Augmented physical, mechanical, and cellular responsiveness of gelatin-aldehyde modified xanthan hydrogel through incorporation of silicon nanoparticles for bone tissue engineering.

Bioactive scaffolds fabricated from a combination of organic and inorganic biomaterials are a promising approach for addressing defects in bone tissue engineering. In the present study, a self-crosslinked nanocomposite hydrogel, composed of gelatin/aldehyde-modified xanthan (Gel-AXG) is successfully developed by varying concentrations of porous silicon nanoparticles (PSiNPs). The effect of PSiNPs incorporation on physical, mechanical, and biological performance of the nanocomposite hydrogel is evaluated. Morphological analysis reveals formation of highly porous 3D microstructures with interconnected pores in all nanocomposite hydrogels. Increased content of PSiNPs results in a lower swelling ratio, reduced porosity and pore size, which in turn impeded media penetration and slowed down the degradation process. In addition, remarkable enhancements in dynamic mechanical properties are observed in Gel-AXG-8%Si (compressive strength: 0.6223 MPa at 90 % strain and compressive modulus: 0.054 MPa), along with improved biomineralization ability via hydroxyapatite formation after immersion in simulated body fluid (SBF). This optimized nanocomposite hydrogel provides a sustained release of Si ions at safe dose levels. Furthermore, in-vitro cytocompatibility studies using MG-63 cells exhibited remarkable performance in terms of cell attachment, proliferation, and ALP activity for Gel-AXG-8%Si. These findings suggest that the prepared nanocomposite hydrogel holds promising potential as a scaffold for bone tissue engineering.

Characteristics of SARS-CoV2 that may be useful for nanoparticle pulmonary drug delivery.

As a non-invasive method of local and systemic drug delivery, the administration of active pharmaceutical ingredients (APIs) via the pulmonary route represents an ideal approach for the therapeutic treatment of pulmonary diseases. The pulmonary route provides a number of advantages, including the rapid absorption which results from a high level of vascularisation over a large surface area and the successful avoidance of first-pass metabolism. Aerosolization of nanoparticles (NPs) is presently under extensive investigation and exhibits a high potential for targeted delivery of therapeutic agents for the treatment of a wide range of diseases. NPs need to possess specific characteristics to facilitate their transport along the pulmonary tract and appropriately overcome the barriers presented by the pulmonary system. The most challenging aspect of delivering NP-based drugs via the pulmonary route is developing colloidal systems with the optimal physicochemical parameters for inhalation. The physiochemical properties of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been investigated as a template for the synthesis of NPs to assist in the formulation of virus-like particles (VLPs) for pharmaceutical delivery, vaccine production and diagnosis assays.

Dissolving microneedle-assisted long-acting Liraglutide delivery to control type 2 diabetes and obesity.

Integrating nanoparticles (NPs) as a smart and targeted tool for drug delivery with dissolving microneedle (DMN) patch, the non-invasive device for drug delivery, is a promising for future therapeutic delivery applications. Liraglutide (Lira) encapsulation in poly (lactic-co-glycolic acid) (PLGA) NPs provides a sustained release of Lira to 15 days in a biphasic profile which 80% of released content happens in the first 8 days. Embedding such sustained release NPs in the DMN comprising poly vinyl pyrrolidone (PVP) 50% w/v, eliminates the need for Lira subcutaneous injection. Additionally, NPs containing DMN enhance mechanical strength of needles to 5.31 N compared to DMN with pure Lira content which was 4.32 N. The flexible backing layer of the DMN was obtained via blending of PVP and poly vinyl alcohol (PVA) in 10% w/v. Circular dichroism (CD) analysis showed that Lira encapsulated in NPs maintained its native secondary structure even after solidification in DMN. In this study, the capacity of 2 kinds of 500 µm and 1000 µm needles to deliver the desired dose of drug was obtained based on experimental and mathematical methods.

Impact of resveratrol-mediated increase in uterine artery blood flow on fetal haemodynamics, blood pressure and oxygenation in sheep.

NEW FINDINGS: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised. ABSTRACT: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123-124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted.

Nanomaterial and advanced technologies in transdermal drug delivery.

Transdermal drug delivery (TDD) is an alternative method of drug administration for drugs whose delivery by conventional oral, topical, intravenous and intramuscular methods is of limited efficacy. Recent advances in TDD involve the use of nanoparticles (NPs), which exhibit a great potential to enhance drug permeation across the skin. NPs can also provide controlled release, the ability to deliver both hydrophilic and hydrophobic drugs and reduce side effects, and when used in a TDD method they are also non-invasive. Another developing technology for TDD employs skin patches containing microneedles. Microneedles represent a painless and minimally invasive method of TDD in which micron-sized pores are created in the epidermis to allow delivery of drugs to the blood vessels present in the dermal layer of the skin. New researches have focussed on combining different TDD approaches to overcome previous constraints of drug delivery via conventional methods.

Active Targeting Towards and Inside the Brain based on Nanoparticles: A Review.

BACKGROUND: Treatment of neurological diseases using systemic and non-surgical techniques presents a significant challenge in medicine. This challenge is chiefly associated with the condensation and coherence of the brain tissue. METHODS: The coherence structure of the brain is due to the presence of the blood-brain barrier (BBB), which consists of a continuous layer of capillary endothelial cells. The BBB prevents most drugs from entering the brain tissue and is highly selective, permitting only metabolic substances and nutrients to pass through. RESULTS: Although this challenge has caused difficulties for the treatment of neurological diseases, it has opened up a broad research area in the field of drug delivery. Through the utilization of nanoparticles (NPs), nanotechnology can provide the ideal condition for passing through the BBB. CONCLUSION: NPs with suitable dimensions and optimum hydrophobicity and charge, as well as appropriate functionalization, can accumulate in the brain. Furthermore, NPs can facilitate the targeted delivery of therapeutics into the brain areas involved in Alzheimer's disease, Parkinson's disease, stroke, glioma, migraine, and other neurological disorders. This review describes these methods of actively targeting specific areas of the brain.

Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant ewe and increases fetal but not cardiac growth.

KEY POINTS: Substrate restriction during critical developmental windows of gestation programmes offspring for a predisposition towards cardiovascular disease in adult life. This study aimed to determine the effect of maternal resveratrol (RSV) treatment in an animal model in which chronic fetal catheterisation is possible and the timing of organ maturation reflects that of the human. Maternal RSV treatment increased uterine artery blood flow, fetal oxygenation and fetal weight. RSV was not detectable in the fetal circulation, indicating that it may not cross the sheep placenta. This study highlights RSV as a possible intervention to restore fetal substrate supply in pregnancies affected by placental insufficiency. ABSTRACT: Suboptimal in utero environments with reduced substrate supply during critical developmental windows of gestation predispose offspring to non-communicable diseases such as cardiovascular disease (CVD). Improving fetal substrate supply in these pregnancies may ameliorate the predisposition these offspring have toward adult-onset CVD. This study aimed to determine the effect of maternal resveratrol (RSV) supplementation on uterine artery blood flow and the direct effects of RSV on the fetal heart in a chronically catheterised sheep model of human pregnancy. Maternal RSV treatment significantly increased uterine artery blood flow as measured by phase contrast magnetic resonance imaging, mean gestational fetal PaO2 and SaO2 as well as fetal weight. RSV was not detectable in the fetal circulation, and mRNA and protein expression of the histone/protein deacetylase SIRT1 did not differ between treatment groups. No effect of maternal RSV supplementation on AKT/mTOR or CAMKII signalling in the fetal left ventricle was observed. Maternal RSV supplementation is capable of increasing fetal oxygenation and growth in an animal model in which cardiac development parallels that of the human.

Porous silicon-poly(ε-caprolactone) film composites: evaluation of drug release and degradation behavior.

This work focuses on an evaluation of novel composites of porous silicon (pSi) with the biocompatible polymer ε-polycaprolactone (PCL) for drug delivery and tissue engineering applications. The degradation behavior of the composites in terms of their morphology along with the effect of pSi on polymer degradation was monitored. PSi particles loaded with the drug camptothecin (CPT) were physically embedded into PCL films formed from electrospun PCL fiber sheets. PSi/PCL composites revealed a release profile of CPT (monitored via fluorescence spectroscopy) in accordance with the Higuchi release model, with significantly lower burst release percentage compared to pSi microparticles alone. Degradation studies of the composites, using gravimetric analysis, differential scanning calorimetry (DSC), and field emission scanning electron microscopy (FESEM), carried out in phosphate-buffered saline (PBS) under simulated physiological conditions, indicated a modest mass loss (15%) over 5 weeks due to pSi dissolution and minor polymer hydrolysis. DSC results showed that, relative to PCL-only controls, pSi suppressed crystallization of the polymer film during PBS exposure. This suppression affects the evolution of surface morphology during this exposure that, in turn, influences the degradation behavior of the polymer. The implications of the above properties of these composites as a possible therapeutic device are discussed.

Electrospun Composites of Polycaprolactone and Porous Silicon Nanoparticles for the Tunable Delivery of Small Therapeutic Molecules.

This report describes the use of an electrospun composite of poly(ε-caprolactone) (PCL) fibers and porous silicon (pSi) nanoparticles (NPs) as an effective system for the tunable delivery of camptothecin (CPT), a small therapeutic molecule. Both materials are biodegradable, abundant, low-cost, and most importantly, have no known cytotoxic effects. The composites were treated with and without sodium hydroxide (NaOH) to investigate the wettability of the porous network for drug release and cell viability measurements. CPT release and subsequent cell viability was also investigated. We observed that the cell death rate was not only affected by the addition of our CPT carrier, pSi, but also by increasing the rate of dissolution via treatment with NaOH. This is the first example of loading pSi NPs as a therapeutics nanocarrier into electronspun PCL fibers and this system opens up new possibilities for the delivery of molecular therapeutics.

Manipulating human dendritic cell phenotype and function with targeted porous silicon nanoparticles.

Dendritic cells (DC) are the most potent antigen-presenting cells and are fundamental for the establishment of transplant tolerance. The Dendritic Cell-Specific Intracellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN; CD209) receptor provides a target for dendritic cell therapy. Biodegradable and high-surface area porous silicon (pSi) nanoparticles displaying anti-DC-SIGN antibodies and loaded with the immunosuppressant rapamycin (Sirolimus) serve as a fit-for-purpose platform to target and modify DC. Here, we describe the fabrication of rapamycin-loaded DC-SIGN displaying pSi nanoparticles, the uptake efficiency into DC and the extent of nanoparticle-induced modulation of phenotype and function. DC-SIGN antibody displaying pSi nanoparticles favourably targeted and were phagocytosed by monocyte-derived and myeloid DC in whole human blood in a time- and dose-dependent manner. DC preconditioning with rapamycin-loaded nanoparticles, resulted in a maturation resistant phenotype and significantly suppressed allogeneic T-cell proliferation.

Novel Gd-Loaded Silicon Nanohybrid: A Potential Epidermal Growth Factor Receptor Expressing Cancer Cell Targeting Magnetic Resonance Imaging Contrast Agent.

Continuing our research efforts in developing mesoporous silicon nanoparticle-based biomaterials for cancer therapy, we employed here porous silicon nanoparticles as a nanocarrier to deliver contrast agents to diseased cells. Nanoconfinement of small molecule Gd-chelates (L1-Gd) enhanced the T1 contrast dramatically compared to distinct Gd-chelate (L1-Gd) by virtue of its slow tumbling rate, increased number of bound water molecules, and their occupancy time. The newly synthesized Gd-chelate (L1-Gd) was covalently grafted on silicon nanostructures and conjugated to an antibody specific for epidermal growth factor receptor (EGFR) via a hydrazone linkage. The salient feature of this nanosized contrast agent is the capability of EGFR targeted delivery to cancer cells. Mesoporous silicon nanoparticles were chosen as the nanocarrier because of their high porosity, high surface area, and excellent biodegradability. This type of nanosized contrast agent also performs well in high magnetic fields.

Oral Mucosal Epithelial Cells Grown on Porous Silicon Membrane for Transfer to the Rat Eye.

Dysfunction of limbal stem cells or their niche can result in painful, potentially sight-threatening ocular surface disease. We examined the utility of surface-modified porous-silicon (pSi) membranes as a scaffold for the transfer of oral mucosal cells to the eye. Male-origin rat oral mucosal epithelial cells were grown on pSi coated with collagen-IV and vitronectin, and characterised by immunocytochemistry. Scaffolds bearing cells were implanted into normal female rats, close to the limbus, for 8 weeks. Histology, immunohistochemistry and a multiplex nested PCR for sry were performed to detect transplanted cells. Oral mucosal epithelial cells expanded on pSi scaffolds expressed the corneal epithelial cell marker CK3/12. A large percentage of cells were p63+, indicative of proliferative potential, and a small proportion expressed ABCG2+, a putative stem cell marker. Cell-bearing scaffolds transferred to the eyes of live rats, were well tolerated, as assessed by endpoint histology. Immunohistochemistry for pan-cytokeratins demonstrated that transplanted epithelial cells were retained on the pSi membranes at 8 weeks post-implant, but were not detectable on the central cornea using PCR for sry. The pSi scaffolds supported and retained transplanted rat oral mucosal epithelial cells in vitro and in vivo and recapitulate some aspects of an artificial stem cell niche.

Porous silicon for drug delivery applications and theranostics: recent advances, critical review and perspectives.

INTRODUCTION: Porous silicon (pSi) engineered by electrochemical etching has been used as a drug delivery vehicle to address the intrinsic limitations of traditional therapeutics. Biodegradability, biocompatibility, and optoelectronic properties make pSi a unique candidate for developing biomaterials for theranostics and photodynamic therapies. This review presents an updated overview about the recent therapeutic systems based on pSi, with a critical analysis on the problems and opportunities that this technology faces as well as highlighting pSi's growing potential. Areas covered: Recent progress in pSi-based research includes drug delivery systems, including biocompatibility studies, drug delivery, theranostics, and clinical trials with the most relevant examples of pSi-based systems presented here. A critical analysis about the technical advantages and disadvantages of these systems is provided along with an assessment on the challenges that this technology faces, including clinical trials and investors' support. Expert opinion: pSi is an outstanding material that could improve existing drug delivery and photodynamic therapies in different areas, paving the way for developing advanced theranostic nanomedicines and incorporating payloads of therapeutics with imaging capabilities. However, more extensive in-vivo studies are needed to assess the feasibility and reliability of this technology for clinical practice. The technical and commercial challenges that this technology face are still uncertain.

Delivery of Flightless I Neutralizing Antibody from Porous Silicon Nanoparticles Improves Wound Healing in Diabetic Mice.

Flightless I (Flii) is elevated in human chronic wounds and is a negative regulator of wound repair. Decreasing its activity improves healing responses. Flii neutralizing antibodies (FnAbs) decrease Flii activity in vivo and hold significant promise as healing agents. However, to avoid the need for repeated application in a clinical setting and to protect the therapeutic antibody from the hostile environment of the wound, suitable delivery vehicles are required. In this study, the use of porous silicon nanoparticles (pSi NPs) is demonstrated for the controlled release of FnAb to diabetic wounds. We achieve FnAb loading regimens exceeding 250 µg antibody per mg of vehicle. FnAb-loaded pSi NPs increase keratinocyte proliferation and enhance migration in scratch wound assays. Release studies confirm the functionality of the FnAb in terms of Flii binding. Using a streptozotocin-induced model of diabetic wound healing, a significant improvement in healing is observed for mice treated with FnAb-loaded pSi NPs compared to controls, including FnAb alone. FnAb-loaded pSi NPs treated with proteases show intact and functional antibody for up to 7 d post-treatment, suggesting protection of the antibodies from proteolytic degradation in wound fluid. pSi NPs may therefore enable new therapeutic approaches for the treatment of diabetic ulcers.

"Thunderstruck": Plasma-Polymer-Coated Porous Silicon Microparticles As a Controlled Drug Delivery System.

Controlling the release kinetics from a drug carrier is crucial to maintain a drug's therapeutic window. We report the use of biodegradable porous silicon microparticles (pSi MPs) loaded with the anticancer drug camphothecin, followed by a plasma polymer overcoating using a loudspeaker plasma reactor. Homogenous "Teflon-like" coatings were achieved by tumbling the particles by playing AC/DC's song "Thunderstruck". The overcoating resulted in a markedly slower release of the cytotoxic drug, and this effect correlated positively with the plasma polymer coating times, ranging from 2-fold up to more than 100-fold. Ultimately, upon characterizing and verifying pSi MP production, loading, and coating with analytical methods such as time-of-flight secondary ion mass spectrometry, scanning electron microscopy, thermal gravimetry, water contact angle measurements, and fluorescence microscopy, human neuroblastoma cells were challenged with pSi MPs in an in vitro assay, revealing a significant time delay in cell death onset.

Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition Temperature-Responsive Coating.

This paper reports on the fabrication of a pSi-based drug delivery system, functionalized with an initiated chemical vapor deposition (iCVD) polymer film, for the sustainable and temperature-dependent delivery of drugs. The devices were prepared by loading biodegradable porous silicon (pSi) with a fluorescent anticancer drug camptothecin (CPT) and coating the surface with temperature-responsive poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM-co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) via iCVD. CPT released from the uncoated oxidized pSi control with a burst release fashion (∼21 nmol/(cm(2) h)), and this was almost identical at temperatures both above (37 °C) and below (25 °C) the lower critical solution temperature (LCST) of the switchable polymer used, pNIPAM-co-DEGDVE (28.5 °C). In comparison, the burst release rate from the pSi-pNIPAM-co-DEGDVE sample was substantially slower at 6.12 and 9.19 nmol/(cm(2) h) at 25 and 37 °C, respectively. The final amount of CPT released over 16 h was 10% higher at 37 °C compared to 25 °C for pSi coated with pNIPAM-co-DEGDVE (46.29% vs 35.67%), indicating that this material can be used to deliver drugs on-demand at elevated temperatures. pSi coated with pAS also displayed sustainable drug delivery profiles, but these were independent of the release temperature. These data show that sustainable and temperature-responsive delivery systems can be produced by functionalization of pSi with iCVD polymer films. Benefits of the iCVD approach include the application of the iCVD coating after drug loading without causing degradation of the drug commonly caused by exposure to factors such as solvents or high temperatures. Importantly, the iCVD process is applicable to a wide array of surfaces as the process is independent of the surface chemistry and pore size of the nanoporous matrix being coated.

Nanostructured Silicon-Based Fingerprint Dusting Powders for Enhanced Visualization and Detection by Mass Spectrometry.

Porous silicon microparticles (pSi MPs) functionalized with fluorescent dyes (lissamine and carboxy-5-fluorescein) and intrinsically luminescent pSi MPs were explored as novel fingerprint dusting powders. The versatility of luminescent pSi MPs is demonstrated through time-gated imaging of their long-lived (lifetime>28 µs) near-IR emission, and mass spectrometry analysis of fingerprints dusted with luminescent pSi MPs to provide further information on exogenous small molecules present in latent fingerprints.

Surface engineering of porous silicon to optimise therapeutic antibody loading and release.

The proinflammatory cytokine, tumor necrosis factor-α (TNF-α), is elevated in several diseases such as uveitis, rheumatoid arthritis and non-healing chronic wounds. Adding Infliximab, a chimeric IgG1 monoclonal antibody raised against TNF-α, to chronic wound fluid can neutralise human TNF-α, thereby providing a potential therapeutic option for chronic wound healing. However, to avoid the need for repeated application in a clinical setting, and to protect the therapeutic antibody from the hostile environment of the wound, suitable delivery vehicles are required. Porous silicon (pSi) is a biodegradable high surface area material commonly employed for drug delivery applications. In this study, the use of pSi microparticles (pSi MPs) for the controlled release of Infliximab to disease environments, such as chronic wounds, is demonstrated. Surface chemistry and pore parameters for Infliximab loading are first optimised in pSi films and loading conditions are transferred to pSi MPs. Loading regimens exceeding 60 µg of Infliximab per mg of pSi are achieved. Infliximab is released with zero-order release kinetics over the course of 8 days. Critically, the released antibody remains functional and is able to sequester TNF-α over a weeklong timeframe; suitable for a clinical application in chronic wound therapy.

Biomolecule detection in porous silicon based microcavities via europium luminescence enhancement.

In this paper, we demonstrate the detection of europium-complex-labeled streptavidin in a porous silicon microcavity (pSiMC) via luminescence enhancement. The pSiMC platform was modified for optimized luminescence enhancement which encompassed changing the pore size of the microcavity to ensure molecular infiltration and adjusting the optical quality of the microcavity. Characterization of the optimized surface was performed by infrared spectroscopy, interferometric reflectance spectroscopy and luminescence measurements. Luminescence enhancement of the bound Eu(iii) complex by a factor of 3 was observed on the optimized pSiMC as compared to that on a single pSi layer. The ability of a pSiMC to act as a luminescence enhancing sensor was confirmed using streptavidin as a model analyte on a biotin-modified pSiMC. The sensor was able to detect Eu(iii) complex labeled streptavidin with a concentration as low as 150 nM. Furthermore, streptavidin was selectively detected when spiked in human wound fluid. The concept of detecting Eu(iii) labeled bioconjugates on pSiMC may be incorporated into the design of highly sensitive and specific point-of-care biosensors.

Porous silicon-based nanostructured microparticles as degradable supports for solid-phase synthesis and release of oligonucleotides.

We describe the preparation of several types of porous silicon (pSi) microparticles as supports for the solid-phase synthesis of oligonucleotides. The first of these supports facilitates oligonucleotide release from the nanostructured support during the oligonucleotide deprotection step, while the second type of support is able to withstand the cleavage and deprotection of the oligonucleotides post synthesis and subsequently dissolve at physiological conditions (pH = 7.4, 37°C), slowly releasing the oligonucleotides. Our approach involves the fabrication of pSi microparticles and their functionalisation via hydrosilylation reactions to generate a dimethoxytrityl-protected alcohol on the pSi surface as an initiation point for the synthesis of short oligonucleotides.