Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

An extracorporeal blood-cleansing device for sepsis therapy

Nature Medicine volume 20, pages 1211–1216 (2014)Cite this article

Subjects

Abstract

Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin—mannose-binding lectin (MBL)—that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Magnetic opsonin and biospleen device.
Figure 2: Magnetic capture efficiency of the biospleen device in vitro.
Figure 3: In vivo blood cleansing using the biospleen blood-cleansing device in a rat bacteremia model.
Figure 4: In vivo blood cleansing using the biospleen device in a rat acute endotoxic shock model.

Similar content being viewed by others

Accession codes

Primary accessions

NCBI Reference Sequence

References

  1. Bone, R.C. The pathogenesis of sepsis. Ann. Intern. Med. 115, 457–469 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Hotchkiss, R.S. & Karl, I.E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Kumar, A. Optimizing antimicrobial therapy in sepsis and septic shock. Crit. Care Clin. 25, 733–751 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Anonymous. Focus on sepsis. Nat. Med. 18, 997 (2012).

  6. O'Brien, T.F. Global surveillance of antibiotic resistance. N. Engl. J. Med. 326, 339–340 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Lineaweaver, W. et al. Topical antimicrobial toxicity. Arch. Surg. 120, 267–270 (1985).

    Article  CAS  PubMed  Google Scholar 

  8. Garnacho-Montero, J. et al. Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis. Crit. Care 10, R111 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Stoll, B.J. et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 110, 285–291 (2002).

    Article  PubMed  Google Scholar 

  10. Neff, L.P. et al. Extracorporeal organ support following trauma: the dawn of a new era in combat casualty critical care. J. Trauma Acute Care Surg. 75, S120–S129 (2013).

    Article  PubMed  Google Scholar 

  11. Angus, D.C. Drotrecogin alfa (activated). a sad final fizzle to a roller-coaster party. Crit. Care 16, 107 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chuang, Y.-C., Chang, S.-C. & Wang, W.-K. High and increasing Oxa-51 DNA load predict mortality in Acinetobacter baumannii bacteremia: implication for pathogenesis and evaluation of therapy. PLoS ONE 5, e14133 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gijs, M.A.M. Magnetic bead handling on-chip: new opportunities for analytical applications. Microfluid. Nanofluidics 1, 22–40 (2004).

    CAS  Google Scholar 

  14. Kang, J.H., Choi, S., Lee, W. & Park, J.-K. Isomagnetophoresis to discriminate subtle difference in magnetic susceptibility. J. Am. Chem. Soc. 130, 396–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Kang, J.H. et al. A combined micromagnetic-microfluidic device for rapid capture and culture of rare circulating tumor cells. Lab Chip 12, 2175 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Xia, N. et al. Combined microfluidic-micromagnetic separation of living cells in continuous flow. Biomed. Microdevices 8, 299–308 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Yung, C.W., Fiering, J., Mueller, A.J. & Ingber, D.E. Micromagnetic-microfluidic blood cleansing device. Lab Chip 9, 1171 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Dommett, R.M., Klein, N. & Turner, M.W. Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens 68, 193–209 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sheriff, S., Chang, C.Y. & Ezekowitz, R.A.B. Human mannose-binding protein carbohydrate recognition domain trimerizes through a triple alpha-helical coiled-coil. Nat. Struct. Biol. 1, 789–794 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Lo, K.M. et al. High level expression and secretion of Fc-X fusion proteins in mammalian cells. Protein Eng. 11, 495–500 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Neth, O. et al. Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect. Immun. 68, 688–693 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Townsend, R., Read, R.C., Turner, M.W., Klein, N.J. & Jack, D.L. Differential recognition of obligate anaerobic bacteria by human mannose-binding lectin. Clin. Exp. Immunol. 124, 223–228 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Takahashi, K., Ip, W.E., Michelow, I.C. & Ezekowitz, R.A.B. The mannose-binding lectin: a prototypic pattern recognition molecule. Curr. Opin. Immunol. 18, 16–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Orsini, J. et al. Microbiological profile of organisms causing bloodstream infection in critically ill patients. J. Clin. Med. Res. 4, 371–377 (2012).

    PubMed  PubMed Central  Google Scholar 

  25. Castanheira, M., Farrell, S.E., Krause, K.M., Jones, R.N. & Sader, H.S. Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob. Agents Chemother. 58, 833–838 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morrow, B.J. et al. Activities of carbapenem and comparator agents against contemporary US Pseudomonas aeruginosa isolates from the CAPITAL surveillance program. Diagn. Microbiol. Infect. Dis. 75, 412–416 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Mebius, R.E. & Kraal, G. Structure and function of the spleen. Nat. Rev. Immunol. 5, 606–616 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Meijer, H.E.H., Singh, M.K. & Anderson, P.D. On the performance of static mixers: a quantitative comparison. Prog. Polym. Sci. 37, 1333–1349 (2012).

    Article  CAS  Google Scholar 

  29. Jayakumar, J.S., Mahajani, S.M., Mandal, J.C., Iyer, K.N. & Vijayan, P.K. CFD analysis of single-phase flows inside helically coiled tubes. Comput. Chem. Eng. 34, 430–446 (2010).

    Article  CAS  Google Scholar 

  30. Pass, L.J., Schloerb, P.R., Pearce, F.J. & Drucker, W.R. Cardiopulmonary response of the rat to Gram-negative bacteremia. Am. J. Physiol. 246, H344–H350 (1984).

    CAS  PubMed  Google Scholar 

  31. Wiesel, P. et al. Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1–deficient mice. Circulation 102, 3015–3022 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Netea, M.G. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 24, 254–258 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Janz, D.R. et al. Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit. Care Med. 41, 784–790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rello, J. Severity of pneumococcal pneumonia associated with genomic bacterial load. Chest 136, 832 (2009).

    Article  PubMed  Google Scholar 

  35. Levy, S.B. & Marshall, B. Antibacterial resistance worldwide: causes, challenges and responses. Nat. Med. 10, S122–S129 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Takahashi, K. et al. Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation. Immunobiology 216, 96–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Neth, O. et al. Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect. Immun. 68, 688–693 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Townsend, R., Read, R.C., Turner, M.W., Klein, N.J. & Jack, D.L. Differential recognition of obligate anaerobic bacteria by human mannose-binding lectin. Clin. Exp. Immunol. 124, 223–228 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Takahashi, K., Ip, W.E., Michelow, I.C. & Ezekowitz, R.A.B. The mannose-binding lectin: a prototypic pattern recognition molecule. Curr. Opin. Immunol. 18, 16–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Gilmore, J.M., Scheck, R.A., Esser-Kahn, A.P., Joshi, N.S. & Francis, M.B. N-terminal protein modification through a biomimetic transamination reaction. Angew. Chem. Int. Ed. Engl. 45, 5307–5311 (2006).

    Article  PubMed  Google Scholar 

  41. Scheck, R.A. & Francis, M.B. Regioselective labeling of antibodies through N-terminal transamination. ACS Chem. Biol. 2, 247–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Witus, L.S. et al. Identification of highly reactive sequences for PLP-mediated bioconjugation using a combinatorial peptide library. J. Am. Chem. Soc. 132, 16812–16817 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shim, M., Shi Kam, N.W., Chen, R.J., Li, Y. & Dai, H. Functionalization of carbon nanotubes for biocompatibility and biomolecular recognition. Nano Lett. 2, 285–288 (2002).

    Article  CAS  Google Scholar 

  44. Åkerman, M.E., Chan, W.C.W., Laakkonen, P., Bhatia, S.N. & Ruoslahti, E. Nanocrystal targeting in vivo. Proc. Natl. Acad. Sci. USA 99, 12617–12621 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Korin, N. et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 337, 738–742 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Takahashi, K. et al. Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation. Immunobiology 216, 96–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Petersen, S.V., Thiel, S., Jensen, L., Steffensen, R. & Jensenius, J.C. An assay for the mannan-binding lectin pathway of complement activation. J. Immunol. Methods 257, 107–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Vorup-Jensen, T. et al. Recombinant expression of human mannan-binding lectin. Int. Immunopharmacol. 1, 677–687 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Michelow, I.C. et al. A novel l-ficolin/mannose-binding lectin chimeric molecule with enhanced activity against Ebola virus. J. Biol. Chem. 285, 24729–24739 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Palaniyar, N. et al. Nucleic acid is a novel ligand for innate, immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J. Biol. Chem. 279, 32728–32736 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Lakshmi, C., Hanshaw, R.G. & Smith, B.D. Fluorophore-linked zinc(ii)dipicolylamine coordination complexes as sensors for phosphatidylserine-containing membranes. Tetrahedron 60, 11307–11315 (2004).

    Article  CAS  Google Scholar 

  52. Lee, J.-J. et al. Synthetic ligand-coated magnetic nanoparticles for microfluidic bacterial separation from blood. Nano Lett. 14, 1–5 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Ji, X., Gewurz, H. & Spear, G.T. Mannose binding lectin (MBL) and HIV. Mol. Immunol. 42, 145–152 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Beck, A. & Reichert, J.M. Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies. MAbs 3, 415–416 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Xia, N. et al. Combined microfluidic-micromagnetic separation of living cells in continuous flow. Biomed. Microdevices 8, 299–308 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Yung, C.W., Fiering, J., Mueller, A.J. & Ingber, D.E. Micromagnetic–microfluidic blood cleansing device. Lab Chip 9, 1171 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Wiesel, P. et al. Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1–deficient mice. Circulation 102, 3015–3022 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Kang, J.H. et al. A combined micromagnetic-microfluidic device for rapid capture and culture of rare circulating tumor cells. Lab Chip 12, 2175 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Kang, J.H., Choi, S., Lee, W. & Park, J.-K. Isomagnetophoresis to discriminate subtle difference in magnetic susceptibility. J. Am. Chem. Soc. 130, 396–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Ling, F. & Zhang, X. A numerical study on mixing in the Kenics static mixer. Chem. Eng. Commun. 136, 119–141 (1995).

    Article  CAS  Google Scholar 

  61. Jayakumar, J.S., Mahajani, S.M., Mandal, J.C., Iyer, K.N. & Vijayan, P.K. CFD analysis of single-phase flows inside helically coiled tubes. Comput. Chem. Eng. 34, 430–446 (2010).

    Article  CAS  Google Scholar 

  62. Ofsthun, N.J., Jensen, J.C. & Kray, M. Effect of high hematocrit and high blood flow rates on transmembrane pressure and ultrafiltration rate in hemodialysis. Blood Purif. 9, 169–176 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Krisper, P. & Stauber, R.E. Technology insight: artificial extracorporeal liver support—how does Prometheus compare with MARS? Nat. Clin. Pract. Nephrol. 3, 267–276 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ordodi, V.L. et al. Artificial device for extracorporeal blood oxygenation in rats. Artif. Organs 32, 66–70 (2008).

    PubMed  Google Scholar 

  66. Lee, H.B. & Blaufox, M.D. Blood volume in the rat. J. Nucl. Med. 26, 72–76 (1985).

    CAS  PubMed  Google Scholar 

  67. Kang, J.H. & Park, J.-K. Magnetophoretic continuous purification of single-walled carbon nanotubes from catalytic impurities in a microfluidic device. Small 3, 1784–1791 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Cooper, R.M. A Generic Pathogen Capture Technology for Sepsis Diagnosis (MIT Press, 2013).

  69. Onderdonk, A.B., Weinstein, W.M., Sullivan, N.M., Bartlett, J.G. & Gorbach, S.L. Experimental intra-abdominal abscesses in rats: quantitative bacteriology of infected animals. Infect. Immun. 10, 1256–1259 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Liang, J. et al. Enhanced clearance of a multiple antibiotic resistant Staphylococcus aureus in rats treated with PGG-glucan is associated with increased leukocyte counts and increased neutrophil oxidative burst activity. Int. J. Immunopharmacol. 20, 595–614 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Parker, S.J. & Watkins, P.E. Experimental models of Gram-negative sepsis. Br. J. Surg. 88, 22–30 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Pass, L.J., Schloerb, P.R., Pearce, F.J. & Drucker, W.R. Cardiopulmonary response of the rat to Gram-negative bacteremia. Am. J. Physiol. 246, H344–H350 (1984).

    CAS  PubMed  Google Scholar 

  73. Remick, D.G., Newcomb, D.E., Bolgos, G.L. & Call, D.R. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13, 110–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Mammoto, A. et al. Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics. Nat. Commun. 4, 1759 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Lindqvist, R. Estimation of Staphylococcus aureus growth parameters from turbidity data: characterization of strain variation and comparison of methods. Appl. Environ. Microbiol. 72, 4862–4870 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Defense Advanced Research Projects Agency grant N66001-11-1-4180 and contract HR0011-13-C-0025, Department of Defense/Center for Integration of Medicine and Innovative Technology and the Wyss Institute for Biologically Inspired Engineering at Harvard University. We thank M. Montoya-Zavala and D. Breslau for micromachining of the blood-cleansing microdevice and technical support; P. Snell and J. Tomolonis for microbiology assistance; A. Schulte for assistance in biospleen experiments; J. Weaver for help with scanning electron microscopy; R. Betensky for statistical analysis assistance; and A. Onderdonk, M. Puder, A. Nedder and their teams for assistance in developing the rat cecal contents sepsis model. We thank J. Fiering and his team for helpful discussions during the early phase of this project. J.H.K. is a recipient of a Wyss Technology Development Fellowship from the Wyss Institute and a professional development postdoctoral award from Harvard University. Scanning electron microscopy images were obtained at the Center for Nanoscale Systems at Harvard University, supportedby the National Science Foundation under award no. ECS-0335765.

Author information

Author notes

  1. Martin Rottman

    Present address: Current address: Université de Versailles St-Quentin en Yvelines, Versailles, France and Service de Microbiologie, Hôpitaux Universitaires Île de France Ouest, AP-HP, Garches, France.,

  2. Joo H Kang and Michael Super: These authors contributed equally to this work.

Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA

    Joo H Kang, Michael Super, Chong Wing Yung, Ryan M Cooper, Karel Domansky, Amanda R Graveline, Julia B Berthet, Mark J Cartwright, Alexander L Watters, Martin Rottman, Anna Waterhouse, Nazita Gamini, Melissa J Rodas, Anxhela Kole, Thomas M Valentin, Alexander Diaz & Donald E Ingber

  2. Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Joo H Kang, Chong Wing Yung, Ryan M Cooper, Tadanori Mammoto, Heather Tobin, Akiko Mammoto, Amanda Jiang & Donald E Ingber

  3. Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA

    Joo H Kang & Donald E Ingber

  4. Harvard-MIT Health Sciences and Technology Graduate Program, Cambridge, Massachusetts, USA

    Ryan M Cooper

  5. Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Kazue Takahashi

Authors
  1. Joo H Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Super
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chong Wing Yung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryan M Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karel Domansky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amanda R Graveline
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tadanori Mammoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julia B Berthet
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Heather Tobin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark J Cartwright
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alexander L Watters
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Rottman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Anna Waterhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Akiko Mammoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nazita Gamini
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Melissa J Rodas
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anxhela Kole
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Amanda Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Thomas M Valentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Alexander Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kazue Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Donald E Ingber
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.H.K. designed and performed blood-cleansing experiments with assistance from R.M.C., J.B.B., N.G., A.R.G., A.D. and A.W., and analyzed the data and prepared the manuscript. K.D. contributed to the design and integration of the biospleen device. J.H.K., C.W.Y., A.R.G. and H.T. established the rat sepsis models, and J.H.K. and A.R.G. conducted animal studies with help from T.M., A.M. and A.J.; C.W.Y. designed the prototype biospleen device and obtained preliminary data. M.S. and A.L.W. designed, engineered and produced FcMBL with assistance from M.J.R., J.B.B. and A.K.; M.S., M.J.C. and M.R. performed blood analysis for quantitating LPS levels with help from N.G. and helped establish an endotoxemia model in rats. T.M.V. fabricated devices, performed scanning electron microscopy and assisted with conducting studies. K.T. performed experiments to characterize FcMBL versus native MBL. D.E.I. led efforts to design the device and the opsonin, assisted in data analysis and helped write the manuscript.

Corresponding author

Correspondence to Donald E Ingber.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Table 1 (PDF 8622 kb)

The fabrication and the magnetic separation principle of the biospleen:

Schematic drawing and microscopic video showing how the biospleen device is fabricated and how the magnetically opsonized pathogens are separated from the blood channel under flow. Because it is difficult to observe the cell movement across the blood channel in the biospleen device, we demonstrated this in a microfluidic device fabricated from optically clear poly(dimethylsiloxane) (PDMS). To mimic pathogens captured by the magnetic opsonins, fluorescent magnetic particles (8 μm, 1.1g ml–1, UMC4F, Bang Laboratories, Inc., IN, USA) were spiked into human banked blood (1ml) and flowed at 10 μl min–1. (MOV 2662 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, J., Super, M., Yung, C. et al. An extracorporeal blood-cleansing device for sepsis therapy. Nat Med 20, 1211–1216 (2014). https://doi.org/10.1038/nm.3640

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3640

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing