Micro-hydrogel injectables that deliver effective CAR-T immunotherapy against 3D solid tumor spheroids

Suraiya, Anisha B.; Evtimov, Vera; Truong, Vinh X.; Boyd, Richard; Forsythe, John S.; Boyd, Nicholas

doi:10.1016/j.tranon.2022.101477

Cited by 12 publications

(11 citation statements)

References 42 publications

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“…These studies suggest that some cells are more vulnerable when exposed to fluid shear than others 32,33 suggesting that the effects should be verified for each individual cell type tested. However, in our previous work, the flow rate ratio of 4:1 mL −1 (oil versus hydrogel phase) was applied to several cell types (mesenchymal stromal cells, 5,26 human fetal chondroprogenitor cells, 29 human articular chondrocytes, 29 CAR-T cells, 27 coculture of hematopoietic stem cells, and OP9-DL cells (bone marrow stromal cells transduced to express the Notch ligand, Delta-like 1 or 4)) 22 without any negative effects on cell viability. A further reduction in microgel size was achieved by using minimal ID tubing (1.44 mm), which allowed the 33G needle to be used (Figure 4D).…”

Section: Anticipated Resultsmentioning

confidence: 99%

“…The gelatin provides cell recognition function for cell adhesion and remodeling, while the PEG improves the mechanical properties, enabling a highly biocompatible system that has been proven to support cell viability and function. , However, other polymer formulations, such as the inclusion of functionalized hyaluronic acid are possible, providing the hydrogel precursor can flow through the device and be cross-linked by light postmicrogel fabrication. The procedure can also be adapted for varying cell types. , …”

Section: Introductionmentioning

confidence: 99%

“…The procedure can also be adapted for varying cell types. 22,27 Here, we present a detailed methodology for fabricating various microfluidic devices with adjustable nozzle parts to produce microgels of different sizes. Additionally, we describe the process employed to encapsulate human bone marrowderived mesenchymal stromal cells (hBMSCs) within microgels composed of a photo-cross-linkable gelatin-PEG hydrogel.…”

Section: Introductionmentioning

confidence: 99%

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Cell Microencapsulation within Gelatin-PEG Microgels Using a Simple Pipet Tip-Based Device

Nguyen,

Li,

Hung

et al. 2023

ACS Biomater. Sci. Eng.

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Microgels are microscale particles of hydrogel that can be laden with cells and used to create macroporous tissue constructs. Their ability to support cell−ECM and cell−cell interactions, along with the high levels of nutrient and metabolite exchange facilitated by their high surface area-to-volume ratio, means that they are attracting increasing attention for a variety of tissue regeneration applications. Here, we present methods for fabricating and modifying the structure of microfluidic devices using commonly available laboratory consumables including pipet tips and PTFE and silicon tubing to produce microgels. Different microfluidic devices realized the controlled generation of a wide size range (130−800 μm) of microgels for cell encapsulation. Subsequently, we describe the process of encapsulating mesenchymal stromal cells in microgels formed by photo-cross-linking of gelatin-norbornene and PEG dithiol. The introduced pipet-based chip offers simplicity, tunability, and versatility, making it easily assembled in most laboratories to effectively produce cell-laden microgels for various applications in tissue engineering.

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Section: Anticipated Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell Microencapsulation within Gelatin-PEG Microgels Using a Simple Pipet Tip-Based Device

Nguyen,

Li,

Hung

et al. 2023

ACS Biomater. Sci. Eng.

Self Cite

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“…[ 59 ] Another study combined norbornene‐functionalized gelatin (GelNB) with thiol modified linear PEG to generate micro‐hydrogels with a pipette tip‐based microfluidic device. [ 60 ] A general solid tumor target, the CAR‐72 receptor was fused on to T cells and encapsulated in these micro‐hydrogels to be delivered peritumorally; hydrogel modestly improved expansion and effectively reduced tumor size. [ 60 ] Both studies highlight the benefit of hydrogel delivery and prove that the local administration and sustained release of CAR‐T cells can significantly improve therapeutic effect.…”

Section: Delivery Of T Cells Stimulated Ex Vivomentioning

confidence: 99%

Hydrogel‐Based Strategies to Enhance T‐Cell Performance for Solid Tumor Immunotherapy

Kim

2023

Advanced Therapeutics

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The solid tumor microenvironment presents many challenges for immunotherapy that must be addressed for clinical relevance. This review will highlight research that has attempted to tackle these challenges and summarize recent therapeutic approaches to enhance both native and engineered T cell functions through hydrogel delivery. Different types of hydrogels are presented in this paper and organized based on purpose of the research: activation and expansion, delivery methods, co‐delivery of immunostimulating agents, and overcoming tumor microenvironment barriers. Perspectives in the future of solid cancer immunotherapy are also discussed to share opinion on necessary research for the success in this field.

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“…In this regard, GelNB hydrogels, either crosslinked by thiol-norbornene photocrosslinking or iEDDA click reaction, have been used for the in situ delivery and transfection of micro RNA (miRNA) in stem cells, [106] for activating or releasing transforming growth factor 𝛽 (TGF𝛽), [55,107] and for delivery of chimeric antigen receptor (CAR-) T cells (CAR-T cells). [108] Carthew et al performed in situ transfection of pro-osteogenic miRNAs in hMSCs encapsulated within a LAP and light-crosslinked GelNB-PEGdiSH hydrogel. [106] Higher mineralization and osteogenic gene expression were observed in hMSCs with in situ transfections of miR-100-5p and miR-143-3p.…”

Section: Delivery Carriersmentioning

confidence: 99%

Orthogonally Crosslinked Gelatin‐Norbornene Hydrogels for Biomedical Applications

Lin,

Frahm,

Afolabi

2023

Macromolecular Bioscience

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The thiol‐norbornene photo‐click reaction has exceptionally fast crosslinking efficiency compared with chain‐growth polymerization at equivalent macromer contents. The orthogonal reactivity between norbornene and thiol/tetrazine permits crosslinking of synthetic and naturally derived macromolecules with modularity, including poly(ethylene glycol) (PEG)‐norbornene (PEGNB), gelatin‐norbornene (GelNB), among others. For example, collagen‐derived gelatin contains both cell adhesive motifs (e.g., Arg‐Gly‐Asp or RGD) and protease‐labile sequences, making it an ideal macromer for forming cell‐laden hydrogels. First reported in 2014, GelNB is increasingly used in orthogonal crosslinking of biomimetic matrices in various applications. GelNB can be crosslinked into hydrogels using multi‐functional thiol linkers (e.g., dithiothreitol (DTT) or PEG‐tetra‐thiol (PEG4SH) via visible light or longwave ultraviolet (UV) light step‐growth thiol‐norbornene reaction or through an enzyme‐mediated crosslinking (i.e., horseradish peroxidase, HRP). GelNB‐based hydrogels can also be modularly crosslinked with tetrazine‐bearing macromers via inverse electron‐demand Diels‐Alder (iEDDA) click reaction. This review surveys the various methods for preparing GelNB macromers, the crosslinking mechanisms of GelNB‐based hydrogels, and their applications in cell and tissue engineering, including crosslinking of dynamic matrices, disease modeling, and tissue regeneration, delivery of therapeutics, as well as bioprinting and biofabrication.

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Micro-hydrogel injectables that deliver effective CAR-T immunotherapy against 3D solid tumor spheroids

Cited by 12 publications

References 42 publications

Cell Microencapsulation within Gelatin-PEG Microgels Using a Simple Pipet Tip-Based Device

Cell Microencapsulation within Gelatin-PEG Microgels Using a Simple Pipet Tip-Based Device

Hydrogel‐Based Strategies to Enhance T‐Cell Performance for Solid Tumor Immunotherapy

Orthogonally Crosslinked Gelatin‐Norbornene Hydrogels for Biomedical Applications

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