Article | Published:

Control of cerebral ischemia with magnetic nanoparticles

Nature Methods volume 14, pages 160166 (2017) | Download Citation

  • A Corrigendum to this article was published on 27 April 2017

This article has been updated


The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 10 April 2017

    In the version of this article initially published, the middle cerebral artery was incorrectly referred to as the middle carotid artery. The error has been corrected in the HTML and PDF versions of the article as of 10 April 2017.


  1. 1.

    et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131, e29–e322 (2015).

  2. 2.

    & Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol. Biochem. Behav. 87, 179–197 (2007).

  3. 3.

    , , & Experimental studies of ischemic brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn. J. Stroke 8, 1–8 (1986).

  4. 4.

    , , & Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91 (1989).

  5. 5.

    , , , & A modified mini-stroke model with region-directed reperfusion in rat cortex. J. Cereb. Blood Flow Metab. 28, 973–983 (2008).

  6. 6.

    et al. A rat model of reproducible cerebral infarction using thrombotic blood clot emboli. J. Cereb. Blood Flow Metab. 12, 484–490 (1992).

  7. 7.

    , , & Differences in clot preparation determine outcome of recombinant tissue plasminogen activator treatment in experimental thromboembolic stroke. Stroke 34, 2019–2024 (2003).

  8. 8.

    , , , & Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann. Neurol. 17, 497–504 (1985).

  9. 9.

    , , , & Cerebral blood flow restoration and reperfusion injury after ultraviolet laser-facilitated middle cerebral artery recanalization in rat thrombotic stroke. Stroke 33, 428–434 (2002).

  10. 10.

    et al. Induction of ischemic stroke in awake freely moving mice reveals that isoflurane anesthesia can mask the benefits of a neuroprotection therapy. Front. Neuroenergetics 6, 1 (2014).

  11. 11.

    , , , & Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat. Neurosci. Lett. 118, 269–272 (1990).

  12. 12.

    Bench to bedside: the quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab. 26, 1465–1478 (2006).

  13. 13.

    et al. Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke. Nat. Methods 3, 99–108 (2006).

  14. 14.

    , & Hardware and methodology for targeting single brain arterioles for photothrombotic stroke on an upright microscope. J. Neurosci. Methods 170, 35–44 (2008).

  15. 15.

    et al. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat. Neurosci. 16, 55–63 (2013).

  16. 16.

    , & Animal models of ischemic stroke and their application in clinical research. Drug Des. Devel. Ther. 9, 3445–3454 (2015).

  17. 17.

    , & Nano-magnetic particles used in biomedicine: core and coating materials. Mater. Sci. Eng. C Mater. Biol. Appl. 33, 2465–2475 (2013).

  18. 18.

    , & Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7, 771–782 (2008).

  19. 19.

    et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

  20. 20.

    & Neodymium-iron-boron permanent magnets. J. Magn. Magn. Mater. 100, 57–78 (1991).

  21. 21.

    Neonatal brain injury. N. Engl. J. Med. 351, 1985–1995 (2004).

  22. 22.

    & Animal models of neonatal stroke. Curr. Opin. Pediatr. 13, 506–516 (2001).

  23. 23.

    et al. A novel reproducible model of neonatal stroke in mice: comparison with a hypoxia-ischemia model. Exp. Neurol. 247, 218–225 (2013).

  24. 24.

    et al. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17, 1304–1308 (1986).

  25. 25.

    , , & Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res. 1035, 24–31 (2005).

  26. 26.

    & Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol. Dis. 85, 234–244 (2016).

  27. 27.

    & Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369–1376 (2007).

  28. 28.

    , & Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

  29. 29.

    & Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 190, 255–266 (2000).

  30. 30.

    et al. Smooth muscle cell phenotypic switching in stroke. Transl. Stroke Res. 5, 377–384 (2014).

  31. 31.

    , & NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135, 145–157 (2008).

  32. 32.

    et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95–110 (2015).

  33. 33.

    et al. Transient ischemic attack—proposal for a new definition. N. Engl. J. Med. 347, 1713–1716 (2002).

  34. 34.

    Perinatal ischemic stroke. Stroke 38, 742–745 (2007).

  35. 35.

    et al. Neuropathologic substrates of ischemic vascular dementia. J. Neuropathol. Exp. Neurol. 59, 931–945 (2000).

  36. 36.

    et al. Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann. Neurol. 62, 406–413 (2007).

  37. 37.

    & Demonstration of “gap junctions” between smooth muscle cells. J. Cell Biol. 44, 215–217 (1970).

  38. 38.

    & Alternative method to calculate the magnetic field of permanent magnets with azimuthal symmetry. Rev. Mex. Fis. E 59, 8–17 (2013).

  39. 39.

    , , & Real-time intravital microscopy of individual nanoparticle dynamics in liver and tumors of live mice. Protoc. Exch. (2013).

  40. 40.

    , & A rapid, simple, and humane method for submandibular bleeding of mice using a lancet. Lab Anim. (NY) 34, 39–43 (2005).

  41. 41.

    , , , & Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376–380 (2012).

  42. 42.

    & Percutaneous intravenous injection in neonatal mice. Lab. Anim. Sci. 49, 328–330 (1999).

  43. 43.

    , , & Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex. Nat. Neurosci. 10, 549–551 (2007).

Download references


We thank W.Z. Sun, L.J. Wu, H. Lü, and L.J. He for advice on live imaging; J. Zheng and A. Fu for advice on MPs; M. Dellinger for advice on H.E. staining; D. Xu and H. Cai for advice on MRI; B. Zhou, I. Shimada, M. Acar, and M. Chen for input concerning SMCs, MCAO and FJC staining; W.L. Du's input for MCAO surgery; T. Taylor, H. Zhu, J.D. Chen, Z.H. Zhang, Z.P. Hu, G.E. Cai, M. Goldberg, F. Chen, L. Smith, and J. Long as well as colleagues at CRI for critical discussion and reading of the manuscript. This work is supported by the National Basic Research Program of China (No. 2015CB352006) and the Science Fund for Creative Research Group of China (No. 61121004) to W.Z.; CRI start-up funds and NINDS K99/R00 (R00NS073735) to W.-P.G.; NIH Director's New Innovator Award (DP2-NS082125) to B. Cui, American Heart Association (14SDG18410020) and NINDS (NS088555) to A.M.S.; and the Dr. Jack Krohmer Professorship in Radiation Physics for X.S. W.-P.G. is a recipient of an NINDS Pathway to Independence Award. W.L. is a recipient of an American Heart Association Postdoctoral Fellowship Award.

Author information


  1. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Jie-Min Jia
    • , Xiaofei Gao
    • , Bo Ci
    •  & Woo-Ping Ge
  2. Department of Chemistry, Stanford University, Stanford, California, USA.

    • Praveen D Chowdary
    •  & Bianxiao Cui
  3. Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, Texas, USA.

    • Wenjun Li
    •  & Shao-Hua Yang
  4. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Aditi Mulgaonkar
    • , Gedaa Hassan
    • , Amit Kumar
    •  & Xiankai Sun
  5. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Erik J Plautz
    •  & Ann M Stowe
  6. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-HuaZhong University of Science and Technology, Wuhan, China.

    • Wei Zhou
  7. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge
  8. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge
  9. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge


  1. Search for Jie-Min Jia in:

  2. Search for Praveen D Chowdary in:

  3. Search for Xiaofei Gao in:

  4. Search for Bo Ci in:

  5. Search for Wenjun Li in:

  6. Search for Aditi Mulgaonkar in:

  7. Search for Erik J Plautz in:

  8. Search for Gedaa Hassan in:

  9. Search for Amit Kumar in:

  10. Search for Ann M Stowe in:

  11. Search for Shao-Hua Yang in:

  12. Search for Wei Zhou in:

  13. Search for Xiankai Sun in:

  14. Search for Bianxiao Cui in:

  15. Search for Woo-Ping Ge in:


W.-P.G., B. Cui, and J.-M.J. conceived the project, and J.-M.J. performed most of the animal experiments and analyzed data. P.D.C. characterized properties of magnets. W.-P.G., X.G., B. Ci, E.J.P., W.L., A.M., G.H., A.K., and W.Z. performed the other experiments. W.-P.G., J.-M.J., P.D.C., X.G., B. Cui, X.S., A.M.S., and S.-H.Y. designed the experiments. W.-P.G., J.-M.J., X.G., P.D.C., B. Cui, A.M., and G.H. wrote the manuscript. All authors reviewed and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bianxiao Cui or Woo-Ping Ge.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14 and Supplementary Table 1.


  1. 1.

    Reversible occlusion of blood vessels.

    Occlusion of an artery as produced by a 0.5-mm micro-magnet. Reperfusion began within seconds once the magnet was removed (black, upper left).

  2. 2.

    Blood cells flowing through blood vessels.

    Cell from whole blood (~10–20 μl, see details in Methods) were labeled with DiO dye (green) and then injected into the tail vein of the same mouse.

  3. 3.

    Loss of SMCs during occlusion in arteries/arterioles.

    SMCs were gradually lost during occlusion of arteries/arterioles from a juvenile mouse. Length of video, 1 h. Red, DsRed fluorescence in NG2DsRedBACtg mice.

  4. 4.

    Blebbing in SMCs after blood occlusion.

    Cells from whole blood (~10–20 μl) were labeled with DiO dye (green) and then injected back into the tail vein of the same mouse. Note that one blood cell cleared a SMC shortly after its blebbing. Red, DsRed fluorescencein NG2DsRedBACtg mice. Length of video, 1 h, 54 min.

About this article

Publication history





Further reading