Exploring the frontiers: The potential and challenges of bioactive scaffolds in osteosarcoma treatment and bone regeneration

Abstract

The standard treatment for osteosarcoma combines surgery with chemotherapy, yet it is fraught with challenges such as postoperative tumor recurrence and chemotherapy-induced side effects. Additionally, bone defects after surgery often surpass the body's regenerative ability, affecting patient recovery. Bioengineering offers a novel approach through the use of bioactive scaffolds crafted from metals, ceramics, and hydrogels for bone defect repair. However, these scaffolds are typically devoid of antitumor properties, necessitating the integration of therapeutic agents. The development of a multifunctional therapeutic platform incorporating chemotherapeutic drugs, photothermal agents (PTAs), photosensitizers (PIs), sound sensitizers (SSs), magnetic thermotherapeutic agents (MTAs), and naturally occurring antitumor compounds addresses this limitation. This platform is engineered to target osteosarcoma cells while also facilitating bone tissue repair and regeneration. This review synthesizes recent advancements in integrated bioactive scaffolds (IBSs), underscoring their dual role in combating osteosarcoma and enhancing bone regeneration. We also examine the current limitations of IBSs and propose future research trajectories to overcome these hurdles.

Keywords: Bone regeneration; Chemotherapy; Integrated bioactive scaffolds; Osteosarcoma; Surgery.

Graphical abstract

Fig. 1

Summary diagram of the use of IBSs for osteosarcoma treatment and bone regeneration (Created with Biorender.com).

Scheme 1

This paper provides a systematic overview of the utilization of IBSs as a multifaceted platform for osteosarcoma treatment and the facilitation of bone tissue regeneration. This review encompasses a range of strategic approaches, including biomaterial-directed strategies that leverage the inherent properties of scaffold materials, drug delivery strategies that aim to optimize the release of therapeutic agents, environmental response strategies that adapt to the local biological environment, and multimodal therapeutic strategies that combine various treatment modalities to increase overall efficacy. (Created with Biorender.com).

Fig. 2

Metal scaffold. (A) Antitumor mechanism of the rLDO samples. Reproduced with permission from Ref. [21], Copyright @ 2022 Small. [B) Schematic structure of a 3D printed porous titanium alloy scaffold loaded with cisplatin/hydrogel. Reproduced with permission from Ref. [23], Copyright @ 2021 Bioactive Materials. (C) Schematic of the preparation process of LDH-H₂ and its in vivo antitumor and bone-binding properties. Reproduced with permission from Ref. [25], Copyright @ 2022 ACS Applied Materials @Interfaces. (D) Fs-BP-DOX@PDA for synergistic photothermal chemotherapy of osteosarcoma in mice. Reproduced with permission from Ref. [27], copyright @ 2022 ACS Applied Materials @Interfaces.

Fig. 3

Ceramic scaffold. (A) Schematic representation of the preparation and function of Se/Sr/Zn-HA and Se/Sr/Zn-HA-PCLs for tumor therapy, bone defect repair and antibacterial treatment. Reproduced with permission from Ref. [53], Copyright @ 2024 Bioactive Materials. (B) A 3D-printed TCP-FePSe₃ scaffold was used as an all-in-one platform to inhibit osteosarcoma recurrence and promote bone regeneration after surgery Reproduced with permission from Ref. [62], Copyright @ 2023 Small. (C) Schematic representation of TBGS fabrication, ablation of bone cancer and regeneration of bone tissue. Reproduced with permission from Ref. [75], Copyright @ 2019 Advanced Science. (D) BCN@AKT scaffolds for osteosarcoma cell photothermal therapy and subsequent repair of tumor-induced bone defects as an integrated strategy. Reproduced with permission from Ref. [93], Copyright @ 2020 Chemical Engineering journal.

Fig. 4

Hydrogel scaffold. (A) Schematic illustration of synergistic photothermal chemotherapy of bone tumors and enhancement of osteogenesis with the injectable BPNS/DOX/CS hydrogel. Reproduced with permission from Ref. [107], Copyright @ 2023 International Journal of Biological Macromolecules. (B) MBRs induced mild hyperthermia-starvation therapy to treat bone tumors and accelerate bone defect repair. Reproduced with permission from Ref. [112], Copyright @ 2023 Journal of Nanobiotechnology. (C) Synthesis route of the MeCFO/GelMA hydrogel and schematic diagram of magnetothermal therapy. Reproduced with permission from Ref. [113], Copyright @ 2023 Frontiers. (D) 3D-printed ADA-GEL/Lys-Ce-MSN Holder. Reproduced with permission from Ref. [119], Copyright @ 2022 Macromolecular Bioscience.

Fig. 5

Biomaterial-directed strategies. (A) Antitumor and segmental bone defect healing capacity of n-HA-loaded titanium scaffolds. Reproduced with permission from Ref. [57], Copyright @ 2019 Science Advances. (B) Mechanism of action of chitosan in tumor suppression. Reproduced with permission from Ref. [96], Copyright @ 2020 Materials Science and Engineering: C.

Fig. 6

Drug delivery strategies. (A) Schematic illustration of the in vivo specific antitumor immune response to an implanted 3D scaffolded vaccine. Reproduced with permission from Ref. [138], Copyright @ 2021 Advanced Materials. (B) Schematic of the oxygen-producing hydrogel (GHCAC) used to overcome tumor hypoxia to enhance synergistic photodynamic/gas therapy. Reproduced with permission from Ref. [140], Copyright @ 2020 ACS Applied Materials & Interfaces.

Fig. 7

Environmental response strategy. (A) Schematic of the MgO₂/PLGA composite scaffold preparation and its postoperative antimicrobial, anti-osteosarcoma and bone regeneration mechanisms. Reproduced with permission from Ref. [143], Copyright @ 2023 Advanced Materials. (B) 3D-printed bilayer PGPC-PGPH porous scaffolds and their anti-osteosarcoma and bone-enhancing mechanisms. Reproduced with permission from Ref. [148], Copyright @ 2024 Bioactive Materials.

Fig. 8

Preparation of IBSs. (A)Schematic representation of ZA functionalized polycaprolactone scaffold preparation and biological studies. Reproduced with permission from Ref. [160], Copyright @ 2023 International Journal of Biological Macromolecules. (B) Schematic of the design and preparation of a multiphase bone-ligament-osteointegration branch (BLB) for ACL repair. Reproduced with permission from Ref. [161], Copyright @ 2024 Bioactive Materials. (C) Schematic of 3D printed PLGA/Mg scaffolds as an integrated platform for postoperative osteosarcoma recurrence inhibition and bone regeneration. Reproduced with permission from Ref. [165], Copyright @ 2021 Biomaterials. (D) Schematic representation of a CMB@BG scaffold equipped with self-assembled CMB nanowheel crystals with photothermal catalysis as a three-in-one solution for osteosarcoma. Reproduced with permission from Ref. [167], Copyright @ 2023 Advanced Materials.

Fig. 9

Modification of IBSs. (A) RGD/GS scaffolds functionalized by site-specific enzymatic reactions were used to recruit MSCs from skeletal muscle, which were then implanted into bone defects. Reproduced with permission from Ref. [173], Copyright @ 2022 Journal of Colloid and Interface Science. (B) Schematic of 3D nanofiber scaffold preparation. Reproduced with permission from Ref. [176], Copyright @ 2019 Journal of Colloid and Interface Science.

Fig. 10

Summary of IBSs. By carefully selecting and processing a variety of bioactive materials, researchers have successfully developed IBSs. These scaffolds employ a variety of ingenious design strategies that combine anti-osteosarcoma efficacy with the ability to promote bone regeneration, effectively addressing the challenges of tumor cell retention and bone defect repair after osteosarcoma surgery. In the future, research and development of IBSs will focus on three main directions: in situ, precision and long-term treatment (Created with Biorender.com).