Table 2.
Preclinical studies using hydrogel delivery of cell therapeutics since 2016.
| 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 | |
AMI: acute myocardial infarction; MI: myocardial infarction; I/R: ischemia/reperfusion; BADSC: brown adipose tissue-derived stem cells; MSC: mesenchymal stromal cell; AT: adipose tissue; BM: bone marrow; WJ: Wharton’s jelly; PL: placental; UC: umbilical cord; iVPCs: induced vascular progenitor cells; EPCs: endothelial progenitor cells; EV: extracellular vesicles; CPC: cardiac progenitor cells; EDC: Explant derived cardiac stem cells; CM: cardiomyocytes; iPSCs: induced pluripotent stem cells; ESCs: embryonic stem cells; LVEF: left ventricular ejection function; PEG: polyethylene glycol; PDMS: polydimethylsiloxane; IGF: insulin-like growth factor; IM: intramyocardial; LVEF: left ventricular ejection fraction.