AccScience Publishing / IJB / Volume 10 / Issue 2 / DOI: 10.36922/ijb.1465

Development of 3D-bioprinted artificial blood vessels loaded with rapamycin-nanoparticles for ischemic repair

Jaewoo Choi1,2† Eun Ji Lee1,2† Hye Ji Lim1,2 Dong Myoung Lee1,2 Deokhyeon Yoon1,2 Gi Hoon Yang3 Eunjeong Choi3 Hojun Jeon3 Kyeong Hyeon Lee4 Yong-Il Shin4,5 Sang-Cheol Han6 Woong Bi Jang1,2* Sang-Mo Kwon1,2*
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1 Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
2 Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
3 Research Institute of Additive Manufacturing and Regenerative Medicine, Baobab Healthcare Inc., 55 Hanyangdaehak-Ro, Ansan, Gyeonggi-do 15588, South Korea
4 Science of Convergence, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
5 Department of Rehabilitation Medicine, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
6 CEN Co., Ltd. Nano-Convergence Center, 761 Muan-ro, Miryang 50404, Republic of Korea
IJB 2024, 10(2), 1465
Submitted: 5 August 2023 | Accepted: 3 October 2023 | Published: 15 January 2024
(This article belongs to the Special Issue 3D printing of bioinspired materials)
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Vascular diseases, including ischemic conditions and restenosis, pose significant challenges in clinical practice. Restenosis, the re-narrowing of blood vessels after interventions such as stent placement, remains a major concern despite advances in medical interventions. Addressing these challenges requires innovative approaches that promote vascular regeneration and prevent restenosis. By leveraging the capabilities of three-dimensional (3D) printing technology, artificial blood vessels with lumen can be precisely constructed in customizable sizes, closely mimicking the natural vascular architecture. This approach allows for the incorporation of therapeutic agents and cells to enhance the functionality of the fabricated vessels. In the present study, we investigated the fabrication and characterization of artificial blood vessels using 3D printing technology, with the focus on achieving precise control over the vessel dimensions and architecture to ensure optimal functionality. The use of 3D printing enabled the creation of patient-specific blood vessels with tailored sizes and geometries, providing a personalized solution for vascular treatment. Furthermore, we explored the integration of nanoparticles loaded with therapeutic drugs within the 3D-printed blood vessels. Specifically, rapamycin, a potent drug for preventing restenosis, was encapsulated within the nanoparticles to enable controlled drug release. This approach aimed to address the challenge of restenosis by delivering the drug directly to the affected site and maintaining its therapeutic concentration over an extended period. Additionally, the study investigated the incorporation of endothelial progenitor cells (EPCs), which promote re-endothelialization essential for vascular regeneration and long-term vessel functionality, within the artificial blood vessels. The 3D-printed blood vessels provide an ideal environment for the integration and growth of these cells, further enhancing their regenerative potential. By combining 3D printing technology, drug-loaded nanoparticles, and EPCs, this study demonstrated the potential of this approach in fabricating functional artificial blood vessels.

3D bioprinting
Tissue engineering
Artificial blood vessel
Endothelial progenitor cells
This research was supported by the Korean Fund for Regenerative Medicine (KFRM) granted by the Korean Government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (21A0101L1).
  1. Pittman RN, 2011, Regulation of tissue oxygenation, in Integrated Systems Physiology: From Molecule to Function to Disease, San Rafael, CA.
  2. Tang QR, Xue H, Zhang Q, et al., 2021, Evaluation of the clinical efficacy of stem cell transplantation in the treatment of spinal cord injury: A systematic review and meta-analysis. Cell Transplant, 30:9636897211067804. doi: 10.1177/09636897211067804
  3. Mao AS, Mooney DJ, 2015, Regenerative medicine: Current therapies and future directions. Proc Natl Acad Sci U S A, 112(47):14452-14459. doi: 10.1073/pnas.1508520112
  4. Zakrzewski W, Dobrzynski M, Szymonowicz M, et al., 2019, Stem cells: Past, present, and future. Stem Cell Res Ther, 10(1):68. doi: 10.1186/s13287-019-1165-5
  5. Dzobo K, Thomford NE, Senthebane DA, et al., 2018, Advances in regenerative medicine and tissue engineering: innovation and transformation of medicine. Stem Cells Int, 2018:2495848. doi: 10.1155/2018/2495848
  6. Serbo JV, Gerecht S, 2013, Vascular tissue engineering: Biodegradable scaffold platforms to promote angiogenesis. Stem Cell Res Ther, 4(1):8. doi: 10.1186/scrt156
  7. Kwon SG, Kwon YW, Lee TW, et al., 2018, Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater Res, 22:36. doi: 10.1186/s40824-018-0148-4
  8. Song HG, Rumma RT, Ozaki CK, et al., 2018, Vascular tissue engineering: Progress, challenges, and clinical promise. Cell Stem Cell, 22(3):340-354. doi: 10.1016/j.stem.2018.02.009
  9. Wakabayashi T, Naito H, 2023, Cellular heterogeneity and stem cells of vascular endothelial cells in blood vessel formation and homeostasis: Insights from single-cell RNA sequencing. Front Cell Dev Biol, 11:1146399. doi: 10.3389/fcell.2023.1146399
  10. Carmeliet P, Jain RK, 2011, Molecular mechanisms and clinical applications of angiogenesis. Nature, 473(7347):298-307. doi: 10.1038/nature10144
  11. Majewska A, Wilkus K, Brodaczewska K, et al., 2021, Endothelial cells as tools to model tissue microenvironment in hypoxia-dependent pathologies. Int J Mol Sci, 22(2). doi: 10.3390/ijms22020520
  12. Phelps EA, Garcia AJ, 2010, Engineering more than a cell: Vascularization strategies in tissue engineering. Curr Opin Biotechnol, 21(5):704-709. doi: 10.1016/j.copbio.2010.06.005
  13. Munisso MC, Yamaoka T, 2020, Circulating endothelial progenitor cells in small-diameter artificial blood vessel. J Artif Organs, 23(1):6-13. doi: 10.1007/s10047-019-01114-6
  14. Chambers SEJ, Pathak V, Pedrini E, et al., 2021, Current concepts on endothelial stem cells definition, location, and markers. Stem Cells Transl Med, 10(Suppl 2):S54-S61. doi: 10.1002/sctm.21-0022
  15. Yoder MC, 2012, Human endothelial progenitor cells. Cold Spring Harb Perspect Med, 2(7):a006692. doi: 10.1101/cshperspect.a006692
  16. Peters EB, 2018, Endothelial progenitor cells for the vascularization of engineered tissues. Tissue Eng Part B Rev, 24(1):1-24. doi: 10.1089/ten.TEB.2017.0127
  17. Zhang F, King MW, 2022, Immunomodulation strategies for the successful regeneration of a tissue-engineered vascular graft. Adv Healthc Mater, 11(12):e2200045. doi: 10.1002/adhm.202200045
  18. Wang D, Xu Y, Li Q, et al., 2020, Artificial small-diameter blood vessels: Materials, fabrication, surface modification, mechanical properties, and bioactive functionalities. J Mater Chem B, 8(9):1801-1822. doi: 10.1039/c9tb01849b
  19. Hu K, Li Y, Ke Z, et al., 2022, History, progress and future challenges of artificial blood vessels: A narrative review. Biomater Transl, 3(1):81-98. doi: 10.12336/biomatertransl.2022.01.008
  20. Ozbolat IT, Hospodiuk M, 2016, Current advances and future perspectives in extrusion-based bioprinting. Biomaterials, 76:321-343. doi: 10.1016/j.biomaterials.2015.10.076
  21. Fu Z, Naghieh S, Xu C, et al., 2021, Printability in extrusion bioprinting. Biofabrication, 13(3). doi: 10.1088/1758-5090/abe7ab
  22. Yang GH, Kang D, An S, et al., 2022, Advances in the development of tubular structures using extrusion-based 3D cell-printing technology for vascular tissue regenerative applications. Biomater Res, 26(1):73. doi: 10.1186/s40824-022-00321-2
  23. Angelopoulos I, Allenby MC, Lim M, et al., 2020, Engineering inkjet bioprinting processes toward translational therapies. Biotechnol Bioeng, 117(1):272-284. doi: 10.1002/bit.27176
  24. Li X, Liu B, Pei B, et al., 2020, Inkjet bioprinting of biomaterials. Chem Rev, 120(19):10793-10833. doi: 10.1021/acs.chemrev.0c00008
  25. Suntornnond R, Ng WL, Huang X, et al., 2022, Improving printability of hydrogel-based bio-inks for thermal inkjet bioprinting applications via saponification and heat treatment processes. J Mater Chem B, 10(31): 5989-6000. doi: 10.1039/d2tb00442a
  26. Li W, Mille LS, Robledo JA, et al., 2020, Recent advances in formulating and processing biomaterial inks for vat polymerization-based 3D printing. Adv Healthc Mater, 9(15):e2000156. doi: 10.1002/adhm.202000156
  27. Yu C, Schimelman J, Wang P, et al., 2020, Photopolymerizable biomaterials and light-based 3D printing strategies for biomedical applications. Chem Rev, 120(19): 10695-10743. doi: 10.1021/acs.chemrev.9b00810
  28. Xu X, Awad A, Robles-Martinez P, et al., 2021, Vat photopolymerization 3D printing for advanced drug delivery and medical device applications. J Control Release, 329:743-757. doi: 10.1016/j.jconrel.2020.10.008
  29. Ali A, Saeed S, Hussain R, et al., 2023, Synthesis and characterization of silica, silver-silica, and zinc oxide-silica nanoparticles for evaluation of blood biochemistry, oxidative stress, and hepatotoxicity in albino rats. Acs Omega, 8(23):20900-20911. doi: 10.1021/acsomega.3c01674
  30. Chen S, Greasley SL, Ong ZY, et al., 2020, Biodegradable zinc-containing mesoporous silica nanoparticles for cancer therapy. Mater Today Adv, 6:100066. doi: 10.1016/j.mtadv.2020.100066
  31. Waksman R, Ajani AE, Pichard AD, et al., 2004, Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions: The Oral rapamune to inhibit restenosis (ORBIT) study. J Am Coll Cardiol, 44(7):1386-1392. doi: 10.1016/j.jacc.2004.06.069
  32. Rosner D, McCarthy N, Bennett M, 2005, Rapamycin inhibits human in stent restenosis vascular smooth muscle cells independently of pRB phosphorylation and p53. Cardiovasc Res, 66(3):601-610. doi: 10.1016/j.cardiores.2005.01.006
  33. Voisard R, Zellmann S, Muller F, et al., 2007, Sirolimus inhibits key events of restenosis in vitro/ex vivo: Evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratios. BMC Cardiovasc Disord, 7:15. doi: 10.1186/1471-2261-7-15
  34. Brara PS, Moussavian M, Grise MA, et al., 2003, Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation, 107(13):1722-1724. doi: 10.1161/01.CIR.0000066282.05411.17
  35. Kim J, Kim HS, Lee N, et al., 2008, Multifunctional uniform nanoparticles composed of a magnetite nanocrystal core and a mesoporous silica shell for magnetic resonance and fluorescence imaging and for drug delivery. Angew Chem Int Ed Engl, 47(44):8438-8441. doi: 10.1002/anie.200802469
  36. Zhou Q, Doherty J, Akk A, et al., 2022, Safety profile of rapamycin perfluorocarbon nanoparticles for preventing cisplatin-induced kidney injury. Nanomaterials (Basel), 12(3). doi: 10.3390/nano12030336
  37. Earla R, Cholkar K, Gunda S, et al., 2012, Bioanalytical method validation of rapamycin in ocular matrix by QTRAP LC-MS/ MS: Application to rabbit anterior tissue distribution by topical administration of rapamycin nanomicellar formulation. J Chromatogr B Analyt Technol Biomed Life Sci, 908:76-86. doi: 10.1016/j.jchromb.2012.09.014
  38. Lee JH, Lee SH, Choi SH, et al., 2015, The sulfated polysaccharide fucoidan rescues senescence of endothelial colony-forming cells for ischemic repair. Stem Cells, 33(6):1939-1951. doi: 10.1002/stem.1973
  39. Bonaca MP, Hamburg NM, Creager MA, 2021, Contemporary medical management of peripheral artery disease. Circ Res, 128(12):1868-1884. doi: 10.1161/CIRCRESAHA.121.318258
  40. Gul F, Janzer SF, 2023, Peripheral Vascular Disease, StatPearls, Treasure Island (FL).
  41. Chin K, 2011, In-stent restenosis: The gold standard has changed. EuroIntervention, 7(Suppl K):K43-K46. doi: 10.4244/EIJV7SKA7
  42. Rao J, Pan Bei H, Yang Y, et al., 2020, Nitric oxide-producing cardiovascular stent coatings for prevention of thrombosis and restenosis. Front Bioeng Biotechnol, 8:578. doi: 10.3389/fbioe.2020.00578
  43. Perkins LE, 2010, Preclinical models of restenosis and their application in the evaluation of drug-eluting stent systems. Vet Pathol, 47(1):58-76. doi: 10.1177/0300985809352978
  44. Nowicki M, Castro NJ, Rao R, et al., 2017, Integrating three-dimensional printing and nanotechnology for musculoskeletal regeneration. Nanotechnology,28(38):382001. doi: 10.1088/1361-6528/aa8351
  45. Fischetti T, Borciani G, Avnet S, et al., 2023, Incorporation/ enrichment of 3D bioprinted constructs by biomimetic nanoparticles: Tuning printability and cell behavior in bone models. Nanomaterials (Basel), 13(14). doi: 10.3390/nano13142040
  46. Johannesson J, Pathare MM, Johansson M, et al., 2023, Synergistic stabilization of emulsion gel by nanoparticles and surfactant enables 3D printing of lipid-rich solid oral dosage forms. J Colloid Interface Sci, 650(Pt B):1253-1264. doi: 10.1016/j.jcis.2023.07.055
  47. Remaggi G, Bergamonti L, Graiff C, et al., 2023, Rapid prototyping of 3D-printed AgNPs- and nano-TiO(2)-embedded hydrogels as novel devices with multiresponsive antimicrobial capability in wound healing. Antibiotics (Basel), 12(7). doi: 10.3390/antibiotics12071104
  48. Liu Y, Li K, Liu B, et al., 2010, A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery. Biomaterials, 31(35):9145-9155. doi: 10.1016/j.biomaterials.2010.08.053
  49. Tripathi D, Srivastava M, Rathour K, et al., 2023, A promising approach of dermal targeting of antipsoriatic drugs via engineered nanocarriers drug delivery systems for tackling psoriasis. Drug Metab Bioanal Lett. doi: 10.2174/2949681016666230803150329
  50. Mitchell MJ, Billingsley MM, Haley RM, et al., 2021, Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov, 20(2):101-124. doi: 10.1038/s41573-020-0090-8
  51. Kasravi M, Ahmadi A, Babajani A, et al., 2023, Immunogenicity of decellularized extracellular matrix scaffolds: A bottleneck in tissue engineering and regenerative medicine. Biomater Res, 27(1):10. doi: 10.1186/s40824-023-00348-z
  52. Pinnock CB, Meier EM, Joshi NN, et al., 2016, Customizable engineered blood vessels using 3D printed inserts. Methods, 99:20-27. doi: 10.1016/j.ymeth.2015.12.015
  53. Kakisis JD, Liapis CD, Breuer C, et al., 2005, Artificial blood vessel: The Holy Grail of peripheral vascular surgery. J Vasc Surg, 41(2):349-354. doi: 10.1016/j.jvs.2004.12.026
  54. Marx SO, Totary-Jain H, Marks AR, 2011, Vascular smooth muscle cell proliferation in restenosis. Circ Cardiovasc Interv, 4(1):104-111. doi: 10.1161/CIRCINTERVENTIONS.110.957332
  55. Huang C, Zhao J, Zhu Y, 2020, Drug-eluting stent targeting Sp-1-attenuated restenosis by engaging YAP-mediated vascular smooth muscle cell phenotypic modulation. J Am Heart Assoc, 9(1):e014103. doi: 10.1161/JAHA.119.014103
  56. Huang C, Zhang W, Zhu Y, 2019, Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway. Am J Physiol Heart Circ Physiol, 317(3):H541-H551. doi: 10.1152/ajpheart.00089.2019
  57. Yetisgin AA, Cetinel S, Zuvin M, et al., 2020, Therapeutic nanoparticles and their targeted delivery applications. Molecules, 25(9). doi: 10.3390/molecules25092193
  58. Falke LL, van Vuuren SH, Kazazi-Hyseni F, et al., 2015, Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres. Biomaterials, 42:151-160. doi: 10.1016/j.biomaterials.2014.11.042
  59. Cheng X, Xie Q, Sun Y, 2023, Advances in nanomaterial-based targeted drug delivery systems. Front Bioeng Biotechnol, 11:1177151. doi: 10.3389/fbioe.2023.1177151
  60. Chen EP, Toksoy Z, Davis BA, et al., 2021, 3D bioprinting of vascularized tissues for in vitro and in vivo applications. Front Bioeng Biotechnol, 9:664188. doi: 10.3389/fbioe.2021.664188
  61. Papaioannou TG, Manolesou D, Dimakakos E, et al., 2019, 3D bioprinting methods and techniques: Applications on artificial blood vessel fabrication. Acta Cardiol Sin, 35(3):284-289. doi: 10.6515/ACS.201905_35(3).20181115A
  62. Tajabadi M, Goran Orimi H, Ramzgouyan MR, et al., 2022, Regenerative strategies for the consequences of myocardial infarction: Chronological indication and upcoming visions. Biomed Pharmacother, 146:112584 doi: 10.1016/j.biopha.2021.112584
  63. Craparo EF, Cabibbo M, Conigliaro A, et al., 2021, Rapamycin-loaded polymeric nanoparticles as an advanced formulation for macrophage targeting in atherosclerosis. Pharmaceutics, 13(4). doi: 10.3390/pharmaceutics13040503
  64. Shi Y, Jiao C, Lu X, et al., 2022, Rapamycin nanoparticles improves drug bioavailability in PLAM treatment by interstitial injection. Orphanet J Rare Dis, 17(1):349. doi: 10.1186/s13023-022-02511-6
  65. Chen Y, Zeng Y, Zhu X, et al., 2021, Significant difference between sirolimus and paclitaxel nanoparticles in anti-proliferation effect in normoxia and hypoxia: The basis of better selection of atherosclerosis treatment. Bioact Mater, 6(3):880-889. doi: 10.1016/j.bioactmat.2020.09.005
Conflict of interest
The authors declare no conflicts of interest.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing