Multiple functions of microfluidic platforms: Characterization and applications in tissue engineering and diagnosis of cancer.

Microfluidic system, or lab-on-a-chip, has grown explosively. This system has been used in research for the first time and then entered in the clinical section. Due to economic reasons, this technique has been used for screening of laboratory and clinical indices. The microfluidic system solves some difficulties accompanied by clinical and biological applications. In this review, the interpretation and analysis of some recent developments in microfluidic systems in biomedical applications with more emphasis on tissue engineering and cancer will be discussed. Moreover, we try to discuss the features and functions of microfluidic systems.

Second harmonic generation microscopy, biaxial mechanical tests and fiber dispersion models in human skin biomechanics.

Advanced numerical simulations of the mechanical behavior of human skin require thorough calibration of the material's constitutive models based on experimental ex vivo mechanical tests along with images of tissue microstructure for a variety of biomedical applications. In this work, a total of 14 human healthy skin samples and 4 additional scarred skin samples were experimentally analyzed to gain deep insights into the biomechanics of human skin. In particular, second harmonic generation (SHG) microscopy was used to extract detailed images of the distribution of collagen fibers, which were subsequently processed using a three-dimensional Fourier transform-based method recently proposed by the authors to quantify the distribution of fiber orientations. Mechanical tests under both biaxial and uniaxial loading were performed to calibrate the relevant mechanical parameters of two widely used constitutive models of soft fiber-reinforced biological tissues that account for non-symmetrical fiber dispersion. The calibration of the models allowed us to identify correlations between the mechanical parameters of the constitutive models considered. STATEMENT OF SIGNIFICANCE: Constitutive models for soft collagenous tissues can accurately reproduce the complex nonlinear and anisotropic mechanical behavior of skin. However, a comprehensive analysis of both microstructural and mechanical parameters is still missing for human skin. In this study, these parameters are determined by combining biaxial mechanical tests and SHG stacks of collagen fibers on ex vivo healthy human skin samples. The constitutive parameters are provided for two widely used hyperelastic models and enable accurate characterization of skin mechanical behavior for advanced numerical simulations.

Fourier transform-based method for quantifying the three-dimensional orientation distribution of fibrous units.

Several materials and tissues are characterized by a microstructure composed of fibrous units embedded in a ground matrix. In this paper, a novel three-dimensional (3D) Fourier transform-based method for quantifying the distribution of fiber orientations is presented. The method allows for an accurate identification of individual fiber families, their in-plane and out-of-plane dispersion, and showed fast computation times. We validated the method using artificially generated 3D images, in terms of fiber dispersion by considering the error between the standard deviation of the reconstructed and the prescribed distributions of the artificial fibers. In addition, we considered the measured mean orientation angles of the fibers and validated the robustness using a measure of fiber density. Finally, the method is employed to reconstruct a full 3D view of the distribution of collagen fiber orientations based on in vitro second harmonic generation microscopy of collagen fibers in human and mouse skin. The dispersion parameters of the reconstructed fiber network can be used to inform mechanical models of soft fiber-reinforced materials and biological tissues that account for non-symmetrical fiber dispersion.

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications.

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow's disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow's disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

Mechanical behavior and collagen structure of degenerative mitral valve leaflets and a finite element model of primary mitral regurgitation.

Degenerative mitral valve disease is the main cause of primary mitral regurgitation with two phenotypes: fibroelastic deficiency (FED) often with localized myxomatous degeneration and diffuse myxomatous degeneration or Barlow's disease. Myxomatous degeneration disrupts the microstructure of the mitral valve leaflets, particularly the collagen fibers, which affects the mechanical behavior of the leaflets. The present study uses biaxial mechanical tests and second harmonic generation microscopy to examine the mechanical behavior of Barlow and FED tissue. Three tissue samples were harvested from a FED patient and one sample is from a Barlow patient. Then we use an appropriate constitutive model by excluding the collagen fibers under compression. Finally, we built an FE model based on the echocardiography of patients diagnosed with FED and Barlow and the characterized material model and collagen fiber orientation. The Barlow sample and the FED sample from the most affected segment showed different mechanical behavior and collagen structure compared to the other two FED samples. The FE model showed very good agreement with echocardiography with 2.02±1.8 mm and 1.05±0.79 mm point-to-mesh distance errors for Barlow and FED patients, respectively. It has also been shown that the exclusion of collagen fibers under compression provides versatility for the material model; it behaves stiff in the belly region, preventing excessive bulging, while it behaves very softly in the commissures to facilitate folding. STATEMENT OF SIGNIFICANCE: This study quantifies for the first time the collagen microstructure and mechanical behavior of degenerative mitral valve (DMV) leaflets. These data will then be used for the first disease-specific finite element (FE) model of DMV. While current surgical repair of DMV is based on surgical experience, FE modeling has the potential to support decision-making and make outcomes predictable. We adopt a constitutive model to exclude collagen fiber under compressions, an important consideration when modeling the mitral valve, where the leaflets are folded to ensure complete closure. The results of this study provide essential data for understanding the relationship between collagen microstructure and degenerative mitral valve mechanics.

A Comparative Analysis of Orthotopic and Subcutaneous Pancreatic Tumour Models: Tumour Microenvironment and Drug Delivery.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology.

Biomechanics of mitral valve leaflets: Second harmonic generation microscopy, biaxial mechanical tests and tissue modeling.

Collagen fibers are the main load carrier in the mitral valve (MV) leaflets. Their orientation and dispersion are an important factor for the mechanical behavior. Most recent studies of collagen fibers in MVs lack either entire thickness study or high transmural resolution. The present study uses second harmonic generation (SHG) microscopy in combination with planar biaxial mechanical tests to better model and examine collagen fibers and mechanical properties of MV leaflets. SHG in combination with tissue clearing enables the collagen fibers to be examined through the entire thickness of the MV leaflets. Planar biaxial mechanical tests, on the other hand, enable the characterization of the mechanical tissue behavior, which is represented by a structural tissue model. Twelve porcine MV leaflets are examined. The SHG recording shows that the mean fiber angle for all samples varies on average by ±12° over the entire thickness and the collagen fiber dispersion changes strongly over the thickness. A constitutive model based on the generalized structure tensor approach is used for the associated tissue characterization. The model represents the tissue with three mechanical parameters plus the mean fiber direction and the dispersion, and predicts the biomechanical response of the leaflets with a good agreement (average r2=0.94). It is found that the collagen structure can be represented by a mean direction and a dispersion with a single family of fibers despite the variation in the collagen fiber direction and the dispersion over the entire thickness of MV leaflets. STATEMENT OF SIGNIFICANCE: Despite its prominent role in the mechanical behavior of mitral valve (MV) leaflets, the collagen structure has not yet been investigated over the entire thickness with high transmural resolution. The present study quantifies the detailed through thickness collagen fiber structure and examines the effects of its variation on MV tissue modeling. This is important because the study evaluates the assumption that the collagen fibers can be modeled with a representative single fiber family despite the variation across the thickness. In addition, the current comprehensive data set paves the way for quantifying the disruption of collagen fibers in myxomatous MV leaflets associated with disrupted collagen fibers.

An effective nano drug delivery and combination therapy for the treatment of Tuberculosis.

Drug resistance in tuberculosis is exacerbating the threat this disease is posing to human beings. Antibiotics that were once effective against the causative agent, Mycobacterium tuberculosis (Mtb), are now no longer usable against multi- and extensively drug-resistant strains of this pathogen. To address this issue, new drug combinations and novel methods for targeted drug delivery could be of considerable value. In addition, studies have shown that the use of the antidepressant drug fluoxetine, a serotonin reuptake inhibitor, can be useful in the treatment of infectious diseases, including bacterial infections. In this study, an isoniazid and fluoxetine-conjugated multi-walled carbon nanotube nanofluid were designed to increase drug delivery efficiency alongside eliminating drug resistance in vitro. The prepared nanofluid was tested against Mtb. Expression levels of inhA and katG mRNAs were detected by Real-time PCR. ELISA was applied to measure levels of cytokine secretion (TNF-α, and IL-6) from infected macrophages treated with the nano delivery system. The results showed that these nano-drug delivery systems are effective for fluoxetine at far lower doses than for free drugs. Fluoxetine also has an additive effect on the effect of isoniazid, and their concomitant use in the delivery system can have significant effects in treating infection of all clinical strains of Mtb. In addition, it was found that the expression of isoniazid resistance genes, including inhA, katG, and the secretion of cytokines TNFα and IL6 under the influence of this drug delivery system is well regulated. It was shown that the drug conjugation can improve the antibacterial activity of them in all strains and these two drugs have an additive effect on each other both in free and conjugated forms. This nano-drug delivery method combined with host targeted molecules could be a game-changer in the development of a new generation of antibiotics that have high therapeutic efficiencies, low side effects, and the potential to overcome the problem of drug resistance.

Is a simplified Finite Element model of the gluteus region able to capture the mechanical response of the internal soft tissues under compression?

BACKGROUND: Internal soft tissue strains have been shown to be one of the main factors responsible for the onset of Pressure Ulcers and to be representative of its risk of development. However, the estimation of this parameter using Finite Element (FE) analysis in clinical setups is currently hindered by costly acquisition, reconstruction and computation times. Ultrasound (US) imaging is a promising candidate for the clinical assessment of both morphological and material parameters. METHOD: The aim of this study was to investigate the ability of a local FE model of the region beneath the ischium with a limited number of parameters to capture the internal response of the gluteus region predicted by a complete 3D FE model. 26 local FE models were developed, and their predictions were compared to those of the patient-specific reference FE models in sitting position. FINDINGS: A high correlation was observed (R = 0.90, p-value < 0.01). A sensitivity analysis showed that the most influent parameters were the mechanical behaviour of the muscle tissues, the ischium morphology and the external mechanical loading. INTERPRETATION: Given the progress of US for capturing both morphological and material parameters, these results are promising because they open up the possibility to use personalised simplified FE models for risk estimation in daily clinical routine.

Enhanced osteogenic differentiation of mesenchymal stem cells on metal-organic framework based on copper, zinc, and imidazole coated poly-l-lactic acid nanofiber scaffolds.

The presence of inorganic bioactive minerals with polymers can accelerate and promote several processes including: bone cell joining, proliferation, differentiation, and expression of osteogenic proteins. In this study, zinc (Zn), copper (Cu), and imidazole metal-organic framework (MOF) nanoparticles were synthesized and coated over poly-l-lactic acid (PLLA) nanofibrous scaffolds for bone tissue engineering application. The surface and bioactive features of the scaffolds were characterized. The osteogenic potential of the scaffolds on human adipose tissue-derived mesenchymal stem cells (MSCs) was evaluated. Zn-Cu imidazole MOF coated PLLA scaffolds (PLLA@MOF) showed a comparable rate of MSC proliferation with the pure PLLA scaffolds and tissue culture plate (TCP). However, the PLLA@MOF potential of osteogenic differentiation was significantly greater than either pristine PLLA scaffolds or TCP. Hence, coating Zn-Cu imidazole MOF has a significant effect on the osteogenesis of MSC. Therefore, PLLA@MOF is novel scaffolds with bioactive components which are crucial for osteoconductivity and also able to provoke the osteogenesis and angiogenesis.

A novel route for electrosynthesis of CuCr(2)O(4) nanocomposite with p-type conductive polymer as a high performance material for electrochemical supercapacitors.

In this work, supercapacitive performance of polypyrrole copper chromate nano particles (Ppy/CuCr2O4 NPs) was studied. CuCr2O4 NPs with the average size of 20nm were synthesized simply by hydrothermal method and the composite electrodes were then electropolymerized on the surface of glassy carbon electrode. Common surface analysis techniques such as scanning electron microscopy (SEM), transmission electron microscopy(TEM) and Fourier transform infrared (FTIR) were used to study the morphology and structure of the composite. Furthermore, for electrochemical evaluation of composite electrodes, techniques including cyclic voltammetry (CV), galvanostatic charge discharge (CD) and impedance spectroscopy (EIS) were used. Using cyclic voltammetry, the specific capacitance values of Ppy and Ppy/CuCr2O4 NPs were calculated to be 109 and 508 F g-1, respectively. Results show that using CuCr2O4 NPs in the structure of polymeric films led to increased specific capacitance of composite electrodes more than four times that of poly pyrrole. Increasing the conductivity and stability of composite electrodes through continuous cycles are the other advantages of using CuCr2O4 NPs as active materials in a polymeric structure.