Microfluidic Directed Synthesis of Alginate Nanogels with Tunable Pore Size for Efficient Protein Delivery

Abstract

Alginate is a biopolymer with favorable pH-sensitive properties for oral delivery of peptides and proteins. However, conventional alginate nanogels have limitations such as low encapsulation efficiency because of drug leaching during bead preparation and burst release in high pH values. These shortcomings originate from large pore size of the nanogels. In this work, we proposed an on-chip hydrodynamic flow focusing approach for synthesis of alginate nanogels with adjustable pore size to achieve fine-tunable release profile of the encapsulated bioactive agents. It is demonstrated that the microstructure of nanogels can be controlled through adjusting flow ratio and mixing time directed on microfluidic platforms consisting of cross-junction microchannels. In this study, the average pore size of alginate nanogels (i.e., average molecular weight between cross-links, Mc) was related to synthesis parameters. Mc was calculated from equations based on equilibrium swelling theory and proposed methods to modify the theory for pH-sensitive nanogels. In the equations we derived, size and compactness of nanogels are key factors, which can be adjusted by controlling the flow ratio. It was found that increase in flow ratio increases the size of nanogels and decreases their compactness. The size of on-chip generated nanogels for flow ratio of 0.02-0.2 was measured to be in the range of 68-138 nm. Moreover, a method based on the Mie theory was implemented to estimate the aggregation number (Nagg) of polymer chains inside the nanogels as an indicator of compactness. According to the size and compactness results along with equations of modified swelling theory, Mc obtained to be in the range of 0.5-0.8 kDa. The proposed method could be considered as a promising approach for efficient polypeptides encapsulation and their sustained release.

Continuous Production of Water‐Soluble Nanocrystals through Anti‐Solvent Precipitation in a Fluidic Device

“…At Qt=300 μL/min, the NaCl nanocrystals showed a broad size distribution in the range of 20 to 40 nm, which got narrower in size range from 17 to 24 nm at Qt=750 μL/min. In this method, Qt determines the residence time of the NaCl nanocrystals in the fluidic device and thus the extent of growth for the nanocrystals . The termination of crystal growth was marked by the time point at which the mixed solution entered the collection phase because the free Na + and Cl − ions would be immediately dispersed in the excess ethanol.…”

“…In this method, Qt determines the residence time of the NaCl nanocrystals in the fluidic device and thus the extent of growth for the nanocrystals. [30] The termination of crystal growth was marked by the time point at which the mixed solution entered the collection phase because the free Na + and Cl À ions would be immediately dispersed in the excess ethanol. The NaCl concentration would sharply drop to a level, below the minimum level needed to sustain crystal growth.…”

Autonomous Drug Release Systems with Disease Symptom‐Associated Triggers

“…The swelling of the anionic networks at basic media promotes the opening of pores and the release of encapsulated drug molecules. The reverse effect takes place at low pH values, making the polyacid‐based networks shrink and retaining the drug molecules from the outside environment . Polyacid‐based hydrogels have been widely used for oral drug delivery as they can protect the drugs from proteolytic degradation in the stomach and deliver the drugs to the intestine within a neutral environment .…”

“…The reverse effect takes place at low pH values, making the polyacid-based networks shrink and retaining the drug molecules from the outside environment. [77][78][79] Polyacid-based hydrogels have been widely used for oral drug delivery as they can protect the drugs from proteolytic degradation in the stomach and deliver the drugs to the intestine within a neutral environment. [80] Poly(acrylamidoglycolic acid) (PAGA), an important acrylamide-based polymer, has been extensively utilized in biomedical applications due to its biocompatibility and ability to remove toxic metal ions.…”

Application of minimally invasive injectable conductive hydrogels as stimulating scaffolds for myocardial tissue engineering

“…11,12 The hydrogels can be natural, synthetic or a mixture of them. 6,[13][14][15][16][17] Hydrogels in injectable form provide a less invasive delivery technique, reduce the healing time and diminish the risk of infection. To be injectable, they should be formed in situ due to physical and/or chemical crosslinking.…”