Osteosarcoma is a dominating malignant bone tumor with high mortality due to pulmonary metastases. Furthermore, because of the cancer cell erosion and surgery resection, osteosarcoma always causes ...bone defects, which means dysfunction and disfigurement are seldom inevitable. Although various advanced treatments (e.g. chemotherapy, immunotherapy, radiotherapy) are coming up, the 5-year survival rate for osteosarcoma with metastases is still dismal. In line with this, the more potent treatments for osteosarcoma are in high demand. Curcumin, a perennial herb, has been reportedly applied in the therapy of various types of tumors via different mechanisms.
In vitro
, it has also been reported that curcumin can inhibit the proliferation of osteosarcoma cell lines and can be used to repair bone defects. This seems curcumin is a promising candidate in osteosarcoma treatment. However, due to its congenital property like hydrophobicity, and low bioavailability, affecting its anticancer effect, clinical applications of curcumin are highly limited. To enhance its performance in cancer therapies, some synergist approaches with curcumin have emerged. The present review presents some prospective ones (i.e. combinations with immunotherapy, chemotherapeutics, bone tissue engineering, and biomaterials) applied in osteosarcoma treatment. Additionally, with the advancements of photodynamic therapy in cancer therapy, this review also prospects the combination of curcumin with photodynamic therapy in osteosarcoma treatment.
The repair of critical-sized bone defects is still challenging in the fields of implantology, maxillofacial surgery and orthopaedics. Current therapies such as autografts and allografts are ...associated with various limitations. Cytokine-based bone tissue engineering has been attracting increasing attention. Bone-inducing agents have been locally injected to stimulate the native bone-formation activity, but without much success. The reason is that these drugs must be delivered slowly and at a low concentration to be effective. This then mimics the natural method of cytokine release. For this purpose, a suitable vehicle was developed, the so-called biomimetic coating, which can be deposited on metal implants as well as on biomaterials. Materials that are currently used to fill bony defects cannot by themselves trigger bone formation. Therefore, biological functionalization of such materials by the biomimetic method resulted in a novel biomimetic coating onto different biomaterials. Bone morphogenetic protein 2 (BMP-2)-incorporated biomimetic coating can be a solution for a large bone defect repair in the fields of dental implantology, maxillofacial surgery and orthopaedics. Here, we review the performance of the biomimetic coating both in vitro and in vivo.
Osteosarcoma (OS) is an aggressive tumor with a rare incidence. Extended surgical resections are the prevalent treatment for OS, which may cause critical-size bone defects. These bone defects lead to ...dysfunction, weakening the post-surgical quality of patients' life. Hence, an ideal therapeutic agent for OS should simultaneously possess anti-cancer and bone repair capacities. Curcumin (CUR) has been reported in OS therapy and bone regeneration. However, it is not clear how CUR suppresses OS development. Conventionally, CUR is considered a natural antioxidant in line with its capacity to promote the nuclear translocation of a nuclear transcription factor, nuclear factor erythroid 2 (NRF2). After nuclear translocation, NRF2 can activate the transcription of some antioxidases, thereby circumventing excess reactive oxygen species (ROS) that are deleterious to cells. Intriguingly, this research demonstrated that, in vitro, 10 and 20 μM CUR increased the intracellular ROS in MG-63 cells, damaged cells' DNA, and finally caused apoptosis of MG-63 cells, although increased NRF2 protein level and the expression of NRF2-regulated antioxidase genes were identified in those two groups.
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•An optimally designed titanium scaffold with similar mechanical properties to human cortical bone was 3D-printed.•The scaffold surface was coated with bone morphogenic protein-2 ...integrated biomimetic calcium phosphate coating to enhance biocompatibility.•The nano-structured biomimetic coating works as a carrier and can release bone morphogenic protein-2 in a cell-mediated manner.•The biomimetic calcium phosphate coating promoted repair of mandibular bone defects in beagle dogs.
Biocompatibility and osteoconductivity of porous scaffolds can be improved through coating technique by creating micro- and nanostructures on the surfaces. In this study, a biomimetic approach was used to construct a bone morphogenetic protein-2 (BMP-2) integrated calcium phosphate (CaP) coating on the surface of porous titanium scaffolds. In vitro characterizations showed that the scaffolds had mechanical properties comparable to those of the human cortical bone. The biomimetic coating has a nano-scaled surface structure, which releases BMP-2 in a stable and effective manner. Bicortical bone defects were prepared in the bilateral mandibles of beagle dogs, and the coated and uncoated scaffolds were fixed in the bone defects for 8 weeks. Based on micro-CT and histological analysis results, the biomimetic coating significantly promoted bone formation in the titanium scaffold. The coated scaffold group had significantly higher bone volume fraction, bone area fraction, and bone-to-implant contact results than the uncoated scaffold group. Besides, hematological indexes and histopathology results of the visceral organs confirmed the scaffold and coating's biocompatibility. Accordingly, the current study demonstrates that BMP-2 integrated biomimetic CaP coating can significantly promote bone formation in porous titanium scaffolds and benefit the healing process of the bicortical mandibular defect in beagle dogs.
Most materials used clinically for filling critical-sized bone defects (CSBD), such as deproteinized bovine bone (DBB), lack osteoinductivity so that their therapeutic effects are far from ...satisfactory. The effect of bone morphogenic protein 2 (BMP2)-coprecipitated biomimetic calcium phosphate granules (BMP2-cop.BioCaP) on osteoinduction of DBB graft(s) during CSBD healing is still unknown. We investigated whether BMP2-cop.BioCaP affects the osteoinductivity of DBB, bone formation, and foreign body reaction during CSBD healing. DBB + BMP2-cop.BioCaP, DBB, DBB + BMP2, DBB + BioCaP, and autologous bone grafts were implanted in the CSBD of sheep. Bone formation, DBB/BioCaP degradability, foreign body reaction, and osteoinductivity of DBB were analyzed histologically and histomorphometrically at week 4 and 8. Combination of BMP2-cop.BioCaP and DBB healed CSBD as effectively as autologous bone grafts. About 95% of the BMP2-cop.BioCaP had been degraded and replaced by new bone at week 8 in the DBB + BMP2-cop.BioCaP-group. Foreign body reaction was reduced in the DBB + BMP2-cop.BioCaP-group compared to the other groups. The independent use of the BMP2-cop.BioCaP did not achieve a satisfactory bone repair. In conclusion, the BMP2-cop.BioCaP showed good degradability and biocompatibility, and enhanced osteoinductivity of DBB during CSBD healing in sheep, suggesting BMP2-cop.BioCaP as a potential osteoinducer to enhance the therapeutic effects of the graft materials in clinic.
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•A Ti6Al4V scaffold with optimal designing parameters and mechanical properties similar to cancellous bone was 3D-printed.•To improve biocompatibility, a porous micro/nanostructured ...biomimetic calcium phosphate coating was applied to the scaffold.•Using the coating as a carrier, bone morphogenic protein-2 was consistently and uniformly released in a cell-mediated manner.•The bone morphogenic protein-2 integrated coating induced an even distribution of new bone formation within the scaffold.
The use of Ti6Al4V in bone engineering is limited, due to the biological inertia of the surface. In this study, a porous Ti6Al4V scaffold with mechanical properties similar to cancellous bone was designed and 3D-printed. Under physiological conditions, the scaffold was immersed firstly in a 5-fold-concentrated simulated body fluid, then ina supersaturated CaP solution containing BMP-2, to form a bone-like porous micro/nano structured biomimetic coating on the surface. Scaffolds were implanted in the muscle pouches created in six beagle dogs and were retrieved four weeks later for histologic and histomorphometric analysis. Results showed that BMP-2 integrated biomimetic CaP coating induced ectopic bone formation, which was absent in other two groups. Soft tissue infiltrated the scaffold's outside 1 mm layer, while the new-formed bone was evenly distributed in the longitudinal and horizontal directions within the rest of the scaffold based on BA/TA, BIC and BA measurements. In conclusion, the BMP-2 incorporated biomimetic CaP coating creates a micro/nano surface structure on the Ti6Al4V scaffold, which helps to increase biocompatibility. The integrated BMP-2 is capable of inducing ectopic bone formation in vivo. The proposed combination may have the potential for bone reconstruction, but further studies are needed to explore its clinical applicability.
Abstract As an alternative to an autologous bone graft, deproteinized bovine bone (DBB) is widely used in the clinical dentistry. Although DBB provides an osteoconductive scaffold, it is not capable ...of enhancing bone regeneration because it is not osteoinductive. In order to render DBB osteoinductive, bone morphogenetic protein 2 (BMP-2) has previously been incorporated into a three dimensional reservoir (a biomimetic calcium phosphate coating) on DBB, which effectively promoted the osteogenic response by the slow delivery of BMP-2. The aim of this study was to investigate the therapeutic effectiveness of such coating on the DBB granules in repairing a large cylindrical bone defect (8 mm diameter, 13 mm depth) in sheep. Eight groups were randomly assigned to the bone defects: (i) no graft material; (ii) autologous bone; (iii) DBB only; (iv) DBB mixed with autologous bone; (v) DBB bearing adsorbed BMP-2; (vi) DBB bearing a coating but no BMP-2; (vii) DBB bearing a coating with adsorbed BMP-2; and (viii) DBB bearing a coating-incorporated depot of BMP-2. 4 and 8 weeks after implantation, samples were withdrawn for a histological and a histomorphometric analysis. Histological results confirmed the excellent biocompatibility and osteoconductivity of all the grafts tested. At 4 weeks, DBB mixed with autologous bone or functionalized with coating-incorporated BMP-2 showed more newly-formed bone than the other groups with DBB. At 8 weeks, the volume of newly-formed bone around DBB that bore a coating-incorporated depot of BMP-2 was greatest among the groups with DBB, and was comparable to the autologous bone group. The use of autologous bone and BMP-2 resulted in more bone marrow formation. Multinucleated giant cells were observed in the resorption process around DBB, whereas histomorphometric analysis revealed no significant degradation of DBB. In conclusion, it was shown that incorporating BMP-2 into the calcium phosphate coating of DBB induced strong bone formation around DBB for repairing a critical-sized bone defect.
Abstract We investigated the inflammatory response to, and the osteoinductive efficacies of, four polymers (collagen, Ethisorb™, PLGA and Polyactive® ) that bore either an adsorbed (fast-release ...kinetics) or a calcium-phosphate-coating-incorporated (slow-release kinetics) depot of BMP-2. Titanium-plate-supported discs of each polymer ( n = 6 per group) were implanted at an ectopic (subcutaneous) ossification site in rats ( n = 48). Five weeks later, they were retrieved for a histomorphometric analysis of the volumes of ectopic bone and foreign-body giant cells (a gauge of inflammatory reactivity), and the degree of polymer degradation. For each polymer, the osteoinductive efficacy of BMP-2 was higher when it was incorporated into a coating than when it was directly adsorbed onto the material. This mode of BMP-2 carriage was consistently associated with an attenuation of the inflammatory response. For coated materials, the volume density of foreign-body giant cells was inversely correlated with the volume density of bone ( r2 = 0.96), and the volume density of bone was directly proportional to the surface-area density of the polymer ( r2 = 0.97). Following coating degradation, other competitive factors, such as the biocompatibility and the biodegradability of the polymer itself, came into play.
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