gels Article Thermosensitive Polyester Hydrogel for Application of Immunosuppressive Drug Delivery System in Skin Allograft I-En Wu 1,† , Madonna Rica Anggelia 2,† , Sih-Yu Lin 1 , Chiao-Yun Chen 1 , I-Ming Chu 1, * and Cheng-Hung Lin 2, *   Citation: Wu, I.-E.; Anggelia, M.R.; Lin, S.-Y.; Chen, C.-Y.; Chu, I.-M.; Lin, C.-H. Thermosensitive Polyester Hydrogel for Application of Immunosuppressive Drug Delivery System in Skin Allograft. Gels 2021, 7, 229. https://doi.org/10.3390/ gels7040229 Academic Editor: Ali Tamayol Received: 25 October 2021 Accepted: 19 November 2021 Published: 23 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 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/). 1 Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan; k2258s91@icloud.com (I.-E.W.); jolin552283@gmail.com (S.-Y.L.);chiaoyun.chen@rochester.edu (C.-Y.C.) 2 Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung Memorial Medical College, Chang Gung University, Taoyuan 333, Taiwan; mranggelia@yahoo.com or mranggelia@cgmh.org.tw * Correspondence: chuiming123@gmail.com or imchu@che.nthu.edu.tw (I.-M.C.); lukechlin@gmail.com or lukechlin@cgmh.org.tw (C.-H.L.); Tel.: +886-3-5713704 (I.-M.C.); +886-3-3281200 (C.-H.L.) † Both authors contributed equally to this work. Abstract: Tacrolimus (FK506) is a common immunosuppressive drug that is capable of suppressing acute rejection reactions, and is used to treat patients after allotransplantation. A stable and suitable serum concentration of tacrolimus is desirable for better therapeutic effects. However, daily drug administration via oral or injection routes is quite inconvenient and may encounter drug overdose or low patient compliance problems. In this research, our objective was to develop an extended delivery system using a thermosensitive hydrogel of poly ethylene glycol, D,L-lactide (L), and ǫ-caprolactone (CL) block copolymer, mPEG-PLCL, as a drug depot. The formulation of mPEG-PLCL and 0.5% PVP-dissolved tacrolimus was studied and the optimal formulation was obtained. The in vivo data showed that in situ gelling is achieved, a stable and sustained release of the drug within 30 days can be maintained, and the hydrogel was majorly degraded in that period. Moreover, improved allograft survival was achieved. Together, these data imply the potential of the current formulation for immunosuppressive treatments. Keywords: thermosensitive; tacrolimus; allotransplantation 1. Introduction Hydrogels are formed by crosslinking hydrophilic polymers, either through chemical or physical interactions. They can be applied to many biomedical needs, such as drug delivery and tissue engineering [1–8]. Thermosensitive hydrogel, which can form gel in situ at the body temperature, is especially useful as a depot for the delivery of therapeutics with minimal invasiveness [9,10]. Therapeutic drugs or cells can be easily mixed in the sol-phase of the hydrogels before injection and be stably released from the gel-phase inside the body. Thermosensitive hydrogels synthesized from poly (ethylene glycol)-polyester copoly- mers are suitable for biomedical applications due to their good biocompatibility and gel-forming properties [11]. The mild in-situ gelling reaction for ease of encapsulation and sustained release of therapeutic agents or cells [12] while the degradation rate of hydrogels can be modified to suit the particular applications by choosing proper ester monomer constituents. In our previous study [13], we successfully developed a ther- mosensitive mPEG-amino hydrogel for sustained release of a hydrophobic drug, which is tacrolimus. However, the degradation rates of this type of hydrogels were very slow, so the depot persisted more than 3 months. It raises concerns about fibrosis formation at the injected site [14,15]. Therefore, poly (ethylene glycol)-polyester hydrogel is investigated Gels 2021, 7, 229. https://doi.org/10.3390/gels7040229 https://www.mdpi.com/journal/gels