TABLE 2.

Summary of common bioactive factors and stem cells delivered by biomaterials in the treatment of IS.

Bioactive factors/Stem cells	The animal models	Biomaterials	Administration routes	Therapeutic mechanisms	Therapeutic effects	References
BDNF	Permanent dMCAO in rats	Thiol-modified HA hydrogel (HyStem®-C)	8 days after surgery, intracranial implantation in the lesion area	Decreasing the number of microglia, astrocytes, and phagocytes in the striatum	Reducing infarct volume and neuroinflammation	Ravina et al., 2018
CDNF	MCAO in rats	Self-assembling peptide RADA16-I hydrogel	7 days after surgery, intracerebroventricular injection	Accelerating the proliferation and migration of NSCs in SVZ and differentiation of NSCs in the ischemic penumbra area of the cerebral cortex by ERK1/2 and STAT3 signal pathway	Neuroprotection, neurogenesis	Liu X. et al., 2022
Ang-1 and VEGF	PTI in cortical area	pH-sensitive peptide nanofiber-based self-assembling hydrogel (PuraMatrix™)	14 days after surgery, lesion center injection	Promoting revascularization and neuronal survival in brain regions surrounding ischemic infarct	Angiogenesis, sensorimotor recovery	Yanev et al., 2022
VEGF	MCAO in rats	CBD-short peptide-PR1P binding VEGF to collagen hydrogels	30 min after MCAO, iPSCs ilateral cerebral cortex injection	Mitigating inflammation response, cell apoptosis, and facilitating angiogenesis and neuronal sparing in the ischemic region of brain	Neuroprotection, angiogenesis	Yin et al., 2022
bFGF and SDF-1α	PTI in rats	Glycosaminoglycan-based hybrid hydrogel encapsulated with polyelectrolyte complex nanoparticles	7 days after surgery, intracranial implantation in lesion area	Recruitment and regulation of endogenous NSCs via the signal response of MMP	Enhancing neurogenesis and angiogenesis	Jian et al., 2018
SDF-1α	Permanent MCAO in rats	pH-sensitive polymer micelle PUASM	24 h after surgery, intracranial implantation in iPSCs ilateral striatum	pH-triggered releasing SDF-1α in acid microenvironment of ischemic brain area	Neurogenesis and angiogenesis	Kim et al., 2015
EPO and EGF	ET-1 induced stroke model in mice	HAMC hydrogel loaded with two types of polymeric nanoparticles: EPO in PLGA and pegylated EGF into PLGA core with a poly (sebacic acid) coating	4 days after surgery, intra-epicortical injection	On-demand confining the nanoparticle; in SVZ, increasing the number of NSPCs; in peri-ischemic area, reducing the number of microglia, astrocytes, and macrophagocytes, inhibiting neuronal apoptosis and increasing the number of mature neurons	Neurogenesis and anti-inflammation	Wang et al., 2013
Human ESC-derived cortical progenitor stem cell	ET-1 induced stroke model in rats	SAP hydrogel based on laminin-derived epitope	6 days and 3 weeks after surgery, intracortical injection	Promoting survival of transplanted NPCs and neovascularization; axonal outgrowth and circuit replacement; mitigating cortical atrophy	Progressive sensorimotor improvements	Somaa et al., 2017
Mouse iPSCs-derived NPCs	Sensorimotor cortex mini-stroke model in mice	Chondroitin sulfate-A hydrogel binding bFGF	7 days after surgery, intracranial transplantations in infarct core	Increasing levels of p-STAT3 and p-AKT; and the number of microvessels	Angiogenesis and sensorimotor improvements	McCrary et al., 2020
Human iPSCs derived cortically specified neuroepithelial progenitor cells	ET-1 induced stroke model in rats	HAMC hydrogels	7 days after surgery, intracranial transplantations at cortical lesion regions	Increasing NeuN + host neurons	Neurological function recovery	Payne et al., 2019
Bone marrow MSCs	MCAO in mice	Carbon-nanotubes-doped sericin scaffold based on 3D print technology	2 weeks after surgery, intracranial injection into stroke cavity	Shape-memory graft to fill the cavity; promoting stem cells survival and the differentiation toward mature neurons	Cavity repair	Wang et al., 2021a

Ang1, angiopoietin-1; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast factor; CBD, collagen-binding domain; CDNF, cerebral dopamine neurotrophic factor; cNEPs, cortical neuroepithelial progenitor cells; dMCAO, distal middle cerebral artery occlusion; EGF, epidermal growth factor; EPO, erythropoietin; ET-1, endothelin-1; iPSCs, induced pluripotent stem cells; ESC, embryonic stem cells; VEGF, vascular endothelial growth factor; HA, hyaluronic acid; HAMC, hyaluronan methylcellulose; MSCs, mesenchymal stem cells; MMP, matrix metallopeptidase 9; NPCs, neural progenitor cell; NSCs, neural stem cells; NSPCs, neural stem progenitor cell; p-AKT, phosphorylated protein kinase B; PLGA, poly-lactide-co-glycolide; PUASM, polymer poly urethane amino sulfamethazine; PTI, photothrombotic ischemia; SAP, self-assembly of peptides; SDF-1α, stromal-derived factor-1α; STAT, signal transducer and activator of transcription; SVZ, subventricular zone.