  Citation: Capuana, E.; Lopresti, F.; Ceraulo, M.; La Carrubba, V. Poly-L-Lactic Acid (PLLA)-Based Biomaterials for Regenerative Medicine: A Review on Processing and Applications. Polymers 2022, 14, 1153. https://doi.org/10.3390/ polym14061153 Academic Editors: Ángel Serrano-Aroca and Xiao Hu Received: 20 January 2022 Accepted: 9 March 2022 Published: 14 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). polymers Review Poly- L-Lactic Acid (PLLA)-Based Biomaterials for Regenerative Medicine: A Review on Processing and Applications Elisa Capuana 1 , Francesco Lopresti 1, *, Manuela Ceraulo 1 and Vincenzo La Carrubba 1,2 1 Department of Engineering, University of Palermo, RU INSTM, Viale delle Scienze, 90128 Palermo, Italy; elisa.capuana@unipa.it (E.C.); manuela.ceraulo@unipa.it (M.C.); vincenzo.lacarrubba@unipa.it (V.L.C.) 2 ATeN Center, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy * Correspondence: francesco.lopresti01@unipa.it Abstract: Synthetic biopolymers are effective cues to replace damaged tissue in the tissue engineering (TE) field, both for in vitro and in vivo application. Among them, poly-L-lactic acid (PLLA) has been highlighted as a biomaterial with tunable mechanical properties and biodegradability that allows for the fabrication of porous scaffolds with different micro/nanostructures via various approaches. In this review, we discuss the structure of PLLA, its main properties, and the most recent advances in overcoming its hydrophobic, synthetic nature, which limits biological signaling and protein absorption. With this aim, PLLA-based scaffolds can be exposed to surface modification or combined with other biomaterials, such as natural or synthetic polymers and bioceramics. Further, various fabrication technologies, such as phase separation, electrospinning, and 3D printing, of PLLA-based scaffolds are scrutinized along with the in vitro and in vivo applications employed in various tissue repair strategies. Overall, this review focuses on the properties and applications of PLLA in the TE field, finally affording an insight into future directions and challenges to address an effective improvement of scaffold properties. Keywords: poly-L-lactic acid (PLLA); tissue engineering; regenerative medicine 1. Introduction Tissue engineering (TE) is a multidisciplinary field that encompasses life sciences and engineering to develop biological substitutes that replace, repair, and improve the functions of tissues [1–3]. Scaffolds, along with cells and growth factors, play a crucial role in achieving the purpose of TE. An ideal scaffold should mimic the native extracellular matrix (ECM), an endogenous substance that surrounds cells and provides spatial and me- chanical signals aiding cellular development and morphogenesis [4]. Scaffolds need to be biodegradable materials whose degradation must be synchronic with the tissue growth [5,6]. Therefore, the actual challenge of TE is to fabricate scaffolds with adequate physical and biological properties leading to proper cell growth while ensuring appropriate mechanical properties for the in vivo environment [7,8]. Among the biodegradable polymers used for tissue engineering, poly-L-lactic acid (PLLA) has been widely studied because of its interesting mechanical properties and tailorable biodegradability [9]. As a result, it can maintain mechanical and structural integrity during in vitro and in vivo applications while supporting tissue formation [10–12]. PLLA belongs to the PLA family, and, compared to PDLA (created through the polymerization of D-lactide), it exhibits higher crystallinity, chemical stability, and degradation resistance to enzymes and, as a consequence, a much longer resorption time [1,13–15]. Moreover, the degradation of PLLA produces L-lactic acid, which is harmless to the human body, while D-lactic acid, produced by PDLA, is slightly harmful [16]. In addition, PLLA is synthesized from eco-sustainable processes, which do not use oil sources or poorly cleaned catalysts, and is approved by the FDA for its non-cytotoxicity, suggesting that PLLA-based scaffolds could effectively promote tissue Polymers 2022, 14, 1153. https://doi.org/10.3390/polym14061153 https://www.mdpi.com/journal/polymers