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.