**6. Conclusions**

Nature has originated a huge number of biomaterials with high levels of sophisticated structures and functions, evolved over many thousands of years in di fferent environments. The term "bioinspiration" refers to a product or process which can translate a certain biological design into useful technologies, such as self-cleaning surfaces, self-healing materials, natural interfaces etc. [9]. Many e fforts have been made in the last decade in the development of biomimetic materials with similarity to the natural materials of the body [96] and bioinspired engineering has been put forward as a valuable tool for the development of clinically relevant materials and structures for regenerative sciences [9]. For engineers and clinicians, a grea<sup>t</sup> challenge in repair/regeneration approaches is represented by the necessity to closely mimic the complex architectures of the human body and the properties and functions of the ECM of the native tissues [129]. For this purpose, material engineering inspired by the wide range of adaptions in nature represents a useful tool for designing novel clinically relevant materials and structures for regenerative medicine [9]. Bioinspired research will continue to focus on the design of functional biomaterials to control cell–matrix interaction at any length scale [10]; however, some challenging aspects still require more investigation on bioinspired and biomimetic systems, mostly related to the comprehensive understanding of the structure–property relationships of the biological world, the translation of its motifs to a wide combination of materials [2,8], and the regenerative and immunological processes [10]. Among tissue engineering applications, wound managemen<sup>t</sup> still represents a huge challenge for clinicians, and is also a big commercial enterprise, involving a market of about 15 billion US dollars [130]. It continuously requires novel systems and devices to improve clinical outcomes and to provide more e ffective therapeutic options because of the multiple factors involved in the healing process, which can adversely a ffect the di fferent stages of the wound healing and determine the failure of conventional approaches [106]. An ideal wound dressing should be able to maintain a moist environment while removing the excess exudate, should protect the wound from contaminants and from further trauma also when removed, and should ensure comfort and good thermal conditions and gaseous exchange [131].

In this scenario, proteins in general could be employed in addition or in place of classical synthetic polymers [2] and silk materials, particularly, have attracted more attention because of their excellent bioresponse and capability to be replaced by native tissues [1].

Compared with other synthetic or natural polymers for biomedical application, silk fibroin presents several advantages. Among them, the thermal stability up to about 200 ◦C and environmental stability are of grea<sup>t</sup> importance for biomedical application [132]. Indeed, compared to other fibrous proteins such as collagen, fibroin o ffers multiple options for sterilization, such as ethylene oxide, γ-radiation and 70% ethanol. Autoclaving of fibroin sca ffolds does not a ffect their structure and properties, while collagen denatures at these temperatures [133,134]. Moreover, compared to biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), which can increase local pH and a ffect cellular processes due to the degradation products of aliphatic polyester, the protein biopolymers have degradation products mostly consisting of amino acids that can be resorbed by cells [134]. Moreover, the degradation of silk can be controlled in function of processing parameters and crystallinity [132]. In terms of biological responses involved in wound healing application, SF biomaterials demonstrated higher activity compared to commercially available collagen materials. Hashimoto et al. demonstrated di fferent behaviors in human fibroblasts cultured on collagen biomaterials and fibroin-based biomaterials. In particular, silk fibroin induced higher gene expression for wound repair than collagen film, and also higher cell motility due to weaker cell–fibroin interactions than collagen [135]. Due to its intrinsic biological features involving improved cell migration and proliferation, and wound healing properties, silk fibroin represents an extremely valuable option among biomaterials [39] as a good candidate for fabrication of novel natural wound dressings for a wide range of skin injuries. Some limitations still need to be solved for a systematic use of silk proteins in biomedical fields, among which is the limited number of companies producing high quality non-hydrolyzed fibroin.

Furthermore, compared to other large-scale produced polymers, fibroin is more expensive and involves sericulture and silkworm rearing, which represent an intense part of the activities for silk production [136]. However, beyond its use in the textile field, the development of multi-level silk fibroin structures can become the focus of future research in connection between academic and industrial sectors [48], o ffering multiple opportunities for future healthcare applications [132].

**Author Contributions:** F.P. and M.P. equally contributed to this review article, collecting data from literature and writing the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
