Growth of human breast tissues from patient cells in 3D hydrogel scaffolds.

BACKGROUND: Three-dimensional (3D) cultures have proven invaluable for expanding human tissues for basic research and clinical applications. In both contexts, 3D cultures are most useful when they (1) support the outgrowth of tissues from primary human cells that have not been immortalized through extensive culture or viral infection and (2) include defined, physiologically relevant components. Here we describe a 3D culture system with both of these properties that stimulates the outgrowth of morphologically complex and hormone-responsive mammary tissues from primary human breast epithelial cells. METHODS: Primary human breast epithelial cells isolated from patient reduction mammoplasty tissues were seeded into 3D hydrogels. The hydrogel scaffolds were composed of extracellular proteins and carbohydrates present in human breast tissue and were cultured in serum-free medium containing only defined components. The physical properties of these hydrogels were determined using atomic force microscopy. Tissue growth was monitored over time using bright-field and fluorescence microscopy, and maturation was assessed using morphological metrics and by immunostaining for markers of stem cells and differentiated cell types. The hydrogel tissues were also studied by fabricating physical models from confocal images using a 3D printer. RESULTS: When seeded into these 3D hydrogels, primary human breast epithelial cells rapidly self-organized in the absence of stromal cells and within 2 weeks expanded to form mature mammary tissues. The mature tissues contained luminal, basal, and stem cells in the correct topological orientation and also exhibited the complex ductal and lobular morphologies observed in the human breast. The expanded tissues became hollow when treated with estrogen and progesterone, and with the further addition of prolactin produced lipid droplets, indicating that they were responding to hormones. Ductal branching was initiated by clusters of cells expressing putative mammary stem cell markers, which subsequently localized to the leading edges of the tissue outgrowths. Ductal elongation was preceded by leader cells that protruded from the tips of ducts and engaged with the extracellular matrix. CONCLUSIONS: These 3D hydrogel scaffolds support the growth of complex mammary tissues from primary patient-derived cells. We anticipate that this culture system will empower future studies of human mammary gland development and biology.

Biofilm Inhibition on Medical Devices and Implants Using Carbon Dots: An Updated Review.

Biofilms are an intricate community of microbes that colonize solid surfaces, communicating via a quorum-sensing mechanism. These microbial aggregates secrete exopolysaccharides facilitating adhesion and conferring resistance to drugs and antimicrobial agents. The escalating global concern over biofilm-related infections on medical devices underscores the severe threat to human health. Carbon dots (CDs) have emerged as a promising substrate to combat microbes and disrupt biofilm matrices. Their numerous advantages such as facile surface functionalization and specific antimicrobial properties, position them as innovative anti-biofilm agents. Due to their minuscule size, CDs can penetrate microbial cells, inhibiting growth via cytoplasmic leakage, reactive oxygen species (ROS) generation, and genetic material fragmentation. Research has demonstrated the efficacy of CDs in inhibiting biofilms formed by key pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Consequently, the development of CD-based coatings and hydrogels holds promise for eradicating biofilm formation, thereby enhancing treatment efficacy, reducing clinical expenses, and minimizing the need for implant revision surgeries. This review provides insights into the mechanisms of biofilm formation on implants, surveys major biofilm-forming pathogens and associated infections, and specifically highlights the anti-biofilm properties of CDs emphasizing their potential as coatings on medical implants.

Current aspects of organoid technology for biomaterial toxicity analysis.

Organoids provide us an opportunity to understand how diseases affect cellular physiology, human tissues or organs. They are indespensible tools for biomaterial toxicity analysis, drug discovery and regenerative medicine.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.

Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.

Polyester nanomedicines targeting inflammatory signaling pathways for cancer therapy.

The growth of cancerous cells and their responses towards substantial therapeutics are primarily controlled by inflammations (acute and chronic) and inflammation-associated products, which either endorse or repress tumor progression. Additionally, major signaling pathways, including NF-κB, STAT3, inflammation-causing factors (cytokines, TNF-α, chemokines), and growth-regulating factors (VEGF, TGF-ß), are vital regulators responsible for the instigation and resolution of inflammations. Moreover, the conventional chemotherapeutics have exhibited diverse limitations, including poor pharmacokinetics, unfavorable chemical properties, poor targetability to the disease-specific disease leading to toxicity; thus, their applications are restricted in inflammation-mediated cancer therapy. Furthermore, nanotechnology has demonstrated potential benefits over conventional chemotherapeutics, such as it protected the incorporated drug/bioactive moiety from enzymatic degradation within the systemic circulation, improving the physicochemical properties of poorly aqueous soluble chemotherapeutic agents, and enhancing their targetability in specified carcinogenic cells rather than accumulating in the healthy cells, leading reduced cytotoxicity. Among diverse nanomaterials, polyester-based nanoparticulate delivery systems have been extensively used to target various inflammation-mediated cancers. This review summarizes the therapeutic potentials of various polyester nanomaterials (PLGA, PCL, PLA, PHA, and others)-based delivery systems targeting multiple signaling pathways related to inflammation-mediated cancer.

Advances in designing of polymeric micelles for biomedical application in brain related diseases.

In recent years, unique physicochemical properties of amphiphilic block copolymers have been utilized to design the polymeric micelles for brain-specific delivery of drugs, proteins, peptides and genes. Their unique properties such as nano-size, charge-switching ability, stimuli-responsive cargo release, flexible structure, and self-assembly enable them to overcome limitations of conventional dosage forms that include rapid drug release, drug efflux, and poor brain bioavailability, and poor stability. These limitations hinder their therapeutic efficacy in treating brain diseases. Their ease of functionalization and enhanced penetration and retention effect make them suitable nanocarriers for the diagnosis of various brain diseases. In this context, the present manuscript provides an insight into the progress made in the functionalization of micelles such as the incorporation of stimuli-sensitive moieties in copolymers, conjugation of cargo molecules with the core-forming block via responsive smart linkers, and conjugation of active ligands and imaging moieties with the corona forming block for brain targeting and imaging. Further, the review also expounds on the role of polymeric micelles in delivering neurotherapeutic to the brain. Some patents related to polymeric micelles formulated for brain delivery are also enlisted.

Recent Progress in Development of Dressings Used for Diabetic Wounds with Special Emphasis on Scaffolds.

Diabetic wound (DW) is a secondary application of uncontrolled diabetes and affects about 42.2% of diabetics. If the disease is left untreated/uncontrolled, then it may further lead to amputation of organs. In recent years, huge research has been done in the area of wound dressing to have a better maintenance of DW. These include gauze, films, foams or, hydrocolloid-based dressings as well as polysaccharide- and polymer-based dressings. In recent years, scaffolds have played major role as biomaterial for wound dressing due to its tissue regeneration properties as well as fluid absorption capacity. These are three-dimensional polymeric structures formed from polymers that help in tissue rejuvenation. These offer a large surface area to volume ratio to allow cell adhesion and exudate absorbing capacity and antibacterial properties. They also offer a better retention as well as sustained release of drugs that are directly impregnated to the scaffolds or the ones that are loaded in nanocarriers that are impregnated onto scaffolds. The present review comprehensively describes the pathogenesis of DW, various dressings that are used so far for DW, the limitation of currently used wound dressings, role of scaffolds in topical delivery of drugs, materials used for scaffold fabrication, and application of various polymer-based scaffolds for treating DW.

Retained biliary plastic stents - lest we forget.

Prolonged indwelling of endoscopically placed biliary plastic stents may lead to complications. We conducted a retrospective analysis of patients who underwent endoscopic retrograde cholangio-pancreaticography (ERCP) at our centre in 2017 and were noted to have retained biliary plastic stents ( > 3 months after an index ERCP). A total of 127 patients had previously placed biliary plastic stents, out of which 45 (35.4%) were retained. The median age of the latter was 52 years (range = 22-79 years) with 27 (60%) patients being men. The median duration of the retained stents was 144 days (range = 94-3292 days). The majority of the patients were asymptomatic. However, 9 (20%) patients had cholangitis, 2 (4.4%) had choledocholithiasis, 2 (4.4%) had cholangitic abscess and 1 (2.2%) developed septicaemia. Fortunately, all these complications could be managed medically and endoscopically. Retention of biliary plastic stents is a problem often overlooked and underestimated in clinical practice. Various measures need to be instituted to create awareness of this entity to prevent undesirable outcomes.

Recent trends in biodegradable polyester nanomaterials for cancer therapy.

Biodegradable polyester nanomaterials-based drug delivery vehicles (DDVs) have been largely used in most of the cancer treatments due to its high biological performance and wider applications. In several previous studies, various biodegradable and biocompatible polyester backbones were used which are poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL), poly(propylene fumarate) (PPF), poly(lactic-co-glycolic acid) (PLGA), poly(propylene carbonate) (PPC), polyhydroxyalkanoates (PHA), and poly(butylene succinate) (PBS). These polyesters were fabricated into therapeutic nanoparticles that carry drug molecules to the target site during the cancer disease treatment. In this review, we elaborately discussed the chemical synthesis of different synthetic polyesters and their use as nanodrug carriers (NCs) in cancer treatment. Further, we highlighted in brief the recent developments of metal-free semi-aromatic polyester nanomaterials along with its role as cancer drug delivery vehicles.

Breast tissue regeneration is driven by cell-matrix interactions coordinating multi-lineage stem cell differentiation through DDR1.

Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in stromal tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and function. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through a collagen receptor. Discoidin domain receptor tyrosine kinase 1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells via Notch signaling to differentiate and form lobules. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that lead to formation of a complex ductal-lobular network.

Metal-free semi-aromatic polyester as nanodrug carrier: A novel tumor targeting drug delivery vehicle for potential clinical application.

Polyester nanomaterials have been widely used in drug delivey application from a longer period of time. This study reports the synthesis of metal-free semi-aromatic polyester (SAP) nanomaterial for drug delivery and evaluate its in vivo acute and systemic toxicity for potential clinical application. The ring opening coplymerization of commercially available cyclohexene oxide (CHO) and phthalic anhydride (PA) monomers was carried out to synthesize fully alternating poly(CHO-co-PA) copolymer using metal-free activators. The obtained low Mn SAP was found to be biocompatible, hemocompataible and biodegradable nature. This copolymer was first-time used to fabricate curcumin (CUR) loaded nanoparticles (NPs). These NPs were physicochemically characterized by thermogravimetric analyzer (TGA), X-ray diffraction (XRD), and UV/visible spectrophotometer analysis. Further, these negatively charged core-shell spherical NPs exhibited slow sustained release behavior of CUR with anomalous transport and further displayed its higher intracellular uptake in SiHa cells at different time-periods compared to free CUR. In vitro anti-cancer therapeutic effects of free CUR and poly(CHO-alt-PA)-CUR NPs were evaluated on different cancer cells. We observed the increased cytotoxicity of CUR NPs with low IC50 values compared to free CUR. These results were further substantiated with ex vivo data where, a significant reduction was observed in CUR NPs treated tumor spheroid's size as compared to free CUR. Furthermore, the different doses of metal-free poly(CHO-alt-PA) nanomaterial were tested for its acute and systemic toxicity in BALB/c mice. We did not observe any significant toxicity of tested nanomaterial on vital organs, blood cells and the body weight of mice. Our study suggest that this metal-free SAP nanomaterial can be used for potential clinical application.

Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics.

Recent research has been directed to the use of biocompatible and biodegradable metal-free fully alternating polyester nanomaterial in drug delivery application. The practice of triethyl borane (Et3B)/Bis(triphenylphosphoranylidene)ammonium chloride (PPNCl) Lewis pair as non-metallic catalyst was carried out to synthesize alternating copolymer of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) (poly(tBGE-alt-PA) copolymer) of low Mnvia nearly controlled ring-opening copolymerization (ROCOP) reaction. This biocompatible, hemocompatible, and biodegradable copolymer was used in the fabrication of different nanodrug formulations (NDFs) loaded with doxorubicin (DOX), curcumin (CUR) and their combination. Transmission electron microscope (TEM) imaging showed the spherical shape and core-shell internal structure for all NDFs with an average particle diameter ranging between 200 and 250 nm. X-ray diffraction (XRD) analysis displayed the amorphous nature of both DOX and CUR after their entrapment into the copolymer matrix. Differential scanning colorimetry (DSC) analysis presented no potential chemical interactions between the drug and copolymer. The cellular drug uptake study showed the increased uptake for all NDFs compared to free drug and exhibited higher DOX and CUR accumulation in dual-drug loaded nanoparticles treated pancreatic cancer (MIA PaCa-2) cells. The in vitro drug release kinetic study displayed the slow sustained drug release behavior with anomalous transport for both DOX and CUR in a defined physiological environment. Further, the anti-tumor efficacy of all NDFs was examined on several different cancer cell lines and maximum cytotoxicity was observed in MIA PaCa-2 cells with low inhibitory concentration (IC50) values. These NDFs inhibited the proliferation of MIA PaCa-2 cells due to cell cycle arrest in G2/M phase. In result, MIA PaCa-2 cells underwent apoptosis with significant changes in mitochondrial membrane potential and increased reactive oxygen species (ROS) level. In future, this study will open several novel insights related to the use of such biocompatible and biodegradable metal-free polyesters in targeted drug delivery, tissue engineering and other biomedical applications.

Interprofessional Education: An Approach to Improve Healthcare Outcomes.

Interprofessional education (IPE) approach allows learners from different health professions viz. - medical, dental, nursing, physiotherapy, psychotherapy, psychology etc., learn from, learn with, and learn about, each other. The scope of learning depends upon the requirements and curriculum. Interprofessional education can help in creating a workforce that learns to perform collaborative practice thereby ensuring better health-care outcomes. Medical educators' and practitioners' understanding about teaching, learning, and assessment of IPE is rudimentary. Strategies to incorporate IPE in regular curricula need to be debated and barriers associated with its implementation require to be identified. This review highlights the teaching-learning and assessment tools for IPE and discusses potential challenges in its implementation.

Do we need a different staging system for tongue and gingivobuccal complex squamous cell cancers?

OBJECTIVES: To determine the need for a separate staging system for gingivobuccal complex squamous cell cancers (GBCSCC) based on 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data from one institution. PATIENTS AND METHODS: An Institutional Review Board (IRB)-approved retrospective analysis was performed on an oral cavity cancer patient database. Patients from 1985 to 2012 with primary surgical treatment for biopsy-proven squamous cell cancer (SCC) from either the oral tongue (TSCC Group) or gingivobuccal complex (GBCSCC Group), were selected as two separate subgroups. The clinicopathologic data were used to stage the patients based on the American Joint Committee on Cancer 7th edition. Survival outcomes including 5-year OS, RFS, and DSS were calculated and analyzed. A multivariate analysis was performed to identify if subsite was an independent predictor for the survival outcomes, adjusting for other variables. A p-value of less than .05 was considered statistically significant. RESULTS: 936 patients with TSCC and 486 patients with GBCSCC were considered eligible for the analysis. Patients with GBCSCC were more likely to be older (p < .001) and presented with more advanced disease (p < .001) compared to patients with TSCC. Unadjusted hazard ratio (HR) suggested GBCSCC had poor OS compared to TSCC. However, after adjusting for other variables, the adjusted HR was not significant (p = .593). There was no difference in 5-year DSS or RFS in either of the study groups. CONCLUSION: With similar survival outcomes by stage, there is no justification for using a different staging system for GBCSCC.

Molecular interactions in celecoxib-PVP-meglumine amorphous system.

Stabilization of the amorphous form of a drug is conferred by additives that interact with it at the molecular level. Ternary systems of celecoxib, poly(vinyl pyrrolidone) (PVP) and meglumine were studied for molecular interactions responsible for enhanced drug stability and solubility in amorphous form. Meglumine was found to lower the glass transition temperature (T(g)) of the drug due to its plasticization effect. However, the presence of PVP masked its destabilizing effect and provided net anti-plasticization to the celecoxib-PVP-meglumine (7:2:1 w/w) ternary amorphous system. Positive deviation of the experimentally determined T(g mix) value for this composition, from those predicted by the Gordon-Taylor/Kelley-Bueche equation, inferred molecular interaction between the three species, which was also supported by band shifts from their Fourier-transform infra-red (FTIR) spectra. Further, shift of differential scanning calorimetry (DSC) melting endotherms of celecoxib in its amorphous systems from those observed for crystalline celecoxib confirmed the complexation between these components, which was also substantiated by molecular modelling studies that showed H-bonding of -S=O, 2-N of the pyrazole ring and -C-F groups of celecoxib with -O-H group of meglumine. These molecular interactions of amorphous celecoxib with meglumine were found to be the potential cause for enhanced stability and solubility of the celecoxib-PVP-meglumine ternary system.

Modeling of drug release from celecoxib-PVP-meglumine amorphous systems.

An empirical assessment of drug release from amorphous systems of celecoxib (CEL), poly(vinyl pyrrolidone) (PVP), and meglumine (MEG) was performed and compared with that for its crystalline form. CEL-PVP (4:1 w/w) binary and CEL-PVP-MEG (7:2:1 w/w) ternary amorphous systems provided higher drug dissolution. Mathematical modeling of drug release data was found to best fit the Hixson-Crowell release model. The biphasic drug release during a 6-h duration exhibited higher release kinetics in the first phase due to the presence of drug in amorphous form. The release kinetics subdued in the latter phase due to ongoing devitrification process in amorphous systems. A comprehensive understanding of drug release from amorphous systems will accentuate the rationalized design of amorphous drug delivery systems.

Conversion of rice straw to monomeric phenols under supercritical methanol and ethanol.

Hydrothermal liquefaction of rice straw has been carried out using various organic solvents (CH3OH, C2H5OH) at different temperatures (250, 280 and 300 °C) and residence times (15, 30 and 60 min) to understand the effect of solvent and various reaction parameters on product distribution. Maximum liquid product yield (47.52 wt%) was observed using ethanol at 300 °C and 15 min reaction time. FTIR and NMR ((1)H and (13)C) of liquid product indicate that lignin in rice straw was converted to various monomeric phenols. GC-MS of the liquid product showed the presence of various phenol and guaiacol derivatives. Main compounds observed in liquid product were phenol, 4-ethylphenol, 4-ethyl-2-methoxyphenol (4-ethylguaiacol), 2,6-dimethoxyphenol (syringol), 2-isopropyl-5-methylphenol (thymol). Powder XRD and SEM of bio-residue showed that rice straw was decomposed to low molecular weight monomeric phenols.

Amorphous drug delivery systems: molecular aspects, design, and performance.

The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.

Spray drying for generation of a ternary amorphous system of celecoxib, PVP, and meglumine.

Generation of amorphous forms of a poorly soluble drug by solid dispersion techniques has been a subject of intensive research for decades. Apart from the stability of the dispersions, development of a suitable production technology is a major challenge to the successful commercialization of these products. Coprocessing of celecoxib (CEL), poly(vinyl pyrrolidone), and meglumine by spray drying resulted in an amorphous drug product that provided enhanced solubility and stability to an otherwise poorly soluble crystalline form of CEL. The spray-drying process parameters were optimized to provide an amorphous product with required characteristics. The product was stable for 3 months under the accelerated stability storage conditions. This technique can serve as a suitable means for generating a ready-to-formulate amorphous drug-additive(s) composite that can be directly filled into hard gelatin capsules.