Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds

Koh, Jaekyung; Griffin, Donald R.; Archang, Maani M.; Feng, An‐Chieh; Horn, Thomas; Margolis, Michael; Zalazar, David; Segura, Tatiana; Scumpia, Philip O.; Carlo, Dino Di

doi:10.1002/smll.201903147

Cited by 88 publications

(96 citation statements)

References 49 publications

(62 reference statements)

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“…Our current method to fabricate MAP scaffolds for use in vivo utilizes the coagulation enzyme FXIIIa, which is a transglutaminase. [ 2,5,11 ] The HMPs are packed and linked between K and Q peptides, recognized by FXIIIa, on their surface. For applications in wound healing, polyethylene glycol (PEG) HMPs annealed with FXIIIa in situ have been shown to promote cutaneous tissue regeneration by supporting cell migration and support tissue structure formation.…”

Section: Figurementioning

confidence: 99%

Click by Click Microporous Annealed Particle (MAP) Scaffolds

Darling

Sideris

et al. 2020

Adv Healthcare Materials

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density of 0.58 and jamming can occur. In our laboratory, we crosslink HMPs to each other to generate a stable scaffold, rather than rely on jamming such that the void spaces surrounding the beads are sufficiently large for cellular growth and the scaffold is structurally stable. We termed these bulk hydrogels microporous annealed particle (MAP) scaffolds due to the micron sized voids (pores) formed in between packed beads. MAP scaffolds support modifications with bioactive ligands to modulate cell behavior, can be used for cell culture in vitro, [1][2][3][4][5][6][7][8] and support tissue ingrowth in vivo. [2][3][4][5] Of particular interest is that injection of MAP scaffolds into wound sites results in reduced inflammation and improved tissue regeneration. [3,4,9,10] We have shown that the innate microporosity of MAP scaffolds enables a greater prorepair response in the wound site after stroke compared to a nonporous gel of the same composition. [5] The "plug and play" modularity of MAP building blocks enables the incorporation of different materials, signals, and crosslinking schemes to tune the scaffolds for unique tissue engineering applications. Herein, we demonstrate the generation of hyaluronic acid HMPs, the modification of HMPs with ligands, and the crosslinking of HMPs to form MAP scaffolds using thiol-norbornene and tetrazine-norbornene click reactions and their use in vitro and in vivo.HMP interlinking to form MAP scaffolds can be achieved upon injection due to the shear thinning properties of these granular materials and the use of biocompatible mechanisms for annealing. Our current method to fabricate MAP scaffolds for use in vivo utilizes the coagulation enzyme FXIIIa, which is a transglutaminase. [2,5,11] The HMPs are packed and linked between K and Q peptides, recognized by FXIIIa, on their surface. For applications in wound healing, polyethylene glycol (PEG) HMPs annealed with FXIIIa in situ have been shown to promote cutaneous tissue regeneration by supporting cell migration and support tissue structure formation. In vivo responses to these injectable PEG MAP scaffolds include re-epithelialization, vascular development, and growth of hair follicles. [2] Utilizing the native extracellular matrix component hyaluronic acid (HA) with FXIIIa for scaffold fabrication accelerates brain repair processes after stroke. [5] Compared to both sham injections and nonporous gels, HA MAP reduces Macroporous scaffolds are being increasingly used in regenerative medicine and tissue repair. While the recently developed microporous annealed particle (MAP) scaffolds have overcome issues with injectability and in situ hydrogel formation, limitations with respect to tunability to be able to manipulate hydrogel strength and rigidity for broad applications still exist. To address these key issues, here hydrogel microparticles (HMPs) of hyaluronic acid (HA) are synthesized using the thiol-norbornene click reaction and then HMPs are subsequently annealed into a porous scaffold using the tetrazine-norbornene click reacti...

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Section: Figurementioning

confidence: 99%

Click by Click Microporous Annealed Particle (MAP) Scaffolds

Darling

Sideris

et al. 2020

Adv Healthcare Materials

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“…The Segura lab also demonstrated this concept in vivo, where stiffness, degradability, and adhesive ligand concentration could all be varied to control the immunogenic response and cell infiltration into the porous scaffold. [135] Microgel scaffold modulus has been varied from several Pascals (Pa) for endothelial cell network formation, [134] several hundred Pascals to match vocal fold tissue strength, [64] several kPa for differentiation of stem cell spheroids, [136] to several MPa in doubly cross-linked networks for supporting degenerated intervertebral discs. [137] The wide range of achievable mechanics, as well as the ability to independently tune multiple parameters, demonstrate how microgel mechanics can be designed to mimic the ECM of specific tissues in order to optimize culture for specific cell types.…”

Section: Scaffold Propertiesmentioning

confidence: 99%

“…Scaffold properties (e.g., stiffness, degradability, and ligand presentation) can be modified to tune the regenerative properties and biological response to the material ( Figure 5B). [135] As microgels serve as individual building blocks in assembled scaffolds and may be tuned and functionalized independently, this approach may be exploited to include multiple different cues within a single scaffold for rapid wound healing. While microgel assembled networks have been used sparingly for in vivo applications, their inherent porosity can provide immediate advantages for regenerating tissue more effectively compared to bulk injectable materials.…”

Section: Assembled Microgelsmentioning

confidence: 99%

Designing Microgels for Cell Culture and Controlled Assembly of Tissue Microenvironments

Caldwell

Aguado

2019

Adv Funct Materials

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Micrometer‐sized hydrogels, termed microgels, are emerging as multifunctional platforms that can recapitulate tissue heterogeneity in engineered cell microenvironments. The microgels can function as either individual cell culture units or can be assembled into larger scaffolds. In this manner, individual microgels can be customized for single or multicell coculture applications, or heterogeneous populations can be used as building blocks to create microporous assembled scaffolds that more closely mimic tissue heterogeneities. The inherent versatility of these materials allows user‐defined control of the microenvironments, from the order of singly encapsulated cells to entire 3D cell scaffolds. These hydrogel scaffolds are promising for moving towards personalized medicine approaches and recapitulating the multifaceted microenvironments that exist in vivo.

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“…The stroke model was performed as previously described. Briefly, a permanent cortical photothrombotic stroke was induced on young adult C57BL/6 male mice (8)(9)(10)(11)(12) weeks) obtained from Jackson laboratories (Bar Harbor, ME). The mice were anesthetized with 5% isoflurane and placed in a stereotactic setup.…”

Section: Resultsmentioning

confidence: 99%

“…Our current method to fabricate MAP scaffolds for use in vivo utilizes the coagulation enzyme FXIIIa, which is a transglutaminase 2,5,11 . The HMPs are packed and linked between K and Q peptides, recognized by FXIIIa, on their surface.…”

Section: Introductionmentioning

confidence: 99%

Click by Click Microporous Annealed Particle (MAP) Scaffolds

Darling

Sideris

et al. 2019

Preprint

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AbstractMacroporous scaffolds are being increasingly used in regenerative medicine and tissue repair. While our recently developed microporous annealed particle (MAP) scaffolds have overcome issues with injectability and in situ hydrogel formation, limitations with respect to tunability to be able to manipulate hydrogel strength and rigidity for broad applications still exist. To address these key issues, here we synthesized hydrogel microparticles (HMPs) of hyaluronic acid (HA) using the thiol-norbornene click reaction and then subsequently annealed HMPs into a porous scaffold using the tetrazine-norbornene click reaction. This assembly method allowed for straightforward tuning of bulk scaffold rigidity by varying the tetrazine to norbornene ratio, with increasing tetrazine resulting in increasing scaffold storage modulus, Young’s modulus, and maximum stress. These changes were independent of void fraction. Further incorporation of human dermal fibroblasts (HDFs) throughout the porous scaffold revealed the biocompatibility of this annealing strategy as well as differences in proliferation and cell-occupied volume. Finally, injection of porous HA-Tet MAP scaffolds into an ischemic stroke model showed this chemistry is biocompatible in vivo with reduced levels of inflammation and astrogliosis as previously demonstrated for other crosslinking chemistries.

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Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds

Cited by 88 publications

References 49 publications

Click by Click Microporous Annealed Particle (MAP) Scaffolds

Click by Click Microporous Annealed Particle (MAP) Scaffolds

Designing Microgels for Cell Culture and Controlled Assembly of Tissue Microenvironments

Click by Click Microporous Annealed Particle (MAP) Scaffolds

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