Endogenously triggered delivery of therapeutics from injectable microgels for muscle regeneration
Biomaterials
Orthopaedics, Traumatology, Reconstructive Surgery
Final Report Abstract
Granular hydrogels are an emerging class of biomaterials for tissue engineering applications. Compared to traditional bulk hydrogels, granular hydrogels are assembled through the packing of hydrogel microparticles and combine multiple desirable features including inherent porosity, modular design, and injectability. These features permit minimally invasive injection into sites of tissue damage, local delivery of multiple therapeutics, and endogenous cell invasion leading to improved integration with host tissue. Being a relatively nascent field, much remains to be explored about how different processing variables impact the properties of granular hydrogels and affect its utility for biomedical applications. The focus of this DFG-funded individual fellowship was on (a) the establishment of methods to characterize the unique properties of granular hydrogels, (b) leveraging these methods to investigate how particle fabrication method impacts eventual granular hydrogel properties, and (c) improve granular hydrogel functionality through innovative particle design. During the course of this fellowship, I established methods to characterize the structural and biological properties of granular hydrogels. These characterization methods provided novel insights into the structural organization of granular hydrogels – more specifically on how microparticle size and processing influence overall porosity, size and number of pores, and how these pores are interconnected in the three dimensional space. A novel 3D angiogenic sprouting assay was also established to screen how granular hydrogel properties influence cell sprouting and invasion behavior. The methods were crucial to optimize biomaterial formulations for in vivo studies. In another study, we investigated how the microparticle fabrication method influences eventual granular hydrogel properties. The findings from this study highlighted how particle size distribution (monodisperse vs. polydisperse) and shape (spherical vs. fragmented) impacted particle packing, granular hydrogel porosity, rheological properties, and syringe extrusion behavior. Finally, towards making the next generation of injectable granular hydrogels that integrate with host tissue and accelerate cell invasion, we investigated the impact of changing particle shape from isotropic spheres to anisotropic rods. Rod-shaped particles formed granular hydrogels that had anisotropic and interconnected pores, with pore size and number influenced by particle shape and degree of packing. Robust in vitro sprouting of endothelial cells from embedded cellular spheroids was observed with rod-shaped particles, including higher sprouting densities and sprout lengths when compared to hydrogels with spherical particles. Cell and vessel invasion into granular hydrogels when injected subcutaneously in vivo were significantly greater with rodshaped particles, whereas a gradient of cellularity was observed with spherical particles. Overall, this work demonstrated potentially superior functional properties of granular hydrogels with rodshaped particles for tissue repair. In summary, this fellowship resulted in new advances and developments in the field of novel, injectable granular hydrogels for endogenous tissue engineering applications.
Publications
- Granular Hydrogels for Endogenous Tissue Repair, Biomaterials and Biosystems 1, 100008, 2021
TH Qazi, JA Burdick
(See online at https://doi.org/10.1016/j.bbiosy.2021.100008) - Influence of microgel fabrication technique on granular hydrogel properties, ACS Biomaterials Science and Engineering, 7, 4269, 2021
VG Muir, TH Qazi, J Shan, J Groll, JA Burdick
(See online at https://doi.org/10.1021/acsbiomaterials.0c01612) - Anisotropic rod-shaped particles influence injectable granular hydrogel properties and cell invasion. Advanced Materials, 2109194, 2022
TH Qazi, J Wu, VG Muir, S Weintraub, S Gullbrand, D Lee, D Issadore, JA Burdick
(See online at https://doi.org/10.1002/adma.202109194) - Methods to characterize granular hydrogel rheological properties, porosity, and cell invasion. ACS Biomaterials Science and Engineering, 8(4), 1427-1442, 2022
TH Qazi, VG Muir, JA Burdick
(See online at https://doi.org/10.1021/acsbiomaterials.1c01440) - Programming hydrogels to probe spatiotemporal cell biology. Cell Stem Cell, 29(5), 678-691, 2022
TH Qazi, M Blatchley, MD Davidson, FM Yavitt, ME Cooke, KS Anseth, JA Burdick
(See online at https://doi.org/10.1016/j.stem.2022.03.013) - Simultaneous one-pot interpenetrating network formation to expand 3D processing capabilities. Advanced Materials, 2202261, 2022
AP Dhand, MD Davidson, JH Galarraga, TH Qazi, RC Locke, RL Mauck, JA Burdick
(See online at https://doi.org/10.1002/adma.202202261) - Sticking together: Injectable granular hydrogels with increased functionality via dynamic covalent inter-particle crosslinking, Small, 2201115, 2022
VG Muir, TH Qazi, S Weintraub, BOT Maldonado, PE Arratia, JA Burdick
(See online at https://doi.org/10.1002/smll.202201115)
