Multi-Functional Composite Scaffolds for Cancer Therapy and Tissue Engineering

Cancer is the main cause of human death. Many methods have been well established for cancer therapy. The traditional methods include chemotherapy, radiotherapy and surgical resection. Chemotherapy uses anti-tumor drugs to treat the patients. The drugs can kill tumor cells or inhibit the proliferation and migration of tumor cells. A large number of drugs have been used in clinic. However, chemotherapeutic drugs can not only kill tumor cells, but also affect the functions of normal cells because most of chemotherapeutic drugs do not have tumor cell-targeting capacity. Side effects to normal cells and drug resistance after long-term administration are the main problems of chemotherapeutic drugs. Radiotherapy uses high-energy x-ray, γ-ray, electron beams or protons to destroy tumor cells. Exposure of normal cells to radio irradiation can also cause severe side effect. Surgical resection can directly remove the tumor tissues and is widely used in clinic if the tumor tissues are visible and not metastasized. However, sometimes it is difficult to eliminate all the tumor cells by surgical resection. Furthermore, surgical resection is frequently accompanied with large defects, which are difficult to self-heal. Furthermore, in recent years, immunotherapy and hyperthermia therapy have been developed rapidly for cancer therapy. Immunotherapy uses natural immune system for inhibiting primary and metastatic tumor growth. Hyperthermia therapy is based on high temperatureinduced damage of proteins and structure to trigger tumor cells apoptosis or necrosis. As one of the hyperthermia therapy methods, photothermal therapy uses the photothermal conversion agents to absorb near infrared (NIR) light and convert it to heat, thereby leading to the destruction of cancer cells.


Introduction
Furthermore, surgical resection is frequently accompanied with large defects, which are difficult to self-heal. Furthermore, in recent years, immunotherapy and hyperthermia therapy have been developed rapidly for cancer therapy. Immunotherapy uses natural immune system for inhibiting primary and metastatic tumor growth. Hyperthermia therapy is based on high temperatureinduced damage of proteins and structure to trigger tumor cells apoptosis or necrosis. As one of the hyperthermia therapy methods, photothermal therapy uses the photothermal conversion agents to absorb near infrared (NIR) light and convert it to heat, thereby leading to the destruction of cancer cells.
Although some success of the above-mentioned methods has been achieved, each treatment has its respective limitation.

ARTICLE INFO Abstract
Eradication of remaining and metastatic cancer cells to protect cancer recurrence remains a challenge for cancer therapy. Meanwhile regeneration of large defect after surgical resection is desirable for improving the quality of life of the patients. In recent years, multi-functional composite scaffolds with both excellent ablation effect on cancer cells and promotive effect on tissue regeneration have been reported for simultaneous cancer therapy and tissue engineering. Photothermal conversion nanoparticles and reagents have been hybridized with biocompatible polymers or bioceramics to generate the multi-functional photothermal scaffolds. Photothermal ablation, activation of immune cells and promotive tissue regeneration have been demonstrated by in vitro cell culture and in vivo animal experiments. The review summarizes the latest developments of these multi-functional composite scaffolds.

Preparation of Composite Scaffolds and Application for Photothermal Tumor Ablation
Hyperthermal reagents such as iron oxide nanopartciles, gold nanoperticles, carbon nanotubes, graphene, ceramic nanoparticles and polydopamine have been incorporated in biocompatible and biodegradable polymers and bioceramics to generate multifunctional scaffolds for hyperthermal cancer therapy and tissue engineering [1][2][3][4][5][6][7][8][9][10][11][12]. Composite porous scaffolds of iron oxide (Fe 3 O 4 ) nanoparticles have been prepared by incorporating them into gelatin porous matrices [1]. tumor-bearing mouse. Composite scaffolds of nano-hydroxyapatite and reduced graphene oxide sheets [11], CuFeSe 2 nanocrystals and bioactive glass [12] have also been reported for the multi-functional applications. The advantages of these composite scaffolds for photothermal therapy are their holding capacity of a large amount of nanoparticles in the implantation site and repeated heating under NIR irradiation. When tumor cells migrate into the composite porous scaffolds, the tumor cells can be captured by the porous structures or the targeting ligand and then effectively killed by NIR irradiation.

Activation of Immune Cells by Composite Scaffolds
The photothermal composite scaffolds can not only be used to ablate primary tumor cells at the implantation sites but also be expected to activate immune cells to attack metastatic tumor cells. The results indicate that the AuNRs65/gelatin composite scaffolds support adipogenic differentiation of hMSCs and may be useful for adipose tissue engineering [6]. Both gold nanopartciles and gelatin porous scaffolds have shown promotive effects on differentiation of hMSCs for tissue engineering applications [15][16][17][18][19]. Incorporation of calcium phosphate nanoparticles can further promote osteogenic differentiation of hMSCs [20].
The PDA/alginate composite scaffolds have promotive effect on proliferation of human breast epithelial cells when the cells are cultured in composite scaffolds [8]. The PD/BC composite scaffolds support adhesion and proliferation of human osteoblast-like cells and human bone marrow stromal cells during in vitro cell culture [9]. In vivo implantation of the PD/BC composite scaffolds in critical-sized femoral defects of rabbits shows the promotive effect of the composite scaffolds on bone tissue regeneration [9]. The

Conclusion
Composite scaffolds of photothermal reagents and biocompatible materials have been designed and prepared for cancer therapy.
The composite scaffolds have multi-functions to photothermally ablate tumor cells, activate immune cells and promote tissue regeneration. The composite scaffolds will provide useful platform for simultaneous cancer therapy and tissue engineering.