Phan V H Giang, Murugesan Mohanapriya, Huong Ha, Le Thanh-Tam, Phan Thuy-Hien, Manivasagan Panchanathan, Mathiyalagan Ramya, Jang Eue-Soon, Yang Deok Chun, Li Yi, Thambi Thavasyappan
Biomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam.
Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin si, Gyeonggi do 17104, Republic of Korea.
ACS Appl Mater Interfaces. 2022 Sep 28;14(38):42812-42826. doi: 10.1021/acsami.2c05864. Epub 2022 Sep 16.
-gel-forming thermoresponsive copolymers have been widely exploited in controlled delivery applications because their critical gel temperature is similar to human body temperature. However, there are limitations to controlling the delivery of biologics from a hydrogel network because of the poor networking and reinforcement between the copolymer networks. This study developed an -forming robust injectable and 3D printable hydrogel network based on cellulose nanocrystals (CNCs) incorporated amphiphilic copolymers, poly(ε-caprolactone--lactide)--poly(ethylene glycol)--poly(ε-caprolactone--lactide (PCLA). In addition, the physicochemical and mechanical properties of injectable hydrogels were controlled by physically incorporating CNCs with amphiphilic PCLA copolymers. CNCs played an unprecedented role in physically reinforcing the PCLA copolymers' micelle network via intermicellar bridges. Apart from that, the free-flowing closely packed rod-like CNCs incorporated PCLA micelle networks at low temperature transformed to a stable viscoelastic hydrogel network at physiological temperature. CNC incorporated PCLA copolymer sols effectively coordinated with hydrophobic doxorubicin and water-soluble lysozyme by a combination of hydrophobic and hydrogen bonding interaction and controlled the release of biologics. As shown by the 3D printing results, the biocompatible PCLA hydrogels continuously extruded during printing had good injectability and maintained high shape fidelity after printing without any secondary cross-linking steps. The interlayer bonding between the printed layers was high and formed stable 3D structures up to 10 layers. Subcutaneous injection of free-flowing CNC incorporated PCLA copolymer sols to BALB/c mice formed a hydrogel instantly and showed controlled biodegradation of the hydrogel depot without induction of toxicity at the implantation sites or surrounding tissues. At the same time, the antitumor effect on the MDA-MB-231 tumor xenograft model demonstrated that DOX-loaded hydrogel formulation significantly inhibited the tumor growth. In summary, the CNC incorporated biodegradable hydrogels developed in this study exhibit a prolonged release with special release kinetics for hydrophobic and hydrophilic biologics.
凝胶形成型热响应性共聚物因其临界凝胶温度与人体体温相似，已在控释应用中得到广泛应用。然而，由于共聚物网络之间的网络形成和增强效果不佳，在控制生物制剂从水凝胶网络中的释放方面存在局限性。本研究基于掺入纤维素纳米晶体（CNCs）的两亲性共聚物聚（ε-己内酯-丙交酯）-聚（乙二醇）-聚（ε-己内酯-丙交酯）（PCLA），开发了一种形成凝胶的坚固可注射且可3D打印的水凝胶网络。此外，通过将CNCs与两亲性PCLA共聚物物理混合来控制可注射水凝胶的物理化学和机械性能。CNCs通过胶束间桥在物理增强PCLA共聚物的胶束网络方面发挥了前所未有的作用。除此之外，在低温下掺入PCLA胶束网络的自由流动紧密堆积的棒状CNCs在生理温度下转变为稳定的粘弹性水凝胶网络。掺入CNC的PCLA共聚物溶胶通过疏水作用和氢键相互作用有效地与疏水性阿霉素和水溶性溶菌酶配位，并控制生物制剂的释放。如3D打印结果所示，在打印过程中连续挤出的生物相容性PCLA水凝胶具有良好的可注射性，并且在打印后无需任何二次交联步骤即可保持高形状保真度。打印层之间的层间结合力很高，可形成多达10层的稳定3D结构。将自由流动的掺入CNC的PCLA共聚物溶胶皮下注射到BALB/c小鼠体内可立即形成水凝胶，并显示出水凝胶储库的可控生物降解，而不会在植入部位或周围组织中诱导毒性。同时，对MDA-MB-231肿瘤异种移植模型的抗肿瘤作用表明，载有阿霉素的水凝胶制剂显著抑制了肿瘤生长。总之，本研究开发的掺入CNC的可生物降解水凝胶对疏水性和亲水性生物制剂表现出具有特殊释放动力学的延长释放。
