Macroflux® Microprojection Array Patch Technology: A New and Efficient Approach for Intracutaneous Immunization
Purpose. We evaluated the Macroflux® microprojection array patch technology as a novel system for intracutaneous delivery of protein antigens.
Methods. Macroflux® microprojection array systems (330-μm microprojection length, 190 microprojections/cm2, 1- and 2-cm2 area) were coated with a model protein antigen, ovalbumin (OVA), to produce a dry-film coating. After system application, microprojection penetration depth, OVA delivery, and comparative immune responses were evaluated in a hairless guinea pig model.
Results. Macroflux® microprojections penetrated into hairless guinea pig skin at an average depth of 100 μm with no projections deeper than 300 μm. Doses of 1 to 80 μg of OVA were delivered via 1- or 2-cm2 systems by varying the coating solution concentration and wearing time. Delivery rates were as high as 20 μg in 5 s. In a prime and boost dose immune response study, OVA-coated Macroflux® was most comparable to equivalent doses injected intradermally. Higher antibody titers were observed when OVA was administered with the microprojection array or intradermally at low doses (1 and 5 μg). Macroflux® administration at 1- and 5-μg doses gave immune responses up to 50-fold greater than that observed after the same subcutaneous or intramuscular dose. Dry coating an adjuvant, glucosaminyl muramyl dipeptide, with OVA on the Macroflux® resulted in augmented antibody responses.
Conclusions. Macroflux® skin patch technology provides rapid and reproducible intracutaneous administration of dry-coated antigen. The depth of skin penetration targets skin immune cells; the quantity of antigen delivered can be controlled by formulation, patch wearing time, and system size. This novel needle-free patch technology may ultimately have broad applications for a wide variety of therapeutic vaccines to improve efficacy and convenience of use.
Unable to display preview. Download preview PDF.
- 1.J. D. Bos. Skin Immune System (SIS). Cutaneous Immunology and Clinical Immunodermatology CRC Press, New York, 1997.Google Scholar
- 2.K. E. Fichtelius, O. Groth, and S. Liden. The skin, a first level lymphoid organ? Int. Arch. Allergy Appl. Immunol. 37:607–620 (1970).Google Scholar
- 3.R. C. Yu, D. C. Abrams, M. Alaibac, and A. C. Chu. Morphological and quantitative analysis of normal epidermal Langerhans cells using confocal scanning laser microscopy. Br. J. Dermatol. 131:843–848 (1994).Google Scholar
- 4.J. H. Brooks, L. H. Criep, and F. L. Ruben. Intradermal administration of bivalent and monovalent influenza vaccines. Ann. Allergy 39:110–112 (1977).Google Scholar
- 5.W. Halperin, W. I. Weiss, R. Altman, M. A. Diamond, K. J. Black, A. W. Iaci, H. C. Black, and M. Goldfield. A comparison of the intradermal and subcutaneous routes of influenza vaccination with a/new jersey/76 (swine flu) and a/victoria/75: Report of a study and review of the literature. Am. J. Public Health 69:1247–1250 (1979).Google Scholar
- 6.E. A. Henderson, T. J. Louie, K. Ramotar, D. Ledgerwood, K. M. Hope, and A. Kennedy. Comparison of higher-dose intradermal hepatitis B vaccination to standard intramuscular vaccination of health care workers. Infect. Control Hosp. Epidemiol. 21:264–269 (2000).Google Scholar
- 7.T. Propst, A. Propst, K. Lhotta, W. Vogel, and P. Konig. Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination. Am. J. Kidney Dis. 32:1041–1045 (1998).Google Scholar
- 8.R. Panchagnula, K. Stemmer, and W. A. Ritschel. Animal models for transdermal drug delivery. Methods Find. Exp. Clin. Pharmacol. 19:335–341 (1997).Google Scholar
- 9.H. Sueki, C. Gammal, K. Kudoh, and A. M. Kligman. Hairless guinea pig skin: Anatomical basis for studies of cutaneous biology. Eur. J. Dermatol. 10:357–364 (2000).Google Scholar
- 10.S. Kumar, H. Char, S. Patel, D. Piemontese, K. Iqbal, A. W. Malick, E. Neugroschel, and C. R. Behl. Effect of iontophoresis on in vitro skin permeation of an analogue of growth hormone releasing factor in the hairless guinea pig model. J. Pharm. Sci. 81:635–639 (1992).Google Scholar
- 11.K. C. Moon, R. C. Wester, and H. I. Maibach. Diseased skin models in the hairless guinea pig skin: In vivo percutaneous absorption. Dermatologica 180:8–12 (1990).Google Scholar
- 12.T. Horio, H. Miyauchi, and Y. Asada. The hairless guinea pig as an experimental animal in photodermatology. Photodermatol. Photoimmunol. Photomed. 8:69–72 (1991).Google Scholar
- 13.P. J. Bobrowski, R. Capiola, and Y. M. Centifanto. Latent herpes simplex virus reactivation in the guinea pig. An animal model for recurrent disease. Int. J Dermatol. 30:29–35 (1991).Google Scholar
- 14.S. K. Brantley, S. F. Davidson, and S. K. Das. A dose-related curve of wound tensile strength following ultraviolet irradiation in the hairless guinea pig. Am. J. Med. Sci. 302:75–81 (1991).Google Scholar
- 15.A. Fullerton and J. Serup. Topical D-vitamins: Multiparametric comparison of the irritant potential of calcipotriol, tacalcitol, and calcitriol in a hairless guinea pig model. Contact Dermatitis 36: 184–190 (1997).Google Scholar
- 16.P. W. Lowry, C. Sabella, C. M. Koropchak, B. N. Watson, H. M. Thackray, G. M. Abbruzzi, and A. M. Arvin. Investigation of the pathogenesis of varicella-zoster virus infection in guinea pigs by using polymerase chain reaction. J. Infect. Dis. 16:78–83 (1993).Google Scholar
- 17.D. L. Ruble, J. J. Elliot, D. M. Waag, and G. P. Jaax. A refined guinea pig model for evaluated delayed-type hypersensitivity reaction caused by Q fever vaccines. Lab. Anim. Sci. 44:608–612 (1994).Google Scholar
- 18.H. Miyauchi and T. Horio. A new animal model for contact dermatitis: The hairless guinea pig. J. Dermatol. 19:140–145 (1992).Google Scholar
- 19.D. F. Woodward, A. L. Nieves, L. S. Williams, C. S. Spada, S. B. Hawley, and J. L. Duenes. A new hairless strain of guinea pig: Characterization of the cutaneous morphology and pharmacology. In H. I. Maibach and N. J. Lowe, (eds.), Models in Dermatology Vol. 4, Karger, Basel 1989, pp. 71–78.Google Scholar
- 20.M. Cormier, A. P. Neukermans, B. Block, F. T. Theeuwes, and A. A. Amkraut. Device for enhancing transdermal agent delivery or sampling. European Patent 0914178, 1999.Google Scholar
- 21.A. Enk and S. Katz. Early molecular events in the induction phase of contact sensitivity. Proc. Natl. Acad. Sci. USA 89:1398–1402 (1992).Google Scholar
- 22.H. Fan, Q. Lin, G. R. Morrissey, and P. A. Khavari. Immunization via hair follicles by topical application of naked DNA to normal skin. Nat. Biotechnol. 17:870–872 (1999).Google Scholar
- 23.G. M. Glenn, M. Rao, G. R. Matyas, and C. R. Alving. Skin immunization made possible by cholera toxin. Nature 391:851 (1998).Google Scholar
- 24.N. Puri, E. H. Weyand, S. M. Abdel-Rahman, and P. J. Sinko. An investigation on the intradermal route as an effective means of immunization for microparticulate vaccine delivery systems. Vaccine 18:2600–2612 (2000).Google Scholar
- 25.C. A. Herrick, H. MacLeod, E. Glusac, R. E. Tigelaar, and K. Bottomly. Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4. J. Clin. Invest. 105:765–775 (2000).Google Scholar
- 26.L. F. Wang, J. Y. Lin, K. H. Hsieh, and R. H. Lin. Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J. Immunol. 156:4077–4082 (1996).Google Scholar
- 27.D. C. Tang, Z. Shi, and D. T. Curiel. Vaccination onto bare skin. Nature 388:729–730 (1997).Google Scholar
- 28.G. M. Glenn, D. N. Taylor, X. Li, S. Frankel, A. Montemarano, and C. R. Alving. Transcutaneous immunization: A human vaccine delivery strategy using a patch. Nat. Med. 6:1403–1406 (2000).Google Scholar