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Decellularized Tissue-Induced Cellular Recruitment for Tissue Engineering and Regenerative Medicine

  • S.I. : Bioengineering and Enabling Technologies II
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Abstract

Biomaterials that recapitulate the native in vivo microenvironment are promising to facilitate tissue repair and regeneration when used in combination with relevant growth factors (GFs), chemokines, cytokines, and other small molecules and cell sources. However, limitations with the use of exogenous factors and ex vivo cell expansion has prompted cell-/GF-free tissue engineering strategies. Additionally, conventional chemotaxis assays for studying cell migration behavior provide limited information, lack long-term stability, and fail to recapitulate physiologically relevant conditions. In this study, articular cartilage tissue-based biomaterials were developed via a rapid tissue decellularization protocol. The decellularized tissue was further processed into a hydrogel through solubilization and self-assembly. Chemotactic activity of the tissue-derived gel was investigated using sophisticated cellular migration assays. These tissue-derived extracellular matrix (ECM) biomaterials retain biochemical cues of native tissue and stimulate the chemotactic migration of hBMSCs in 2D and 3D cell migration models using a real-time chemotaxis assay. This strategy, in a way, developed a new paradigm in tissue engineering where cartilage tissue repair and regeneration can be approached with decellularized cartilage tissue in the place of an engineered matrix. This strategy can be further expanded for other tissue-based ECMs to develop cell-/GF-free tissue engineering and regenerative medicine strategies for recruiting endogenous cell populations to facilitate tissue repair and regeneration.

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References

  1. Amini, A. R., C. T. Laurencin, and S. P. Nukavarapu. Bone tissue engineering: recent advances and challenges. Crit. Rev. Biomed. Eng. 40(5):363–408, 2012.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Amini, A., and S. Nukavarapu. Oxygen-tension controlled matrices for enhanced osteogenic cell survival and performance. Ann. Biomed. Eng. 42(6):1261–1270, 2014. https://doi.org/10.1007/s10439-014-0990-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blum, J. C., T. L. Schenck, A. Birt, R. E. Giunta, and P. S. Wiggenhauser. Artificial decellularized extracellular matrix improves the regenerative capacity of adipose tissue derived stem cells on 3D printed polycaprolactone scaffolds. J. Tissue Eng. 12:20417314211022240, 2021. https://doi.org/10.1177/20417314211022242.

    Article  CAS  Google Scholar 

  4. Brown, C., X. Pan, and A. Hassid. Nitric oxide and C-type atrial natriuretic peptide stimulate primary aortic smooth muscle cell migration via a cGMP-dependent mechanism. Circ. Res. 84(6):655–667, 1999. https://doi.org/10.1161/01.RES.84.6.655.

    Article  CAS  PubMed  Google Scholar 

  5. Bzymek, R., et al. Real-time two- and three-dimensional imaging of monocyte motility and navigation on planar surfaces and in collagen matrices: roles of Rho. Sci. Rep. 6(1):1, 2016. https://doi.org/10.1038/srep25016.

    Article  CAS  Google Scholar 

  6. Caralt, M., et al. Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am. J. Transpl. 15(1):64–75, 2015. https://doi.org/10.1111/ajt.12999.

    Article  CAS  Google Scholar 

  7. Crapo, P. M., T. W. Gilbert, and S. F. Badylak. An overview of tissue and whole organ decellularization processes. Biomaterials. 32(12):3233–3243, 2011. https://doi.org/10.1016/j.biomaterials.2011.01.057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dorcemus, D. L., E. O. George, C. N. Dealy, and S. P. Nukavarapu. Harnessing external cues: development and evaluation of an in vitro culture system for osteochondral tissue engineering. Tissue Eng. Part A. 23(15–16):719–737, 2017. https://doi.org/10.1089/ten.tea.2016.0439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dorcemus, D. L., H. S. Kim, and S. P. Nukavarapu. Gradient scaffold with spatial growth factor profile for osteochondral interface engineering. Biomed. Mater. Bristol Engl. 2020. https://doi.org/10.1088/1748-605X/abd1ba.

    Article  Google Scholar 

  10. Dormann, D., and C. J. Weijer. Chemotactic cell movement during development. Curr. Opin. Genet. Dev. 13(4):358–364, 2003. https://doi.org/10.1016/S0959-437X(03)00087-X.

    Article  CAS  PubMed  Google Scholar 

  11. Elgamoudi, B. A., and V. Korolik. A review of the advantages, disadvantages and limitations of chemotaxis assays for Campylobacter spp. Int. J. Mol. Sci. 23(3):1576, 2022. https://doi.org/10.3390/ijms23031576.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Evans, C. H., et al. Facilitated endogenous repair: making tissue engineering simple, practical, and economical. Tissue Eng. 13(8):1987–1993, 2007. https://doi.org/10.1089/ten.2006.0302.

    Article  CAS  PubMed  Google Scholar 

  13. Fernández-Pérez, J., and M. Ahearne. The impact of decellularization methods on extracellular matrix derived hydrogels. Sci. Rep. 9(1):1, 2019. https://doi.org/10.1038/s41598-019-49575-2.

    Article  CAS  Google Scholar 

  14. Francois, E., D. Dorcemus, and S. Nukavarapu. 1-Biomaterials and scaffolds for musculoskeletal tissue engineering. In: Regenerative Engineering of Musculoskeletal Tissues and Interfaces, edited by S. P. Nukavarapu, J. W. Freeman, and C. T. Laurencin. Woodhead Publishing: Sawston, 2015, pp. 3–23.

    Chapter  Google Scholar 

  15. Freytes, D. O., J. Martin, S. S. Velankar, A. S. Lee, and S. F. Badylak. Preparation and rheological characterization of a gel form of the porcine urinary bladder matrix. Biomaterials. 29(11):1630–1637, 2008. https://doi.org/10.1016/j.biomaterials.2007.12.014.

    Article  CAS  PubMed  Google Scholar 

  16. Gilpin, A., and Y. Yang. Decellularization strategies for regenerative medicine: from processing techniques to applications. BioMed Res. Int. 2017. https://doi.org/10.1155/2017/9831534.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Golebiowska, A. A., and S. P. Nukavarapu. Bio-inspired zonal-structured matrices for bone-cartilage interface engineering. Biofabrication. 14(2):025016, 2022. https://doi.org/10.1088/1758-5090/ac5413.

    Article  Google Scholar 

  18. Herzmann, N., A. Salamon, T. Fiedler, and K. Peters. Analysis of migration rate and chemotaxis of human adipose-derived mesenchymal stem cells in response to LPS and LTA in vitro. Exp. Cell Res. 342(2):95–103, 2016. https://doi.org/10.1016/j.yexcr.2016.03.016.

    Article  CAS  PubMed  Google Scholar 

  19. Igwe, J. C., P. E. Mikael, and S. P. Nukavarapu. Design, fabrication and in vitro evaluation of a novel polymer-hydrogel hybrid scaffold for bone tissue engineering. J. Tissue Eng. Regen. Med. 8(2):131–142, 2014. https://doi.org/10.1002/term.1506.

    Article  CAS  PubMed  Google Scholar 

  20. Ikada, Y. Challenges in tissue engineering. J. R. Soc. Interface. 3(10):589–601, 2006. https://doi.org/10.1098/rsif.2006.0124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ivanov, A. A., A. V. Kuznetsova, O. P. Popova, T. I. Danilova, and O. O. Yanushevich. Modern approaches to acellular therapy in bone and dental regeneration. Int. J. Mol. Sci. 22(24):13454, 2021. https://doi.org/10.3390/ijms222413454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jin, W., et al. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ. 6:e6072, 2018. https://doi.org/10.7717/peerj.6072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kamimura, Y., H. Cai, and P. N. Devreotes. 6-TORC2 and chemotaxis in Dictyostelium discoideum. In: The Enzymes, edited by F. Tamanoi, and M. N. Hall. Academic Press: NewYork, 2010, pp. 125–142.

    Google Scholar 

  24. Karkanitsa, M., P. Fathi, T. Ngo, and K. Sadtler. Mobilizing endogenous repair through understanding immune reaction with biomaterials. Front. Bioeng. Biotechnol. 9:730938, 2021. https://doi.org/10.3389/fbioe.2021.730938.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim, Y., H. Ko, I. K. Kwon, and K. Shin. Extracellular matrix revisited: roles in tissue engineering. Int. Neurourol. J. 20(Suppl 1):S23-29, 2016. https://doi.org/10.5213/inj.1632600.318.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kim, H. S., S. G. Kumbar, and S. P. Nukavarapu. Biomaterial-directed cell behavior for tissue engineering. Curr. Opin. Biomed. Eng. 17:100260, 2021. https://doi.org/10.1016/j.cobme.2020.100260.

    Article  CAS  PubMed  Google Scholar 

  27. Kim, H. S., S. G. Kumbar, and S. P. Nukavarapu. Amorphous silica fiber matrix biomaterials: an analysis of material synthesis and characterization for tissue engineering. Bioact. Mater. 19:155–166, 2023. https://doi.org/10.1016/j.bioactmat.2022.04.002.

    Article  CAS  PubMed  Google Scholar 

  28. Kim, Y. S., M. Majid, A. J. Melchiorri, and A. G. Mikos. Applications of decellularized extracellular matrix in bone and cartilage tissue engineering. Bioeng. Transl. Med. 4(1):83–95, 2019. https://doi.org/10.1002/btm2.10110.

    Article  PubMed  Google Scholar 

  29. Kowalczewski, C. J., and J. M. Saul. Biomaterials for the delivery of growth factors and other therapeutic agents in tissue engineering approaches to bone regeneration. Front. Pharmacol. 2018. https://doi.org/10.3389/fphar.2018.00513.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kusindarta, D. L., and H. Wihadmadyatami. The role of extracellular matrix in tissue regeneration. Tissue Regen. 2018. https://doi.org/10.5772/intechopen.75728.

    Article  Google Scholar 

  31. Langer, R., and J. P. Vacanti. Tissue engineering. Science. 260(5110):920–926, 1993.

    Article  CAS  PubMed  Google Scholar 

  32. Larouche, J., S. Sheoran, K. Maruyama, and M. M. Martino. Immune regulation of skin wound healing: mechanisms and novel therapeutic targets. Adv. Wound Care. 7(7):209–231, 2018. https://doi.org/10.1089/wound.2017.0761.

    Article  Google Scholar 

  33. Liu, H., et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS ONE. 7(4):e34608, 2012. https://doi.org/10.1371/journal.pone.0034608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luo, Z., et al. Comparison of various reagents for preparing a decellularized porcine cartilage scaffold. Am. J. Transl. Res. 11(3):1417–1427, 2019.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Marquez-Curtis, L. A., and A. Janowska-Wieczorek. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. BioMed Res. Int. 13:561098, 2013. https://doi.org/10.1155/2013/561098.

    Article  CAS  Google Scholar 

  36. Mikael, P. E., A. A. Golebiowska, S. G. Kumbar, and S. P. Nukavarapu. Evaluation of autologously derived biomaterials and stem cells for bone tissue engineering. Tissue Eng. Part A. 26(19–20):1052–1063, 2020. https://doi.org/10.1089/ten.tea.2020.0011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mikael, P. E., H. S. Kim, and S. P. Nukavarapu. Hybrid extracellular matrix design for cartilage-mediated bone regeneration. J. Biomed. Mater. Res. B. 106(1):300–309, 2018. https://doi.org/10.1002/jbm.b.33842.

    Article  CAS  Google Scholar 

  38. Moghadasi, S., et al. A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine. J. Transl. Med. 19(1):302, 2021. https://doi.org/10.1186/s12967-021-02980-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moroni, F., and T. Mirabella. Decellularized matrices for cardiovascular tissue engineering. Am. J. Stem Cells. 3(1):1–20, 2014.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Muinonen-Martin, A. J., D. M. Veltman, G. Kalna, and R. H. Insall. An improved chamber for direct visualisation of chemotaxis. PLoS ONE. 5(12):e15309, 2010. https://doi.org/10.1371/journal.pone.0015309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Naderi, H., M. M. Matin, and A. R. Bahrami. Review paper: Critical issues in tissue engineering: biomaterials, cell sources, angiogenesis, and drug delivery systems. J. Biomater. Appl. 26(4):383–417, 2011. https://doi.org/10.1177/0885328211408946.

    Article  CAS  PubMed  Google Scholar 

  42. Nukavarapu, S. P., J. W. Freeman, and C. T. Laurencin (eds.). Related Titles. Regenerative Engineering of Musculoskeletal Tissues and Interfaces. Sawston: Woodhead Publishing, 2015. https://doi.org/10.1016/B978-1-78242-301-0.09001-7.

    Book  Google Scholar 

  43. Oliveira, É. R., et al. Advances in growth factor delivery for bone tissue engineering. Int. J. Mol. Sci. 22(2):903, 2021. https://doi.org/10.3390/ijms22020903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Park, J. S., et al. Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal. Proc. Natl. Acad. Sci. USA. 111(16):5896–5901, 2014. https://doi.org/10.1073/pnas.1402087111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park, S., H. Jang, B. S. Kim, C. Hwang, G. S. Jeong, and Y. Park. Directional migration of mesenchymal stem cells under an SDF-1α gradient on a microfluidic device. PLoS ONE. 12(9):e0184595, 2017. https://doi.org/10.1371/journal.pone.0184595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pati, F., et al. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat. Commun. 5:3935, 2014. https://doi.org/10.1038/ncomms4935.

    Article  CAS  PubMed  Google Scholar 

  47. Rodrigues, M., N. Kosaric, C. A. Bonham, and G. C. Gurtner. Wound healing: a cellular perspective. Physiol. Rev. 99(1):665–706, 2019. https://doi.org/10.1152/physrev.00067.2017.

    Article  CAS  PubMed  Google Scholar 

  48. Saldin, L. T., M. C. Cramer, S. S. Velankar, L. J. White, and S. F. Badylak. Extracellular matrix hydrogels from decellularized tissues: structure and function. Acta Biomater. 49:1–15, 2017. https://doi.org/10.1016/j.actbio.2016.11.068.

    Article  CAS  PubMed  Google Scholar 

  49. Shupe, T., C. Zimmerman, and B. Petersen. Growth factor retention on decellularized rat liver matrices derived from normal and regenerating liver. FASEB J. 26:274.10-274.10, 2012. https://doi.org/10.1096/fasebj.26.1_supplement.274.10.

    Article  Google Scholar 

  50. Solez, K., et al. The bridge between transplantation and regenerative medicine: beginning a new Banff classification of tissue engineering pathology. Am. J. Transpl. 18(2):321–327, 2018. https://doi.org/10.1111/ajt.14610.

    Article  CAS  Google Scholar 

  51. Varanko, A., S. Saha, and A. Chilkoti. Recent trends in protein and peptide-based biomaterials for advanced drug delivery. Adv. Drug Deliv. Rev. 156:133, 2020. https://doi.org/10.1016/j.addr.2020.08.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vargason, A. M., A. C. Anselmo, and S. Mitragotri. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 5(9):9, 2021. https://doi.org/10.1038/s41551-021-00698-w.

    Article  Google Scholar 

  53. Vasaturo, A., S. Caserta, I. Russo, V. Preziosi, C. Ciacci, and S. Guido. A Novel chemotaxis assay in 3-D collagen gels by time-lapse microscopy. PLoS ONE. 7(12):e52251, 2012. https://doi.org/10.1371/journal.pone.0052251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang, X., G. Wang, S. Zingales, and B. Zhao. Biomaterials enabled cell-free strategies for endogenous bone regeneration. Tissue Eng. Part B. 24(6):463–481, 2018. https://doi.org/10.1089/ten.teb.2018.0012.

    Article  Google Scholar 

  55. Yang, Z., et al. Fabrication and repair of cartilage defects with a novel acellular cartilage matrix scaffold. Tissue Eng. Part C. 16(5):865–876, 2009. https://doi.org/10.1089/ten.tec.2009.0444.

    Article  CAS  Google Scholar 

  56. Yin, H., et al. Functional tissue-engineered microtissue derived from cartilage extracellular matrix for articular cartilage regeneration. Acta Biomater. 77:127–141, 2018. https://doi.org/10.1016/j.actbio.2018.07.031.

    Article  CAS  PubMed  Google Scholar 

  57. Zakrzewski, J. L., M. R. M. van den Brink, and J. A. Hubbell. Overcoming immunological barriers in regenerative medicine. Nat. Biotechnol. 32(8):786–794, 2014. https://doi.org/10.1038/nbt.2960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zheng, X.-B., et al. Bone marrow-derived CXCR4-overexpressing MSCs display increased homing to intestine and ameliorate colitis-associated tumorigenesis in mice. Gastroenterol. Rep. 7(2):127–138, 2019. https://doi.org/10.1093/gastro/goy017.

    Article  Google Scholar 

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Acknowledgments

The authors acknowledge support from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (Grant Nos. #R01EB030060 & #R01EB020640). Dr. Nukavarapu also acknowledges funding from NSF EFMA (Grant No. #1908454). The authors thank Dr. Hargis for critically reading the manuscript.

Conflict of interest

The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA

    Aleksandra A. Golebiowska & Syam P. Nukavarapu

  2. Department of Microbiology and Immunology, James Graham Brown Cancer Centre, University of Louisville, Louisville, KY, USA

    Venkatakrishna R. Jala

  3. Department of Materials Science & Engineering, University of Connecticut, Storrs, CT, USA

    Syam P. Nukavarapu

  4. Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT, USA

    Syam P. Nukavarapu

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  1. Aleksandra A. Golebiowska
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  2. Venkatakrishna R. Jala
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Correspondence to Syam P. Nukavarapu.

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Golebiowska, A.A., Jala, V.R. & Nukavarapu, S.P. Decellularized Tissue-Induced Cellular Recruitment for Tissue Engineering and Regenerative Medicine. Ann Biomed Eng (2023). https://doi.org/10.1007/s10439-023-03182-5

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