Methods to speed up wound healing have been a hot topic over the years and scientists are continuously looking for ways to fast track the body’s ability to migrate and replenish cells [1]. One unique method that has been proven to be extraordinarily effective is the use of frog skin. This idea originated from the fact that amphibians can regenerate tissue rapidly, even re-growing whole limbs without scarring [1]. There are several historical examples from around the world where this technique has been utilised. The Chinese have traditionally administered frog skin and secretions from toad parotid glands for regulating internal corporal functions and fertility, as well as a treatment for dog bites [2]. Traditional healers in Nagaland, India used the dorsal skin of frogs to cover the wounds of their patients [3], and Vietnamese surgeons would use amphibian skin as temporary grafts for napalm burn wounds when there was a lack of medical supplies in the Vietnam war [4].
Scientists began conducting studies on the subject in the 1980s, the first of which uncovered that the African clawed frog’s skin contained antimicrobial peptides [5]. Later it was discovered that lipids in the skin of several frog species contributed to faster wound healing, however, researchers were unable to pinpoint the exact relationship between frog skin and wound healing [1]. It was not until 2014 that two amphibian antimicrobial peptides, temporin A and B, were linked specifically to cellular regeneration. Temporin A and B interact with epidermal growth factor receptors to attract keratinocytes, the predominant epidermal cell type located on the outer dermal layer, and so it was concluded Temporin A and B directly speed up wound healing [6]. A year later, a more specific role for these peptides was characterised in the wound healing process, and it was confirmed that they could affect human skin cells, too [7]. A more readily available antimicrobial peptide which was known to combat pathogens in humans, esculentins, was tested in cultures that mimicked human skin [7]. No signs of toxicity were identified, and it was found that esculentins successfully induced cellular migration: wounds treated with esculentins were 100% healed within 12 hours, vs. 82% of wounds healed in the control samples [1,7]. Several other studies have since confirmed the considerable wound healing properties and anti-microbial effects of frog’s skin, and research remains ongoing to further unravel the cellular and molecular mechanisms that underlie the innate immune function of amphibian skin and it’s defence against pathogens [8, 9].
The effects of frog’s skin have been found to go beyond surface wound healing, too. An award-winning global research project started by Chris Shaw from Queen’s University, Belfast, has been collecting amphibian proteins to generate a growing bank of biological data to document the effects of peptides from frog’s skin [9]. Peptides from two frog species, when used in a controlled and targeted way, allow for the regulation of angiogenesis (the formation of new blood vessels). A peptide from the Waxy Monkey Frog can be used to ‘switch off’ angiogenesis. Inhibiting blood vessel growth can prevent the spread of tumours and may eradicate tumours entirely in some cases – this has the potential to transform some cancer cases from terminal illnesses into manageable conditions [9]. Another peptide from the Giant Firebellied Toad can ‘switch on’ angiogenesis and stimulate blood vessel growth. This could be developed to treat conditions that require rapid blood vessel formation and repair such as organ transplants, wound healing, damage caused by strokes or heart conditions, and diabetic ulcers [9]. This project is ongoing and is in collaboration with Professor Pingfan Rao who works at the Institute of Biotechnology at the University of Fuzhou, China [9]. More students are being recruited to extend the scope of the project and it will be very interesting to see what else they uncover!
More research in this field is warranted as there is still much to learn. More information could lead to the development of innovative products that, with the help of wound dressings, could facilitate faster recoveries from wounds. This would be especially valuable in improving the quality of life for those with impaired wound healing abilities. Not to mention, there is value in taking this research further to explore its potentials in developing treatments for patients undergoing cancer, organ transplants, heart conditions, strokes, and diabetic ulcers.
Mia Georgiou
References:
[1] Advanced Tissue. 2015. Frogs And Wound Healing: What’s The Connection?. [online] Available at: <https://advancedtissue.com/2015/07/frogs-and-wound-healing-whats-the-connection/> [Accessed 21 August 2020].
[2] Govender, T., Dawood, A., Esterhuyse, A. and Katerere, D., 2012. Antimicrobial Properties Of The Skin Secretions Of Frogs. [online] Scielo.org.za. Available at: <http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S0038-23532012000300012> [Accessed 21 August 2020].
[3] Purna Sai K, Neelakanta P, Babu R, Babu M. Investigation on wound healing by using amphibian skin. Indian J Exp Biol. 1995;33:673-676. PMid:8557310
[4] Le TT. Vietnamese experience in the treatment of burns. Hanoi: Gioi Publishers; 1992.
[5] M, Zasloff. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proceedings of the National Academy of Sciences Aug 1987, 84 (15) 5449-5453; DOI: 10.1073/pnas.84.15.5449
[6] Antonio Di Grazia, Vincenzo Luca, Li-av T. Segev-Zarko, Yechiel Shai, Maria Luisa Mangoni. Temporins A and B Stimulate Migration of HaCaT Keratinocytes and Kill Intracellular Staphylococcus aureus. Antimicrobial Agents and Chemotherapy Apr 2014, 58 (5) 2520-2527; DOI: 10.1128/AAC.02801-13
[7] Di Grazia, A., Cappiello, F., Imanishi, A., Mastrofrancesco, A., Picardo, M., Paus, R. and Mangoni, M., 2015. The Frog Skin-Derived Antimicrobial Peptide Esculentin-1a(1-21)NH2 Promotes the Migration of Human HaCaT Keratinocytes in an EGF Receptor-Dependent Manner: A Novel Promoter of Human Skin Wound Healing?. PLOS ONE, 10(6), p.e0128663.
[8] Rezazade Bazaz, M., Mashreghi, M., Mahdavi Shahri, N., Mashreghi, M., Asoodeh, A., Behnam Rassouli, M. and Golmohammadzadeh, S., 2013. Pharmaceutical application of frog skin on full-thickness skin wound healing in mice. Pharmaceutical Biology, 51(12), pp.1600-1606.
[9] Skin, T., 2020. The Healing Properties Of Frog Skin. [online] Science 2.0. Available at: <https://www.science20.com/news_articles/healing_properties_frog_skin-81800> [Accessed 21 August 2020].
