A self-cleaning, mechanically robust membrane for minimizing the foreign body reaction: towards extending the lifetime of sub-Q glucose biosensors

Abstract

Long-term, subcutaneously implanted continuous glucose biosensors have the potential to improve diabetes management and reduce associated complications. However, the innate foreign body reaction (FBR) both alters the local glucose concentrations in the surrounding tissues and compromises glucose diffusion to the biosensor due to the recruitment of high-metabolizing inflammatory cells and the formation of a dense, collagenous fibrous capsule. Minimizing the FBR has mainly focused on “passively antifouling” materials that reduce initial cellular attachment, including poly(ethylene glycol) (PEG). Instead, the membrane reported herein utilizes an “actively antifouling” or “self-cleaning” mechanism to inhibit cellular attachment through continuous, cyclic deswelling/reswelling in response to normal temperature fluctuations of the subcutaneous tissue. This thermoresponsive double network (DN) membrane is based on N-isopropylacrylamide (NIPAAm) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) (75:25 and 100:0 NIPAAm:AMPS in the 1st and 2nd networks, respectively; “DN-25%”). The extent of the FBR reaction of a subcutaneously implanted DN-25% cylindrical membrane was evaluated in rodents in parallel with a PEG-diacrylate (PEG-DA) hydrogel as an established benchmark biocompatible control. Notably, the DN-25% implants were more than 25× stronger and tougher than the PEG-DA implants while maintaining a modulus near that of subcutaneous tissue. From examining the FBR at 7, 30 and 90 days after implantation, the thermoresponsive DN-25% implants demonstrated a rapid healing response and a minimal fibrous capsule (~20–25 µm), similar to the PEG-DA implants. Thus, the dynamic self-cleaning mechanism of the DN-25% membranes represents a new approach to limit the FBR while achieving the durability necessary for long-term implantable glucose biosensors.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Frost M, Meyerhoff ME. In vivo chemical sensors: tackling biocompatibility. Anal Chem. 2006;78:7370–77. https://doi.org/10.1021/ac069475k.

    CAS  Article  Google Scholar 

  2. 2.

    Wisniewski N, Moussy F, Reichert WM. Characterization of implantable biosensor membrane biofouling. Fresenius’ J Anal Chem. 2000;366:611–21. https://doi.org/10.1007/s002160051556.

    CAS  Article  Google Scholar 

  3. 3.

    Rebrin K, Fischer U, Hahn von Dorsche H, von Woetke T, Abel P, Brunstein E. Subcutaneous glucose monitoring by means of electrochemical sensors: fiction or reality? J Biomed Eng. 1992;14:33–40. https://doi.org/10.1016/0141-5425(92)90033-H.

    CAS  Article  Google Scholar 

  4. 4.

    Nichols SP, Koh A, Storm WL, Shin JH, Schoenfisch MH. Biocompatible materials for continuous glucose monitoring devices. Chem Rev. 2013;113:2528–49. https://doi.org/10.1021/cr300387j.

    CAS  Article  Google Scholar 

  5. 5.

    Caccomo S. FDA approves first continuous glucose monitoring system with a fully implantable glucose sensor and compatible mobile app for adults with diabetes. U.S. Food & Drug Administration; 2018. https://www.fda.gov/news-events/press-announcements/fda-approves-first-continuous-glucose-monitoring-system-fully-implantable-glucosesensor-and. Accessed 21 Jun 2019.

  6. 6.

    Ratner BD, Bryant SJ. Biomaterials: where we have been and where we are going. Annu Rev Biomed Eng. 2004;6:41–75. https://doi.org/10.1146/annurev.bioeng.6.040803.140027.

    CAS  Article  Google Scholar 

  7. 7.

    Wang C, Yu B, Knudsen B, Harmon J, Moussy F, Moussy Y. Synthesis and performance of novel hydrogels coatings for implantable glucose sensors. Biomacromolecules. 2008;9:561–7. https://doi.org/10.1021/bm701102y.

    CAS  Article  Google Scholar 

  8. 8.

    Novak MT, Yuan F, Reichert WM. Modeling the relative impact of capsular tissue effects on implanted glucose sensor time lag and signal attenuation. Anal Bioanal Chem. 2010;398:1695–1705. https://doi.org/10.1007/s00216-010-4097-6.

    CAS  Article  Google Scholar 

  9. 9.

    Gerritsen M, Jansen JA, Lutterman JA. Performance of subcutaneously implanted glucose sensors for continuous monitoring. Neth J Med. 1999;54:167–79. https://doi.org/10.1016/S0300-2977(99)00006-6.

    CAS  Article  Google Scholar 

  10. 10.

    Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100. https://doi.org/10.1016/j.smim.2007.11.004.

    CAS  Article  Google Scholar 

  11. 11.

    Onuki Y, Bhardwaj U, Papadimitrakopoulos F, Burgess DJ. A review of the biocompatibility of implantable devices: current challenges to overcome foreign body response. J Diabetes Sci Technol. 2008;2:1003–15. https://doi.org/10.1177/193229680800200610.

    Article  Google Scholar 

  12. 12.

    Daley JM, Shearer JD, Mastrofrancesco B, Caldwell MD. Glucose metabolism in injured tissue: a longitudinal study. Surgery. 1990;107:187–92.

    CAS  Google Scholar 

  13. 13.

    Quinn CAP, Connor RE, Heller A. Biocompatible, glucose-permeable hydrogel for in situ coating of implantable biosensors. Biomaterials. 1997;18:1665–70. https://doi.org/10.1016/S0142-9612(97)00125-7.

    CAS  Article  Google Scholar 

  14. 14.

    Espadas-Torre C, Meyerhoff ME. Thrombogenic properties of untreated and poly(ethylene oxide)-modified polymeric matrixes useful for preparing intraarterial ion-selective electrodes. Anal Chem. 1995;67:3108–3114. https://doi.org/10.1021/ac00114a003.

    CAS  Article  Google Scholar 

  15. 15.

    Quinn CP, Pathak CP, Heller A, Hubbell JA. Photo-crosslinked copolymers of 2-hydroxyethyl methacrylate, poly(ethylene glycol) tetra-acrylate and ethylene dimethacrylate for improving biocompatibility of biosensors. Biomaterials. 1995;16:389–96. https://doi.org/10.1016/0142-9612(95)98856-9.

    CAS  Article  Google Scholar 

  16. 16.

    Yu B, Wang C, Ju YM, West L, Harmon J, Moussy Y, et al. Use of hydrogel coating to improve the performance of implanted glucose sensors. Biosens Bioelectron. 2008;23:1278–84. https://doi.org/10.1016/j.bios.2007.11.010.

    CAS  Article  Google Scholar 

  17. 17.

    Ratner BD. Surface modification of polymers: chemical, biological and surface analytical challenges. Biosens Bioelectron. 1995;10:797–804. https://doi.org/10.1016/0956-5663(95)99218-A.

    CAS  Article  Google Scholar 

  18. 18.

    Nishida K, Sakakida M, Ichinose K, Uemura T, Uehara M, Kajiwara K, et al. Development of a ferrocene-mediated needle-type glucose sensor covered with newly designed biocompatible membrane, 2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate. Med Prog Technol. 1995;21:91–103.

    CAS  Google Scholar 

  19. 19.

    Lewis AL. Phosphorylcholine-based polymers and their use in the prevention of biofouling. Colloids Surf B Biointerfaces. 2000;18:261–75. https://doi.org/10.1016/S0927-7765(99)00152-6.

    CAS  Article  Google Scholar 

  20. 20.

    Bryers JD, Giachelli CM, Ratner BD. Engineering biomaterials to integrate and heal: the biocompatibility paradigm shifts. Biotechnol Bioeng. 2012;109:1898–1911. https://doi.org/10.1002/bit.24559.

    CAS  Article  Google Scholar 

  21. 21.

    Sharkawy AA, Klitzman B, Truskey GA, Reichert WM. Engineering the tissue which encapsulates subcutaneous implants. III. Effective tissue response times. J Biomed Mater Res. 1998;40:598–605.

    CAS  Article  Google Scholar 

  22. 22.

    Brauker JH, Carr-Brendel VE, Martinson LA, Crudele J, Johnston WD, Johnson RC. Neovascularization of synthetic membranes directed by membrane microarchitecture. J Biomed Mater Res. 1995;29:1517–24. https://doi.org/10.1002/jbm.820291208.

    CAS  Article  Google Scholar 

  23. 23.

    Abraham AA, Means AK, Clubb FJ, Fei R, Locke AK, Gacasan EG, et al. Foreign body reaction to a subcutaneously implanted self-cleaning, thermoresponsive hydrogel membrane for glucose biosensors. ACS Biomater Sci Eng. 2018;4:4104–4111. https://doi.org/10.1021/acsbiomaterials.8b01061.

    CAS  Article  Google Scholar 

  24. 24.

    Fei R, Means AK, Abraham AA, Locke AK, Coté GL, Grunlan MA. Self-cleaning, thermoresponsive P(NIPAAm-co-AMPS) double network membranes for implanted glucose biosensors. Macromol Mater Eng. 2016;301:935–43. https://doi.org/10.1002/mame.201600044.

    CAS  Article  Google Scholar 

  25. 25.

    Cummins BM, Li M, Locke AK, Birch DJS, Vigh G, Coté GL. Overcoming the aggregation problem: a new type of fluorescent ligand for ConA-based glucose sensing. Biosens Bioelectron. 2015;63:53–60. https://doi.org/10.1016/j.bios.2014.07.015.

    CAS  Article  Google Scholar 

  26. 26.

    Locke AK, Means AK, Dong P, Nichols TJ, Coté GL, Grunlan MA. A layer-by-layer approach to retain a fluorescent glucose sensing assay within the cavity of a hydrogel membrane. ACS Appl Bio Mater. 2018. https://doi.org/10.1021/acsabm.8b00267.

    Article  Google Scholar 

  27. 27.

    Bolles RC, Duncan PM. Daily course of activity and subcutaneous body temperature in hungry and thirsty rats. Physiol Behav. 1969;4:87–9. https://doi.org/10.1016/0031-9384(69)90018-3.

    Article  Google Scholar 

  28. 28.

    Shido O, Sakurada S, Kohda W, Nagasaka T. Day–night changes of body temperature and feeding activity in heat-acclimated rats. Physiol Behav. 1994;55:935–9. https://doi.org/10.1016/0031-9384(94)90082-5.

    CAS  Article  Google Scholar 

  29. 29.

    Kort WJ, Hekking-Weijma JM, Tenkate MT, Sorm V, VanStrik R. A microchip implant system as a method to determine body temperature of terminally ill rats and mice. Lab Anim. 1998;32:260–9. https://doi.org/10.1258/002367798780559329.

    CAS  Article  Google Scholar 

  30. 30.

    Fei R, George JT, Park J, Grunlan MA. Thermoresponsive nanocomposite double network hydrogels. Soft Matter. 2012;8:481–87. https://doi.org/10.1039/C1SM06105D.

    CAS  Article  Google Scholar 

  31. 31.

    Fei R, George JT, Park J, Means AK, Grunlan MA. Ultra-strong thermoresponsive double network hydrogels. Soft Matter. 2013;9:2912–19. https://doi.org/10.1039/C3SM27226E.

    CAS  Article  Google Scholar 

  32. 32.

    Pailler-Mattei C, Bec S, Zahouani H. In vivo measurements of the elastic mechanical properties of human skin by indentation tests. Med Eng Phys. 2008;30:599–606. https://doi.org/10.1016/j.medengphy.2007.06.011.

    CAS  Article  Google Scholar 

  33. 33.

    Liang X, Boppart SA. Biomechanical properties of in vivo human skin from dynamic optical coherence elastography. IEEE Trans Biomed Eng. 2010;57:953–59. https://doi.org/10.1109/TBME.2009.2033464.

    Article  Google Scholar 

  34. 34.

    Li C, Guan G, Reif R, Huang Z, Wang RK. Determining elastic properties of skin by measuring surface waves from an impulse mechanical stimulus using phase-sensitive optical coherence tomography. J R Soc Interface. 2012;9:831–41. https://doi.org/10.1098/rsif.2011.0583.

    Article  Google Scholar 

  35. 35.

    Gacasan EG, Sehnert RM, Ehrhardt DA, Grunlan MA. Templated, macroporous PEG‐DA hydrogels and their potential utility as tissue engineering scaffolds. Macromol Mater Eng. 2017;302:1600512. https://doi.org/10.1002/mame.201600512.

    Article  Google Scholar 

  36. 36.

    Hou Y, Schoener CA, Regan KR, Munoz-Pinto D, Hahn MS, Grunlan MA. Photo-cross-linked PDMSstar-PEG hydrogels: synthesis, characterization, and potential application for tissue engineering scaffolds. Biomacromolecules. 2010;11:648–56. https://doi.org/10.1021/bm9012293.

    CAS  Article  Google Scholar 

  37. 37.

    Choi WJ, Robinovitch SN. Pressure distribution over the palm region during forward falls on the outstretched hands. J Biomech. 2011;44:532–39. https://doi.org/10.1016/j.jbiomech.2010.09.011.

    CAS  Article  Google Scholar 

  38. 38.

    Helton KL, Ratner BD, Wisniewski NA. Biomechanics of the sensor-tissue interface—effects of motion, pressure, and design on sensor performance and foreign body response—part II: examples and application. J Diabetes Sci Technol. 2011;5:647–56. https://doi.org/10.1177/193229681100500318.

    Article  Google Scholar 

  39. 39.

    Blakney AK, Swartzlander MD, Bryant SJ. The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J Biomed Mater Res A. 2012;100:1375–86. https://doi.org/10.1002/jbm.a.34104.

    Article  Google Scholar 

  40. 40.

    Anderson JM. Biological responses to materials. Annu Rev Mater Res. 2001;31:81–110. https://doi.org/10.1146/annurev.matsci.31.1.81.

    CAS  Article  Google Scholar 

  41. 41.

    Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am. 1997;77:509–28. https://doi.org/10.1016/S0039-6109(05)70566-1.

    CAS  Article  Google Scholar 

  42. 42.

    Metz CN. Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci. 2003;60:1342–50. https://doi.org/10.1007/s00018-003-2328-0.

    CAS  Article  Google Scholar 

  43. 43.

    Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81.

    CAS  Article  Google Scholar 

  44. 44.

    Adam SA, Bruce K ATG, Monty RW. Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties. J Biomed Mater Res. 1997;37:401–12.

    Article  Google Scholar 

Download references

Acknowledgements

Funding from the NIH/NIDDK (1R01DK095101-01A1) is gratefully acknowledged. This work was supported, in part, by funding from the National Science Foundation Engineering Research Center for Precise Advanced Technologies and Health Systems for Underserved Populations (PATHS-UP) (Award No. 1648451) and funding from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. A.K.M. thanks the NSF Graduate Research Fellowship Program (NSF GRFP M1703014).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Melissa A. Grunlan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Means, A.K., Dong, P., Clubb, F.J. et al. A self-cleaning, mechanically robust membrane for minimizing the foreign body reaction: towards extending the lifetime of sub-Q glucose biosensors. J Mater Sci: Mater Med 30, 79 (2019). https://doi.org/10.1007/s10856-019-6282-2

Download citation

Keywords

  • Biocompatibility
  • Thermoresponsive
  • Hydrogel
  • PNIPAAm
  • Double network