quantifying-three-dimensional-cell-migration-within-into-granular

Quantifying Three-Dimensional Cell Migration Within and Into Granular Hydrogel Biomaterials

Granular hydrogel scaffolds hold significant potential in regenerative medicine, functioning either as carriers for cell delivery or as interfaces for ...

University of Virginia

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.

In silico optimization of heparin microislands in microporous annealed particle (MAP) hydrogel for endothelial cell migration.

Biomaterial-enabled de novo formation of non-fibrotic tissue in situ would provide an important tool to physicians. One example application, glottic insufficiency, is a debilitating laryngeal disorder wherein vocal folds do not fully close, resulting in difficulty speaking and swallowing. Preferred management of glottic insufficiency includes bulking of vocal folds via injectable fillers, however, the current options have associated drawbacks including inflammation, accelerated resorption, and foreign body response. We developed a novel iteration of microporous annealed particle (MAP) scaffold designed to provide persistent augmentation. Following a 14-month study of vocal fold augmentation using a rabbit vocal paralysis model, most MAP scaffolds were replaced with tissue de novo that matched the mixture of fibrotic and non-fibrotic collagens of the contralateral vocal tissue. Further, persistent tissue augmentation in MAP-treated rabbits was observed via MRI and via superior vocal function at 14 months relative to the clinical standard.

De novo tissue formation using custom microporous annealed particle hydrogel provides long-term vocal fold augmentation.

Volumetric muscle loss (VML) from severe traumatic injuries results in irreversible loss of contractile tissue and permanent functional deficits. These injuries resist endogenous healing and clinical treatment due to excessive inflammation, leading to fibrosis, muscle fiber denervation, and impaired regeneration. Using a rodent tibialis anterior VML model, this study demonstrates microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration. Unlike bulk (nanoporous) hydrogel scaffolds, MAP scaffolds enhance integration by preventing a foreign body reaction, slowing implant degradation, and promoting regenerative macrophage polarization. Cell migration and angiogenesis occur throughout the implant before MAP scaffold degradation, with muscle fibers and neuromuscular junctions forming within the scaffolds. These structures continue developing as the implant degrades, suggesting MAP hydrogel scaffolds offer a promising therapeutic approach for VML injuries.

Article	Year
In silico optimization of heparin microislands in microporous annealed particle (MAP) hydrogel for endothelial cell migration. Acta biomaterialia\| PubMed ID: 35660016	2022
De novo tissue formation using custom microporous annealed particle hydrogel provides long-term vocal fold augmentation. NPJ Regenerative medicine\| PubMed ID: 36823180	2023
Cell-scale porosity minimizes foreign body reaction and promotes innervated myofiber formation after volumetric muscle loss. NPJ Regenerative medicine\| PubMed ID: 40025057	2025

Don Griffin

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