Hydrazone-Linkage-Based Self-Healing and Injectable Xanthan–Poly(ethylene glycol) Hydrogels for Controlled Drug Release and 3D Cell Culture

Sharma, Peeyush; Taneja, Sagarika; Singh, Yashveer

doi:10.1021/acsami.8b07310

Cited by 97 publications

(93 citation statements)

References 69 publications

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“… 77 , 78 In addition, drug delivery applications have utilized PEG hydrogels because of their biocompatibility and tunable degradation properties. 79 Features of hydrogels that may be important in various applications include mesh size, chemical composition, stiffness, and the presence of ligands or functional groups that interact with the cell surfaces.…”

Section: Resultsmentioning

confidence: 99%

Impact of Four Common Hydrogels on Amyloid-β (Aβ) Aggregation and Cytotoxicity: Implications for 3D Models of Alzheimer’s Disease

et al. 2020

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The physiochemical properties of hydrogels utilized in 3D culture can be used to modulate cell phenotype and morphology with a striking resemblance to cellular processes that occur in vivo . Indeed, research areas including regenerative medicine, tissue engineering, in vitro cancer models, and stem cell differentiation have readily utilized 3D biomaterials to investigate cell biological questions. However, cells are only one component of this biomimetic milieu. In many models of disease such as Alzheimer’s disease (AD) that could benefit from the in vivo -like cell morphology associated with 3D culture, other aspects of the disease such as protein aggregation have yet to be methodically considered in this 3D context. A hallmark of AD is the accumulation of the peptide amyloid-β (Aβ), whose aggregation is associated with neurotoxicity. We have previously demonstrated the attenuation of Aβ cytotoxicity when cells were cultured within type I collagen hydrogels versus on 2D substrates. In this work, we investigated the extent to which this phenomenon is conserved when Aβ is confined within hydrogels of varying physiochemical properties, notably mesh size and bioactivity. We investigated the Aβ structure and aggregation kinetics in solution and hydrogels composed of type I collagen, agarose, hyaluronic acid, and polyethylene glycol using fluorescence correlation spectroscopy and thioflavin T assays. Our results reveal that all hydrogels tested were associated with enhanced Aβ aggregation and Aβ cytotoxicity attenuation. We suggest that confinement itself imparts a profound effect, possibly by stabilizing Aβ structures and shifting the aggregate equilibrium toward larger species. If this phenomenon of altered protein aggregation in 3D hydrogels can be generalized to other contexts including the in vivo environment, it may be necessary to reevaluate aspects of protein aggregation disease models used for drug discovery.

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Section: Resultsmentioning

confidence: 99%

Impact of Four Common Hydrogels on Amyloid-β (Aβ) Aggregation and Cytotoxicity: Implications for 3D Models of Alzheimer’s Disease

et al. 2020

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“…Hydrazone crosslinked hydrogels have an excellent record of biological performance in tissue engineering scaffolds, 3D bioprinting, as well as drug and growth factor delivery. Toward leveraging this chemistry for clinical translation, Purcell et al .…”

Section: Dynamic Covalent Chemistry To Form Hydrogelsmentioning

confidence: 99%

“…25 Toward tuning stability, gelation kinetics, and mechanical properties of hydrazone-based systems, recent studies have been reported on incorporation of neighboring heteroatom (N3) for delocalization of the developing N2 positive charge, 197 combination of ketone (slow reacting) and aldehyde (fast reacting) groups, 198 and reinforcement through cellulose nanocrystals. 199 Hydrazone crosslinked hydrogels have an excellent record of biological performance in tissue engineering scaffolds, [200][201][202] 3D bioprinting, 203 as well as drug 24,25 and growth factor 26 delivery. Toward leveraging this chemistry for clinical translation, Purcell et al developed bioresponsive HA hydrogels based on hydrazone linkages and encapsulated heparin binding recombinant TIMP-3 to limit the progression to heart failure in a porcine model of myocardial infarction.…”

Section: Dynamic Covalent Chemistry To Form Hydrogelsmentioning

confidence: 99%

Recent advances in shear‐thinning and self‐healing hydrogels for biomedical applications

Uman

Dhand

Burdick

2019

J of Applied Polymer Sci

237

215

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Shear‐thinning and self‐healing hydrogels are being investigated in various biomedical applications including drug delivery, tissue engineering, and 3D bioprinting. Such hydrogels are formed through dynamic and reversible interactions between polymers or polypeptides that allow these shear‐thinning and self‐healing properties, including physical associations (e.g., hydrogen bonds, guest–host interactions, biorecognition motifs, hydrophobicity, electrostatics, and metal–ligand coordination) and dynamic covalent chemistry (e.g., Schiff base, oxime chemistry, disulfide bonds, and reversible Diels–Alder). Their shear‐thinning properties allow for injectability, as the hydrogel exhibits viscous flow under shear, and their self‐healing nature allows for stabilization when shear is removed. Hydrogels can be formulated as uniform polymer and polypeptide assemblies, as hydrogel nanocomposites, or in granular hydrogel form. This review focuses on recent advances in shear‐thinning and self‐healing hydrogels that are promising for biomedical applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48668.

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“…The bioactivity of HA hydrogels has been utilized in stem cell differentiation and patient cancer cell expansion for personalized medicine [71–72]. In addition, drug delivery applications have utilized PEG hydrogels due to their biocompatibility and tunable degradation properties [73]. Features of hydrogels that may be important in applications include mesh size, chemical composition, stiffness, and the presence of ligands or functional groups that interact with the cell surfaces.…”

Section: Discussionmentioning

confidence: 99%

Impact of four common hydrogels on amyloid-β (Aβ) aggregation and cytotoxicity: Implications for 3D models of Alzheimer’s disease

Simpson

Szeto

Boukari

et al. 2019

Preprint

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The properties of a hydrogel utilized in 3D culture can influence cell phenotype and morphology, yielding striking similarities to cellular processes that occur in vivo. Indeed, research areas including regenerative medicine, tissue engineering, cancer models, and stem cell cultures have readily utilized 3D biomaterials to investigate cell biological questions. However, cells are only one component of this milieu. Macromolecules play roles as bioactive factors and physical structures. Yet, investigations of macromolecular biophysics largely focus on pure molecules in dilute solution. Biophysical processes such as protein aggregation underlie diseases including Alzheimer’s disease, which is hallmarked by accumulated neurotoxic amyloid-β (Aβ) aggregates. Previously, we demonstrated that Aβ cytotoxicity is attenuated when cells are cultured within type I collagen hydrogels vs. on 2D substrates. Here, we investigated whether this phenomenon is conserved when Aβ is confined within hydrogels of varying physiochemical properties, notably mesh size and bioactivity. We investigated Aβ structure and aggregation kinetics in solution and in hydrogels (collagen, agarose, hyaluronic acid and polyethylene glycol) using fluorescence correlation spectroscopy and thioflavin T assays. Our results reveal that all hydrogels tested were associated with Aβ cytotoxicity attenuation. We suggest that confinement itself imparts a profound effect, possibly by stabilizing Aβ structures and shifting the aggregate equilibrium toward larger species. It is likely that the milieu that exist within cells and tissues also influences protein-protein interactions; thus, we suggest that it is critical to evaluate whether protein structure, function, and stability are altered in 3D systems vs. ideal solutions and 2D culture.

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Hydrazone-Linkage-Based Self-Healing and Injectable Xanthan–Poly(ethylene glycol) Hydrogels for Controlled Drug Release and 3D Cell Culture

Cited by 97 publications

References 69 publications

Impact of Four Common Hydrogels on Amyloid-β (Aβ) Aggregation and Cytotoxicity: Implications for 3D Models of Alzheimer’s Disease

Impact of Four Common Hydrogels on Amyloid-β (Aβ) Aggregation and Cytotoxicity: Implications for 3D Models of Alzheimer’s Disease

Recent advances in shear‐thinning and self‐healing hydrogels for biomedical applications

Impact of four common hydrogels on amyloid-β (Aβ) aggregation and cytotoxicity: Implications for 3D models of Alzheimer’s disease

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