Indocyanine green in gynecologic surgery: Where do we stand? A literature review and meta-analysis.

The main objective of this study was to review and perform a meta-analysis of current literature on the use of indocyanine green for sentinel lymph node detection in pelvic gynecologic cancer. We included all studies focusing on indications and procedures associated with the use of ICG in gynecologic surgery and available on the Medline and Pubmed database. For the meta-analysis, random effect models were used for estimation of the 95 % detection rate and 95 % confidence interval, and stratified analyses by cancer type, concentration and localization of injection were performed. A total of 147 articles were included, of which 91 were studied in a meta-analysis. Results concerning detection rate by indocyanine green injection site were found to be 95.1 % and 97.3 % respectively for intracervical injection in 2 or 4 quadrants, and 77.0 % and 94.8 % for hysteroscopic and intradermal injection respectively. Results concerning detection rate by cancer type were 95.8 %, 95.2 %, 94.7 % and 95.7 % respectively for cervical, endometrial, vulvar and endometrial/cervical cancers. Finally, the results concerning detection rate by indocyanine green concentration were 91.2 %, 95.7 %, 96.7 % and 97.7 % for concentrations of <1.25 mg/ml, 1.25 mg/ml, 2.5 mg/ml and 5 mg/ml respectively. In conclusion, indocyanine green is shown to allow highlighting of sentinel lymph nodes with good reliability with an overall indocyanine green detection rate of 95.5 %. Our literature review revealed that indocyanine green feasibility has also been demonstrated in several surgical contexts, notably for reconstructive surgery and detection of endometriosis.

Magnetic bioactive glass nano-heterostructures: a deeper insight into magnetic hyperthermia properties in the scope of bone cancer treatment.

Primary bone cancers commonly involve surgery to remove the malignant tumor, complemented with a postoperative treatment to prevent cancer resurgence. Studies on magnetic hyperthermia, used as a single treatment or in synergy with chemo- or radiotherapy, have shown remarkable success in the past few decades. Multifunctional biomaterials with bone healing ability coupled with hyperthermia property could thus be of great interest to repair critical bone defects resulting from tumor resection. For this purpose, we designed superparamagnetic and bioactive nanoparticles (NPs) based on iron oxide cores (γ-Fe2O3) encapsulated in a bioactive glass (SiO2-CaO) shell. Nanometric heterostructures (122 ± 12 nm) were obtained through a two-step process: co-precipitation of 16 nm sized iron oxide NPs, followed by the growth of a bioactive glass shell via a modified Stöber method. Their bioactivity was confirmed by hydroxyapatite growth in simulated body fluid, and cytotoxicity assays showed they induced no significant death of human mesenchymal stem cells after 7 days. Calorimetric measurements were carried out under a wide range of alternating magnetic field amplitudes and frequencies, considering clinically relevant parameters, and some were made in viscous medium (agar) to mimic the implantation conditions. The experimental specific loss power was predictable with respect to the Linear Response Theory, and showed a maximal value of 767 ± 77 W gFe-1 (769 kHz, 23.9 kA m-1 in water). An interesting value of 166 ± 24 W gFe-1 was obtained under clinically relevant conditions (157 kHz, 23.9 kA m-1) for the heterostructures immobilized in agar. The good biocompatibility, bioactivity and heating ability suggest that these γ-Fe2O3@SiO2-CaO NPs are a promising biomaterial to be used as it is or included in a scaffold to heal bone defects resulting from bone tumor resection.

Copper-Doped Biphasic Calcium Phosphate Powders: Dopant Release, Cytotoxicity and Antibacterial Properties.

Cytotoxicity and antibacterial properties associated with the dopant release of Cu-doped Biphasic Calcium Phosphate (BCP) powders, mainly composed of hydroxyapatite mixed with ß-tricalcium phosphate powders, were investigated. Twelve BCP ceramics were synthesized at three different sintering temperatures (600 °C, 900 °C and 1200 °C) and four copper doping rates (x = 0.0, 0.05, 0.10 and 0.20, corresponding to the stoichiometric amount of copper in Ca10Cux(PO4)6(OH)2-2xO2x). Cytotoxicity assessments of Cu-doped BCP powders, using MTT assay with human-Mesenchymal Stem Cells (h-MSCs), indicated no cytotoxicity and the release of less than 12 ppm of copper into the biological medium. The antibacterial activity of the powders was determined against both Gram-positive (methicillin-sensitive (MS) and methicillin resistant (MR) Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The Cu-doped biomaterials exhibited a strong antibacterial activity against MSSA, MRSA and E. coli, releasing approximatively 2.5 ppm after 24 h, whereas 10 ppm were required to induce an antibacterial effect against P. aeruginosa. This study also demonstrated that the culture medium used during experiments can directly impact the antibacterial effect observed; only 4 ppm of Cu2+ were effective for killing all the bacteria in a 1:500 diluted TS medium, whereas 20 ppm were necessary to achieve the same result in a rich, non-diluted standard marrow cell culture medium.

Biological properties of copper-doped biomaterials for orthopedic applications: A review of antibacterial, angiogenic and osteogenic aspects.

Copper is an essential trace element required for human life, and is involved in several physiological mechanisms. Today researchers have found and confirmed that Cu has biological properties which are particularly useful for orthopedic biomaterials applications such as implant coatings or biodegradable filler bone substitutes. Indeed, Cu exhibits antibacterial functions, provides angiogenic ability and favors osteogenesis; these represent major key points for ideal biomaterial integration and the healing process that follows. The antibacterial performances of copper-doped biomaterials present an interesting alternative to the massive use of prophylactic antibiotics and help to limit the development of antibiotic resistance. By stimulating blood vessel growth and new bone formation, copper contributes to the improved bio-integration of biomaterials. This review describes the bio-functional advantages offered by Cu and focuses on the antibacterial, angiogenic and osteogenic properties of Cu-doped biomaterials with potential for orthopedic applications.

Unravelling the Impact of Calcium Content on the Bioactivity of Sol-Gel-Derived Bioactive Glass Nanoparticles.

Sol-gel-derived bioactive glass nanoparticles (BGNs) are fascinating materials for bone regeneration. In the literature, it can be found that their specific surface area and their calcium content (Ca/Si ratio) are the two key parameters impacting strongly the particles' bioactivity. Nevertheless, in most studies, in vitro bioactivity tests are performed on a series of materials where both the composition and the specific surface area are varied. It is thus difficult to unravel the effect of each parameter independently. In this study, spherical and monodispersed BGNs with different Ca/Si ratios and a similar specific surface area have been synthesized by a modified Stöber method in order to specify the impact of the calcium content only. The mineralization studies performed in simulated body fluid showed that the bioactivity increases with the amount of calcium incorporated in the glass matrix. However, this effect is not significant in the composition interval studied (7-15% mol of CaO). Such a result proves that the effective Ca/Si ratio is not the major parameter that affects the bioactivity of sol-gel binary BGs. In vitro biocompatibility assessment during 3 and 7 days using human mesenchymal stem cells in contact with the sample showing the fastest mineralization proved its noncytotoxicity. Hence, biomedical applications can be intended for this sample.

Cu-doping of calcium phosphate bioceramics: From mechanism to the control of cytotoxicity.

In this study, the Cu-doping mechanism of Biphasic Calcium Phosphate (BCP) was thoroughly investigated, as was its ionic release behavior, in order to elucidate cytotoxicity features of these bioceramics. BCP are composed of hydroxyapatite (Ca10(PO4)6(OH)2) and ß-TCP (Ca3(PO4)2). The two phases present two different doping mechanisms. Incorporation into the ß-TCP structure is achieved at around 700 °C thanks to a substitution mechanism leading to the Cu-doped Ca3-xCux(PO4)2 compound. Incorporation into the HAp structure is achieved thanks to an interstitial mechanism that is limited to a Cu-poor HAp phase for temperatures below 1100 °C (Ca10Cux(PO4)6(OH)2-2xO2x with x < 0.1). Above 1100 °C, the same interstitial mechanism leads to the formation of a Cu-rich HAp mixed-valence phase (Ca10Cu2+xCu+y(PO4)6(OH)2-2x-yO2x+y with x + y ∼ 0.5). The formation of both high-temperature Cu-doped α-TCP and Cu3(PO4)2 phases above 1100 °C induces a transformation into the Cu-rich HAp phase on cooling. The linear OCuO oxocuprate entity was confirmed by EXAFS spectroscopy, and the mixed Cu+/Cu2+ valence was evidenced by XPS analyses. Ionic releases (Cu+/Cu2+, Ca2+, PO42- and OH-) in water and in simulated body media were investigated on as-synthesized ceramics to establish a pretreatment before biological applications. Finally the cytotoxicity of pretreated disks was evaluated, and results confirm that Cu-doped BCP samples are promising bioceramics for bone substitutes and/or prosthesis coatings. STATEMENT OF SIGNIFICANCE: Biphasic Calcium Phosphates (BCP) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (ß-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of copper cation in order to correctly interpret the behavior of the Cu-doped bioceramic in biological fluid. The understanding of the copper doping mechanism, related to doping mechanism of others 3d-metal cations, makes it possible to explain the rates and kinetic of release of the dopant in biological medium. Finally, the knowledge of the behavior of the copper doped ceramic in biological environment allowed the tuning of its cytotoxicity properties. The present study resulted on pre-treated ceramic disks which have been evaluated as promising biocompatible ceramic for bone substitute and/or prosthesis coating: good adherence of bone marrow cells with good cell viability.