Biomaterial application strategies to enhance stem cell-based therapy for ischemic stroke

Table 1 Biomaterial applications to enhance the therapeutic potential of stem/progenitor cells for ischemic stroke treatment

Ref.	Type and source of stem cells	Type of biomaterials used	Biomaterial-based optimization strategy	Type of ischemic stroke model	Beneficial outcomes
Yang et al[12], 2015	MSCs from human adipose tissue	PβAE	Genetically engineered hMSCs to overexpress GDNF using PβAE	Hypoxic-ischemic mice brains	Enhanced neurobehavioral functions of animals after transplantation in ischemic stroke model
Lin et al[22], 2017	MSCs from SD rat bone marrow	ASP-SPION nanocomplex	Conjugation of cationic amylose and SPIONs to produce cationic nanoparticles	MCAO SD rats	A rapid and highly efficient approach for MSCs magnetic labelling, with no destructive effects on cells
Huang et al[24], 2017	MSCs from bone marrow of 3 wk male SD rat	PA-CLEVSRKNC peptide	MSCs co-modified with PA-CLEVSRKNC peptide	MCAO SD rats	Effectively guide and homing a large amount of MSCs to the ischemic brain directly and enhanced miR-133b expression level
Tian et al[26], 2018	MSC-derived exosomes from mouse	cRGD-Exo	[c(RGDyK)] peptide conjugated to MSCs exosome and loaded with curcumin	MCAO mice	Successfully targeted ischemic area, with inflammatory response and cellular apoptosis were suppressed effectively in the lesion region
Kim et al[34], 2020	MSC-derived exosomes from rat	MNV	MNV derived from IONP-harboring MSCs	MCAO rats	Ischemic lesion targeting, and the therapeutic outcome improved
Zamproni et al[40], 2019	MSCs from bone marrow from adult C57/BI6 mouse	PLA-PRM scaffolds	PRM microspheres produced by RJS and conjugated with the MSCs in the scaffold	MCAO mice	Retention time of MSCs in the injury site increased, possibly through upregulation of α6-integrin and CXCL12
Hsu et al[43], 2021	MSCs from mouse HUVEC and umbilical cord blood	3D MSCs/ECs spheroids	Preassembled 3D spheroids with MSCs and vascular ECs	MCAO mice	Cell retention, structural and motor function recovery significantly improved in the ischemic stroke brain
Ghuman et al[49], 2021	NSCs from SVZ of 2-mo-old mouse	PEG microspheres	PEG microsphere encapsulated the NSCs and ECs with suspension in ECM hydrogel	Photothrombotic and MCAO rats	Provision of ideal microenvironment, with highly efficient cell delivery to the damaged area
Ge et al[53], 2022	NSCs from neocortices of day 14.5 mouse embryo	LbL-NSCs	LbL assembly of NSCs using gelatin and HA	Distal MCAO mice	LbL-NSCs engraftment enhanced NSC survival and neurogenesis; promotion of endogenous neuroblasts migration to the ischemic region
Shabani et al[56], 2022	NSCs from 14-d-old murine embryo	PLGA-PEG	NSC encapsulation within PLGA-PEG and loaded with Reelin	Photothrombotic mice	PLGA-PEG with Reelin enhanced the NSCs proliferation, survival and differentiation
Li et al[59], 2022	NSCs from hippocampus of fetal rat	MNBs	MNBs were fabricated through self-assembly of PSCE-modified (γ-Fe2O3SPIONPs) and internalized within NSCs in the ratio of 1:10	Photothrombotic mice	MNBs activate Plezo1-Ca2+ -BMP2/Smad signaling pathway, inducing NSCs differentiation; efficiently tracking and imaging the MNBs-labelled NSCs using MRI and ultrasound
Zhang et al[67], 2021	Mouse iPSC cell line	3D microscaffold culture using AATS medium	Simplified and chemically defined AATS medium for robust production of iPSCs-derived ECs and SMCs	Permanent MCAO mice	ECs and SMCs successfully grown in simple, cost effective AATS medium, allowing GMP large scale production of these cells
McCrary et al[68], 2022	Mouse iPSC cell line	CS-A + iPSCs-NPCs	iPSCs-derived NPCs were encapsulated in CS-A hydrogel	MCAO mice	Promote regenerative microglia/macrophage response via IL-10 accumulation; improvements of post-stroke neuropsychiatric deficits
Zhang et al[72], 2013	NPCs from cerebellum of neonatal mouse	fmSiO4@SPION	SPIONs were modified with fmSiO4 to label and track the NPCs	MCAO mice	Labelled cells successfully migrating to the lesion with highly effective cell imaging and cell tracking
Somaa et al[73], 2017	NPCs from human ESC	SAP hydrogel scaffold	SAP hydrogel scaffold was synthesized using laminin-derived epitope (IKVAV)	MCAO rats	Embedding in a self-assembling scaffold formed de novo "bio-bridges" between the lesions for prolonged survival, therapeutic efficacy and integration of neural grafts
Li et al[78], 2013	EPCs from human umbilical cord blood	SiO4@ SPIONs	EPCs were labelled with SiO4@SPIONs and magnetic exterior to guide the cell migration to ischemic area	Transient MCAO mice	Dual benefit of cell homing and cell tracking were achieved; Atrophic volume of brain was reduced while the microvessel density and VEGF expression were increased
Wang et al[80], 2019	EPCs from human umbilical cord blood	Alkyl-PEI encapsulated SPIONs	Alkyl-PEI/SPIONs were used to direct delivery of siRNA to EPCs	Photothrombotic mice	PHD2 silencing in EPCs improved the migration and survival of the cells through elevation of CXCR4 and HIF-1α expression
Payne et al[82], 2019	NEPCs from human fibroblasts	HAMC hydrogel	HAMC as co-delivery agent to deliver cortically specified-NEPCs into a specific ischemic area	MCAO SD rats	HAMC led to cell survival along the migration process for more mature cells formation and increased host tissue repairs
Fujioka et al[86], 2017	Neuroblasts	Laminin-rich hydrogel	Laminin-rich scaffold was developed with β1 integrins to facilitate neuronal migration toward an injured area	MCAO mice	Able to mimic the vasculature and increased neuroblasts chain formation and migration toward the infarct area of brain tissue

ASP: Spermine-modified amylose; cRGD-Exo: Cyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide-exosome; c(RGDyK): Cyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide; CS-A: Chondroitin sulfate-A; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; EC: Endothelial cell; ECM: Extracellular matrix; EPC: Endothelial progenitor cell; ESC: Embryonic stem cell; fmSiO4@SPION: Fluorescent mesoporous silica-coated superparamagnetic iron 1 oxide nanoparticle; GDNF: Glial cell-derived neurotrophic factor; GMP: Good manufacturing practice; HA: Hyaluronic acid; HAMC: Hyaluronan methylcellulose; HIF-1α: Hypoxia-inducible factor 1-alpha; HUVEC: Human umbilical vein epithelial cell; ; IL-10: Interleukin-10; iPSCs: Induced pluripotent stem cells; IKVAV: Ile-lys-Val-ala-Val; IONP: Iron-oxide nanoparticle; LbL-NSCs: Layer-by-layer assembly of NSCs; MNV: Magnetic nanovesicles; MCAO: Middle cerebral artery occlusion; miR-133b: MicroRNA 133b; MSC: Mesenchymal stem cell; MNBs: Magnetic nanobubbles; MRI: Magnetic resonance imaging; NEPC: Neuroepithelial progenitor cell; NPC: Neural progenitor cell; NSC: Neural stem cell; PA: Palmitic acid; PβAE: Poly (β-amino esters); PEG: Polyethylene glycol; PEI: Polyethylenimine; PHD2: Prolyl hydroxylase 2; PLA-PRM; Polylactic acid polymeric rough microfibers; PSCE: Poly-glucose sorbitol carboxymethyl ether; RJS: Rotary jet spinning; SAP: Self-assembling peptide; SD: Sprague-Dawley; SiO4@SPION: Silica-coated superparamagnetic iron 1 oxide nanoparticle; SMCs: Smooth muscle cells; SPION: Superparamagnetic iron oxide nanoparticle; SVZ: Subventricular zone.