Machine Learning-Aided Microdroplets Breakup Characteristic Prediction in Flow-Focusing Microdevices by Incorporating Variations of Cross-Flow Tilt Angles.

Controlling droplet breakup characteristics such as size, frequency, regime, and droplet quality within flow-focusing microfluidic devices is critical for different biomedical applications of droplet microfluidics such as drug delivery, biosensing, and nanomaterial preparation. The development of a prediction platform capable of forecasting droplet breakup characteristics can significantly improve the iterative design and fabrication processes required for achieving desired performance. The present study aims to develop a multipurpose platform capable of predicting the working conditions of user-specific droplet size and frequency and reporting the quality of the generated droplets, regime, and hydrodynamical breakup characteristics in flow-focusing microdevices with different cross-junction tilt angles. Four different neural network-based prediction platforms were compared to accurately estimate capsule size, generation rate, uniformity, and circle metric. The trained capsule size and frequency networks were optimized using the heuristic optimization approach for establishing the Pareto optimal solution plot. To investigate the transition of the droplet generation regime (i.e., squeezing, dripping, and jetting), two different classification models (LDA and MLP) were developed and compared in terms of their prediction accuracy. The MLP model outperformed the LDA model with a cross-validation measure evaluated as 97.85%, demonstrating that the droplet quality and regime prediction models can provide an engineering judgment for the decision maker to choose between the suggested solutions on the Pareto front. The study followed a comprehensive hydrodynamical analysis of the junction angle effect on the dispersed thread formation, pressure, and velocity domains in the orifice.

Composite Microgels for Imaging-Monitored Tracking of the Delivery of Vascular Endothelial Growth Factor to Ischemic Muscles.

Monitoring the supply of vascular endothelial growth factor (VEGF) to ischemic tissues provides information on its biodistribution and delivery to meet the requirements of therapeutic angiogenesis and tissue engineering applications. We herein report the use of microfluidically generated microgels containing VEGF-conjugated fluorescent carbon dots (CDs) (VEGF-CDs), a gelatin-phenol conjugate, and silk fibroin for imaging-monitored tracking of VEGF delivery to ischemic muscles. An in vitro release study and a bioactivity assay indicated that the VEGF-CDs were released in a sustained manner with high bioactivity. The microgels showed a high angiogenesis potential, along with a strong fluorescent signal, for the chicken chorioallantoic membrane and chick embryo. Imaging and studies of therapeutic modalities of the composite microgels indicated their effective localization in ischemic tissues and sustained VEGF release, which resulted in enhanced therapeutic angiogenesis of ischemic muscles. This work reveals the success of using VEGF-loaded composite polymer microgels for efficient and monitored VEGF delivery by intramuscular administration for ischemic disease treatment.

Simultaneous Modeling of Young's Modulus, Yield Stress, and Rupture Strain of Gelatin/Cellulose Acetate Microfibrous/Nanofibrous Scaffolds Using RSM.

Electrospinning is a promising method to fabricate bioengineered scaffolds, thanks to utilizing various types of biopolymers, flexible structures, and also the diversity of output properties. Mechanical properties are one of the major components of scaffold design to fabricate an efficacious artificial substitute for the natural extracellular matrix. Additionally, fiber orientations, as one of the scaffold structural parameters, could play a crucial role in the application of fabricated fibrous scaffolds. In this study, gelatin was used as a highly biocompatible polymer in blend with cellulose acetate (CA), a polysaccharide, to enhance the achievable range of mechanical characteristics to fabricated fibrous electrospun scaffolds. By altering input variables, such as polymers concentration, weight ratio, and mandrel rotation speed, scaffolds with various mechanical and morphological properties could be achieved. As expected, the electrospun scaffold with a higher mandrel rotation speed shows higher fiber alignment. A wide range of mechanical properties were gained through different values of polymer ratio and total concentration. A general improvement in mechanical strength was observed by increasing the concentration and CA content in the solution, but contradictory effects, such as high viscosity in more concentrated solutions, influenced the mechanical characteristics as well. A response surface method was applied on experimental results in order to describe a continuous variation of Young's modulus, yield stress, and strain at rupture. A full quadratic version of equations with the 95% confidence level was applied for the response modeling. This model would be an aid for engineers to adjust mandrel rotation speed, solution concentration, and gelatin/CA ratio to achieve desired mechanical and structural properties.

Carbon Dots Conjugated with Vascular Endothelial Growth Factor for Protein Tracking in Angiogenic Therapy.

One of the challenges of using growth factors for tissue regeneration is to monitor their biodistributions and delivery to injured tissues for minimally invasive detection. In the present study, tracking of human vascular endothelial growth factor (VEGF) was achieved by chemically linking it to photoluminescent carbon dots (CDs). Carbon dots were synthesized by the hydrothermal method and, subsequently, conjugated with VEGF using carbodiimide coupling. ELISA and western blot analysis revealed that VEGF-conjugated CDs preserve the binding affinity of VEGF to its antibodies. We also show that VEGF-conjugated CDs maintain the functionality of VEGF for tube formation and cell migration. The VEGF-conjugated CDs were also used for in vitro imaging of human umbilical vein endothelial cells. The results of this work suggest that cell-penetrating VEGF-conjugated CDs can be used for growth factor protein tracking in therapeutic and tissue engineering applications.

Promoted chondrogenesis of hMCSs with controlled release of TGF-ß3 via microfluidics synthesized alginate nanogels.

The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-ß3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

A simple coating method of PDMS microchip with PTFE for synthesis of dexamethasone-encapsulated PLGA nanoparticles.

Dexamethasone is a widely used drug in medical and biological applications. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this anti-inflammatory drug in poly(lactic-co-glycolic acid) (PLGA) nanoparticles can minimize uncontrolled issues. As dexamethasone-encapsulated PLGA nanoparticles are synthesized in the presence of organic solvents, poly(dimethylsiloxane) (PDMS)-based microchannels collapse due to the swelling problem. In present study, PTFE nanoparticles were used for the surface modification of the microchannels to prevent absorption and adhesion of solvents into the microchannels' wall. The contact angle analysis of microchips after coating showed that the surface of microchannels bear the superhydrophobicity feature (140.30°) and SEM images revealed that PTFE covered the surface of PDMS, favorably. Then, the prepared microchip was tested for the synthesis of dexamethasone-loaded nanoparticles. SEM and atomic force microscopy (AFM) images of the synthesized nanoparticles represented that there was not any evidence of adhesion or absorption of nanoparticles. Furthermore, the monodispersity of nanoparticles was discernible. As AFM results revealed, the average diameters of 47, 63, and 82 nm were achieved for flow ratios of 0.01, 0.05, and 0.1, respectively. To evaluate the drug efficiency, cumulative release and encapsulation efficiency were analyzed which showed much more efficiency than the synthesized nanoparticles in the bulk mode. In addition, MTT test revealed that nanoparticles could be considered as a non-toxic material. Since the synthesis of drug-loaded nanoparticles is ubiquitous in laboratory experiments, the approach presented in this study can render more versatility in this regard.

Electrospinning of PVA/chitosan nanocomposite nanofibers containing gelatin nanoparticles as a dual drug delivery system.

Nanofibrous core-sheath nanocomposite dual drug delivery system based on poly(vinyl alcohol) (PVA)/chitosan/lidocaine hydrochloride loaded with gelatin nanoparticles were successfully prepared by the electrospinning method. Gelatin nanoparticles were prepared by nanoprecipitation and were then loaded with erythromycin antibiotic agent with the average particle size of ∼175 nm. The morphology of gelatin nanoparticles observed by field emission scanning electron microscopy (FE-SEM) was shown to be optimal at the concentration of 1.25 wt % of gelatin in aqueous phase by addition of 20 µL of glutaraldehyde 5% as the crosslinking agent. The nanoparticles were also characterized by dynamic light scattering, zeta potential measurement, and Fourier transform infrared spectroscopy (FTIR). The best bead free morphology for the PVA/chitosan nanofibrous mats were obtained at the solution weight ratio of 96/4. The nanofibrous mats were analyzed by swelling studies, FTIR and antibacterial tests. In vitro dual release profile of the core-sheath nanofibers was also studied within 72 h and showed the release efficiency equal to 84.69 and 75.13% for lidocaine hydrochloride and erythromycin, respectively. According to release exponent n, the release of lidocaine hydrochloride from the sheath part of the matrix is quasi-Fickian diffusion mechanism, while the release of erythromycin is based on anomalous or non-Fickian mechanisms.