microfluidic-synthesis-microgel-building-blocks-for-microporous

Microfluidic Synthesis of Microgel Building Blocks for Microporous Annealed Particle Scaffold

The microporous annealed particle (MAP) scaffold platform is a subclass of granular hydrogels. It is composed of an injectable slurry of microgels that ...

University of Virginia

The purpose of this study was to develop and provide evidence of a novel permanent injectable biomaterial for vocal fold augmentation with the potential to treat glottic incompetence by evaluating its performance in two animal models.

Development of a microporous annealed particle hydrogel for long-term vocal fold augmentation.

Microporous annealed particle (MAP) scaffolds consist of a slurry of hydrogel microspheres that undergo annealing to form a solid scaffold. MAP scaffolds have contained functional groups with dual abilities to participate in Michael-type addition (gelation) and radical polymerization (photoannealing). Functional groups with efficient Michael-type additions react with thiols and amines under physiological conditions, limiting usage for therapeutic delivery. We present a heterofunctional maleimide/methacrylamide 4-arm PEG macromer (MethMal) engineered for selective photopolymerization compatible with multiple polymer backbones. Rheology using two classes of photoinitiators demonstrates advantageous photopolymerization capabilities. Functional assays show benefits for therapeutic delivery and 3D printing without impacting cell viability.

Selective and Improved Photoannealing of Microporous Annealed Particle (MAP) Scaffolds.

Mimicking growth factor-ECM interactions for promoting cell migration is a powerful technique to improve tissue integration with biomaterial scaffolds for the regeneration of damaged tissues. This has been attempted by scaffold-mediated controlled delivery of exogenous growth factors; however, the predetermined nature of this delivery can limit the scaffold's ability to meet each wound's unique spatiotemporal regenerative needs and presents translational hurdles. To address this limitation, we present a new approach to growth factor presentation by incorporating heparin microislands, which are spatially isolated heparin-containing microparticles that can reorganize and protect endogenous local growth factors via heterogeneous sequestration at the microscale  and result in functional improvements in wound healing. More specifically, we incorporated our heparin microislands within microporous annealed particle (MAP) scaffolds, which allows facile tuning of microenvironment heterogeneity through ratiometric mixing of microparticle sub-populations. In this manuscript, we demonstrate the ability of heparin microislands to heterogeneously sequester applied growth factor and control downstream cell migration . Further, we present their ability to significantly improve wound healing outcomes (epidermal regeneration and re-vascularization) in a diabetic wound model relative to two clinically relevant controls.

Heparin Microislands in Microporous Annealed Particle Scaffolds for Accelerated Diabetic Wound Healing.

Biomaterials capable of generating growth factor gradients have shown success in guiding tissue regeneration, as growth factor gradients are a physiologic driver of cell migration. Of particular importance, a focus on promoting endothelial cell migration is vital to angiogenesis and new tissue formation. Microporous Annealed Particle (MAP) scaffolds represent a unique niche in the field of regenerative biomaterials research as an injectable biomaterial with an open porosity that allows cells to freely migrate independent of material degradation. Recently, we have used the MAP platform to heterogeneously include spatially isolated heparin-modified microgels (heparin microislands) which can sequester growth factors and guide cell migration. In in vitro sprouting angiogenesis assays, we observed a parabolic relationship between the percentage of heparin microislands and cell migration, where 10% heparin microislands had more endothelial cell migration compared to 1% and 100%. Due to the low number of heparin microisland ratios tested, we hypothesize the spacing between microgels can be further optimized. Rather than use purely empirical methods, which are both expensive and time intensive, we believe this challenge represents an opportunity to use computational modeling. Here we present the first agent-based model of a MAP scaffold to optimize the ratio of heparin microislands. Specifically, we develop a two-dimensional model in Hybrid Automata Library (HAL) of endothelial cell migration within the unique MAP scaffold geometry. Finally, we present how our model can accurately predict cell migration trends in vitro, and these studies provide insight on how computational modeling can be used to design particle-based biomaterials. STATEMENT OF SIGNIFICANCE: : While the combination of experimental and computational approaches is increasingly being used to gain a better understanding of cellular processes, their combination in biomaterials development has been relatively limited. Heparin microislands are spatially isolated heparin microgels; when located within a microporous annealed particle (MAP) scaffold, they can sequester and release growth factors. Importantly, we present the first agent-based model of MAP scaffolds to optimize the ratio of heparin microislands within the scaffold to promote endothelial cell migration. We demonstrate this model can accurately predict trends in vitro, thus opening a new avenue of research to aid in the design of MAP scaffolds.

Article	Year
Development of a microporous annealed particle hydrogel for long-term vocal fold augmentation. The Laryngoscope\| PubMed ID: 31821567	2020
Selective and Improved Photoannealing of Microporous Annealed Particle (MAP) Scaffolds. ACS biomaterials science & engineering\| PubMed ID: 33423459	2021
Heparin Microislands in Microporous Annealed Particle Scaffolds for Accelerated Diabetic Wound Healing. Advanced functional materials\| PubMed ID: 34539306	2021
In silico optimization of heparin microislands in microporous annealed particle (MAP) hydrogel for endothelial cell migration. Acta biomaterialia\| PubMed ID: 35660016	2022

Lauren Pruett

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