No abstract

Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.

Titanium is an ideal material choice for orthopaedic and dental implants, and hence a significant amount of research has been focused towards augmenting the therapeutic efficacy of titanium surfaces. More recently the focus has shifted to nano-engineered implants fabricated via anodization to generate self-ordered nanotubular structures composed of titania (TiO). These structures (titania nanotubes/TNTs) enable local drug delivery and tailorable cellular modulation towards achieving desirable effects like enhanced osseointegration and antibacterial action. However, the mechanical stability of such modifications is often ignored and remains underexplored, and any delamination or breakage in the TNTs modification can initiate toxicity and lead to severe immuno-inflammatory reactions. This review details and critically evaluates the progress made in relation to this aspect of TNT based implants, with a focus on understanding the interface between TNTs and the implant surface, treatments aimed at augmenting mechanical stability and strategies for advanced mechanical testing within the bone micro-environment ex vivo and in vivo. This review article extends the existing knowledge in this domain of TNTs implant technology and will enable improved understanding of the underlying parameters that contribute towards mechanically robust nano-engineered implants that can withstand the forces associated with implant surgical placement and the load bearing experienced at the bone/implant interface.

To endow titanium (Ti) with antibacterial properties, different concentrations of zinc oxide (ZnO) nanoparticles were decorated on anodized titanium dioxide (TiO2) nanotubes by a simple hydrothermal treatment method. The particle sizes of ZnO, which were evenly distributed and tightly adherent to the walls of the Ti nanotubes, ranged from 20-50 nm. Results from this study showed that Zn was released from the TiO2 nanotubes in a constant, slow, and biologically inspired manner. Importantly, the results showed that the ZnO decorated TiO2 nanotubular samples inhibited Streptococcus mutants and Porphyromonas gingivalis growth compared to control unmodified Ti samples. Specifically, S. mutants and P. gingivalis growth were both reduced 45-85% on the ZnO decorated Ti samples compared to Ti controls after 7 days of culture. When examining the mechanism of action, it has been further found for the first time that the ZnO decorated Ti samples inhibited the expression of Streptococcus mutans bacterial adhesion genes. Lastly, the results showed that the same samples which decreased bacterial growth the most (0.015 M precursor Zn(NO3)2 samples) did not inhibit mesenchymal stem cell growth compared to Ti controls for up to 7 days. In summary, results from this study showed that compared to plain TiO2 nanotubes, TiO2 decorated with 0.015 M ZnO provided unprecedented antibacterial properties while maintaining the stem cell proliferation capacity necessary for enhancing the use of Ti in numerous medical applications, particularly in dentistry.

Electrochemically anodized titanium surfaces with titania nanostructures (TNS; nanopores, nanotubes, etc.) have been widely applied as therapeutic bone/dental implant modifications. Despite the numerous advancements in the field of electrochemical anodization (EA), in terms of translation into the current implant market, research gaps in this domain include the lack of fabrication optimization, performed on a substrate of conventional implant surface/geometry, and inadequate mechanical stability. In the current study, we investigate the role of substrate pre-treatment on achieving desired nanotopographies for the purpose of reproducing optimized nanostructures on the complex geometry of commercial implant surfaces, as well as in-depth mechanical stability testing of these nano-engineered coatings. The results confirmed that: (a) substrate polishing/smoothening may be insignificant with respect to fabrication of well-ordered and high quality TNS on micro-rough implants with preserved underlying micro-roughness; (b) optimized outcomes can be successfully translated onto complex geometries characteristic of the current implant market, including dental implant abutments and screws (also applicable to a wider implant market including orthopaedics); (c) mechanical stability testing revealed improved modulus and hardness values as compared to conventional nanotubes/pores. We believe that such optimization advances the existing knowledge of titanium anodization and anodized implants towards integration into the current implant market and successful clinical translation.