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Microneedle-mediated therapy for cardiovascular diseases

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Abstract

Cardiovascular diseases remain a leading cause of global disease burden. To date, the limited drug delivery efficacy confines the therapeutic effect in most conventional approaches, such as intramyocardial injections and vascular devices, due to short-term drug release and low retention within the disease sites. As a typical transdermal medical device with a minimally invasive manner and controlled/sustained drug release pattern, microneedles have gained momentum in the field of cardiovascular therapy, from which several cardiovascular diseases have been benefited to the ultimate therapeutic effects. In this concise review, strategies based on the microneedles for the treatments of cardiovascular diseases are introduced, mainly focus on hypertension, atherosclerosis, thrombus, and myocardial diseases. The limitations at the present stage and perspectives of the next-generation microneedles for cardiovascular therapy are also discussed.

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References

  1. Group, G-N-JGBoCDW. Global burden of cardiovascular diseases and risk factors, 1990–2019: Update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021.

  2. Mensah GA, Roth GA, Fuster V. The global burden of cardiovascular diseases and risk factors: 2020 and beyond. J Am Coll Cardiol. 2019;74(20):2529–32.

    PubMed  Google Scholar 

  3. GBD 2019 Diseases and Injuries Collaborators, G. D. a. I. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2020;396(10258):1204–22.

  4. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J. 1991;121(4 Pt 1):1244–63.

    CAS  PubMed  Google Scholar 

  5. Mesquita ET, Demarchi AV, Bitencourt DdS, Machado PEdA, Badran PM, Almeida RGPd, Jorge AJL. Cardiovascular continuum 25 years - the evolution of an etiopathophysiology model. Int J Cardiovasc Sci. 2016;29(1):56–64.

  6. Jagadeesh G, Balakumar P, Maung-U K (Eds.). Pathophysiology and pharmacotherapy of cardiovascular disease. Switzerland: Springer; 2015.

  7. Husain MJ, Datta BK, Kostova D, Joseph KT, Asma S, Richter P, Jaffe MG, Kishore SP. Access to cardiovascular disease and hypertension medicines in developing countries: an analysis of essential medicine lists, price, availability, and affordability. J Am Heart Assoc. 2020;9(9):e015302.

  8. Hong KU, Bolli R. Cardiac stem cell therapy for cardiac repair. Curr Treat Options Cardiovasc Med. 2014;16(17):324.

    PubMed  PubMed Central  Google Scholar 

  9. Nguyen PK, Neofytou E, Rhee JW, Wu JC. Potential strategies to address the major clinical barriers facing stem cell regenerative therapy for cardiovascular disease: A review. JAMA Cardiol. 2016;1(8):953–62.

    PubMed  PubMed Central  Google Scholar 

  10. Wei K, Serpooshan V, Hurtado C, Diez-Cunado M, Zhao M, Maruyama S, Zhu W, Fajardo G, Noseda M, Nakamura K, Tian X, Liu Q, Wang A, Matsuura Y, Bushway P, Cai W, Savchenko A, Mahmoudi M, Schneider MD, van den Hoff MJ, Butte MJ, Yang PC, Walsh K, Zhou B, Bernstein D, Mercola M, Ruiz-Lozano P. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature. 2015;525(7570):479–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Madonna R, Van Laake LW, Davidson SM, Engel FB, Hausenloy DJ, Lecour S, Leor J, Perrino C, Schulz R, Ytrehus K, Landmesser U, Mummery CL, Janssens S, Willerson J, Eschenhagen T, Ferdinandy P, Sluijter JP. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J. 2016;37(23):1789–98.

    PubMed  PubMed Central  Google Scholar 

  12. Zhu D, Li Z, Huang K, Caranasos TG, Rossi JS, Cheng K. Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair. Nat Commun. 2021;12(1):1412.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang S, Lei D, Yang Q, Yang Y, Jiang C, Shi H, Qian B, Long Q, Chen W, Chen Y, Zhu L, Yang W, Wang L, Hai W, Zhao Q, You Z, Ye X. A perfusable, multifunctional epicardial device improves cardiac function and tissue repair. Nat Med. 2021;27(3):480–90.

    CAS  PubMed  Google Scholar 

  14. Alfonso F, Byrne RA, Rivero F, Kastrati A. Current treatment of in-stent restenosis. J Am Coll Cardiol. 2014;63(24):2659–73.

    PubMed  Google Scholar 

  15. Zheng JF, Guo TT, Tian Y, Wang Y, Hu XY, Chang Y, Qiu H, Dou KF, Tang YD, Yuan JQ, Wu YJ, Yan HB, Qiao SB, Xu B, Yang YJ, Gao RL. Clinical characteristics of early and late drug-eluting stent in-stent restenosis and mid-term prognosis after repeated percutaneous coronary intervention. Chin Med J. 2020;133(22):2674–81.

    PubMed  PubMed Central  Google Scholar 

  16. Hu S, Li Z, Shen D, Zhu D, Huang K, Su T, Dinh PU, Cores J, Cheng K. Exosome-eluting stents for vascular healing after ischaemic injury. Nat Biomed Eng. 2021. https://doi.org/10.1038/s41551-021-00705-0.

  17. Henry S, McAllister DV, Allen MG, Prausnitz MR. Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci. 1998;87(8):922–5.

    CAS  PubMed  Google Scholar 

  18. Ye Y, Yu J, Wen D, Kahkoska AR, Gu Z. Polymeric microneedles for transdermal protein delivery. Adv Drug Deliv Rev. 2018;127:106–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Panda A, Matadh VA, Suresh S, Shivakumar HN, Murthy SN. Non-dermal applications of microneedle drug delivery systems. Drug Deliv Transl Res. 2021. https://doi.org/10.1007/s13346-021-00922-9.

    Article  PubMed  Google Scholar 

  21. Lee K, Goudie MJ, Tebon P, Sun W, Luo Z, Lee J, Zhang S, Fetah K, Kim HJ, Xue Y, Darabi MA, Ahadian S, Sarikhani E, Ryu W, Gu Z, Weiss PS, Dokmeci MR, Ashammakhi N, Khademhosseini A. Non-transdermal microneedles for advanced drug delivery. Adv Drug Deliv Rev. 2020;165–66:41–59.

    Google Scholar 

  22. Go AS, Bauman MA, Coleman King SM, Fonarow GC, Lawrence W, Williams KA, Sanchez E. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension. 2014;63(4):878–85.

  23. Cohuet G, Struijker-Boudier H. Mechanisms of target organ damage caused by hypertension: therapeutic potential. Pharmacol Thera. 2006;111(1):81–98.

    CAS  Google Scholar 

  24. Kaur M, Ita KB, Popova IE, Parikh SJ, Bair DA. Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate. Eur J Pharm Biopharm. 2014;86(2):284–91.

    CAS  PubMed  Google Scholar 

  25. Sardesai M, Shende P. Engineering of nanospheres dispersed microneedle system for antihypertensive action. Curr Drug Deliv. 2020;17(9):776–86.

    CAS  PubMed  Google Scholar 

  26. Lu Y, Aimetti AA, Langer R, Gu Z. Bioresponsive materials. Nat Rev Mater. 2016;2(1):16075.

    Google Scholar 

  27. Varounis C, Katsi V, Nihoyannopoulos P, Lekakis J, Tousoulis D. Cardiovascular hypertensive crisis: recent evidence and review of the literature. Front Cardiovasc Med. 2016;3:51.

    PubMed  Google Scholar 

  28. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest. 2007;131(6):1949–62.

    CAS  PubMed  Google Scholar 

  29. Hottinger DG, Beebe DS, Kozhimannil T, Prielipp RC, Belani KG. Sodium nitroprusside in 2014: A clinical concepts review. J Anaesthesiol Clin Pharmacol. 2014;30(4):462–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Li Y, Liu F, Su C, Yu B, Liu D, Chen HJ, Lin DA, Yang C, Zhou L, Wu Q, Xia W, Xie X, Tao J. Biodegradable therapeutic microneedle patch for rapid antihypertensive treatment. ACS Appl Mater Interfaces. 2019;11(34):30575–84.

    CAS  PubMed  Google Scholar 

  31. Balakumar P, Maung UK, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res. 2016;113(Pt A):600–9.

    PubMed  Google Scholar 

  32. Sarjeant JM, Rabinovitch M. Understanding and treating vein graft atherosclerosis. Cardiovasc Pathol. 2002;11(2):263–71.

    PubMed  Google Scholar 

  33. Subbotin VM. Analysis of arterial intimal hyperplasia: review and hypothesis. Theor Biol Med Model. 2007;4:41.

    PubMed  PubMed Central  Google Scholar 

  34. Seedial SM, Ghosh S, Saunders RS, Suwanabol PA, Shi X, Liu B, Kent KC. Local drug delivery to prevent restenosis. J Vasc Surg. 2013;57(5):1403–14.

    PubMed  PubMed Central  Google Scholar 

  35. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. Circulation. 1996;94(6):1247–54.

    CAS  PubMed  Google Scholar 

  36. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193–202.

    PubMed  Google Scholar 

  37. Schnorr B, Albrecht T. Drug-coated balloons and their place in treating peripheral arterial disease. Exp Rev Med Dev. 2013;10(1):105–14.

    CAS  Google Scholar 

  38. Cortese B, Bertoletti A. Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data. Inter J Cardiol. 2012;161(1):4–12.

    Google Scholar 

  39. Lee K, Lee J, Lee SG, Park S, Yang DS, Lee JJ, Khademhosseini A, Kim JS, Ryu W. Microneedle drug eluting balloon for enhanced drug delivery to vascular tissue. J Control Release. 2020;321:174–83.

    CAS  PubMed  Google Scholar 

  40. Tzafriri AR, Vukmirovic N, Kolachalama VB, Astafieva I, Edelman ER. Lesion complexity determines arterial drug distribution after local drug delivery. J Control Release. 2010;142(3):332–8.

    CAS  PubMed  Google Scholar 

  41. Pires NM, van der Hoeven BL, de Vries MR, Havekes LM, van Vlijmen BJ, Hennink WE, Quax PH, Jukema JW. Local perivascular delivery of anti-restenotic agents from a drug-eluting poly(epsilon-caprolactone) stent cuff. Biomaterials. 2005;26(26):5386–94.

    CAS  PubMed  Google Scholar 

  42. Edelmana ER, Nathan A, Katada M, Gates J, Karnovsky MJ. Perivascular graft heparin delivery using biodegradable polymer wraps. Biomaterials. 2000;21:2279–86.

    CAS  Google Scholar 

  43. Yang C, Burt HM. Drug-eluting stents: Factors governing local pharmacokinetics. Adv Drug Deliv Rev. 2006;58(3):402–11.

    CAS  PubMed  Google Scholar 

  44. Choi CK, Kim JB, Jang EH, Youn YN, Ryu WH. Curved biodegradable microneedles for vascular drug delivery. Small. 2012;8(16):2483–8.

    CAS  PubMed  Google Scholar 

  45. Choi CK, Lee KJ, Youn YN, Jang EH, Kim W, Min BK, Ryu W. Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery. Eur J Pharm Biopharm. 2013;83(2):224–33.

    CAS  PubMed  Google Scholar 

  46. Lee KJ, Park SH, Lee JY, Joo HC, Jang EH, Youn YN, Ryu W. Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury. J Control Release. 2014;192:174–81.

    CAS  PubMed  Google Scholar 

  47. Kim DH, Jang EH, Lee KJ, Lee JY, Park SH, Seo IH, Lee KW, Lee SH, Ryu W, Youn YN. A biodegradable microneedle cuff for comparison of drug effects through perivascular delivery to balloon-injured arteries. Polymers (Basel). 2017;9(2):56.

    Google Scholar 

  48. Lee J, Kim DH, Lee KJ, Seo IH, Park SH, Jang EH, Park Y, Youn YN, Ryu W. Transfer-molded wrappable microneedle meshes for perivascular drug delivery. J Control Release. 2017;268:237–46.

    CAS  PubMed  Google Scholar 

  49. Zhang Y, Yu J, Wang J, Hanne NJ, Cui Z, Qian C, Wang C, Xin H, Cole JH, Gallippi CM, Zhu Y, Gu Z. Thrombin-responsive transcutaneous patch for auto-anticoagulant regulation. Adv Mater. 2017;29(4):1604043.

    Google Scholar 

  50. Yu J, Zhang Y, Yan J, Kahkoska AR, Gu Z. Advances in bioresponsive closed-loop drug delivery systems. Int J Pharm. 2018;544(2):350–7.

    CAS  PubMed  Google Scholar 

  51. Yu J, Zhang Y, Kahkoska AR, Gu Z. Bioresponsive transcutaneous patches. Curr Opin Biotechnol. 2017;48:28–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Boyle AJ, Schulman SP, Hare JM, Oettgen P. Is stem cell therapy ready for patients? Stem cell therapy for cardiac repair ready for the next step. Circulation. 2006;114(4):339–52.

    PubMed  Google Scholar 

  53. Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451(7181):937–42.

    CAS  PubMed  Google Scholar 

  54. Ishikawa K, Weber T, Hajjar RJ. Human cardiac gene therapy. Circ Res. 2018;123(5):601–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, Ali H, Braga L, Gorgodze N, Bernini F, Burchielli S, Collesi C, Zandona L, Sinagra G, Piacenti M, Zacchigna S, Bussani R, Recchia FA, Giacca M. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569(7756):418–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hastings CL, Roche ET, Ruiz-Hernandez E, Schenke-Layland K, Walsh CJ, Duffy GP. Drug and cell delivery for cardiac regeneration. Adv Drug Deliv Rev. 2015;84:85–106.

    CAS  PubMed  Google Scholar 

  57. Hajjar RJ, Ishikawa K. Introducing genes to the heart: all about delivery. Circ Res. 2017;120(1):33–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Seif-Naraghi SB, Singelyn JM, Salvatore MA, Osborn KG, Wang JJ, Sampat U, Kwan OL, Strachan GM, Wong J, Schup-Magoffin PJ. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci Transl Med. 2013;5(173):173ra25.

  59. Shen X, Zhang Y, Gu Y, Xu Y, Liu Y, Li B, Chen L. Sequential and sustained release of SDF-1 and BMP-2 from silk fibroin-nanohydroxyapatite scaffold for the enhancement of bone regeneration. Biomaterials. 2016;106:205–16.

    CAS  PubMed  Google Scholar 

  60. Lin Z, Pu WT. Strategies for cardiac regeneration and repair. Sci Transl Med. 2014; 6(239):239rv1.

  61. Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardio. 2005;46(7):1339–50.

    CAS  Google Scholar 

  62. Tang J, Wang J, Huang K, Ye Y, Su T, Qiao L, Hensley MT, Caranasos TG, Zhang J, Gu Z, Cheng K. Cardiac cell–integrated microneedle patch for treating myocardial infarction. Sci Adv. 2018;4:eaat9365.

  63. Shi H, Xue T, Yang Y, Jiang C, Huang S, Yang Q, Lei D, You Z, Jin T, Wu F, Zhao Q. Microneedle-mediated gene delivery for the treatment of ischemic myocardial disease. Sci Adv. 2020;6:eaaz3621.

  64. Montgomery M, Ahadian S, Davenport Huyer L, Lo Rito M, Civitarese RA, Vanderlaan RD, Wu J, Reis LA, Momen A, Akbari S, Pahnke A, Li RK, Caldarone CA, Radisic M. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. Nat Mater. 2017;16(10):1038–46.

    CAS  PubMed  Google Scholar 

  65. Lee K, Song HB, Cho W, Kim JH, Kim JH, Ryu W. Intracorneal injection of a detachable hybrid microneedle for sustained drug delivery. Acta Biomater. 2018;80:48–57.

    CAS  PubMed  Google Scholar 

  66. Lee Y, Park S, Kim SI, Lee K, Ryu W. Rapidly detachable microneedles using porous water‐soluble layer for ocular drug delivery. Adv Mater Technol. 2020;5(5):1901145.

  67. Li W, Terry RN, Tang J, Feng MR, Schwendeman SP, Prausnitz MR. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat Biomed Eng. 2019;3(3):220–9.

    CAS  PubMed  Google Scholar 

  68. Pukfukdee P, Banlunara W, Rutwaree T, Limcharoen B, Sawutdeechaikul P, Pattarakankul T, Sansureerungsikul T, Toprangkobsin P, Leelahavanichkul A, Panchaprateep R, Asawanonda P, Palaga T, Wanichwecharungruang S. Solid composite material for delivering viable cells into skin tissues via detachable dissolvable microneedles. ACS Appl Bio Mater. 2020;3(7):4581–9.

    CAS  Google Scholar 

  69. Lee K, Xue Y, Lee J, Kim HJ, Liu Y, Tebon P, Sarikhani E, Sun W, Zhang S, Haghniaz R, Celebi-Saltik B, Zhou X, Ostrovidov S, Ahadian S, Ashammakhi N, Dokmeci MR, Khademhosseini A. A patch of detachable hybrid microneedle depot for localized delivery of mesenchymal stem cells in regeneration therapy. Adv Funct Mater. 2020;30(23):2000086.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the grants from Startup Package of Zhejiang University to Y.Z. and Z.G. and the Fundamental Research Funds for the Central Universities 2021FZZX001-47 to Y.Z.

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Ruyi Zhou, Zhen Gu & Yuqi Zhang

  2. Zenomics Inc., Los Angeles, CA, 90095, USA

    Jicheng Yu

  3. Department of General Surgery, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China

    Zhen Gu

  4. Zhejiang Laboratory of Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China

    Zhen Gu

  5. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China

    Zhen Gu

  6. Department of Burns and Wound Center, College of Medicine, Second Affiliated Hospital, Zhejiang University, Hangzhou, 310009, China

    Yuqi Zhang

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Ruyi Zhou drafted the original draft. Jicheng Yu, Yuqi Zhang, and Zhen Gu reviewed and edited the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Zhen Gu or Yuqi Zhang.

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Z.G. is the co-founder of Zenomics Inc., Zencapsule Inc., Lizen Inc., Wskin Inc., and ZCapsule Inc.; J.Y. is the chief scientific officer of Zenomics Inc.; the other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Zhou, R., Yu, J., Gu, Z. et al. Microneedle-mediated therapy for cardiovascular diseases. Drug Deliv. and Transl. Res. 12, 472–483 (2022). https://doi.org/10.1007/s13346-021-01073-7

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