4D printing has a great potential for the manufacturing of soft robotics and medical devices. The alliance of digital light processing (DLP) 3D printing and novel shape-memory photopolymers allows ...for the fabrication of smart 4D-printed medical devices in high resolution and with tailorable functionalities. However, most of the reported 4D-printed materials are nondegradable, which limits their clinical applications. On the other hand, 4D printing of biodegradable shape-memory elastomers is highly challenging, especially when transition points close to physiological temperature and shape fixation under ambient conditions are required. Here, we report the 4D printing of biodegradable shape-memory elastomers with tailorable transition points covering physiological temperature, by using poly(D,L-lactide-co-trimethylene carbonate) methacrylates at various monomer feed ratios. After the programming step, the high-resolution DLP printed stents preserved their folded shape at room temperature, and showed efficient shape recovery at 37 °C. The materials were cytocompatible and readily degradable under physiological conditions. Furthermore, drug-loaded devices with tuneable release kinetics were realized by DLP-printing with resins containing polymers and levofloxacin or nintedanib. This study offers a new perspective for the development of next-generation 4D-printed medical devices.
Digital light 4D printing of biodegradable drug-eluting elastomeric devices with tailorable thermal response at the physiological temperature and tunable drug release. Display omitted
•Biodegradable shape-memory elastomers were DLP printed.•The materials displayed elasticity below and above their transition temperatures.•4D printed elastomeric stents showed efficient shape recovery at 37 °C.•4D printed drug-loaded devices showed tuneable release kinetics.
Arginine-rich antimicrobial peptides (AMPs) are emerging therapeutics of interest. However, their applicability is limited by their short circulation half-life, caused in part by their small size and ...digestion by blood proteases. This study reports a strategy to temporarily mask arginine residues within AMPs with methoxy poly(ethylene glycol). Based on the reagent used, release of AMPs occurred in hours to days in a completely traceless fashion.
In vitro
, conjugates were insensitive to serum proteases, and released native AMP with full
in vitro
bioactivity. This strategy is thus highly relevant and should be adaptable to the entire family of arginine-rich AMPs. It may potentially be used to improve AMP-therapies by providing a more steady concentration of AMP in the blood after a single injection, avoiding toxic effects at high AMP doses, and reducing the number of doses required over the treatment duration.
This study reports a strategy to temporarily mask arginine residues within antimicrobial peptides (AMPs) with methoxy poly(ethylene glycol) (mPEG). PEGylation protects AMPs from serum proteases, and can be released at a pharmaceutically-relevant rate. Fully active and unmodified (
i.e.
, native) AMPs are released with time.
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In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play ...various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms.
A novel approach to provide, thermally sensitive neutral solutions based on chitosan/polyol salt combinations is described. These formulations possess a physiological pH and can be held liquid below ...room temperature for encapsulating living cells and therapeutic proteins; they form monolithic gels at body temperature. When injected in vivo the liquid formulations turn into gel implants in situ. This system was used successfully to deliver biologically active growth factors in vivo as well as an encapsulating matrix for living chondrocytes for tissue engineering applications. This study reports for the first time the use of polymer/polyol salt aqueous solutions as gelling systems, suggesting the discovery of a prototype for a new family of thermosetting gels highly compatible with biological compounds.
The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A ...common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor® EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(
N-vinylpyrrolidone)-block-poly(
d,l-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol®). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX. PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol® was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol® injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration–time curves were inversely related to PM drug loading.
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized primarily by retinal dystrophy, obesity, polydactyly, renal malformations and learning disabilities. Although five ...BBS genes have been cloned, the molecular basis of this syndrome remains elusive. Here we show that BBS is probably caused by a defect at the basal body of ciliated cells. We have cloned a new BBS gene, BBS8, which encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In one family, a homozygous null BBS8 mutation leads to BBS with randomization of left-right body axis symmetry, a known defect of the nodal cilium. We have also found that BBS8 localizes specifically to ciliated structures, such as the connecting cilium of the retina and columnar epithelial cells in the lung. In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis. Finally, we demonstrate that all available Caenorhabditis elegans BBS homologues are expressed exclusively in ciliated neurons, and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport.
A detailed description of equine infectious anemia virus and host responses to it are presented. Current control and eradication of the infection are discussed with suggestions for improvements to ...increase their effectiveness.
A novel injectable in situ gelling thermosensitive chitosan–β-glycerophosphate (C–GP) formulation has been recently proposed for tissue repair and drug delivery. The system can sustain the release of ...macromolecules over a period of several hours to a few days. However, with low-molecular-weight hydrophilic compounds, the release is generally completed within 24 h. In this study, liposomes were added to the C–GP solution and their effect on the viscoelastic properties of the system and release kinetics of encapsulated carboxyfluorescein was investigated. The gelation rate and gel strength were slightly increased by the presence of the liposomes. The in vitro release profiles demonstrated controlled delivery over at least 2 weeks. The release rate strongly depended on the liposome size and composition (i.e. addition of cholesterol), and on the presence of phospholipase in the release medium. The kinetics was not substantially modified when using liposomes prepared with a negatively-charged lipid or a lipid having a high phase transition temperature. These results indicate that the liposome–C–GP system rapidly gels at body temperature, and can sustain the delivery of low-molecular-weight hydrophilic compounds. A mathematical model was proposed to characterize the release kinetics.
Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young ...adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women.
– The fluence of dust particles <10 μm in diameter was recorded by impacts on aluminum foil of the NASA Stardust spacecraft during a close flyby of comet 81P/Wild 2 in 2004. Initial interpretation of ...craters for impactor particle dimensions and mass was based upon laboratory experimental simulations using projectiles less than >10 μm in diameter and the resulting linear relationship of projectile to crater diameter was extrapolated to smaller sizes. We now describe a new experimental calibration program firing very small monodisperse silica projectiles (470 nm–10 μm) at approximately 6 km s−1. The results show an unexpected departure from linear relationship between 1 and 10 μm. We collated crater measurement data and, where applicable, impactor residue data for 596 craters gathered during the postmission preliminary examination phase. Using the new calibration, we recalculate the size of the particle responsible for each crater and hence reinterpret the cometary dust size distribution. We find a greater flux of small particles than previously reported. From crater morphology and residue composition of a subset of craters, the internal structure and dimensions of the fine dust particles are inferred and a “maximum‐size” distribution for the subgrains composing aggregate particles is obtained. The size distribution of the small particles derived directly from the measured craters peaks at approximately 175 nm, but if this is corrected to allow for aggregate grains, the peak in subgrain sizes is at <100 nm.
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