Skip to main content

Advertisement

SpringerLink
Log in

Oral formulation of Wnt inhibitor complex reduces inflammation and fibrosis in intraperitoneal implants in vivo

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The use of implantable biomaterials to replace physiological and anatomical functions has been widely investigated in the clinic. However, the selection of biomaterials is crucial for long-term function, and the implantation of certain biomaterials can cause inflammatory and fibrotic processes, triggering a foreign body reaction that leads to loss of function and consequent need for removal. Specifically, the Wnt signaling pathway controls the healing process of the human body, and its dysregulation can result in inflammation and fibrosis, such as in peritoneal fibrosis. Here, we assessed the effects of daily oral administration of a Wnt pathway inhibitor complex (CD:LGK974) to reduce the inflammatory, fibrotic, and angiogenic processes caused by intraperitoneal implants. CD:LGK974 significantly reduced the infiltration of immune cells and release of inflammatory cytokines in the implant region compared to the control groups. Furthermore, CD:LGK974 inhibited collagen deposition and reduced the expression of pro-fibrotic α-SMA and TGF-β1, confirming fibrosis reduction. Finally, the CD:LGK974 complex decreased VEGF levels and both the number and area of blood vessels formed, suggesting decreased angiogenesis. This work introduces a potential new application of the Wnt inhibitor complex to reduce peritoneal fibrosis and the rejection of implants at the intraperitoneal site, possibly allowing for longer-term functionality of existing clinical biomaterials.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Ratner BD, Zhang G. A history of biomaterials, Fourth Edi. Elsevier. 2020. https://doi.org/10.1016/b978-0-12-816137-1.00002-7.

    Article  Google Scholar 

  2. Zhou G, Groth T. Host responses to biomaterials and anti-inflammatory design—a brief review. Macromol Biosci. 2018;18(8):1800112. https://doi.org/10.1002/mabi.201800112.

    Article  CAS  Google Scholar 

  3. Kohane DS, Langer R. Polymeric biomaterials in tissue engineering. Pediatr Res. 2008;63:487–91. https://doi.org/10.1203/01.pdr.0000305937.26105.e7.

    Article  CAS  PubMed  Google Scholar 

  4. Yu X, Tang X, Gohil SV, Laurencin CT. Biomaterials for bone regenerative engineering. Adv Healthc Mater. 2015;4:1268–85. https://doi.org/10.1002/adhm.201400760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bose S, Volpatti LR, Thiono D, Yesilyurt V, McGladrigan C, Tang Y, Facklam A, Wang A, Jhunjhunwala S, Veiseh O, Hollister-Lock J, Bhattacharya C, Weir GC, Greiner DL, Langer R, Anderson DG. A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells. Nat Biomed Eng. 2020;4:814–26. https://doi.org/10.1038/s41551-020-0538-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. He J, Renard E, Lord P, Cohen D, Gu B, Wang X, Yenduri G, Burgess DJ. Strategies for extended lifetime of implantable intraperitoneal insulin catheters. J Control Release. 2022;341:487–97. https://doi.org/10.1016/j.jconrel.2021.11.038.

    Article  CAS  PubMed  Google Scholar 

  7. Veiseh O, Doloff JC, Ma M, Vegas AJ, Tam HH, Bader AR, Li J, Langan E, Wyckoff J, Loo WS, Jhunjhunwala S, Chiu A, Siebert S, Tang K, Hollister-Lock J, Aresta-Dasilva S, Bochenek M, Mendoza-Elias J, Wang Y, Qi M, Lavin DM, Chen M, Dholakia N, Thakrar R, Lacík I, Weir GC, Oberholzer J, Greiner DL, Langer R, Anderson DG. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater. 2015;14:643–51. https://doi.org/10.1038/nmat4290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32:6692–709. https://doi.org/10.1016/j.biomaterials.2011.05.078.

    Article  CAS  PubMed  Google Scholar 

  9. Campos PP, Andrade SP, Moro L, Ferreira MA, Vasconcelos AC. Cellular proliferation, differentiation and apoptosis in polyether-polyurethane sponge implant model in mice. Histol Histopathol. 2006;21:1263–1270. https://doi.org/10.14670/HH-21.1263.

  10. Castro PR, Marques SM, Campos PP, Cardoso CC, Sampaio FP, Ferreira MAND, Andrade SP. Kinetics of implant-induced inflammatory angiogenesis in abdominal muscle wall in mice. Microvasc Res. 2012;84:9–15. https://doi.org/10.1016/j.mvr.2012.04.003.

    Article  CAS  PubMed  Google Scholar 

  11. Pereira LX, Viana CT, Orellano LA, Almeida SA, Vasconcelos AC, de Miranda Goes A, Birbrair A, Andrade SP, Campos PP. Synthetic matrix of polyether-polyurethane as a biological platform for pancreatic regeneration. Life Sci. 2017;176:67–74. https://doi.org/10.1016/j.lfs.2017.03.015.

  12. Duxbury PJ, Harvey JR. Systematic review of the effectiveness of polyurethane-coated compared with textured silicone implants in breast surgery. J Plast Reconstr Aesthetic Surg. 2016;69:452–60. https://doi.org/10.1016/j.bjps.2016.01.013.

    Article  Google Scholar 

  13. Alzahrani K, Lejeune J, Lakhal W, Morel B, Cook AR, Braïk K, Lardy H, Binet A. Polyurethane versus silicone port a cath: what’s going on at removal? J Pediatr Surg. 2018;53:1417–9. https://doi.org/10.1016/j.jpedsurg.2017.06.025.

    Article  PubMed  Google Scholar 

  14. Laurano R, Boffito M, Abrami M, Grassi M, Zoso A, Chiono V, Ciardelli G. Dual stimuli-responsive polyurethane-based hydrogels as smart drug delivery carriers for the advanced treatment of chronic skin wounds. Bioact Mater. 2021;6:3013–24. https://doi.org/10.1016/j.bioactmat.2021.01.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pontes GH, Carneiro Filho FS, Vargas Guerrero LA, Lipinski LC, de Noronha L, Silva EN, Serra-Guimarães F. Reduced remodeling biomarkers tissue expression in nanotextured compared with polyurethane implants capsules: a study in rats. Aesthetic Surg J. 2021;41:NP664–NP683. https://doi.org/10.1093/asj/sjaa315.

  16. Mendes JB, Campos PP, Ferreira MA, Bakhle YS, Andrade SP. Host response to sponge implants differs between subcutaneous and intraperitoneal sites in mice. J Biomed Mater Res. Part B Appl Biomater. 2007;83:408–415. https://doi.org/10.1002/jbm.b.30810.

  17. Terri M, Trionfetti F, Montaldo C, Cordani M, Tripodi M, Lopez-Cabrera M, Strippoli R. Mechanisms of peritoneal fibrosis: focus on immune cells–peritoneal stroma interactions. Front Immunol. 2021;12:1–17. https://doi.org/10.3389/fimmu.2021.607204.

    Article  CAS  Google Scholar 

  18. Abul AHL, ABBAS K. Patologia básica - Robbins e Cotran. 2016.

  19. Carnicer-Lombarte A, Chen ST, Malliaras GG, Barone DG. Foreign body reaction to implanted biomaterials and its impact in nerve neuroprosthetics. Front Bioeng Biotechnol. 2021;9:1–22. https://doi.org/10.3389/fbioe.2021.622524.

    Article  Google Scholar 

  20. Noskovicova N, Hinz B, Pakshir P. Implant fibrosis and the underappreciated role of myofibroblasts in the foreign body reaction. Cells. 2021;10. https://doi.org/10.3390/cells10071794.

  21. Burgy O, Königshoff M. The WNT signaling pathways in wound healing and fibrosis. Matrix Biol. 2018;68–69:67–80. https://doi.org/10.1016/j.matbio.2018.03.017.

    Article  CAS  PubMed  Google Scholar 

  22. Jung Y, Park J. Wnt signaling in cancer : therapeutic targeting of Wnt signaling beyond β -catenin and the destruction complex. Exp Mol Med. 2020;52:183–91. https://doi.org/10.1038/s12276-020-03806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guo Y, Sun L, Xiao L, Gou R, Fang Y, Liang Y, Wang R, Li N, Liu F, Tang L. Aberrant Wnt/beta-catenin pathway activation in dialysate-induced peritoneal fibrosis. Front Pharmacol. 2017;8:774. https://doi.org/10.3389/fphar.2017.00774.

  24. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–999. https://doi.org/10.1016/j.cell.2017.05.016.

  25. Guimaraes PPG, Tan M, Tammela T, Wu K, Chung A, Oberli M, Wang K, Spektor R, Riley RS, Viana CTR, Jacks T, Langer R, Mitchell MJ. Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes. J Control Release. 2018;290:75–87. https://doi.org/10.1016/j.jconrel.2018.09.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stella VJ, Rajewski RA. Cyclodextrins: their future in drug formulation and delivery. Pharm Res. 1997;14:556–67. https://doi.org/10.1023/A:1012136608249.

    Article  CAS  PubMed  Google Scholar 

  27. Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev. 1994;14:353–86. https://doi.org/10.1002/med.2610140304.

    Article  CAS  PubMed  Google Scholar 

  28. Hirayama F, Uekama K. Cyclodextrin-based controlled drug release system. Adv Drug Deliv Rev. 1999;36(1):125–141. https://doi.org/10.1016/S0169-409X(98)00058-1.

  29. Andrade SP, Machado RDP, Teixeira AS, Belo AV, Tarso AM, Beraldo WT. Sponge-induced angiogenesis in mice and the pharmacological reactivity of the neovasculature quantitated by a fluorimetric method. Microvasc Res. 1997;54:253–61. https://doi.org/10.1006/mvre.1997.2047.

    Article  CAS  PubMed  Google Scholar 

  30. Thompson K, Maltby J, Fallowfield J, Mcaulay M, Millward-Sadler H, Sheron N. Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. Hepatology. 1998;28:1597–606. https://doi.org/10.1002/hep.510280620.

    Article  CAS  PubMed  Google Scholar 

  31. Li JP, Gao Y, Chu SF, Zhang Z, Xia CY, Mou Z, Song XY, He WB, Guo XF, Chen NH. Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcoholand CCl4-induced hepatic fibrosis. Acta Pharmacol Sin. 2014;35:1031–1044. https://doi.org/10.1038/aps.2014.41.

  32. Junqueira LC, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J. 1979;11:447–455. http://www.ncbi.nlm.nih.gov/pubmed/7344781.

  33. Otsu N. A Threshold selection method from gray-level histograms. IEEE Trans Syst Man Cybern. 1979;9:62–6. https://doi.org/10.1109/TSMC.1979.4310076.

    Article  Google Scholar 

  34. Canny J. A computational approach to edge detection. IEEE Trans Pattern Anal Mach Intell PAMI-8. 1986:679–698. https://doi.org/10.1109/TPAMI.1986.4767851.

  35. Schneider HJ, Hacket F, Rüdiger V, Ikeda H. NMR studies of cyclodextrins and cyclodextrin complexes. Chem Rev. 1998;98:1755–85. https://doi.org/10.1021/cr970019t.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. Chu C, Liu L, Rung S, Wang Y, Ma Y, Hu C, Zhao X, Man Y, Qu Y. Modulation of foreign body reaction and macrophage phenotypes concerning microenvironment. J Biomed Mater Res Part A. 2020;108:127–35. https://doi.org/10.1002/jbm.a.36798.

    Article  CAS  Google Scholar 

  38. Mariani E, Lisignoli G, Borzì RM, Pulsatelli L. Biomaterials: foreign bodies or tuners for the immune response? Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20030636.

  39. Kobayashi A, Suzuki Y, Sugai S. Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity. J Toxicol Sci. 2020;45:515–37. https://doi.org/10.2131/jts.45.515.

    Article  CAS  PubMed  Google Scholar 

  40. Ratner AS, Hoffman BD. Blomaterials science - an introduction to materials in medicine. 1996.

  41. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Vanasse G, Harris JL. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. 2013;110:20224–20229. https://doi.org/10.1073/pnas.1314239110.

  42. Feng Y, Ren J, Gui Y, Wei W, Shu B, Lu Q, Xue X, Sun X. Wnt / b -Catenin – promoted macrophage alternative activation contributes to kidney fibrosis. 2018;182–193. https://doi.org/10.1681/ASN.2017040391.

  43. Webber MJ, Langer R. Drug delivery by supramolecular design. Chem Soc Rev. 2017;46:6600–20. https://doi.org/10.1039/c7cs00391a.

    Article  CAS  PubMed  Google Scholar 

  44. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(80):656–661. https://doi.org/10.1126/science.1178331.

  45. Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020;877:173090. https://doi.org/10.1016/j.ejphar.2020.173090.

  46. Shapouri‐Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A. Macrophage plasticity, polarization, and function in health and disease. 2018. https://doi.org/10.1002/jcp.26429.

  47. Diegelmann RF. Cellular biochemical aspects of normal and abnormal wound healing: an overview. J Urol. 1997;157:298–302. https://doi.org/10.1016/S0022-5347(01)65364-3.

    Article  CAS  PubMed  Google Scholar 

  48. Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front Med. 2015;2:59. https://doi.org/10.3389/fmed.2015.00059.

Download references

Acknowledgements

We would like to thank Laboratório de Ressonância Magnética de Alta Resolução (UFMG/LIPq/LAREMAR/ICEx/DQ) and their staff for the access to their analytical facilities.

Funding

P.P.G.G. is supported by CNPq (401390/2020–9; 442731/2020–5), CAPES (88887.513270/2020–00), and FAPEMIG (Rede de Pesquisa Imunobiofar RED-00202-22, Universal 2021 APQ-00826–21). M.J.M. receives support from a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI) and a U.S. National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776). R.M.H. receives support from the National Science Foundation Graduate Research Fellowship (NSF-GRFP).

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Pres. Antônio Carlos, 6627-Pampulha, Belo Horizonte-MG, 31270-901, Brazil

    Ana Luíza de Castro Santos, Natália Jordana Alves da Silva, Celso Tarso Rodrigues Viana, Gabriel Henrique Costa da Silva, Sérgio Ricardo Aluotto Scalzo Júnior, Pedro Augusto Carvalho Costa, Walison Nunes da Silva, Itamar Couto Guedes de Jesus, Frédéric Frézard, Silvia Guatimosim, Silvia Passos Andrade & Pedro Pires Goulart Guimaraes

  2. Department of Biochemistry and Immunology, Federal University of Minas Gerais, Minas Gerais, Belo Horizonte, 31270-901, Brazil

    Mariana T. Q. de Magalhães

  3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Rebecca M. Haley & Michael J. Mitchell

  4. Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte-MG, 31270-901, Brazil

    Letícia Cristine Cardoso dos Santos, Alexander Birbrair & Paula Peixoto Campos

Authors
  1. Ana Luíza de Castro Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natália Jordana Alves da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Celso Tarso Rodrigues Viana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Letícia Cristine Cardoso dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriel Henrique Costa da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sérgio Ricardo Aluotto Scalzo Júnior
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pedro Augusto Carvalho Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Walison Nunes da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Itamar Couto Guedes de Jesus
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander Birbrair
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mariana T. Q. de Magalhães
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Frédéric Frézard
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Silvia Guatimosim
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rebecca M. Haley
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michael J. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Silvia Passos Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Paula Peixoto Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Pedro Pires Goulart Guimaraes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Pedro Pires Goulart Guimaraes, Ana Luíza de Castro Santos, Silvia Passos Andrade, and Paula Peixoto Campos contributed to the study conception and design. Ana Luíza de Castro Santos, Natália Jordana Alves da Silva, Celso Tarso Rodrigues Viana, Letícia Cristine Cardoso dos Santos, Gabriel Henrique Costa da Silva, Sérgio Ricardo Aluotto Scalzo Júnior, Pedro Augusto Carvalho Costa, Walison da Silva Nunes, Itamar Couto Guedes de Jesus, and Mariana T. Q. de Magalhães, performed experiments and collected data. Pedro Pires Goulart Guimaraes, Frédéric Frézard, Silvia Guatimosim, Rebecca M. Haley, Michael J. Mitchell, Silvia Passos Andrade, Paula Peixoto Campos, and Mariana T. Q. de Magalhães discussed the results and strategy. The first draft of the manuscript was written by Pedro Pires Goulart Guimaraes, Ana Luíza de Castro Santos, Sérgio Ricardo Aluotto Scalzo Júnior, and Pedro Augusto Carvalho Costa, which was edited by Frédéric Frézard, Silvia Guatimosim, Rebecca M. Haley, Michael J. Mitchell, Silvia Passos Andrade, Paula Peixoto Campos, and Alexander Birbrair. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Pedro Pires Goulart Guimaraes.

Ethics declarations

Ethics approval and consent to participate

The protocols for animal experimentation were approved by the Ethics Committee at the Federal University of Minas Gerais (CEUA/UFMG) (Protocol No. 282/2018). All procedures were performed following the standards established in the guidelines and policies of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals.

Consent for publication

Not applicable. No human studies have been performed in this research.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 727 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Castro Santos, A.L., da Silva, N.J.A., Viana, C.T.R. et al. Oral formulation of Wnt inhibitor complex reduces inflammation and fibrosis in intraperitoneal implants in vivo. Drug Deliv. and Transl. Res. 13, 1420–1435 (2023). https://doi.org/10.1007/s13346-023-01303-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-023-01303-0

Keywords

Search

Navigation