Nutrition and genetics govern the complex molecular order in living organisms. The metabolic processing of nutrients thermodynamically defends this order against deteriorating into a higher entropy state. However, the efficiency of activities involved in this processing, such as cellular proliferation and the synthesis of extracellular collagen, diminishes over time, causing skin aging. Nevertheless, specific bioactive substances can intervene to alter this natural age progression.
For instance, retinol can be converted into vitamin A, which can bind to cytosolic retinoic acid, binding proteins and thereby initiating a cascade of biochemical activities involved in keratinocyte and fibroblast growth and differentiation.1 Another example is vitamin C, which is involved in the expression of collagen genes, the post-translational modification of collagen into stable collagen2-3 and the inhibition of harmful reactive oxygen species formation.4
For bioactive chemicals to exercise anti-aging benefits they must be present in skin tissues and cells. Their local delivery is generally preferred over oral treatment to avoid potentially undesired effects such as hepatic metabolism, unregulated distribution to other organs, toxicity from buildup in other organs5-9 and poor skin distribution from decreased vasculature in aged skin.10
Retinol and retinoic acid are excellent examples of bioactives whose localized, targeted administration better benefit the user. Although these compounds exert anti-aging actions – by stimulating the growth and proliferation of keratinocytes, fibroblasts and endothelial cells; inhibiting matrix metalloproteinase levels; and activating collagen synthesis – their high accumulation in the upper epidermis often causes skin flaking and drying.11, 12 Furthermore, attempts to achieve accumulation deeper in the dermis from high doses of orally administered retinoids, e.g., retinol and retinoic acid, can negatively affect the brain and neurological system,6, 9 and possibly cause liver damage.7 Notably, it is difficult to deliver a high enough dosage topically to the dermis without causing higher accumulation in the epidermis.13
Dissolvable microneedles (DMNs), first demonstrated in 2005, offer an alternative delivery approach.14 Made of biocompatible materials, they dissolve in the skin tissue and are metabolized by the body. Bioactive compounds can be encapsulated into DMNs and directly delivered into skin tissue. One of their drawbacks, however, is they typically require two or more hours to completely dissolve into the skin tissue. This long application time results in the prolonged opening of skin channels at the needle insertion points, which increases the risk of skin ablation and infection.15 On the other hand, a short application time results in the incomplete deposition of needles and their cargoes into the skin.
Proposed here is a solution to this issue: detachable microneedles (DTMNs). Rather than relying solely on their dissolution into skin for delivery, these microneedles detach from the base within two minutes of application.15, 16 The present article explores DTMNs applied via patches as a means to deliver bioactive ingredients into the skin without causing high accumulation in the stratum corneum. Tests were performed to verify the amount of cargo deposited by DTMNs into human skin, porcine skin and a silicone model. In addition, DTMNs were tested in human volunteers for potential skin irritation and clinical anti-aging effects against fine lines and age spots.
Read the full article in the May edition of C&T magazine.
- Zasada, M. and Budzisz, E. (2019). Retinoids: Active molecules influencing skin structure formation in cosmetic and dermatological treatments. Postepy Dermatol Alergol. 36(4) 392-397.
- Duarte, T.L., Cooke, M.S. and Jones, G.D.D. (2009). Gene expression profiling reveals new protective roles for vitamin C in human skin cells. Free Radic Biol Med 46(1) 78-87.
- Salo, A.M. and Myllyharju, J. (2021). Prolyl and lysyl hydroxylases in collagen synthesis. Exp Dermatol 30(1) 38-49.
- Pandel, R., Poljšak, B., Godic, A. and Dahmane, R. (2013). Skin photoaging and the role of antioxidants in its prevention. ISRN Dermatol 930164.
- Bozhkov, A., Ionov, I., Kurhuzova, N., Novikova, A., Katerynych, O. and Akzhyhitov, R. (2022). Vitamin A intake forms resistance to hypervitaminosis A and affects the functional activity of the liver. Clin Nutr Open Science. 41 82-97.
- Bremner, J.D. (2021). Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed. J Affect Disord. 6 100230.
- Carazo, A., Macáková, K., Matoušová, K., Krcmová, L.K., Protti, M. and Mladenka, P. (2021). Vitamin A update: Forms, sources, kinetics, detection, function, deficiency, therapeutic use and toxicity. Nutrients [online]. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157347/
- Cheruvattath, R., Orrego, M., ... Vargas, H.E., et al. (2006). Vitamin A toxicity: When one a day doesn't keep the doctor away. Liver Transplant. 12(12) 1888-1891.
- Drew, C.J.G., O'Reilly, K.C., Lane, M.A. and Bailey, S.J. (2011). Chronic administration of 13-cis-retinoic acid does not alter the number of serotoninergic neurons in the mouse raphe nuclei. Neurosci. 172 66-73.
- Bentov, I. and Reed, M.J. (2015). The effect of aging on the cutaneous microvasculature. Microvasc Res. 100 25-31.
- Szyma´nski, Ł., Skopek, R., ... Zelent, A., et al. (2020). Retinoic acid and its derivatives in skin. Cells [online]. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764495/
- Varani, J., Fligiel, H., Zhang, J., Aslam, M.N., Lu, Y., Dehne, L.A. and Keller, E.T. (2003). Separation of retinoid-induced epidermal and dermal thickening from skin irritation. Arch Dermatol. 295(6) 255-262.
- Schaefer, H. (1993). Penetration and percutaneous absorption of topical retinoids: A review. Skin Pharmacol Physiol. 6 17-23.
- Park, J.-H., Allen, M.G. and Prausnitz, M.R. (2005). Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery. J Control Release.104(1) 51-66.
- Sawutdeechaikul, P., Kanokrungsee, S., ... Wanichwecharungruang, S., et al. (2021). Detachable dissolvable microneedles: Intra-epidermal and intradermal diffusion, effect on skin surface and application in hyperpigmentation treatment. Sci Rep. 11(1) 24114.
- Pukfukdee, P., Banlunara, W., ... Wanichwecharungruang, S., et al. (2020). Solid composite material for delivering viable cells into skin tissues via detachable dissolvable microneedles. ACS Appl Bio Mater. 3(7) 4581-4589.