In recent years, both tissue engineering and microfluidics have significantly contributed in engineering of in vitro skin substitutes to test the penetration of chemicals or to replace damaged skins. Organ-on-chip platforms have been recently inspired by the integration of microfluidics and biomaterials in order to develop physiologically relevant disease models. However, the application of organ-on-chip on the development of skin disease models is still limited and needs to be further developed. The impact of tissue engineering, biomaterials and microfluidic platforms on the development of skin grafts and biomimetic in vitro skin models is reviewed. The integration of tissue engineering and microfluidics for the development of biomimetic skin-on-chip platforms is further discussed, not only to improve the performance of present skin models, but also for the development of novel skin disease platforms for drug screening processes.
We have designed and validated a set of robust and non-toxic protocols for directly evaluating the properties of engineered neural tissue. These protocols characterize the mechanical properties of engineered neural tissues and measure their electrophysical activity. The protocols obtain elastic moduli of very soft fibrin hydrogel scaffolds and voltage readings from motor neuron cultures. Neurons require soft substrates to differentiate and mature, however measuring the elastic moduli of soft substrates remains difficult to accurately measure using standard protocols such as atomic force microscopy or shear rheology. Here we validate a direct method for acquiring elastic modulus of fibrin using a modified Hertz model for thin films. In this method, spherical indenters are positioned on top of the fibrin samples, generating an indentation depth that is then correlated with elastic modulus. Neurons function by transmitting electrical signals to one another and being able to assess the development of electrical signaling serves is an important verification step when engineering neural tissues. We then validated a protocol wherein the electrical activity of motor neural cultures is measured directly by a voltage sensitive dye and a microplate reader without causing damage to the cells. These protocols provide a non-destructive method for characterizing the mechanical and electrical properties of living spinal cord tissues using novel biosensing methods.
Therapeutic drugs can penetrate tissues by diffusion and advection. In a healthy tissue, the interstitial fluid is composed of an influx of nutrients and oxygen from blood vessels. In the case of cancerous tissue, the interstitial fluid is poorly drained because of the lack of lymphatic vasculature, resulting in an increase in interstitial pressure. Furthermore, cancer cells invade healthy tissue by pressing and pushing the surrounding environment, creating an increase in pressure inside the tumor area. This results in a large differential pressure between the tumor and the healthy tissue, leading to an increase in extracellular matrix (ECM) stiffness. Because of high interstitial pressure in addition to matrix stiffening, penetration and distribution of systemic therapies are limited to diffusion, decreasing the efficacy of cancer treatment. This work reports on the development of a microfluidic system that mimics in vitro healthy and cancerous microenvironments using collagen I and gelatin methacryloyl (GelMA) composite hydrogels. The microfluidic device developed here contains a simplistic design with a central chamber and two lateral channels. In the central chamber, hydrogel composites were used to mimic the ECM, whereas lateral channels simulated capillary vessels. The transport of fluorescein sodium salt and fluorescently labeled gold nanoparticles from capillary-mimicking channels through the ECM-mimicking hydrogel was explored by tracking fluorescence. By tuning the hydrogel composition and concentration, the impact of the tumor microenvironment properties on the transport of those species was evaluated. In addition, breast cancer MCF-7 cells were embedded in the hydrogel composites, displaying the formation of 3D clusters with high viability and, consequently, the development of an in vitro tumor model.
Three-dimensional bioprinting can fabricate precisely controlled 3D tissue constructs. This process uses bioinks—specially tailored materials that support the survival of incorporated cells—to produce tissue constructs. The properties of bioinks, such as stiffness and porosity, should mimic those found in desired tissues to support specialized cell types. Previous studies by our group validated soft substrates for neuronal cultures using neural cells derived from human-induced pluripotent stem cells (hiPSCs). It is important to confirm that these bioprinted tissues possess mechanical properties similar to native neural tissues. Here, we assessed the physical and mechanical properties of bioprinted constructs generated from our novel microsphere containing bioink. We measured the elastic moduli of bioprinted constructs with and without microspheres using a modified Hertz model. The storage and loss modulus, viscosity, and shear rates were also measured. Physical properties such as microstructure, porosity, swelling, and biodegradability were also analyzed. Our results showed that the elastic modulus of constructs with microspheres was 1032 ± 59.7 Pascal (Pa), and without microspheres was 728 ± 47.6 Pa. Mechanical strength and printability were significantly enhanced with the addition of microspheres. Thus, incorporating microspheres provides mechanical reinforcement, which indicates their suitability for future applications in neural tissue engineering.
Gold nanoparticles have emerged as a prominent tool in nanomedicine, particularly for applications in cancer diagnostic and treatment. One of the challenges for the successful implementation of gold nanoparticles in cancer therapy is their delivery to the specific cancer area within the tumor microenvironment. The presence of cancer enables a poorly organized vascularization system, increasing the pressure with the microenvironment, limiting the uptake of particles. The physicochemical properties of the gold nanoparticles (size, shape, and surface charge) also have a significant effect on diffusion to the tumor site and cellular uptake. In this work, we analyzed the transport of 10 nm gold nanoparticles with different surface charges (neutral, negative, and positive) through a hydrogel composite. Three-dimensional in vitro models composed of breast cancer cells loaded in the hydrogel composite were used for the qualitative and quantitative evaluation of cellular uptake of the gold nanoparticles. Surprisingly, an inverse correlation between the diffusion coefficients of the nanoparticles and cellular uptake was demonstrated. Positively charged gold nanoparticles displayed high cellular uptake, although their diffusion coefficient indicated slow transport through the hydrogel matrix. Neutral particles, on the other hand, displayed fast diffusion but the lowest cellular uptake. The results obtained indicate that nanoparticle diffusion and cellular uptake should be studied together in realistic in vitro models for a true evaluation of transport in tumor microenvironments.
It is shown by photometric and fluorimetric analysis, along with supporting theoretical calculations, that hydroxy-substituted benzo[b]quinolizinium derivatives display the characteristic features of organic photoacids. Specifically, the experimental and theoretical results confirm the strong acidity of these compounds in the excited state (pK* < 0). The combination of the prototropic properties of 8- and 9-hydroxybenzo[b]quinolizinium with the particular solvent-solute interactions of the excited acid and its conjugate base leads to a pronounced fluorosolvatochromism, hence the emission maxima shift from 468 nm (8-hydroxybenzo[b]quinolizinium) or 460 nm (9-hydroxybenzo[b]quinolizinium) in CHCN to 507 and 553 nm in DMF, respectively. This novel type of photoacid represents several features that may be used for applications as water-soluble fluorescent probes or as a source for the photoinduced supply of acidity.
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