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.

An In Vitro Model to Test the Influence of Immune Cell Secretome on Mesenchymal Stromal Cell Osteogenic Differentiation.

Immune cells and their soluble factors have an important role in the bone healing process. Modulation of the immune response, therefore, offers a potential strategy to enhance bone formation. To investigate the influence of the immune system on osteogenesis, we developed and applied an in vitro model that incorporates both innate and adaptive immune cells. Human peripheral blood mononuclear cells (PBMCs) were isolated and cultured for 24 h and subsequently stimulated with immune-modulatory agents; C-class CpG oligodeoxynucleotide (CpG ODN C), polyinosinic acid-polycytidylic acid [Poly(I:C)], and lipopolysaccharide (LPS); all pathogen recognition receptor agonists, that target Toll-like receptors (TLRs) 9, 3, and 4, respectively. The conditioned medium (CM) obtained from PBMCs after 24 h was used to investigate its effects on the metabolic activity and osteogenic differentiation capacity of human bone marrow-derived mesenchymal stromal cells (MSCs). Conditioned media from unstimulated PBMCs did not affect the metabolic activity and osteogenic differentiation capacity of MSCs. The CM from CpG ODN C and LPS-stimulated PBMCs increased alkaline phosphatase activity (ALP) of MSCs by approximately threefold as compared with the unstimulated control, whereas Poly(I:C) CM did not enhance ALP activity of MSCs. Moreover, direct stimulation of MSCs with the immune-modulatory stimuli did not result in increased ALP. These results demonstrate that soluble factors present in CM from PBMCs stimulated with immune-modulatory factors enhance osteogenesis of MSCs. This in vitro model can serve as a tool in screening immune-modulatory stimulants from a broad variety of immune cells for (indirect) effects on osteogenesis and also to identify soluble factors from multiple immune cell types that may modulate bone healing.

Physico-Chemical Characteristics and Posterolateral Fusion Performance of Biphasic Calcium Phosphate with Submicron Needle-Shaped Surface Topography Combined with a Novel Polymer Binder.

A biphasic calcium phosphate with submicron needle-shaped surface topography combined with a novel polyethylene glycol/polylactic acid triblock copolymer binder (BCP-EP) was investigated in this study. This study aims to evaluate the composition, degradation mechanism and bioactivity of BCP-EP in vitro, and its in vivo performance as an autograft bone graft (ABG) extender in a rabbit Posterolateral Fusion (PLF) model. The characterization of BCP-EP and its in vitro degradation products showed that the binder hydrolyses rapidly into lactic acid, lactide oligomers and unaltered PEG (polyethylene glycol) without altering the BCP granules and their characteristic submicron needle-shaped surface topography. The bioactivity of BCP-EP after immersion in SBF revealed a progressive surface mineralization. In vivo, BCP-EP was assessed in a rabbit PLF model by radiography, manual palpation, histology and histomorphometry up to 12 weeks post-implantation. Twenty skeletally mature New Zealand (NZ) White Rabbits underwent single-level intertransverse process PLF surgery at L4/5 using (1) autologous bone graft (ABG) alone or (2) by mixing in a 1:1 ratio with BCP-EP (BCP-EP/ABG). After 3 days of implantation, histology showed the BCP granules were in direct contact with tissues and cells. After 12 weeks, material resorption and mature bone formation were observed, which resulted in solid fusion between the two transverse processes, following all assessment methods. BCP-EP/ABG showed comparable fusion rates with ABG at 12 weeks, and no graft migration or adverse reaction were noted at the implantation site nor in distant organs.