Controlled release of vancomycin from PEGylated fibrinogen polyethylene glycol diacrylate hydrogel.

Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection following cardiac surgery via median sternotomy. Controlled release of suitable antibiotics could allow maximizing drug efficacy and safety, and therefore achieving a desired therapeutic response. In this study, we have developed a vancomycin laden PEGylated fibrinogen-polyethylene glycol diacrylate (PF-PEGDA) hydrogel system that can release vancomycin at a controlled and predictable rate to be applied in SSI prevention. Two configurations were developed to study effect of the hydrogel on drug release, namely, vancomycin laden hydrogel and vancomycin solution on top of blank hydrogel. The relationship between the rigidity of the hydrogel and drug diffusion was found to comply with a universal power law, i.e., softer hydrogels result in a greater diffusion coefficient hence faster release rate. Besides, vancomycin laden hydrogels exhibited burst release, whereas the vancomycin solution on top of blank hydrogels exhibited lag release. A mathematical model was developed to simulate vancomycin permeation through the hydrogels. The permeation of vancomycin can be predicted accurately by using the mathematical model, which provided a useful tool to customize drug loading, hydrogel thickness and stiffness for personalized medication to manage SSI. To evaluate the potential of hydrogels for bone healing applications in cardiovascular medicine, we performed a proof-of-concept median sternotomy in rabbits and applied the hydrogels. The hydrogel formulations accelerated the onset of osteo-genetic processes in rabbits, demonstrating its potential to be used in human.

Nanoparticles for inducing Gaucher disease-like damage in cancer cells.

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.

DNA adductomics aided rapid screening of genotoxic impurities using nucleosides and 3D bioprinted human liver organoids.

Current genotoxicity assessment methods are mainly employed to verify the genotoxic safety of drugs, but do not allow for rapid screening of specific genotoxic impurities (GTIs). In this study, a new approach for the recognition of GTIs has been proposed. It is to expose the complex samples to an in vitro nucleoside incubation model, and then draw complete DNA adduct profiles to infer the structures of potential genotoxic impurities (PGIs). Subsequently, the genotoxicity is confirmed in human by 3D bioprinted human liver organoids. To verify the feasibility of the approach, lansoprazole chloride compound (Lanchlor), a PGI during the synthesis of lansoprazole, was selected as the model drug. After confirming genotoxicity by Comet assay, it was exposed to different models to map and compare the DNA adduct profiles by LC-MS/MS. The results showed Lanchlor could generate diverse DNA adducts, revealing firstly its genotoxicity at molecular mechanism of action. Furthermore, the largest variety and content of DNA adducts were observed in the nucleoside incubation model, while the human liver organoids exhibited similar results with rats. The results showed that the combination of DNA adductomics and 3D bioprinted organoids were useful for the rapid screening of GTIs.

Efficient and accurate personalized product recommendations through frequent item set mining fusion algorithm.

In the realm of personalized product recommendation, addressing the challenges of sparse data and "cold start" has been the primary focus. However, filtering invalid information amidst the overwhelming data on e-commerce platforms remains an underexplored issue. This paper proposes a fusion recommendation algorithm based on frequent item set mining to tackle this problem by compressing the commodity data set and identifying the frequent commodity set. The algorithm not only improves time efficiency by reducing the number of candidate frequent item sets but also generates more accurate recommendations by calculating user-commodity interest rankings and recommending similar products. We first present the existing problems in fusion recommendation algorithms based on frequent item set mining, such as redundant rules, low recommendation accuracy, and the inability to explore deep connections between users and products. Next, we introduce our proposed algorithm, which involves filtering the commodity data set, calculating user-commodity interest rankings, and defining similar product recommendation rules. The algorithm's effectiveness is demonstrated by its ability to adapt to users' dynamic preferences and capture their changing interests in real-time. A comparative analysis using our algorithm and other data mining algorithms reveals a reduction in the number of frequent commodity data sets and weighted frequent item sets, leading to decreased algorithm operation time. This research contributes to the development of more efficient and accurate personalized product recommendation algorithms, enhancing user experience on e-commerce platforms.

Prediction of drug permeation through microneedled skin by machine learning.

Stratum corneum is the outermost layer of the skin preventing external substances from entering human body. Microneedles (MNs) are sharp protrusions of a few hundred microns in length, which can penetrate the stratum corneum to facilitate drug permeation through skin. To determine the amount of drug delivered through skin, in vitro drug permeation testing is commonly used, but the testing is costly and time-consuming. To address this issue, machine learning methods were employed to predict drug permeation through the skin, circumventing the need of conducting skin permeation experiments. By comparing the experimental data and simulated results, it was found extreme gradient boosting (XGBoost) was the best among the four simulation methods. It was also found that drug loading, permeation time, and MN surface area were critical parameters in the models. In conclusion, machine learning is useful to predict drug permeation profiles for MN-facilitated transdermal drug delivery.

Microneedle-enabled therapeutics delivery and biosensing in clinical trials.

Microneedles (MNs) are micron-sized protrusions attached to a range of devices that are used in therapeutic delivery and diagnosis. Because MNs can be self-applied, are painless, and can carry multiple therapeutic agents, they have received extensive attention, and have been widely investigated, for local and systemic therapy. Many researchers are currently working to extend the use of MNs to clinical applications. In this review, we provide an update and analysis on MN-based clinical trials since their inception in 2007. The MNs in clinical trials are classified into five types based on their appearance and properties, including: hollow MNs, MN patches, radiofrequency MNs, MN rollers, and other MNs. The various aspects of MN trials are summarized, such as MN types, clinical trial time, and trial regions. This review aims to present an overview of MN development and provide insights for future research in this field. To our knowledge, this is the first review focused on MN clinical trials which showcases the latest applications of this advanced technology in medicine.

Solubilisation and Enhanced Oral Absorption of Curcumin Using a Natural Non-Nutritive Sweetener Mogroside V.

Background: Curcumin (CUR) is a functional ingredient from the spice turmeric. It has attracted considerable attention recently, owing to its diverse biological activities. However, curcumin has low water solubility, which limited its applications. Some sugar molecules were found to be able to solubilise poorly water-soluble compounds by forming micelles in aqueous solutions. Purpose: To improve the water solubility and oral absorption of CUR, using a non-nutritive natural sweetener, namely, Mogroside V (Mog-V). Methods: A solid dispersion of CUR in Mog-V was prepared using a solvent evaporation method. The solid dispersion was characterised by using X-ray diffraction and differential scanning calorimetry. The solid dispersion can dissolve in water to form micelles with a diameter of ~160 nm, which were characterised by using dynamic light scattering. To find out the mechanism of solubilisation, the aggregation behaviour of Mog-V molecules in aqueous solution was investigated using nuclear magnetic resonance spectroscopy. Finally, oral absorption of CUR in the solid dispersion was evaluated using a rodent model. Results: A solid dispersion was formed in a ratio of 1 CUR to 10 Mog-V by weight. Upon dissolution into water, CUR laden micelles formed via self-assembly of Mog-V molecules, which increased the solubility of CUR by nearly 6000 times compared with pure CUR crystals. In rats, the solid dispersion increased the oral absorption of CUR by 29 folds, compared with CUR crystals. In terms of solubilisation mechanism, it was found that Mog-V self-assembled into micelles with a core-shell structure and CUR molecules were incorporated into the hydrophobic core of the Mog-V micelles. Conclusion: Mog-V can form a solid dispersion with CUR. Upon dissolution in water, the Mog-V in the solid dispersion can self-assemble into micelles, which solubilise CUR and increase its oral absorption.

3D printing for personalised medicines: implications for policy and practice.

The current healthcare dynamic has shifted from one-size-fits-all to patient-centred care, with our increased understanding of pharmacokinetics and pharmacogenomics demanding a switch to more individualised therapies. As the pharmaceutical industry remains yet to succumb to the push of a technological paradigm shift, pharmacists lack the means to provide completely personalised medicine (PM) to their patients in a safe, affordable, and widely accessible manner. As additive manufacturing technology has already established its strength in producing pharmaceutical formulations, it is necessary to next consider methods by which this technology can create PM accessible from pharmacies. In this article, we reviewed the limitations of current pharmaceutical manufacturing methods for PMs, three-dimensional (3D) printing techniques that are most beneficial for PMs, implications of bringing this technology into pharmacy practice, and implications for policy surrounding 3D printing techniques in the manufacturing of PMs.

Consumers' self-reported adherence to directions for non-prescription medicines and the role of risk perception.

BACKGROUND: Non-prescription medicines (NPMs), while relatively safe, are responsible for a small but significant proportion of medication misadventure and inappropriate use may lead to avoidable healthcare cost. Some consumers vary their use of NPMs from the directions provided on packaging or advice from healthcare professionals. Consumers may use NPMs at lower doses or less frequently than directed because of the risk of side effects. PURPOSE: This study aimed to develop and validate a self-report measure for the extent to which consumers' follow directions (FDs) for NPMs. Secondly, it aimed to explore the relationship between risk perception towards NPMs and following directions. METHODS: A cross-sectional study was administered online to participants who belong to an Australian agency which conducts consumer research. Participants were Australian adults who had used NPMs within the last month. Items for the FD-NPM scale were developed and validated. Exploratory factor analysis and confirmatory factor analysis were used to validate the FD-NPM scale. Structural equation modelling (SEM) was employed to explore the relationships between risk perception, covariates, and FDs. RESULTS: There were 403 participants recruited. Less than 20% "always" or "often" self-reported following directions for dose, frequency, or duration of use. Factor analyses confirmed that there are two moderately positively correlated dimensions of FD-NPM (r = 0.46), which were named underuse and overuse. That is, consumers who self-reported underuse of non-prescription medicines were also more likely to self-report overuse. Consumers with high-risk perception towards NPMs, those who were younger and those who were more educated had a greater tendency to not follow directions. CONCLUSION: A new self-report measure, the FD-NPM scale was developed and validated. That people who perceives NPMs to be harmful, tend to underuse and more concerningly, overuse them, is of great interest to clinicians and policymakers who are required to manage risk communications.

Recent progress in three-dimensionally-printed dosage forms from a pharmacist perspective.

OBJECTIVE: Additive manufacturing (AM), commonly known as 3D printing (3DP), has opened new frontiers in pharmaceutical applications. This review is aimed to summarise the recent development of 3D-printed dosage forms, from a pharmacists' perspective. METHODS: Keywords including additive manufacturing, 3D printing and drug delivery were used for literature search in PubMed, Excerpta Medica Database (EMBASE) and Web of Science, to identify articles published in the year 2020. RESULTS: For each 3DP study, the active pharmaceutical ingredients, 3D printers and materials used for the printing were tabulated and discussed. 3DP has found its applications in various dosage forms for oral delivery, transdermal delivery, rectal delivery, vaginal delivery, implant and bone scaffolding. Several topics were discussed in detail, namely patient-specific dosing, customisable drug administration, multidrug approach, varying drug release, compounding pharmacy, regulatory progress and future perspectives. AM is expected to become a common tool in compounding pharmacies to make polypills and personalised medications. CONCLUSION: 3DP is an enabling tool to fabricate dosage forms with intricate structure designs, tailored dosing, drug combinations and controlled release, all of which lend it to be highly conducive to personalisation, thereby revolutionising the future of pharmacy practice.

Enhancement of Skin Delivery of Drugs Using Proposome Depends on Drug Lipophilicity.

The study aims to investigate the propylene glycol-based liposomes named 'proposomes' in enhancing skin permeation of drugs with different physicochemical properties. Ibuprofen, tofacitinib citrate, rhodamine B, and lidocaine were loaded into proposomes. These drug formulations were analyzed for particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro skin permeation. The confocal laser scanning microscopy was performed on skin treated with calcein and rhodamine B laden proposomes. The transdermal delivery relative to physicochemical properties of drugs such as logP, melting point, molecular weight, solubility, etc., were analyzed. We tested the safety of the proposomes using reconstructed human skin tissue equivalents, which were fabricated in-house. We also used human cadaver skin samples as a control. The proposomes had an average diameter of 128 to 148 nm. The drug's entrapment efficiencies were in the range of 42.9-52.7%, translating into the significant enhancement of drug permeation through the skin. The enhancement ratio was 1.4 to 4.0, and linearly correlated to logP, molecular weight, and melting point. Confocal imaging also showed higher skin permeation of calcein and rhodamine B in proposome than in solution. The proposome was found safe for skin application. The enhancement of skin delivery of drugs through proposomes was dependent on the lipophilicity of the drug. The entrapment efficiency was positively correlated with logP of the drug, which led to high drug absorption.

Microstructured Hyaluronic Acid Hydrogel for Tooth Germ Bioengineering.

Tooth loss has been found to adversely affect not just masticatory and speech functions, but also psychological health and quality of life. Currently, teeth replacement options include dentures, bridges, and implants. However, these artificial replacement options remain inferior to biological replacements due to their reduced efficiency, the need for replacements, and the risk of immunological rejection. To this end, there has been a heightened interest in the bioengineering of teeth in recent years. While there have been reports of successfully regenerated teeth, controlling the size and shape of bioengineered teeth remains a challenge. In this study, methacrylated hyaluronic acid (MeHA) was synthesized and microstructured in a hydrogel microwell array using soft lithography. The resulting MeHA hydrogel microwell scaffold resembles the shape of a naturally developing human tooth germ. To facilitate the epithelial-mesenchymal interactions, human adult low calcium high temperature (HaCaT) cells were seeded on the surface of the hydrogels and dental pulp stem cells (DPSCs) were encapsulated inside the hydrogels. It was found that hydrogel scaffolds were able to preserve the viability of both types of cells and they appeared to favor signaling between epithelial and mesenchymal cells, which is necessary in the promotion of cell proliferation. As such, the hydrogel scaffolds offer a promising system for the bioengineering of human tooth germs in vitro.

Enhanced skin retention and permeation of a novel peptide via structural modification, chemical enhancement, and microneedles.

Hyperpigmentation is a common skin condition with serious psychosocial consequences. Decapeptide-12, a novel peptide, has been found to be safer than hydroquinone in reducing melanin content, with efficacy up to more than 50% upon 16 weeks of twice-daily treatment. However, the peptide suffers from limited transcutaneous penetration due to its hydrophilicity and high molecular weight. Therefore, decapeptide-12 was modified by adding a palmitate chain in an attempt to overcome this limitation. Molecular docking results showed that the two peptides exhibited similar biological activity towards tyrosinase. We also tested the effect of chemical penetration enhancers and microneedles to deliver the two peptides into and through skin, using an in vitro human skin permeation method. It was shown that the palm-peptide achieved the best skin retention owing to the increased lipophilicity. In addition, skin permeation of the palm-peptides was enhanced by the chemical skin penetration enhancers, namely, oleic acid and menthol. Skin permeation of the native peptide was enhanced by the microneedle patch but not the chemical skin penetration enhancers. Cutaneous absorption of the palm-peptides was estimated to have achieved its therapeutic concentration within skin. The combinatory approach of using molecular modification, chemical penetration enhancement, and microneedle patch proves to be useful to enhanceskin permeation of the peptides.

Effect of Pharmaceutical Excipients on Intestinal Absorption of Metformin via Organic Cation-Selective Transporters.

Growing evidence has shown that some pharmaceutical excipients can act on drug transporters. The present study was aimed at investigating the effects of 13 commonly used excipients on the intestinal absorption of metformin (MTF) and the underlying mechanisms using Caco-2 cells and an ex vivo mouse non-everted gut sac model. First, the uptake of MTF in Caco-2 cells was markedly inhibited by nonionic excipients including Solutol HS 15, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and crospovidone. Second, transport profile studies showed that MTF was taken up via multiple cation-selective transporters, among which a novel pyrilamine-sensitive proton-coupled organic cation (H+/OC+) antiporter played a key role. Third, Solutol HS 15, polysorbate 40, and polysorbate 60 showed cis-inhibitory effects on the uptake of either pyrilamine (prototypical substrate of the pyrilamine-sensitive H+/OC+ antiporter) or 1-methyl-4-phenylpyridinium (substrate of traditional cation-selective transporters including OCTs, MATEs, PMAT, SERT, and THTR-2), indicating that their suppression on MTF uptake is due to the synergistic inhibition toward multiple influx transporters. Finally, the pH-dependent mouse intestinal absorption of MTF was significantly decreased by Solutol HS 15, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and pyrilamine. In conclusion, this study revealed that a novel transport process mediated by the pyrilamine-sensitive H+/OC+ antiporter contributes to the intestinal absorption of MTF in conjunction with the traditional cation-selective transporters. Mechanistic understanding of the interaction of excipients with cation-selective transporters can improve the formulation design and clinical application of cationic drugs.

Mahuang Decoction Antagonizes Acute Liver Failure via Modulating Tricarboxylic Acid Cycle and Amino Acids Metabolism.

Acute liver failure (ALF) is a serious clinical disorder with high fatality rates. Mahuang decoction (MHD), a well-known traditional Chinese medicine, has multiple pharmacological effects, such as anti-inflammation, anti-allergy, anti-asthma, and anti-hyperglycemia. In this study, we investigated the protective effect of MHD against ALF. In the lipopolysaccharide and D-galactosamine (LPS/D-GalN)-induced ALF mouse model, the elevated activities of the serum alanine and aspartate transaminases as well as the liver pathological damage were markedly alleviated by MHD. Subsequently, a metabolomics study based on the ultrahigh performance liquid chromatograph coupled with Q Exactive Orbitrap mass spectrometry was carried to clarify the therapeutic mechanisms of MHD against ALF. A total of 36 metabolites contributing to LPS/D-GalN-induced ALF were identified in the serum samples, among which the abnormalities of 27 metabolites were ameliorated by MHD. The analysis of metabolic pathways revealed that the therapeutic effects of MHD are likely due to the modulation of the metabolic disorders of tricarboxylic acid (TCA) cycle, retinol metabolism, tryptophan metabolism, arginine and proline metabolism, nicotinate and nicotinamide metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan synthesis, as well as cysteine and methionine metabolism. This study demonstrated for the first time that MHD exerted an obvious protective effect against ALF mainly through the regulation of TCA cycle and amino acid metabolism, highlighting the importance of metabolomics to investigate the drug-targeted metabolic pathways.

Investigating PEGDA and GelMA Microgel Models for Sustained 3D Heterotypic Dermal Papilla and Keratinocyte Co-Cultures.

Hair follicle morphogenesis is heavily dependent on reciprocal, sequential, and epithelial-mesenchymal interaction (EMI) between epidermal stem cells and the specialized cells of the underlying mesenchyme, which aggregate to form the dermal condensate (DC) and will later become the dermal papilla (DP). Similar models were developed with a co-culture of keratinocytes and DP cells. Previous studies have demonstrated that co-culture with keratinocytes maintains the in vivo characteristics of the DP. However, it is often challenging to develop three-dimensional (3D) DP and keratinocyte co-culture models for long term in vitro studies, due to the poor intercellular adherence between keratinocytes. Keratinocytes exhibit exfoliative behavior, and the integrity of the DP and keratinocyte co-cultured spheroids cannot be maintained over prolonged culture. Short durations of culture are unable to sufficiently allow the differentiation and re-programming of the keratinocytes into hair follicular fate by the DP. In this study, we explored a microgel array approach fabricated with two different hydrogel systems. Using poly (ethylene glycol) diacrylate (PEGDA) and gelatin methacrylate (GelMA), we compare their effects on maintaining the integrity of the cultures and their expression of important genes responsible for hair follicle morphogenesis, namely Wnt10A, Wnt10B, and Shh, over prolonged duration. We discovered that low attachment surfaces such as PEGDA result in the exfoliation of keratinocytes and were not suitable for long-term culture. GelMA, on the hand, was able to sustain the integrity of co-cultures and showed higher expression of the morphogens overtime.

Immobilized nanoneedle-like structures for intracellular delivery, biosensing and cellular surgery.

The rapid advancements of nanotechnology over the recent years have reformed the methods used for treating human diseases. Nanostructures including nanoneedles, nanorods, nanowires, nanofibers and nanotubes have exhibited their potential roles in drug delivery, biosensing, cancer therapy, regenerative medicine and intracellular surgery. These high aspect ratio structures enhance targeted drug delivery with spatiotemporal control while also demonstrating their role as an efficient intracellular biosensor with minimal invasiveness. This review discusses the history and emergence of these nanostructures and their fabrication methods. This review also provides an overview of the different applications of nanoneedle systems, further highlighting the importance of greater investigation into these nanostructures for future medicine.

A 3D printed human upper respiratory tract model for particulate deposition profiling.

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current in vitro cascade impactors measure only the aerodynamic particle size distribution, which does not truly represent the in vivo deposition pattern in human respiratory tract. In this study, a human upper respiratory tract model was fabricated using a 3D printer and subsequently characterized for its dimensional accuracy, surface finishing and air leaking. The effects of using a spacer and/or various airflow rates were also investigated. To assess this in vitro model, the deposition pattern of a model drug, namely, salbutamol sulphate, was tested. The resultant deposition pattern of salbutamol sulphate from a metered dose inhaler at 15 L per minute with the spacer, showed no significant difference from that of a published radiological in vivo study performed in adult humans. In addition, it was also found that the deposition pattern of salbutamol at 35 L per minute was comparable to the results of another published study in human. This in vitro model, showing reasonable in vitro-in vivo correlation, may provide opportunities for personalized medicine in special populations or disease states.

High resolution photopolymer for 3D printing of personalised microneedle for transdermal delivery of anti-wrinkle small peptide.

Acetyl-hexapeptide 3 (AHP-3) has good efficacy and safety profile as an anti-wrinkle small peptide. However, its skin permeation is poor due to its hydrophilicity and large molecular weight. 3D printing of personalised microneedles (MN), that contour to the skin surface, offers an attractive alternative for delivery for AHP-3. However, commercially available photocurable resin for 3D printing are not suitable for fabrication of drug loaded delivery systems. In this study, two liquid monomers, namely, polyethylene glycol diacrylate (PEGDA) and vinyl pyrrolidone (VP), were investigated at various proportions, for critical parameters such as mechanical strength of final polymer, rate of polymerisation, rate of swelling of final polymer, 3D printing resolution and safety profile of final polymer. The optimal resin, based on the above parameters, was that of ratio 7 VP: 3 PEGDA in weight. Drug loading into the optimal resin demonstrated that AHP-3 remained stable throughout the fabrication process and there was no effect on the physical properties of final polymer. Using a 3D scanned face model, a personalised MN patch was designed using computer aided design (CAD) software and subsequently fabricated using a Digital Light Processing (DLP) 3D printer, with the optimal resin. In vitro characterisation of fabricated MN patch demonstrated the ability to penetrate human cadaver dermatomed skin and the MN remained intact after compression. The final polymer also had minimal cytotoxicity to human dermal fibroblast. Therefore, personalised MN patch fabricated using the photopolymer can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.