the encapsulation efficiency and duration of release in both polymer systems.