3d-Printed Hydrogel Scaffolds with Sandwich Architecture for Multimodal Therapy of Postoperative Osteosarcoma

Abstract

Inhibiting postoperative tumor recurrence and drug resistance is highly challenging in osteosarcoma therapy. Herein, an engineered sandwich-structured hydrogel scaffold (sandwich/MTO-CuHCF) loading copper hexacyanoferrate nanoparticles (CuHCF) and mitoxantrone (MTO) with multimodal therapy was developed using in situ stacked 3D-printing technology. The sandwich architecture provided distinct compartmentalization of therapeutic agents, thereby mitigating the risk of physicochemical incompatibility. Upon implantation of the sandwich/MTO-CuHCF scaffold at the tumor resection site, CuHCF and MTO were sequentially and sustainably released. On one hand, CuMOF depleted intracellular glutathione and catalyzed a Fenton-like reaction to generate cytotoxic hydroxyl radicals, leading to effective cancer cell killing. On the other hand, the subsequently released MTO, an anthracycline chemotherapeutic agent, induced DNA damage in tumor cells. Notably, the excellent photothermal conversion efficiency of sandwich/MTO-CuHCF under near-infrared irradiation not only enhanced the Fenton-like reaction through localized hyperthermia but also facilitated photothermal ablation of osteosarcoma cells. Remarkably, in a mouse osteosarcoma resection model, the scaffold implantation significantly inhibited tumor recurrence. Our study provides a conceptual framework for the development of implantable scaffolds to achieve effective suppression of postoperative tumor recurrence.

Note:
Funding declaration: This work is supported by the National Natural Science Foundation of China (52202359), the Science and Technology Program of Guangzhou (2025A04J7161), and the Guangdong Provincial Pearl River Talents Program (2021QN02Y141, 2019QN01Y131).

Conflict of Interests: The authors declare that there is no competing financial interest or personal relationships that could influence the work submitted.

Keywords: Osteosarcoma, 3D printing, hydrogel scaffold, postoperative therapy, combination therapy