Bone Tumor Therapy Research Articles

3D-printed Mg-substituted hydroxyapatite/ gelatin methacryloyl hydrogels encapsulated with PDA@DOX particles for bone tumor therapy and bone tissue regeneration

3D-printed Mg-substituted hydroxyapatite/ gelatin methacryloyl hydrogels encapsulated with PDA@DOX particles for bone tumor therapy and bone tissue regeneration

Design and in vitro evaluation of 223Ra/99mTc-loaded spherical nano-hydroxyapatite in bone tumor therapy.

Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223Ra, but the low specific activity (sp.act.) of 223Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223Ra@nHA and a new method to loaded 99mTc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99mTc-MDP was associated with higher labeling rate and stability in comparison to 99mTc. Conclusion: All these findings suggest that using PEG as a template and 99mTc-MDP could be the most effective of synthetic 223Ra/99mTc@nHA.

Innovative Biomaterials for Bone Tumor Treatment and Regeneration: Tackling Postoperative Challenges and Charting the Path Forward.

Surgical resection of bone tumors is the primary approach employed in the treatment of bone cancer. Simultaneously, perioperative interventions, particularly postoperative adjuvant anticancer strategies, play a crucial role in achieving satisfactory therapeutic outcomes. However, the occurrence of postoperative bone tumor recurrence, metastasis, extensive bone defects, and infection are significant risks that can result in unfavorable prognoses or even treatment failure. In recent years, there has been significant progress in the development of biomaterials, leading to the emergence of new treatment options for bone tumor therapy and bone regeneration. This progress report aims to comprehensively analyze the strategic development of unique therapeutic biomaterials with inherent healing properties and bioactive capabilities for bone tissue regeneration. These composite biomaterials, classified into metallic, inorganic non-metallic, and organic types, are thoroughly investigated for their responses to external stimuli such as light or magnetic fields, internal interventions including chemotherapy or catalytic therapy, and combination therapy, as well as their role in bone regeneration. Additionally, an overview of self-healing materials for osteogenesis is provided and their potential applications in combating osteosarcoma and promoting bone formation are explored. Furthermore, the safety concerns of integrated materials and current limitations are addressed, while also discussing the challenges and future prospects.

Revolutionizing bone tumor management: cutting-edge breakthroughs in limb-saving treatments.

Limb salvage surgery has revolutionized the approach to bone tumors in orthopedic oncology, steering away from historical amputations toward preserving limb function and enhancing patient quality of life. This transformative shift underscores the delicate balance between tumor eradication and optimal postoperative function. Primary and metastatic bone tumors present challenges in early detection, differentiation between benign and malignant tumors, preservation of function, and the risk of local recurrence. Conventional methods, including surgery, radiation therapy, chemotherapy, and targeted therapies, have evolved with a heightened focus on personalized medicine. A groundbreaking development in limb salvage surgery is the advent of 3D-printed patient-specific implants, which significantly enhance anatomical precision, stability, and fixation. These implants reduce soft tissue disruption and the associated risks, fostering improved osseointegration and correction of deformities for a more natural and functional postoperative outcome. Biological and molecular research has reshaped the understanding of bone tumors, guiding surgical interventions with advancements such as genomic profiling, targeted intraoperative imaging, precision targeting of molecular pathways, and immunotherapy tailored to individual tumor characteristics. In the realm of imaging technologies, MRI, CT scans, and intraoperative navigation systems have redefined preoperative planning, minimizing collateral damage and optimizing outcomes through accurate resections. Postoperative rehabilitation plays a crucial role in restoring function and improving the quality of life. Emphasizing early mobilization, effective pain management, and a multidisciplinary approach, rehabilitation addresses the physical, psychological, and social aspects of recovery. Looking ahead, future developments may encompass advanced biomaterials, smart implants, AI algorithms, robotics, and regenerative medicine. Challenges lie in standardization, cost-effectiveness, accessibility, long-term outcome assessment, mental health support, and fostering global collaboration. As research progresses, limb salvage surgery emerges not just as a preservation tool but as a transformative approach, restoring functionality, resilience, and hope in the recovery journey. This review summarizes the recent advances in limb salvage therapy for bone tumors over the past decade.

Outcomes in dogs undergoing surgical stabilization and non-stereotactic radiation therapy for axial and appendicular bone tumors.

Information on dogs that undergo radiation therapy (RT) with non-stereotactic protocols in addition to surgical stabilization with implant placement for treatment of bone tumors is limited. Our primary objectives were to describe the clinical characteristics as well as short- and long-term outcomes, including complications, function, and disease progression, in dogs that underwent both surgical stabilization with implant placement and non-stereotactic RT for local treatment of a bone tumor. A bi-institutional retrospective case series was performed. Eight client-owned dogs that underwent both surgical stabilization with implant placement and non-stereotactic RT for local treatment of a bone tumor were included. Tumor types included osteosarcoma or suspected osteosarcoma (5), plasma cell tumor (2), and grade 3 fibrosarcoma (1). Radiation protocols were hypofractionated (palliative intent) in 5 dogs and fractionated (definitive intent) in 3 dogs. Five dogs experienced complications following both RT and surgery, including grade 1 complications in two dogs, a grade 2 complication in one dog, both grade 1 and 2 complications in one dog, and both grade 2 and 3 complications in one dog. Clinical signs subjectively improved in all dogs that had outcomes relative to function documented post-surgery/RT (7). Of these 7 dogs, 4 maintained long-term improvement in function and clinical signs, whereas 3 experienced subsequent recurrence/progression of clinical signs at a median of 133 days (range 91-186) postoperatively in association with biomechanical complications (screw loosening), surgical site infection, and local disease progression in 1 dog each; subsequent treatment resulted in improved clinical signs for each of these 3 dogs, such that overall good long-term functional outcomes were experienced. No dogs required amputation or additional vertebral surgery as salvage for local disease control or palliation. The median progression free interval was 206 days (range 25-1078), and the median survival time was 253 days (range 122-1078) with 1 additional dog lost to follow-up at 575 days. Two dogs experienced local disease progression, and 6 dogs experienced systemic disease progression; both dogs that developed local disease progression received palliative intent RT protocols. In this cohort, dogs with primary bone tumors that underwent surgical stabilization with implant placement and hypofractionated or fractionated non-stereotactic RT for local treatment had a low incidence of major complications, good limb function and ambulation post-treatment, and relatively prolonged survival times despite disease progression.

Multifunctional bioactive glass nanoparticles: surface-interface decoration and biomedical applications.

Developing bioactive materials with multifunctional properties is crucial for enhancing their biomedical applications in regenerative medicine. Bioactive glass nanoparticle (BGN) is a new generation of biomaterials that demonstrate high biocompatibility and tissue-inducing capacity. However, the hard nanoparticle surface and single surface property limited their wide biomedical applications. In recent years, the surface functional strategy has been employed to decorate the BGN and improve its biomedical applications in bone tissue repair, bioimaging, tumor therapy and wound repair. This review summarizes the progress of surface-interface design strategy, customized multifunctional properties and biomedical applications in detail. We also discussed the current challenges and further development of multifunctional BGN to meet the requirements of various biomedical applications.

Fructose-mineralized black phosphorus for syncretic bone regeneration and tumor suppression.

Black phosphorus (BPs) nanosheets with their inherent and selective chemotherapeutic effects have recently been identified as promising cancer therapeutic agents, but challenges in surface functionalization hinder satisfactory enhancement of their selectivity between tumors and normal cells. To address this issue, we developed a novel biomineralization-inspired strategy to synthesize CaBPs-Na2FDP@CaCl2 nanosheets, aiming to achieve enhanced and selective anticancer bioactivity along with accelerated osteoblast activity. Benefiting from the in situ mineralization and fructose modification, CaBPs-Na2FDP@CaCl2 exhibited improved pH-responsive degradation behavior and targeted therapy for osteosarcoma. The in vitro results indicated that CaBPs-Na2FDP@CaCl2 exhibited efficient uptake and quick degradation by GLUT5-positive 143B osteosarcoma cells, enhancing BPs-driven chemotherapeutic effects through ATP level disturbance-mediated apoptosis of tumor cells. Moreover, CaBPs-Na2FDP@CaCl2 underwent gradual degradation into PO43-, Ca2+ and fructose in MC3T3-E1 cells, eliminating systemic toxicity. Intracellular Ca2+ bound to calmodulin (CaM), activating Ca2+/CaM-dependent signaling cascades, thereby enhancing osteoblast differentiation and mineralization in pro-osteoblastic cells. In vivo experiments affirmed the anti-tumor capability, inhibition of tumor recurrence and bone repair promotion of CaBPs-Na2FDP@CaCl2. This study not only broadens the application of BPs in bone tumor therapy but also provides a versatile surface functionalization strategy for nanotherapeutic agents.

Research progress of new multifunctional bone cement in bone tumor therapy

The research progress of new multifunctional bone cement in bone tumor therapy in recent years was reviewed, in order to provide help for the future research of anti-tumor bone cement. The related literature on the treatment of bone tumors with new multifunctional bone cement at home and abroad in recent years was extensively reviewed and summarized. The new multifunctional bone cements include those with the functions of photothermotherapy, magnetic thermotherapy, chemoradiotherapy, and antibacterial after operation, which are discussed from the aspects of anti-tumor, drug controlled release, and cytotoxicity. Controlled drug release has been achieved in multifunctional bone cements by adjusting heat and pH or incorporating particles such as chitosan oligosaccharides and γ-cyclodextrin. At present, multifunctional bone cement with hyperthermia, radiotherapy, and chemotherapy has effectively inhibited the local recurrence and distant metastasis of bone tumors. Broadening the application of bone cement for photothermal and magnetic thermal therapy to deeper bone tumors, investigating more precise controlled release of drug-loaded bone cement, and introducing nanoparticles with both thermal conversion and intrinsic enzymatic activities into bone cement for synergistic anti-tumor therapy are promising research directions. The new multifunctional bone cement inhibits bone tumor cells, promotes new bone formation in bone defects, and prevents incision infection after tumor resection. Certain progress has been made in anti-tumor, antibacterial, drug-controlled release, and reduction of cytotoxicity. Expanding the deeper application range of the new multifunctional bone cement, verifying the safety in clinical application, and focusing on the individualized treatment of the new multifunctional bone cement are the problems that need to be solved in the future.

Spectral Computed Tomography-Guided Radiotherapy of Osteosarcoma utilizing BiOI Nanosheets.

As an aggressive malignant bone tumor, osteosarcoma (OS) is usually found in children and adolescents. Computed tomography (CT) is an important tool for the clinical evaluation of osteosarcoma, but limits to low diagnostic specificity due to single parameters of traditional CT and modest signal-to-noise ratio of clinical iodinated contrast agents. As one kind of spectral CT, dual-energy CT (DECT), with the advantage of a provision of multi-parameter information, makes it possible to acquire the best signal-to-noise ratio image, accurate detection, as well as imaging-guided therapy of bone tumors. Hereby, we synthesized BiOI nanosheets (BiOI NSs) as a DECT contrast agent with superior imaging capability compared to iodine agents for clinical detection of OS. Meanwhile, the synthesized BiOI NSs with great biocompatibility is able to achieve effective radiotherapy (RT) by enhancing X-ray dose deposition at the tumor site, leading to DNA damage, which in turn inhibits tumor growth. This study offers a promising new avenue for DECT imaging-guided treatment of OS. STATEMENT OF SIGNIFICANCE: Osteosarcoma (OS) is a common primary malignant bone tumor. Traditional surgical procedures and conventional CT scans are often used for the treatment and monitoring of OS, but the effects are generally unsatisfactory. In this work, BiOI nanosheets (NSs) was reported for dual-energy CT (DECT) imaging-guided OS radiotherapy. The powerful and constant X-ray absorption of BiOI NSs at any energy guarantees excellent enhanced DECT imaging performance, allowing detailed visualization of OS through images with a better signal-to-noise ratio and guiding radiotherapy process. The deposition of X-rays could be greatly enhanced by Bi atoms to induce serious DNA damage in radiotherapy. Taken together, the BiOI NSs for DECT-guided radiotherapy will greatly improve the current treatment status of OS.

Partial ulnar ostectomy, stereotactic body radiation therapy, and palliative radiation therapy as local limb sparing treatment modalities for ulnar tumors in dogs.

Information on dogs that undergo limb preserving local treatment for ulnar tumors is currently limited. To describe the clinical characteristics and outcomes in dogs that underwent partial ulnectomy or radiation therapy (RT) for ulnar bone tumors, and to evaluate potential risk factors for outcomes as well as pre-treatment factors for association with treatment modality selected. Forty client-owned dogs that underwent partial ulnectomy or RT for an ulnar tumor from July 2006 to July 2021. The medical records database from a single institution were retrospectively reviewed, and data were recorded and analyzed. Radiation therapy was performed in 24 dogs, with 12 stereotactic body RT (SBRT) and 12 palliative RT (PRT) plans, and partial ulnectomy was performed in 16 dogs. Biomechanical complications occurred in 6/12 (50%) dogs that underwent SBRT, 6/12 (50%) dogs that underwent PRT, and 3/16 (18.8%) dogs that underwent ulnectomy. The majority of dogs had a good functional outcome following partial ulnectomy, and no dogs required surgical stabilization of the carpus even with lateral styloid process excision. Pathologic fracture occurred in 4/12 (33.3%) dogs following SBRT and 5/12 (41.7%) dogs following PRT. Local progression or recurrence was documented in 5/12 (41.7%) dogs that underwent SBRT, 2/12 (16.7%) dogs that underwent PRT, and 2/16 (12.5%) dogs that underwent ulnectomy. The overall median survival time was 198 days, and factors that were significantly associated with improved survival time included adjuvant chemotherapy administration and partial ulnectomy as local treatment method for dogs that received chemotherapy. Both RT and ulnectomy were effective and well tolerated local treatment modalities for dogs with ulnar tumors.

A biocompatible adenine-based metal–organic framework for Ca2+ responsive drug delivery

An anionic zinc-adeninate MOF ZJU-64-NH2 has been successfully fabricated by solvothermal method. The high crystallinity of ZJU-64-NH2 was confirmed through powder X-ray diffraction (PXRD) analysis. The cationic model drug procainamide (PA) was efficiently encapsulated into ZJU-64-NH2 through electrostatic interaction, and its loading capacity was determined to be 12.97 wt%. The drug delivery system PA@ZJU-64-NH2 exhibited Ca2+-triggered drug release due to ion exchange, indicating promising potential for bone tumor therapy. The excellent biocompatibility of ZJU-64-NH2 was demonstrated through MTT assay and confocal microscopy imaging.

FePSe3 -Nanosheets-Integrated Cryogenic-3D-Printed Multifunctional Calcium Phosphate Scaffolds for Synergistic Therapy of Osteosarcoma.

Clinical treatment of osteosarcoma encounters great challenges of postsurgical tumor recurrence and extensive bone defect. To develop an advanced artificial bone substitute that can achieve synergistic bone regeneration and tumor therapy for osteosarcoma treatment, a multifunctional calcium phosphate composite enabled by incorporation of bioactive FePSe3 -nanosheets within the cryogenic-3D-printed α-tricalcium phosphate scaffold (TCP-FePSe3 ) is explored. The TCP-FePSe3 scaffold exhibits remarkable tumor ablation ability due to the excellent NIR-II (1064nm) photothermal property of FePSe3 -nanosheets. Moreover, the biodegradable TCP-FePSe3 scaffold can release selenium element to suppress tumor recurrence by activating of the caspase-dependent apoptosis pathway. In a subcutaneous tumor model, it is demonstrated that tumors can be efficiently eradicated via the combination treatment with local photothermal ablation and the antitumor effect of selenium element. Meanwhile, in a rat calvarial bone defect model, the superior angiogenesis and osteogenesis induced by TCP-FePSe3 scaffold have been observed in vivo. The TCP-FePSe3 scaffold possesses improved capability to promote the repair of bone defects via vascularized bone regeneration, which is induced by the bioactive ions of Fe, Ca, and P released during the biodegradation of the implanted scaffolds. The TCP-FePSe3 composite scaffolds fabricated by cryogenic-3D-printing illustrate a distinctive strategy to construct multifunctional platform for osteosarcoma treatment.

Prospects and Advances in Adoptive Natural Killer Cell Therapy for Unmet Therapeutic Needs in Pediatric Bone Sarcomas.

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite aggressive therapy. These therapies can have long-term effects on bone growth, such as decreased bone mineral density and reduced longitudinal growth. New therapeutic approaches are therefore urgently needed for targeting pediatric malignant bone tumors. Harnessing the power of the immune system against cancer has improved the survival rates dramatically in certain cancer types. Natural killer (NK) cells are a heterogeneous group of innate effector cells that possess numerous antitumor effects, such as cytolysis and cytokine production. Pediatric sarcoma cells have been shown to be especially susceptible to NK-cell-mediated killing. NK-cell adoptive therapy confers numerous advantages over T-cell adoptive therapy, including a good safety profile and a lack of major histocompatibility complex restriction. NK-cell immunotherapy has the potential to be a new therapy for pediatric malignant bone tumors. In this manuscript, we review the general characteristics of osteosarcoma and Ewing sarcoma, discuss the long-term effects of sarcoma treatment on bones, and the barriers to effective immunotherapy in bone sarcomas. We then present the laboratory and clinical studies on NK-cell immunotherapy for pediatric malignant bone tumors. We discuss the various donor sources and NK-cell types, the engineering of NK cells and combinatorial treatment approaches that are being studied to overcome the current challenges in adoptive NK-cell therapy, while suggesting approaches for future studies on NK-cell immunotherapy in pediatric bone tumors.

Hierarchically Structured Hydroxyapatite Particles Facilitate the Enhanced Integration and Selective Anti-Tumor Effects of Amphiphilic Prodrug for Osteosarcoma Therapy.

Efficient delivery of cargo into target cells is a formidable challenge in modern medicine. Despite the great promise of biomimetic hydroxyapatite (HA) particles in tissue engineering, their potential applications in bone tumor therapy, particularly their structure-function relationships in cargo delivery to target cells, have not yet been well explored. In this study, biomimetic multifunctional composite microparticles (Bm-cMPs) are developed by integrating an amphiphilic prodrug of curcumin with hierarchically structured HA microspheres (Hs-hMPs). Then, the effects of the hierarchical structure of vehicles on the integration and delivery of cargo as well as the anti-osteosarcoma (OS) effect of the composite are determined. Different hierarchical structures of the vehicles strongly influence the self-assembly behavior of the prodrug. The flake-like crystals of Hs-hMPs enable the highest loading capacity and enhance the stability of the cargo. Compared to the normal cells, OS cells exhibit 3.56-times better uptake of flake-like Hs-hMPs, facilitating the selective anti-tumor effect of the prodrug. Moreover, Bm-cMPs suppress tumor growth and metastasis by promoting apoptosis and inhibiting cell proliferation and tumor vascularization. The findings shed light on the potential application of Bm-cMPs and suggest a feasible strategy for developing an effective targeted therapy platform using hierarchically structured minerals for OS treatment.

Development of a novel regenerative therapy for malignant bone tumors using an autograft containing tumor inactivated by high hydrostatic pressurization (HHP).

Surgical resection of malignant bone tumors leads to significant defects in the normal surrounding tissues that should be reconstructed to avoid amputation. Our research aimed to inactivate osteosarcoma (OS)-affected bone to obtain autologous bone grafts for bone defect reconstruction using a novel therapy called high hydrostatic pressurization (HHP) therapy. The key points are complete tumor death and preservation of the non-denatured native extracellular matrix (ECM) and bone tissue by HHP. Previously, we found that HHP at 200MPa for 10min can completely inactivate cells in normal skin and skin tumors, including malignant melanoma and squamous cell carcinoma while maintaining their original biochemical properties and biological components. Based on our previous research, this study used HHP at 200MPa for 10min to eradicate OS. We prepared an OS cell line (LM8), pressurized it at 200MPa for 10min, and confirmed its inactivation through morphological observation, WST-8 assay, and live/dead assay. We then injected OS cells with or without HHP into the bone marrow of the murine tibia, after which we implanted tumor tissues with or without HHP into the anterior surface of the tibia. After HHP, OS cells did not proliferate and were assessed using a live/dead assay. The pressurized cells and tumors did not grow after implantation. The pressurized bone was well prepared as tumor-free autologous bone tissues, resulting in the complete eradication of OS. This straightforward and short-pressing treatment was proven to process the tumor-affected bone to make a transplantable and tumor-free autologous bone substitute.

3D printed hydrogel/bioceramics core/shell scaffold with NIR-II triggered drug release for chemo-photothermal therapy of bone tumors and enhanced bone repair

The treatment of bone defect caused by osteosarcoma remains an intractable problem. Scaffolds with multi-functions are the potential candidates to kill recurrent tumor and to repair the bone defects after tumorectomy. However, most of these scaffolds employed photothermal therapy using near‐infrared laser inthe first biological window (NIR‐I)with intrinsic poor tissue penetration depth. Some scaffolds loading drugs for chemotherapy generally lack the accurate control of on-demand drugs release to reduce the side effects and enhance the therapeutic efficacy. Herein, 3D printed gelatin/bioceramics core/shell scaffolds were developed with doxorubicin (DOX) loaded gelatin as the core part and SrCuSi4O10 (SC) nanosheets/beta-tricalcium phosphate (β-TCP) as the shell part of the printed filaments. SC nanosheets endowed the scaffolds with photothermal therapy under NIR-IIlaser irradiation. Simultaneously, the generated extensive hyperthermia could induce the gel-sol transition of the gelatin in the core part of the filaments, which subsequently triggered the on-demand DOX release from the loosened gelatin achieving chemo-photothermal therapy. The in vitro and in vivo data demonstrated that chemo-photothermal therapy showed a synergetic effect on anti-tumor. Additionally, the degradation/release of gelatin from the filaments resulted in the hollow channels in the scaffold, which provided clear architectural cues for promoting the ingrowth of bone tissues. Meanwhile, the degradation of the SC nanosheets contributed to the sustained release of bioactive ions (Sr, Cu and Si), which further enhanced vascularized bone regeneration. All these results indicated that the 3D printed DOX loaded gelatin-TCP/SC scaffolds had a great potential application for the treatment of bone defects caused by osteosarcoma in effective killing cancer cells and repairing tumor-induced bone defects.

Design and evaluation of 32P-labeled hydroxyapatite nanoparticles for bone tumor therapy

The clinical diagnosis and treatment of malignant bone tumors are still major clinical challenges due to their high incidence are difficulty. Targeted therapies have become a critical approach to treat bone tumors. In recent years, radiopharmaceuticals have been used widely and have shown potent and efficient results in treating bone tumors, among which 32P and the labeled radiopharmaceuticals play an essential role. In this study, the 32P-labeled hydroxyapatite (HA) was prepared through chemical synthesis (32P-Hap) and physical adsorption (32P-doped-Hap). The in vitro stability of 32P-labeled HA was analyzed to assess the superiority of the new-found chemical synthesis. The radiolabeling yield and stability of chemical synthesis (97.6 ± 0.5%) were significantly improved compared with physical adsorption (92.7 ± 0.4%). Furthermore, the CT results corroborate that 32P-Hap (100 μCi) +DOX group has the highest tumor suppression rate and can effectively reduce bone destruction. The results corroborate the effectiveness of the chemical synthesis and validate the application of 32P-Hap in bone tumors. Therefore, 32P-Hap (100 μCi) + DOX may be an effective strategy for bone metastasis treatments.

Functional anti-bone tumor biomaterial scaffold: construction and application.

Bone tumors, including primary bone tumors and bone metastases, have been plagued by poor prognosis for decades. Although most tumor tissue is removed, clinicians are still confronted with the dilemma of eliminating residual cancer cells and regenerating defective bone tissue after surgery. Therefore, functional biomaterial scaffolds are considered to be the ideal candidates to bridge defective tissues and restrain cancer recurrence. Through functionalized structural modifications or coupled therapeutic agents, they provide sufficient mechanical strength and osteoinductive effects while eliminating cancer cells. Numerous novel approaches such as photodynamic, photothermal, drug-conjugated, and immune adjuvant-assisted therapies have exhibited remarkable efficacy against tumors while exhibiting low immunogenicity. This review summarizes the progress of research on biomaterial scaffolds based on different functionalization strategies in bone tumors. We also discuss the feasibility and advantages of the combined application of multiple functionalization strategies. Finally, potential obstacles to the clinical translation of anti-tumor bone bioscaffolds are highlighted. This review will provide valuable references for future advanced biomaterial scaffold design and clinical bone tumor therapy.

Additively manufactured Bi-functionalized bioceramics for reconstruction of bone tumor defects.

Bone tissue exhibits critical factors for metastatic cancer cells and represents an extremely pleasant spot for further growth of tumors. The number of metastatic bone lesions and primary tumors that arise directly from cells comprised in the bone milieu is constantly increasing. Bioceramics have recently received significant attention in bone tissue engineering and local drug delivery applications. Additionally, additive manufacturing of bioceramics offers unprecedented advantages including the possibilities to fill irregular voids after the resection and fabricate patient-specific implants. Herein, we investigated the recent advances in additively manufactured bioceramics and ceramic-based composites that were used in the local bone tumor treatment and reconstruction of bone tumor defects. Furthermore, it has been extensively explained how to bi-functionalize ceramics-based biomaterials and what current limitations impede their clinical application. We have also discussed the importance of further development into ceramic-based biomaterials and molecular biology of bone tumors to: (1) discover new potential therapeutic targets to enhance conventional therapies, (2) local delivering of bio-molecular agents in a customized and "smart" way, and (3) accomplish a complete elimination of tumor cells in order to prevent tumor recurrence formation. We emphasized that by developing the research focus on the introduction of novel 3D-printed bioceramics with unique properties such as stimuli responsiveness, it will be possible to fabricate smart bioceramics that promote bone regeneration while minimizing the side-effects and effectively eradicate bone tumors while promoting bone regeneration. In fact, by combining all these therapeutic strategies and additive manufacturing, it is likely to provide personalized tumor-targeting therapies for cancer patients in the foreseeable future. STATEMENT OF SIGNIFICANCE: To increase the survival rates of cancer patients, different strategies such as surgery, reconstruction, chemotherapy, radiotherapy, etc have proven to be essential. Nonetheless, these therapeutic protocols have reached a plateau in their effectiveness due to limitations including drug resistance, tumor recurrence after surgery, toxic side-effects, and impaired bone regeneration following tumor resection. Hence, novel approaches to specifically and locally attack cancer cells, while also regenerating the damaged bony tissue, have being developed in the past years. This review sheds light to the novel approaches that enhance local bone tumor therapy and reconstruction procedures by combining additive manufacturing of ceramic biomaterials and other polymers, bioactive molecules, nanoparticles to affect bone tumor functions, metabolism, and microenvironment.

Chemical bonding of Epigallocatechin-3-gallate to the surface of nano-hydroxyapatite to enhance its biological activity for anti-osteosarcoma

Post-surgical defect repair combined with the elimination of residual cancer cells remains a major clinical challenge for the therapy of malignant bone tumors. As a natural product extracted from green tea, epigallocatechin-3-gallate (EGCG) has a wide range of biological activities. In this study, we investigated the anti-osteosarcoma and osteogenic potential of the natural compound EGCG in combination with hydroxyapatite (HA) for the post-operative treatment of osteosarcoma. We have synthesized well-dispersed surface amino-functionalized hydroxyapatite nanoparticles by the template method combined with surface modification techniques. Then, we conjugated EGCG with HA nanoparticles via amido linkage to prevent burst release of the biomolecules and improve their stability. The results showed that the as-prepared HA-EGCG nanoparticles had the same antioxidant activity as pure EGCG. The HA-EGCG nanoparticles demonstrated efficient EGCG release upon enzyme interactions in an acidic tumor environment, facilitating the accumulation of EGCG in tumor tissues and improving its bioavailability. Compared with pure EGCG and HA, HA-EGCG exhibited enhanced anticancer activity in vitro and in vivo. Furthermore, HA-EGCG could effectively promote osteogenic differentiation. This covalent strategy provides a simple method to fabricate a pH and enzyme-mediated delivery platform to refine the stability and bioavailability of EGCG. This research provides a strategy into designing biomaterials combined with EGCG for the potential application in bone diseases.