Injectable Hydrogels for Improving Cardiac Cell Therapy—In Vivo Evidence and Translational Challenges
Abstract
:1. Introduction
2. Injectable Hydrogels
2.1. Natural Hydrogels
2.2. Synthetic Hydrogels
3. Hydrogel Properties and Delivery Depends on Clinical Indication
3.1. Acute Myocardial Infarction
3.2. Chronic Ischemic Heart Failure and Non-Ischemic Dilated Cardiomyopathy
3.3. Coronary Artery By-Pass Graft
4. Cell Therapy Candidates and Hydrogel Requirements
4.1. Mesenchymal Stromal Cells and Endothelial Progenitor Cells
4.2. Cardiopoietic Cells and Cardiomyocytes
5. Current In Vivo Evidence
5.1. Clinical Studies
5.2. Preclinical Studies
6. Important Hydrogel Properties
6.1. Stiffness and Porosity
6.2. Functionalization
6.2.1. Adhesion Motifs
6.2.2. Angiogenesis
6.2.3. Graft Survival and Activity
6.3. Retention is Not Everything
7. Cell Delivery Strategies
7.1. Bulk Delivery
7.2. Microencapsulation
7.3. Single-Cell Coating
7.4. Delivery Route
8. Potential Roadblocks for Clinical Translation
8.1. Start with the End in Mind
8.2. Treatment Scalability and Logistics
8.3. Design and Production
9. Limitations
10. Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | Indication | Cell Type | Hydrogel | Application | Trial Design | ClinicalTrials.gov Identifier |
---|---|---|---|---|---|---|
Menasché, 2018 (ESCORT) | CABG | hESC-derived CV progenitors | Fibrin patch | Patch placed over infarct area | Open label | NCT02057900 |
Chachques, 2007 | CABG | BMMNCs | Collagen scaffold | Collagen scaffold to close injection sites | Open label | N/A |
He, 2020 | CABG | UC-MSC | Collagen hydrogel | Injected cells/hydrogel co-therapy | RCT | NCT02635464 |
Study | Indication | Cell Type | Hydrogel | Functionalization | Application | Functional Outcome Compared to Cells Only | Additional Effects |
---|---|---|---|---|---|---|---|
Adult Stem Cells | |||||||
Bai, 2019 | AMI in rats | Rat BADSC | Cardiac ECM in PBS | Bulk delivery IM | Greater improvement of LVEF than BADSCs | Improved cardiac differentiation of BADSCs | |
Chen, 2020 | AMI in mice | Rat AT-MSC | Transglutaminase cross-linked gelatin | Bulk delivery IM | Only group which sig. improved LVEF | Improved retention and reduced fibrosis compared to ASC in PBS, improved MTT assay, decreased ANP and TNP mRNA | |
Choe, 2019 | AMI in rats | Human UC-MSC | Alginate hydrogel | Graphene oxide +/– reduction | Microencapsulation IM | No sig. improvement | Decreased fibrotic area and increased infarct thickness |
Ciuffreda, 2018 | Subacute MI in rats | Rat BM-MSC | PEG hydrogel | Heparinated | Bulk delivery IM | Only group which sig. improved LVEF | Improved retention |
Firoozi, 2020 | AMI in rats | Human BM-MSC | RADA hydrogel | SDKP peptide integration | Bulk delivery IM | Greater improvement of LVEF than BM-MSCs | Improved retention; hydrogel effect in itself better than BMMSCs; decreased fibrosis |
Follin, 2018 | AMI in immunodeficient rats | Human AT-MSC | Alginate cross-linked with calcium glucuronate | Bulk delivery IM | No difference in improvement | No difference in thickness, perfusion, or fibrosis | |
Gaffey, 2018 | AMI in rats | Rat EPCs | Hyaluronate hydrogel | Adamantane and β-cyclodextrin | Bulk delivery IM | Only sig. LVEF improvement in gel + EPC group | Improved retention, myocardial velocity, and strain |
Gao, 2017 | AMI in rats | Rat BM-MSC | RADA hydrogel | SVVYGLR peptide integration | Bulk delivery IM | Greater improvement of LVEF than BM-MSCs | Decreased collagen content, infarct size, number of vessels, and decreased number of apoptotic MSCs |
Ghanta, 2020 | AMI in rats | Rat AT-MSC | TMTD alginate hydrogel | Capsules delivered epicardially | Greater improvement of LVEF than AT-MSCs | Only decreased fibrosis in the hydrogel group | |
Gottipati, 2019 | AMI in mice | Mice BM-MSC | Photopolymerized gelatin methacrylamide and PEG diacrylate | Coated cells delivery IM | Improved retention by coating (double), similar macrophage density | Coating approach and no clumping tested | |
Jamaiyar, 2017 | AMI in rats | Rat iVPC | PLGA microbundles | Bulk delivery IM | Only group with improved LVEF at four weeks, but no difference in improvement at eight weeks | No difference in infarct length or capillary-to-myocyte ratio | |
Liu, 2017 | Acute I/R in rats | Rat BM-MSC | VEGF-gelatin-alginate-VEGF-gelatin | VEGF encapsulation | Coated cells delivered IV | Greater improvement of LVEF and perfusion than BM-MSC | Increased vascular density in peri-infarct and average area of myocardial islands in the infarct |
Qiao, 2019 | Subacute AMI in rats | Rat AT-MSCs | Porcine cardiac ECM | Bulk delivery IM | Greater improvement in LVEF compared to AT-MSCs alone | Improved hemodynamic function; increased vessel density, expression of Ang-1, and VEGF; decreased fibrosis. | |
Rabbani, 2017 | AMI in rabbits | Human WJ-MSC | PEG hyaluronic acid and chitosan hydrogel | Bulk delivery IM | Greater improvement of LVEF compared to WJ-MSC | Smaller infarct area (SPECT) and increased CD31 density | |
Yao, 2020 | AMI in mice | Human P-MSC | Chitosan hydrogel | IGF-1 C domain | Bulk delivery IM | Only group with sig. improved LVEF | Increased angiogenesis, reduced collagen deposition, and inhibited inflammation |
Yang, 2019 | AMI in mice | Mice BM-MSC | Chitosan thermosensitive hydrogel | Bulk delivery IM | Only group with sig. improved LVEF | Enhanced BM-MSC survival. inhibited inflammation, and alleviated pyroptosis of vascular endothelial cells | |
Xu, 2017 | AMI in rats | Rat BM-MSC | Chitosan hydrogel | Bulk delivery IM | Only group with sig. improved LVEF | Improved BM-MSC retention in the myocardium | |
Wang, 2020 | Chronic MI in minipigs | Human UC-MSCs | Collagen hydrogel | Bulk delivery IM | Greater improvement in cardiac output compared to UC-MSCs alone | Increased retention and myocardial tissue islands in scar tissue; decreased scar area | |
Wu, 2017 | AMI in rats | Rat BM-MSC | DFEFKDFEFKYRGD small molecule hydrogel | Bulk delivery IM | Only group with sig. improved LVEF | Small-molecule hydrogel BM-MSC improved retention compared to BM-MSC alone | |
Extracellular vesicles | |||||||
Chen, 2018 | AMI in rats | Rat EPC EVs | Hyaluronate hydrogel | Adamantane and β-cyclodextrin | Bulk delivery IM | Greater improvement in LVEF compared to EVs alone | Increased vessel density and scar thickness |
Han, 2019 | AMI in rats | Human UCMSC exosome | PA-GHRPS NapFF hydrogel | PA-GHRPS peptide and NapFF integration | Bulk delivery | Greater improvement of LVEF than exosomes | Improved retention, decreased CD68 density and TGF-b |
Lv, 2019 | AMI in rats | Rat BM-MSC derrived EV | Sodium alginate cross-linked with calcium chloride | Bulk delivery | Greater improvement of LVEF than EVs | Decreased infarct size, improved wall thickness, enhanced retention, angiogenesis, and macrophage polarization (CD206) and decreased apoptosis | |
Cardiogenic cell types | |||||||
Bhutani, 2018 | I/R in atymic rats | Human C-kit+ CPC | PEG crosslinked with VPM | RGD or GFOGER or RDG integration | Bulk delivery | Only group with sig. improved LVEEF was non-adhesive RDG | Improved retention at day 28, decreased scar tissue |
Kanda, 2018 | Subacute MI in immunodeficient mice | Human EDC | Agarose with fibronectin and fibrinogen capsulated with PDMS | Coated cells | Greater improvement of LVEF with stiff version of gel | Improved retention. decreased scar size, and increased proliferative cardiomyocytes and non-cardiomyocytes; MMP-12, IL-6, and bFGF increased in cells in stiff gel compared to the other gel | |
Tang, 2017 | AMI in mice and pigs | Human CSCs | Poly (NIPAM-AA) nanogel | Bulk delivery IM | Preserved LVEF compared to cells alone | Improved retention, prevented myocardial T cell inflammation, decreased scar size, amd increased viable myocardium and infarct thickness | |
Cardiomyocytes | |||||||
Gerbin, 2020 | AMI in atymic rats | Human ESC-CM | Collagen gel | Notch ligand delta 1 integraion | Bulk delivery IM | Only group with sig. improved LVEF | Improved graft size |
Li, 2018 | AMI in mice | Mouse iPSC | Self-assembling folic acid modified peptide hydrogel | Bulk delivery IM | Greater improvement of LVEF than cardiac differentiated iPSC | Increased angiogenesis and decreased fibrosis |
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Hoeeg, C.; Dolatshahi-Pirouz, A.; Follin, B. Injectable Hydrogels for Improving Cardiac Cell Therapy—In Vivo Evidence and Translational Challenges. Gels 2021, 7, 7. https://doi.org/10.3390/gels7010007
Hoeeg C, Dolatshahi-Pirouz A, Follin B. Injectable Hydrogels for Improving Cardiac Cell Therapy—In Vivo Evidence and Translational Challenges. Gels. 2021; 7(1):7. https://doi.org/10.3390/gels7010007
Chicago/Turabian StyleHoeeg, Cecilie, Alireza Dolatshahi-Pirouz, and Bjarke Follin. 2021. "Injectable Hydrogels for Improving Cardiac Cell Therapy—In Vivo Evidence and Translational Challenges" Gels 7, no. 1: 7. https://doi.org/10.3390/gels7010007