CardioVascular and Interventional Radiology

, Volume 41, Issue 6, pp 951–958 | Cite as

Long-Term Implantability of Resorbable Carboxymethyl Cellulose/Chitosan Microspheres in a Rabbit Renal Arterial Embolization Model

  • Lihui Weng
  • Davis Seelig
  • Omid Souresrafil
Laboratory Investigation



To determine the physiologic response to resorbable carboxymethyl cellulose/chitosan (CMC/CN) microspheres in a long-term rabbit model, including the clinical response, gross pathology, and histopathology.

Materials and Methods

Six rabbits were embolized with CMC/CN microspheres (300–500 µm) in one kidney via an inferior renal artery branch. Angiography was performed immediately before and after embolization and prior to killing at 6 months (180 ± 7 days, n = 3) and 12 months (365 ± 10 days, n = 3). A complete necropsy was performed on each animal with dissection of the kidneys and harvesting of additional tissues as per ISO-10993-part 6 and ISO-10993-part 11 guidelines. All tissues were processed and stained for pathological analysis.


The caudal third of target kidneys was successfully embolized with CMC/CN microspheres. Over the course of the study, there were neither notable clinical signs in either embolization group nor significant changes in the tissue/body weight ratio between 6- and 12-month time points. Gross examination revealed that all embolized kidneys had morphologic features consistent with infarction resulted from microsphere delivery. The percentage of infarction decreased from 9.1% ± 5.7% at 6 months to 1.9% ± 0.4% at 12 months. Microscopically, infarcted areas demonstrated evidence of chronic injury and repair, including loss of renal parenchyma with replacement fibrosis, tubular regeneration, and minimal to mild lymphoplasmacytic inflammation without any active changes such as necrosis or neutrophilic inflammation.


No systemic toxicity was observed in the animals 6 and 12 months after CMC/CN microspheres delivery. The local tissue response was mild.


Implantability Bioresorbable microspheres Arterial embolization Local effect Systemic toxicity 



This study was partially supported by a research Grant (Weng 2015, 00049685) sponsored by EmboMedics Inc.

Compliance with Ethical Standards

Conflict of interest

Lihui Weng received research grants from EmboMedics and also is a shareholder of EmboMedics Inc. Omid Souresrafil is shareholder of EmboMedics Inc. Davis Seelig has no conflict of interest.

Supplementary material

270_2018_1931_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)


  1. 1.
    Gunn AJ, Sheth RA, Luber B, Huynh MH, Rachamreddy NR, Kalva SP. Predicting outcomes after chemo-embolization in patients with advanced-stage hepatocellular carcinoma: an evaluation of different radiologic response criteria. Cardiovasc Interv Radiol. 2017;40(1):61–8.CrossRefGoogle Scholar
  2. 2.
    Zheng L, Shin JH, Han K, Tsauo J, Yoon HK, Ko GY, Shin JS, Sung KB. Transcatheter arterial embolization for gastrointestinal bleeding secondary to gastrointestinal lymphoma. Cardiovasc Interv Radiol. 2016;39(11):1564–72.CrossRefGoogle Scholar
  3. 3.
    Wasser K, Giebel F, Fischbach R, Tesch H, Landwehr P. Transcatheter arterial chemoembolization of colorectal liver metastases using degradable starch microspheres (Spherex®). Own investigations and review to the literature. Radiologe. 2005;45(7):633–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Brown DB, Pilgram TK, Darcy MD, Fundakowski CE, Lisker-Melman M, Chapman WC, et al. Hepatic arterial chemoembolization for hepatocellular carcinoma: comparison of survival rates with different embolic agents. J Vasc Interv Radiol. 2005;16:1661–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhou B, Wang J, Yan Z. Ginsenoside Rg3 attenuates hepatoma VEGF overexpression after hepatic artery embolization in an orthotopic transplantation hepatocellular carcinoma rat model. Onco Targets Ther. 2014;7:1945–54.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Namur J, Citron SJ, Sellers MT. Embolization of hepatocellular carcinoma with drug–eluting beads: doxorubicin tissue concentration and distribution in patient liver explants. J Hepatol. 2011;55:1332–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Pieper CC, Meyer C, Vollmar B, Hauenstein K, Schild HH, Wilhelm KE. Temporary arterial embolization of liver parenchyma with degradable starch microspheres (EmboCept®S) in a swine model. Cardiovasc Interv Radiol. 2014;38:435–41.CrossRefGoogle Scholar
  8. 8.
    Kang MJ, Park JM, Choi WS, Lee J, Kwak BK, Lee J. Highly spherical and deformable chitosan microspheres for arterial embolization. Chem Pharm Bull. 2010;58:288–92.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang C, Liu J, Gao Q, et al. Preparation and characterization of Pingyangmycin-loaded bovine serum albumin microspheres for embolization therapy. Inter J Pharm. 2007;336:361–6.CrossRefGoogle Scholar
  10. 10.
    Forster RE, Thürmer F, Wallrapp C, et al. Characterisation of physico-mechanical properties and degradation potential of calcium alginate beads for use in embolization. J Mater Sci Mater Med. 2010;21:2243–51.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Flandroy P, Grandfils C, Daenenb B, Snaps F, Dondelinger RF, Jeromeb R. In vivo behavior of poly(d, l)-lactide microspheres designed for chemoembolization. J Control Release. 1997;44:153–70.CrossRefGoogle Scholar
  12. 12.
    Weng L, Rostamzadeh P, Nooryshokry N, Le HC, Golzarian J. In vitro and in vivo evaluation of biodegradable embolic microspheres with tunable anticancer drug release. Acta Biomater. 2013;9:6823–33.CrossRefPubMedGoogle Scholar
  13. 13.
    Weng L, Rusten M, Talaie R, Hairani M, Rosener NK, Golzarian J. Calibrated bioresorbable microspheres (BRMS): a preliminary study on the level of occlusion and arterial distribution in a rabbit kidney model. J Vasc Interv Radiol. 2013;24(10):1567–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Weng L, Seelig D, Rostamzadeh P, Golzarian J. Calibrated bioresorbable microspheres as an embolic agent: an experimental study in a rabbit renal model. J Vasc Interv Radiol. 2015;26(12):1887–94.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Weng L, Tseng HJ, Rostamzadeh P, Golzarian J. In vitro comparative study of drug loading and delivery properties of bioresorbable microspheres and LC bead. Mater Sci Mater. 2016;27(12):174–82.CrossRefGoogle Scholar
  16. 16.
    Remes A, Williams DF. Immune response in biocompatibility. Biomaterials. 1992;13:731–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Spiller KL, Anfang RR, Spiller KJ, Ng J, Nakazawa KR, Daulton JW, Vunjak-Novakovic G. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials. 2014;35:4477–88.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Anderson JM. Mechanisms of inflammation and infection with implanted devices. Cardiovasc Pathol. 1993;2:33–41.CrossRefGoogle Scholar
  19. 19.
    Kumar V, Abbas K, Fausto N, et al. Acute and chronic inflammation. In: Kumar V, Abbas K, Fausto N, et al., editors. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Saunders; 2010. p. 43–78.Google Scholar
  20. 20.
    Anderson JM. Biological responses to materials. Annu Rev Mater Res. 2001;31:81–110.CrossRefGoogle Scholar
  21. 21.
    Costa-Pinto AR, Martins AM, Castelhano-Carlos MJ, et al. In vitro degradation and in vivo biocompatibility of chitosan—poly(butylene succinate) fiber mesh scaffolds. J Bioact Compat Polym. 2014;29(2):137–51.CrossRefGoogle Scholar
  22. 22.
    Shamekhi MA, Rabiee A, Mirzadeh H, Mahdavi H, Mohebbi-Kalhori D, Baghaban Eslaminejad M. Fabrication and characterization of hydrothermal cross-linked chitosan porous scaffolds for cartilage tissue engineering applications. Mater Sci Eng C Mater Biol Appl. 2017;80:532–42.CrossRefPubMedGoogle Scholar
  23. 23.
    ISO 10993-6:2009. Biological evaluation of medical devices-part 6: tests for local effects after implantation. Geneva: International Organization for Standardization; 2009.Google Scholar
  24. 24.
    ISO 10993-11:2009. Biological evaluation of medical devices—part 11: tests for systemic toxicity. Geneva: International Organization for Standardization; 2009.Google Scholar
  25. 25.
    Oryan A, Sahvieh S. Effectiveness of chitosan scaffold in skin, bone and cartilage healing. Int J Biol Macromol. 2017;104:1003–11.CrossRefPubMedGoogle Scholar
  26. 26.
    Sainitya AR, Sriram M, Kalyanaraman V, Dhivya S, Saravanan S, Vairamani M, Sastry TP, Selvamurugan N. Scaffolds containing chitosan/carboxymethyl cellulose/mesoporous wollastonite for bone tissue engineering. Int J Biol Macromol. 2015;80:481–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Ramli NA, Wong TW. Sodium carboxymethylcellulose scaffolds and their physicochemical effects on partial thickness wound healing. Int J Pharm. 2011;403(1–2):73–82.CrossRefPubMedGoogle Scholar
  28. 28.
    Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20(2):86–100.CrossRefPubMedGoogle Scholar
  29. 29.
    Bojar W, Kucharska M, Bubak G, et al. Formation and preclinical evaluation of a new alloplastic injectable bone substitute material. Acta Bioeng Biomech. 2012;14(1):39–44.PubMedGoogle Scholar
  30. 30.
    Wu HD, Ji DY, Chang WJ, Yang JC, Lee SY. Chitosan-based polyelectrolyte complex scaffolds with antibacterial properties for treating dental bone defects. Mater Sci Eng C. 2012;32:207–14.CrossRefGoogle Scholar
  31. 31.
    Aramwit P, Yamdech R, Ampawong S. Controlled release of chitosan and sericin from the microspheres-embedded wound dressing for the prolonged anti-microbial and wound healing efficacy. AAPS J. 2016;18:647–58.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Batth KH, Strandberg JD, White R. Long term follow-up of transcatheter embolization with autologous clot, Oxycel and gelfoam in domestic Swine. Invest Radiol. 1977;12:273–80.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2018

Authors and Affiliations

  1. 1.Department of RadiologyUniversity of MinnesotaMinneapolisUSA
  2. 2.EmboMedics Inc.Golden ValleyUSA
  3. 3.Department of Veterinary Clinical SciencesUniversity of MinnesotaSt. PaulUSA

Personalised recommendations