A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd0 catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd0-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd0-resin combination is due to the in situ generation of 5-fluorouracil. Pd0-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.

Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd0-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd0-cleavable groups in positions that are mechanistically relevant for gemcitabine’s pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs’ cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry.

The effect of pore size and porosity on elastic modulus, strength, cell attachment and cell proliferation was studied for Ti porous scaffolds manufactured via powder metallurgy and sintering. Porous scaffolds were prepared in two ranges of porosities so that their mechanical properties could mimic those of cortical and trabecular bone respectively.Space-holder engineered pore size distributions were carefully determined to study the impact that small changes in pore size may have on mechanical and biological behaviour. The Young's moduli and compressive strengths were correlated with the relative porosity.Linear, power and exponential regressions were studied to confirm the predictability in the characterisation of the manufactured scaffolds and therefore establish them as a design tool for customisation of devices to suit patients' needs. The correlations were stronger for the linear and the power law regressions and poor for the exponential regressions. The optimal pore microarchitecture (i.e. pore size and porosity) for scaffolds to be used in bone grafting for cortical bone was set to <212m with volumetric porosity values of 27-37%, and for trabecular tissues to 300-500m with volumetric porosity values of 54-58%. The pore size range 212-300m with volumetric porosity values of 38-56% was reported as the least favourable to cell proliferation in the longitudinal study of 12 days of incubation.

A variety of materials require functionally graded cellular microstructures whose porosity is engineered to meet specific applications (e.g. mimic bone structure for orthopaedic applications; fulfil mechanical, thermal or acoustic constraints in structural foamed components, etc). Although a huge variety of foams can be manufactured with homogenous porosity, there are no generic processes for controlling the distribution of porosity within the resulting matrix.Motivated by the desire to create a flexible process for engineering heterogeneous foams, the authors have investigated how ultrasound, applied during the formation of a polyurethane foam, affects its cellular structure. The experimental results demonstrated how the parameters of ultrasound exposure (i.e. frequency and applied power) influenced the volume and distribution of pores within the final polyurethane matrix: the data demonstrates that porosity (i.e. volume fraction) varies in direct proportion to both the acoustic pressure and frequency of the ultrasound signal.The effects of ultrasound on porosity demonstrated by this work offer the prospect of a manufacturing process that can adjust the cellular geometry of foam and hence ensure that the resulting characteristics match the functional requirements.

nucleation, growth, packing, stiffening, solidification) some of which are known to be more sensitive to external inputs than others. Consequently, precise detection of the start and end points of each of the polymerisation stages would enable the fine control of material properties such as porosity.The development of such process control can only be pursued if those sensitive stages can be clearly distinguished during the manufacture process. This paper reports how an electrical resistivity tracking method was used to assess the differences in the foaming processes when ultrasound was irradiated to polymeric melts undergoing foaming. The electrical resistivity tracking method is also appraised with regard to its suitability to accurately identify the formation stages in the foam, as described by other authors. The polymerisation reactions associated with foam formation have distinct stages (i.e. nucleation, growth, packing, stiffening, solidification) some of which are known to be more sensitive to external inputs than others. Consequently, precise detection of the start and end points of each of the polymerisation stages would enable the fine control of material properties such as porosity. The development of such process control can only be pursued if those sensitive stages can be clearly distinguished during the manufacture process. This paper reports how an electrical resistivity tracking method was used to assess the differences in the foaming processes when ultrasound was irradiated to polymeric melts undergoing foaming. The electrical resistivity tracking method is also appraised with regard to its suitability to accurately identify the formation stages in the foam, as described by other authors.