Ganan-V1,3 10

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In this review, we fundamentally focus on those tools designed for con-trolled liquid fragmentation. Among these tools, flow focusing and, in par-ticular, axisymmetric flow focusing with discharge in an open environment(also known as 3D flow focusing and commercially as Flow Focusing) haveprovided the most promising combination of mass productivity, control and

reproducibility for massive manufacturing of products (mainly, microencap-sulated stuff) for use in health care and nutrition. A profound revision of thewhole fluid physics behind that remarkable microfluidic tool is also offered,as well as a review of results already obtained in therapeutic applications.

2. Droplet-based microfluidics

2.1. Microfluidics 

In a broad sense, microfluidics can be regarded as the set of methods, pro-cedures, and techniques designed to precisely manipulate fluids which are ge-

ometrically constrained to a submillimeter scale. This manipulation includesthe production of fluid entities such as jets, drops, bubbles, emulsions, andcapsules, as well as the motion, arrangement, separation, and mixing of suchentities to form more complex fluidic structures and induce chemical reac-tions. The physics of fluids on the submillimeter scale is characterized by theimportance of viscous forces, diffusion, and surface effects. On the contrary,liquid inertia and gravity are generally neglected. Microfluidics possesses anenormous relevance in a great variety of fields such as pharmacy, microbi-ology, chemical engineering, and biotechnology. It may revolutionize in themid and long-term future several disciplines, including drug discovery anddelivery, shifting some of the current paradigms of, for instance, cell biology

and tissue engineering.Microfluidic technologies fall into two main categories: continuous (often

referred to as analogical) and droplet-based (digital) microfluidics. The for-mer is based on the manipulation of continuous fluid streams across micro-channels due to the action of external actuators. These actuators includemechanical pumps, integrated mechanical micropumps, and external pres-sure sources. One can also resort to combinations of capillary forces andelectrokinetic mechanisms such as electroosmosis, electrophoresis, and dielec-trophoresis. Continuous-flow microfluidics is suitable for simple biochemicalapplications, including chemical separation. It is less adequate when highdegree of flexibility or system integrations are required, and lacks high fault-tolerance capability. These limitations are partially overcome in droplet-

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