Strategies to enhance efficacy of SPION-labeled stem cell homing by magnetic attraction: a systemic review with meta-analysis

Figures & data

Figure 1 Schematic representation of enhancement of SPION-labeled stem cell homing with magnetic attraction.

Figure 2 Flowchart of the article screening process for inclusion in this review.

Table 1 Characteristics of stem cells and iron oxide nanoparticles labeled in homing experiments

Reference	Stem cell			Superparamagnetic iron oxide nanoparticle (SPION)								Cell viability
	Type	Source	Concentration	Type	Species of metal	[Fe] (µg/mL)	hydrodynamic size (nm)	Coating agent	Charge (zeta potential, mV)	Incubation Time	Efficiency (%)	Methods	Results
Arbab et al (2004)^Citation54	MSC	Human	2x10^4	Feridex	Fe	50	120–180	PLL	n/a	Overnight	n/a	n/a	n/a
Nishida et al (2006)^Citation30	bmSC	Rat	1x10^5	Feridex	Fe	25	120–180	PLL	n/a	24 h	n/a	n/a	n/a
Wilhelm et al (2007)^Citation20	EPC	Human	2x10^4	AMNP	Fe	2 mM, 5 mM, 10 mM	7.5	n/a	negative	15 min to 2 h	40%	Trypan blue	No significant difference
Kyrtatos et al(2009)^Citation23	MSC	Human	1x10^6	Endorem	Fe	500	120–180	n/a	n/a	Overnight	n/a	MTS	No significant difference
Song et al (2010)^Citation15	NSC	Human	4x10^6	Feridex	Fe	25	120–180	PLL	n/a	60 min	n/a	n/a	n/a
Cheng et al (2012)^Citation24	CDC	Rat	5x10^5	SPM	Fe	500:1 SPM/cell ratio	n/a	n/a	n/a	24 h	n/a	CCK8	No significant difference
Yanai et al (2012)^Citation44	MSC	Rat	1x10^6	FluidMag	Fe	50, 250, 500	200	Starch	n/a	2 h	n/a	MTT	No significant difference
Vaněček et al (2012)^Citation21	MSC	Rat	1x10^6	SPION	Fe	15.4	n/a	PLL	−46	72 h	84%	n/a	n/a
Riegler et al (2013)^Citation26	MSC	Rabbit	1x10^6	FluidMAG-D	Fe	620	182±18	Dextran	1±6	24 h	80%	MTS	No significant difference
Landázuri et al (2013)^Citation17	MSC	Human	2x10^6	SPION	Fe	2,10 µg/cm^2	30.8±2.4	n/a	n/a	24 h	100%	MTS	No toxic effect noted
Li et al (2013)^Citation25	MSC	Human	1x10^6	SIO4@SPIONS	Fe	10	124	Silica	−37.5	2 h	n/a	CCK8	No significant difference
Oshima et al (2014)^Citation27	MSC	Human	1x10^5	Resovist	Fe	3.52 *0.5 mol/L	4.2/62	carboxydextran	n/a	24 h	n/a	n/a	n/a
Meng et al (2017)^Citation28	MSC	Human	1x10^3	Molday ION Rhodamine-B	Fe	25	n/a	n/a	n/a	12 h	>80%	MTT	increased
Yun et al (2018)^Citation14	MSC	Mouse	1x10^5	IRB	Fe	15	5.22±0.9	Oleic Acid	+15±0.3	24 h	n/a	CCK8	No significant difference

Abbreviations: MSC, mesenchymal stem cells; bmSC, bone marrow stromal cells; EPC, endothelial progenitor cells; NSC, neural stem cells; CDC, cardiosphere-derived cells; n/a, not indicated; AMNP, anionic magnetic nanoparticles; SPM, superparamagnetic microsphere; SPION, superparamagnetic iron oxide nanoparticles; SIO, silica-coated iron oxide.

Table 2 Experimental designs of homing - in vivo

Reference	Magnetics				Experimental model					In vivo homing
	Type	Force (T)	location	Exposure time	Animal	Animal model	Groups	Route	Dose (cell count)	Duration of experiment	Histological image	Magnetic resonance image	Efficiency (%)*
Arbab et al (2004)^Citation54	NdFeB	0.34	Over the target organ (liver)	1, 8, 15, 22, and 29 days	Rat	n/a	2 groups (4 per magnet exposure time) control: 5	IV (tail vein)	8x10^5–1x10^6	29 days	DAB-enhanced Prussian blue and corresponding HLA-1 staining of serial consecutive sections proved the presence of iron-containing human cells.	Hypointense liver signal after intravenous administration of FE-PLL–labeled MSCs	1-fold increase
Nishida et al (2006)^Citation30	NdFeB	0.38	para-vertebral muscles at T7 level	1 day	Rat/SD	Spinal cord injury	2 groups (magnet group: 5, non-magnet group: 5)	SI (subarachnoid injection)	1x10^5	1 day	Aggregations of GFP-positive cells were observed mainly on the dorsal surface of the spinal cords of rats in the magnet group.	n/a	3-fold increase
Wilhelm et al (2007)^Citation20	NdFeB	0.3	Above the matrigel	18 hrs	Mouse	n/a	n/a	SC (matrigel)	5x10^4	n/a	n/a	18 hrs post injection EPC with magnetic field moved towards the magnet	Movement of EPC toward magnet 18 hrs post injection
Kyrtatos et al (2009)^Citation23	NdFeB	1.195	Adjacent to the ventral aspect of the neck	2 mins	Rat/SD/M 380–420 g	Vascular injury (common carotid artery)	N/A	IA (common carotid artery)	5x10^6	24 h	Application of an external magnetic force using the actuator during and after cell delivery increased CD133 cell engraftment to the injured vascular surface by a factor of 5.4 compared with cell delivery without the magnet.	n/a	1.16-fold increase
Song et al (2010)^Citation15	NdFeB	0.32	External magnet attached with an adhesive in the area above the injury	7 days	Rat/SD/M 250–300 g	Transient focal cerebral ischemia model	3 groups (control, with, and without magnet) Total: N=33	IV (tail vein)	4x10^6	7 days	Area of Prussian blue staining was significantly larger in brain slices from ICM rats as compared with IC rats (2.6±1.6 mm^2 vs 0.7±0.2 mm^2).	n/a	3-fold increase
Cheng et al (2012)^Citation24	NdFeB,	1.3	Above the heart	~3 weeks	Rat/WKY/F	Myocardial infarction model	Total: N=82	Intracoronary injection	5x10^5	3 weeks	More GFP+ cells were evident in the Fe-CDC and magnet group than in the Fe-CDC group in both risk and normal regions.	n/a	6.4-fold increase
Yanai et al (2012)^Citation44	NdFeB	0.26	Within the orbit. limbal incision was made in the superior fornix and magnet pushed back into orbital apex	1 month	Rat S334ter-4 heterozygous transgenic rat	Ocular injury	n/a	DI (vitreous cavity) IV (tail vein)	DI-2x10^5 IV- 1x10^6	1 month	Retinal cryosections identified that magnetic MSCs could be identified in both the outer as well as the inner retina if a magnet had been placed in the orbit.	n/a	Accumulation of 20% in magnet group and 0.6% in non-magnet group
Vaněček et al (2012)^Citation21	NdFeB	0.35	Above the lesion site	At least 1 week to a max of 2 weeks	Rat/Wistar/M 280–300 g	Balloon-induced spinal cord compression lesion model	2 groups Total: N=32 (with magnet: 4, without magnet: 4)	DI (intrathecal injection)	5x10^6	2 weeks	Prussian blue staining colocalized with the GFP signal in serial histological sections. In the control groups, fewer cells were identified in the lesion area.	Larger hypointense signal of SPION-labeled cells in the lesion area of the magnet group in contrast to the weak signal observed in the control group	3-fold increase
Riegler et al (2013)^Citation26	12 element k=3 rabbit Halbach cylinder	0.21	External cylindrical magnet placed around the leg with femoral injury	Immediately after the injury and additional 40 mins	Rabbit/NZW/M 2.0–2.5 kg	femoral artery balloon injury model	n/a	IA (central lumen of femoral artery)	1x10^6	1 day	n/a	50% of the injured vessel circumference was attached with magnetically labeled cells. The application of an external magnetic field during cell delivery lead to a 6.2-fold increase.	6.2 fold increase
Landázuri et al (2013)^Citation17	NdFeB	n/a	Over the proximal portion of the tail vein	n/a	Mouse/ nude 4–5 weeks old	n/a	2 groups (With magnet and without magnet)	IV (tail vein)	2x10^6	Mouse euthanized immediately after cell injection	IF: The signal emitted by DiR was 6.4-fold higher in the presence of the magnet.	n/a	6.4-fold increase
Li et al (2013)^Citation25	n/a	0.3	On the skull of the ischemic hemisphere	120 mins	Mouse/ICR/M 25–30 g	Transient middle cerebral artery occlusion	2 groups	IV (jugular vein)	1x10^6	1 day	Brain atrophy volume was significantly reduced in M-SiO4@SPIONs-EPCs group.	n/a	3-fold increase
Oshima et al (2014)^Citation27	Magnetic device	1.5	n/a	10 mins	Rat/ nude, 9 weeks	Limb muscle injury	9 groups (magnetic force) 3 groups (exposure time)	DI (muscle)	1x10^5	7 days	Masson trichrome staining and IF: 3 weeks after cell transplantation remarkably decreased fibrotic area. Control: 18.0±1.58x10^5 um^2; case: 7.51±0.72x10^2 um^2	n/a	Fibrotic area decreased twice compared to the control group.
Meng et al (2017)^Citation28	NdFeB	0.5	On the surface of the wound	6 hrs/day	Mouse/ BALB/c nude	Skin defect	3 groups (Control, SPIONs-MSCs, SPIONs-MSCs with EMF) total: N=30	DI (wound)	2x10^6	1–7 days	IHC and IF: Increased	Increased SNR, CNR, and displacement at 1, 2, and 7 days	More than 80% of cells were seen in the injury site after 24 hrs.
Yun et al (2018)^Citation14	NdFeB	0.3	Directly on the site of injury	7 days	C57BL mouse	Olfactory injured model	2 groups	DI (nostrils)	n/a	7 days	IF: MSC injection with IRBs under a magnetic field showed significantly higher values compared to both MSC injection without IRBs and MSC injection with IRBs	n/a	3-fold increase

Note: *Versus the control group.

Abbreviations: NdFeB, neodymium iron boron; SD, Sprague-Dawley; M, male; F, Female; WKY, Wistar-Kyoto; NZW, New Zealand White; n/a, not indicated; IV, intravenous, SI, subarachnoid injection, SC, subcutaneous, IA, intra-atrial, DI, direct injection, IHC, immunohistochemistry, IF, immunofluorescence.

Table 3 Experimental designs of migration - in vitro

Reference	Cell			Magnetics				In vitro Migration
	Type	Concentration (cell count)	Labeling Time	Type	Force (T)	Location	Exposure time	Time of test	Histological image	Magnetic resonance image	Efficiency
Arbab et al (2004)^Citation54	HeLa	40,000/cm2	Overnight	NdFeB	0.34	Under the culture dish	48 hrs	48 hrs	High concentration of labeled cells in the area near the edge of magnet.	Hypointense ring above the area magnet was placed	n/a
Wilhelm et al (2007)^Citation20	EPC	5x10^4	15 mins to 2 hrs	Magnetic tip	0.33	Directly on the matrigel test area	18 hrs	18 hrs	Approaching the magnetic tip, vasculogenesis was observed by videomicroscopy in the matrigel in medium containing endothelial growth factors.	Localized EPCs on the site with magnet	n/a
Kyrtatos et al (2009)^Citation23	hMNC	1x10^6	Overnight	NdFeB	1.195	1 mm from the cell	5, 10, 15 s	15 mins	Capture of SPIO-labeled cells in in-vitro flow system in area with magnet	n/a	252-fold increase in the capture of cell 1 mm distance from the magnetic actuator
Song et al (2010)^Citation15	NSC	1x10^5	1 hr	NdFeB	0.32	Below the culture dish	24 hrs	24 hrs	Aggregation of labeled cells in area surrounding the magnet observed.	n/a	n/a
Yanai et al (2012)^Citation44	MSC	n/a	2 hrs	NdFeB	0.26	Below the culture flask	12 hrs	12 hrs	Aggregation of labeled cells in area surrounding the magnet observed.	n/a	n/a
Vaněček et al (2012)^Citation21	MSC	1x10^6	72 hrs	Permanent magnet	0.35	Below the culture dish	48 hrs	48 hrs	Cell evenly distributed in the culture plate in non-magnet group and cells attracted to region above the magnet in the magnet group	n/a	n/a
Riegler et al (2013)^Citation26	MSC	3x10^4	24 hrs	NdFeB	0.44	Below the culture dish	10–120 mins	120 mins	Twice the number of cells attached to the test site were observed	n/a	Doubled cell attachment rate
Landázuri et al (2013)^Citation17	MSC	n/a	24 hrs	NdFeB	1.2	Below the culture dish	4 hrs	4 hrs to 3 days	Cells accumulated on the sites with highest magnetic field gradient	n/a	n/a
Li et al (2013)^Citation25	MSC	1x10^4	2 hrs	No Information	0.3	Below the culture dish	24 hrs	24 hrs	Cells accumulated on the sites with highest magnetic field gradient	n/a	n/a
Yun et al (2018)^Citation14	MSC	1x10^6	24 hrs	Permanent magnet	0.3	Beside the culture plate	24 hrs	24 hrs	Attraction of the cells toward the magnetic field gradient was noted upon fluorescent microscopy	n/a	42.92% of magnetized MSCs adhered to the front

Abbreviations: EPC, endothelial progenitor cell; hMNC, human mononuclear cell; MSC, mesenchymal stem cell; NdFeB, neodymium iron boron; SPION, superparamagnetic iron oxide, n/a, not indicated.

Figure 3 Forest Plot showing hydrodynamic size of nanoparticles and meta-analysis results of mean hydrodynamic size of nanoparticles.

Figure 4 Forest plot showing stem cell observed in the target organ and meta-analysis results for quantitative comparison.

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