Injectable Drug‐Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction

Abstract

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drugreleasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.

From vesicles to materials: bioinspired strategies for fabricating hierarchically structured soft matter

“…The adhesion between adjacent particles can be further improved if they are covalently crosslinked either upon direct contact, [121] light exposure, [70,71] or through enzymatically activated reactions, [68] as exemplified in figure 3 e . The covalent inter-particle crosslinking increases Young's modulus of the granular materials by a factor of 1.5 [70].…”

Anisotropic Rod-Shaped Particles Influence Injectable Granular Hydrogel Properties and Cell Invasion

“…[12,13] Thus, granular hydrogels are ideally suited to promote the invasion of cells and blood vessels when used as injectable scaffolds for tissue repair. These desirable characteristics have motivated the development and application of granular hydrogels towards various biomedical applications including drug delivery, [14,15] immune modulation, [13,16] modular fabrication of biomaterials including with 3D printing, [17–19] and as cell-instructive scaffolds. [20–22]…”

“…In contrast to traditionally used non-porous bulk hydrogels, highly porous granular hydrogels support the invasion of cells and blood vessels within their volume, thereby fostering the requisite biological activity to promote endogenous tissue repair. [4,14,21] While several previous studies have investigated the adhesion, spreading, and migration of single cells throughout granular hydrogels as a function of particle properties, it remains unknown how endothelial cell sprouting – a process that mimics angiogenesis – is influenced by granular hydrogel properties. [34,35] This investigation is challenging in vitro because cells preferentially adhere and proliferate on particle surfaces, which reduces their ability to form lumen-like sprouts.…”

“…[12,13] Thus, granular hydrogels are ideally suited to promote the invasion of cells and blood vessels when used as injectable scaffolds for tissue repair. These desirable characteristics have motivated the development and application of granular hydrogels towards various biomedical applications including drug delivery, [14,15] immune modulation, [13,16] modular fabrication of biomaterials including with 3D printing, [17][18][19] and as cell-instructive scaffolds. [20][21][22] While much of the recent work on granular hydrogels has focused on tuning particle surface chemistry, [12] inter-particle crosslinking, [23] and varying other physical properties including stiffness and degradability, [24,25] the influence of particle shape on interstitial pore characteristics to guide cell invasion has remained relatively unexplored.…”

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

“…One of these approaches was conceived to deliver Forskolin and Repsox, which have previously been used in a reprogramming cocktail [128,141], using microporous annealing particles incapsulated into hydrogel blocks to drive tissue growth and local compound release. Although not aimed at cardiac reprogramming, these experiments showed that chemical reprogramming compounds could be released in a time and space dependent manner, retaining their ability to functionally modulate the activity of CMs, CFs, and ECs both in vitro and in vivo settings [165]. The second experience reports a nanoparticle based simultaneous delivery of CHIR99021 and Fibroblast Growth Factor 1 (FGF1).…”