Ultrasound‐Triggered Enzymatic Gelation

Abstract

Hydrogels are formed using various triggers, including light irradiation, pH adjustment, heating, cooling, or chemical addition. Here, a new method for forming hydrogels is introduced: ultrasound‐triggered enzymatic gelation. Specifically, ultrasound is used as a stimulus to liberate liposomal calcium ions, which then trigger the enzymatic activity of transglutaminase. The activated enzyme catalyzes the formation of fibrinogen hydrogels through covalent intermolecular crosslinking. The catalysis and gelation processes are monitored in real time and both the enzyme kinetics and final hydrogel properties are controlled by varying the initial ultrasound exposure time. This technology is extended to microbubble–liposome conjugates, which exhibit a stronger response to the applied acoustic field and are also used for ultrasound‐triggered enzymatic hydrogelation. To the best of the knowledge, these results are the first instance in which ultrasound is used as a trigger for either enzyme catalysis or enzymatic hydrogelation. This approach is highly versatile and can be readily applied to different ion‐dependent enzymes or gelation systems. Moreover, this work paves the way for the use of ultrasound as a remote trigger for in vivo hydrogelation.

Expanding and optimizing 3D bioprinting capabilities using complementary network bioinks

“…Our demonstration of soft hydrogel printing for astrocyte culture indicates the suitability of complementary network bioinks for the biofabrication of living constructs of soft-tissue origins (e.g., other neural cells, adipose, kidney, pancreas, and lung). While we have presented an extensive library of complementary network bioinks comprising 12 photocrosslinkable polymers, this approach should be generalizable to other hydrogel networks with alternative crosslinking mechanisms, such as those triggered by the addition of chemical crosslinkers, changes in pH, enzyme catalysis, or exposure to ultrasound ( 7 , 27 , 28 ). The only classes of biomaterials that should pose difficulties are those that cannot be made miscible with gelatin and those that rely on an opposing thermal gelation (e.g., poloxamer 407).…”

Stimuli‐Responsive Biomaterials: Scaffolds for Stem Cell Control

“…Ultrasound, pressure waves oscillating at frequencies at or above 20 kHz, can be employed as a powerful remote stimulus for biomaterials. The oscillating pressure [176,177] and resulting mechanical effects generated by ultrasound have been harnessed for various biomedical applications including controlled release from acoustically responsive carriers, [14,[178][179][180] acoustically triggered hydrogelation, [181] enhancement of agent transdermal permeability via sonophoresis, [182] in vitro manipulation of cells into defined geometric assemblies, [183] and the temporary disruption of biological barriers to facilitate drug entry. [184,185] Generated mechanical effects of relevance to delivery include acoustic cavitation, which is the forced size oscillation or growth and collapse of gas microbubbles within a fluid, [186] as well as related fluid streaming.…”

Tailoring Gelation Mechanisms for Advanced Hydrogel Applications

“…Release of crosslinking species from a temperature-responsive carrier -Alginate hydrogels [120] -Fibrinogen hydrogels [120] -PEG-based hydrogels [121] Ultrasound Release of crosslinking species from an ultrasound-responsive carrier -Fibrinogen hydrogels [123]…”

“…Ultrasound-triggered release of cargo has been widely used for drug delivery [122] and has very recently been applied to initiate hydrogelation. [123] There are a number of ultrasound-responsive carriers, including many liposomes, [124,125] micelles, [126] polymersomes, [127] microbubbles, [128,129] and phase-shift nanodroplets. [130] There are also several different mechanisms that can be used for cargo release.…”

“…Microbubbles are commonly used in combination with high‐frequency fields and clinically used focused ultrasound systems, which offers the opportunity to remotely trigger gelation with high spatiotemporal control (≈1 mm) and at high penetration depths (≈ 13 cm focal length for tissue, depending on the parameters used). [ 123,129,133 ]…”