Production and Utility of Extracellular Vesicles with 3D Culture Methods
Abstract
:1. Introduction
2. Subtypes of Extracellular Vesicles
3. Exosomes as a Subset of Extracellular Vesicles—Their Origin and Characteristics
3.1. EVs in Diagnostics
3.2. Therapeutic Application of EVs
3.3. EVs as Drug Carriers
4. Extracellular Vesicle Production and Isolation Methods and Strategies to Enhance Cellular Production of Extracellular Vesicles
5. An Overview of Different 3D Culture Methods
6. Spheroids
7. Hydrogels
8. Hard Porous and Fibrous Scaffolds
Type of Scaffold | Cell Type | Applications | References |
---|---|---|---|
Type I collagen and fibronectin matrix proteins | MSC | Augment performance of lineage specific differentiation of naïve MSCs in bone transplantation | [187] |
Porous β-tricalcium phosphate | iPSC and MSC | Increased angiogenesis and osteogenesis | [188,189,190] |
PCL | MSC and chondrogenic ATDC5 cells | Enhanced osteogenic differentiation | [191,192,193] |
Mineral-doped PLA porous | hAD-MSC | Enhanced osteogenic MSC differentiation | [194] |
Biodegradable PLGA | hAD-MSC | Enhanced osteogenic differentiation and enhanced mineralisation by endogenous cell recruitment | [195,196] |
Tannic-acid-modified sulfonated SPEEK | BM-MSC | Enhanced osteoimmunomodulation by promotion of macrophage polarisation | [197] |
3D-printed porous Ti alloy (Ti6Al4V) | SC | Improved efficacy of Ti alloy scaffolds in bone repair | [198] |
Calcium sulphate hydroxyapatite nanocement | MSC | Enhanced bone mineralisation | [199] |
9. Microcarriers
10. Hollow Fibre Bioreactor
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Vesicle | Size | Origin | Contents | Markers | References |
---|---|---|---|---|---|
Exomeres | ≤50 nm | Unknown | DNA, RNA, miRNAs and lipids | Unclear—More studies are required | [7,30] |
Exosomes | 30–200 nm * | Intra-luminal budding into MVBs and release by MVB fusion with cell membrane | Membrane proteins, different RNA species, lipids and DNA | Tetraspanins, heat-shock proteins, integrins, TSG101, flotillin, MFGE8 and ESCRT components. They include cell-type-specific proteins | [1,3,31,32] |
MVs | 10–1000 nm | Outward budding or blebbing of cell plasma membrane | Membrane proteins, different RNA species, lipids, and DNA | Annexin A1 (on MVs that shed directly from the plasma membrane), integrins, selectins, and CD40 ligand, phosphatidylserine | [3,29,31,32,33] |
Apoptotic bodies | 1–5 µm | Outward blebbing of apoptotic cell plasma membrane | Nuclear fractions, cell organelles and degraded proteins | Annexin V and high amounts of phosphatidylserine | [3,31,32] |
Method | Principles & Materials | Advantages | Disadvantages | References |
---|---|---|---|---|
Differential Ultracentrifugation (dUC) | Physical—Components with imparity of size and density possess various sediment speeds | Gold standard Low cost Pure samples Suitable for large sample volumes | Time-consuming Low yield Repeated and high-speed steps might damage EVs | [19,41,44,91] |
Density Gradient Centrifugation | Physical—Components with imparity of size and density possess various sediment speeds | Higher purity than dUC Maintains EVs intact | Time-consuming Low yield | [19,68] |
Ultrafiltration (UF) | Physical—Filters particles with various sizes and molecular weights | Quick and simple High yield | Low purity EV deformation | [19,41,68,81,91] |
Precipitation | Physical/Chemical—High hydrophilic polymers influence the solubility of EVs | High yield Easy Low cost Concentrates diluted samples | Low purity Potential contaminants (co-purifying protein aggregates) | [19,41,44,81,88] |
Size Exclusion Chromatography (SEC) | Physical/Chemical—Columns packed with pore beads separate particles of various sizes and molecular weights | High yield Pure samples Maintains EVs intact | Potential contaminants (co-purifying protein aggregates) Samples can be diluted | [19,41,44,68,91] |
Immunoaffinity Capture | Chemical—Uses antibodies to interact with specific membrane proteins | Quick High yield Pure samples | Expensive Lack of standardisation | [19,41,44,68,81,91] |
Microfluidics | Physical/Chemical—Based on several principles including immunoaffinity, size and density | High yield Very pure samples | Expensive | [19,44,91] |
Materials Used | Type of Cells/EVs | Applications | References |
---|---|---|---|
Hyaluronic Acid | MSC secretome | Asherman’s syndrome (injured endometrium) | [156] |
Alginate | PPR exosomes/AD-MSC exosomes | Skin regeneration | [157,158] |
Chitosan-based hydrogel with silk fibroin | hUC-MSC treated with miR-675-exosomes/gingival MSC exosomes | Aging-induced vascular disfunction/skin wound healing | [159,160] |
Methylcellulose-chitosan | Placental MSC exosomes | Wound healing | [161] |
Chitosan/chitosan-hyaluronic acid composite hydrogels | miR-126-3p overexpressing MSC exosomes/MSC exosomes/BM-MSC exosomes | Wound healing Ischaemia Skin regeneration | [162,163,164,165] |
Hydroxyapatite embedded hyaluronic acid | UC-MSC exosomes | Bone regeneration | [166] |
Polypetide-based FHE hydrogel | AD-MSC exosomes | Wound healing | [167] |
RGD peptide/peptide-modified adhesive hydrogel | MSC exosomes | AKI repair/SCI treatment | [168,169] |
Polyethylene glycol (PEG) hydrogel | MSC EVs | Chronic liver regeneration | [170] |
Crosslinked hyaluronic acid/PEG hydrogel | MSC EVs | Osteoarthritis | [171] |
Cellular Origin | Fold Increase | Characteristic Alteration | Reference |
---|---|---|---|
MSC (BM-, AD- and hUC-) | 5.7-fold increase | Increased purity | [202] |
hUC-MSC | 18.38-fold increase | Increased inhibition of silica-induced PF | [213] |
hUC-MSC | 20-fold increase | More potent siRNA transfer to neurons | [214] |
BM-MSC | 24-fold increase | Increased neurite length in TG neurons | [215] |
hSF-MSC | 1.6-fold increase | NA | [216] |
SHED | NA | Induce apoptosis in dopaminergic neurons | [217] |
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Casajuana Ester, M.; Day, R.M. Production and Utility of Extracellular Vesicles with 3D Culture Methods. Pharmaceutics 2023, 15, 663. https://doi.org/10.3390/pharmaceutics15020663
Casajuana Ester M, Day RM. Production and Utility of Extracellular Vesicles with 3D Culture Methods. Pharmaceutics. 2023; 15(2):663. https://doi.org/10.3390/pharmaceutics15020663
Chicago/Turabian StyleCasajuana Ester, Mar, and Richard M. Day. 2023. "Production and Utility of Extracellular Vesicles with 3D Culture Methods" Pharmaceutics 15, no. 2: 663. https://doi.org/10.3390/pharmaceutics15020663