Contents

Introduction
In the last decades, the study and development of mimetic skin models have been a hot topic of discussion mainly due to the rising of ethical questions and the establishment of new rules regarding the prohibition of animal testes. The need of new and efficient skin mimetic models remains crucial namely for pharmaceutical, cosmetic and toxicological purposes.
The safety and toxicity of new products and formulations must be assessed prior human application according to the European Union (EU) guidelines and to the Organisation for Economic Cooperation and Development (OECD) guidelines for testing dangerous ingredients for the skin (Kandarova et al., 2004, OECD, 2015, Fentem, 1999, Fentem and Botham, 2004, Worth et al., 1998).
Efficient methods for development and rationalization of drug formulations aiming topical application demand specific skin models capable of estimating the properties and the most suitable drug formulation. After the identification of important penetration and permeation properties (wanted and unwanted) for the drug formulations, its optimization becomes achievable (Flaten et al., 2015).
In line with this facts, several mimetic skin models have been developed and some are already available in the market, while the research continues for further improvements in their quality, complexity and mimetic properties. Different biomimetic materials have been used from the silicone membranes or poly(dimethylsiloxane) (PDMS) models to human cell cultures as well as different technologies to simulate the highly complex and stratified structure of the human skin.
The big challenges in the development of skin substitutes are related with: a) the need of reproducibility in the results obtained using these models; b) their capacity to better mimic the multitude of human skin structure and functions and c) the development of cost-effective skin membrane models (Sarkiri et al., 2019, Flaten et al., 2015). The main focus of the present review is to summarize the currently reported healthy and disease skin mimetic models, discuss the characteristics and applications of these proposals and to identify the new trends in skin engineering.
Human skin – structure and functions
The skin is the major organ of the human body having a surface area ofat ca 2 m2, representing approximately 10% of the body mass for adults (Lee et al., 2006, Ng and Lau, 2015, Sofia A. Costa Lima., 2018). Skin is a physical barrier in the interface between the body and the external environment and constitutes a first-line defence entity for protection of the body, controlling what may enter and exit in the body. Moreover, skin is composed by a network of cells and matrix elements providing multifaceted functions such as the prevention of the body´s dehydration, protection of the body against infectious agents or ultraviolet radiation, thermoregulation, sensation and synthesis of vitamin D (Prausnitz et al., 2012, Sofia A. Costa Lima., 2018, Lee et al., 2006).
The organization of the skin consists of three major layers hypodermis, dermis and epidermis. The type of structure, cellular composition and major components of the three skin layers are summarized in Figure 1 (A and B), and these topics are discussed in more detail on the following subsections.