Solid implantable devices for sustained drug delivery.

Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application.

Development of 3D-printed vaginal devices containing metronidazole for alternative bacterial vaginosis treatment.

Bacterial vaginosis (BV) is an abnormal condition caused by the change of microbiota in the vagina. One of the most common bacteria found in the case of BV is Gardnerella vaginalis, which is categorised as anaerobic facultative bacteria. Currently, the available treatment for BV is the use of antibiotics, such as metronidazole (MTZ), in topical and oral dosage forms. The limitation of the currently available treatment is that multiple administration is required and thus, the patient needs to apply the drug frequently to maintain the drug efficacy. To address these limitations, this research proposed prolonged delivery of MTZ in the form of intravaginal devices made from biodegradable and biocompatible polymers. Semi-solid extrusion (SSE) 3D printing was used to prepare the intravaginal devices. The ratio of high and low molecular weight poly(caprolactone) (PCL) was varied to evaluate the effect of polymer composition on the drug release. The versatility of SSE 3D printer was used to print the intravaginal devices into two different shapes (meshes and discs) and containing two different polymer layers made from PCL and a copolymer of methyl vinyl ether and maleic anhydride (Gantrez™-AN119), which provided mucoadhesive properties. Indeed, this layer made from Gantrez™-AN119 increased ca. 5 times the mucoadhesive properties of the final 3D-printed devices (from 0.52 to 2.57 N). Furthermore, MTZ was homogenously dispersed within the polymer matrix as evidenced by scanning electron microscopy analysis. Additionally, in vitro drug release, and antibacterial activity of the MTZ-loaded intravaginal devices were evaluated. Disc formulations were able to sustain the release of MTZ for 72 h for formulations containing 70/30 and 60/40 ratio of high molecular weight/low molecular weight PCL. On the other hand, the discs containing a 50/50 ratio of high molecular weight/low molecular weight PCL showed up to 9 days of release. However, no significant differences in the MTZ release from the MTZ-loaded meshes (60/40 and 50/50 ratio of high molecular weight/low molecular weight PCL) were found after 24 h. The results showed that the different ratios of high and low molecular weight PCL did not significantly affect the MTZ release. However, the shape of the devices did influence the release of MTZ, showing that larger surface area of the meshes provided a faster MTZ release. Moreover, MTZ loaded 3D-printed discs (5% w/w) were capable of inhibiting the growth of Gardnerella vaginalis. These materials showed clear antimicrobial properties, exhibiting a zone of inhibition of 19.0 ± 1.3 mm. Based on these findings, the manufactured represent a valuable alternative approach to the current available treatment, as they were able to provide sustained release of MTZ, reducing the frequency of administration and thus improving patient compliance.

3D-printed reservoir-type implants containing poly(lactic acid)/poly(caprolactone) porous membranes for sustained drug delivery.

Implantable drug delivery systems are an interesting alternative to conventional drug delivery systems to achieve local or systemic drug delivery. In this work, we investigated the potential of fused-deposition modelling to prepare reservoir-type implantable devices for sustained drug delivery. An antibiotic was chosen as a model molecule to evaluate the potential of this type of technology to prepare implants on-demand to provide prophylactic antimicrobial treatment after surgery. The first step was to prepare and characterize biodegradable rate-controlling porous membranes based on poly(lactic acid) (PLA) and poly(caprolactone) (PCL). These membranes were prepared using a solvent casting method. The resulting materials contained different PLA/PCL ratios. Cylindrical implants were 3D-printed vertically on top of the membranes. Tetracycline (TC) was loaded inside the implants and drug release was evaluated. The results suggested that membranes containing a PLA/PCL ratio of 50/50 provided drug release over periods of up to 25 days. On the other hand, membranes containing lower PCL content did not show a porous structure and accordingly the drug could not permeate to the same extent. The influence of different parameters on drug release was evaluated. It was established that film thickness, drug content and implant size are critical parameters as they have a direct influence on drug release kinetics. In all cases the implants were capable of providing drug release for at least 25 days. The antimicrobial properties of the implants were evaluated against E. coli and S. aureus. The resulting implants showed antimicrobial properties at day 0 and even after 21 days against both type of microorganisms. Finally, the biocompatibility of the implants was evaluated using endothelial cells. Cells exposed to implants were compared with a control group. There were no differences between both groups in terms of cell proliferation and morphology.

Bioenergetic reprogramming plasticity under nitrogen depletion by the unicellular green alga Scenedesmus obliquus.

MAIN CONCLUSION: Simultaneous nitrogen depletion and 3,4-dichlorophenol addition induce a bioenergetic microalgal reprogramming, through strong Cyt b 6 f synthesis, that quench excess electrons from dichlorophenol's biodegradation to an overactivated photosynthetic electron flow and H 2 -productivity. Cellular energy management includes "rational" planning and operation of energy production and energy consumption units. Microalgae seem to have the ability to calculate their energy reserves and select the most profitable bioenergetic pathways. Under oxygenic mixotrophic conditions, microalgae invest the exogenously supplied carbon source (glucose) to biomass increase. If 3,4-dichlorophenol is added in the culture medium, then glucose is invested more to biodegradation rather than to growth. The biodegradation yield is enhanced in nitrogen-depleted conditions, because of an increase in the starch accumulation and a delay in the establishment of oxygen-depleted conditions in a closed system. In nitrogen-depleted conditions, starch cannot be invested in PSII-dependent and PSII-independent pathways for H2-production, mainly because of a strong decrease of the cytochrome b 6 f complex of the photosynthetic electron flow. For this reason, it seems more profitable for the microalga under these conditions to direct the metabolism to the synthesis of lipids as cellular energy reserves. Nitrogen-depleted conditions with exogenously supplied 3,4-dichlorophenol induce reprogramming of the microalgal bioenergetic strategy. Cytochrome b 6 f is strongly synthesized (mainly through catabolism of polyamines) to manage the electron bypass from the dichlorophenol biodegradation procedure to the photosynthetic electron flow (at the level of PQ pool) and consequently through cytochrome b 6 f and PSI to hydrogenase and H2-production. All the above showed that the selection of the appropriate cultivation conditions is the key for the manipulation of microalgal bioenergetic strategy that leads to different metabolic products and paves the way for a future microalgal "smart" biotechnology.

The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate.

We have previously shown that perinatal hypoxic/ischemic injury (HII) may cause selective vulnerability of the mesencephalic dopaminergic neurons of human neonate. In the present study, we investigated the effect of perinatal HII on the noradrenergic neurons of the locus coeruleus (LC) of the same sample. We studied immunohistochemically the expression of tyrosine hydroxylase (TH, first limiting enzyme for catecholamine synthesis) in LC neurons of 15 autopsied infants (brains collected from the Greek Brain Bank) in relation to the neuropathological changes of acute or chronic HII of the neonatal brain. Our results showed that perinatal HII appears to affect the expression of TH and the size of LC neurons of the human neonate. In subjects with neuropathological lesions consistent with abrupt/severe HII, intense TH immunoreactivity was found in almost all neurons of the LC. In most of the neonates with neuropathological changes of prolonged or older injury, however, reduction in cell size and a decrease or absence of TH staining were observed in the LC. Intense TH immunoreactivity was found in the LC of 3 infants of the latter group, who interestingly had a longer survival time and had been treated with anticonvulsant drugs. Based on our observations and in view of experimental evidence indicating that the reduction of TH-immunoreactive neurons occurring in the LC after perinatal hypoxic insults persists into adulthood, we suggest that a dysregulation of monoaminergic neurotransmission in critical periods of brain development in humans is likely to predispose the survivors of perinatal HII, in combination with genetic susceptibility, to psychiatric and/or neurological disorders later in life.