Polysaccharide-based hydrogels for medical devices, implants and tissue engineering: A review.

Hydrogels are highly biocompatible biomaterials composed of crosslinked three-dimensional networks of hydrophilic polymers. Owing to their natural origin, polysaccharide-based hydrogels (PBHs) possess low toxicity, high biocompatibility and demonstrate in vivo biodegradability, making them great candidates for use in various biomedical devices, implants, and tissue engineering. In addition, many polysaccharides also show additional biological activities such as antimicrobial, anticoagulant, antioxidant, immunomodulatory, hemostatic, and anti-inflammatory, which can provide additional therapeutic benefits. The porous nature of PBHs allows for the immobilization of antibodies, aptamers, enzymes and other molecules on their surface, or within their matrix, potentiating their use in biosensor devices. Specific polysaccharides can be used to produce transparent hydrogels, which have been used widely to fabricate ocular implants. The ability of PBHs to encapsulate drugs and other actives has been utilized for making neural implants and coatings for cardiovascular devices (stents, pacemakers and venous catheters) and urinary catheters. Their high water-absorption capacity has been exploited to make superabsorbent diapers and sanitary napkins. The barrier property and mechanical strength of PBHs has been used to develop gels and films as anti-adhesive formulations for the prevention of post-operative adhesion. Finally, by virtue of their ability to mimic various body tissues, they have been explored as scaffolds and bio-inks for tissue engineering of a wide variety of organs. These applications have been described in detail, in this review.

Bioanalytical liquid chromatography-tandem mass spectrometry method development and validation for quantification of lurasidone in rat plasma using ion pairing agent.

A bioanalytical method was developed and validated for determining lurasidone (LUR) in rat plasma. The analyte and internal standard were extracted from rat plasma using a liquid-liquid extraction method. The mobile phase consisted of methanol, acetonitrile and water, with an ion pairing agent, 0.1% heptafluorobutyric acid, added to minimise the matrix effect. The detection was achieved using a tandem mass spectrometer (API 2000) in positive ion multiple reaction monitoring mode. All parameters were validated, including selectivity, specificity, carry-over effect, linearity, precision, accuracy, matrix effect, sensitivity and stability. The linearity range was from 5.0 to 1200.0 ng/mL with a correlation coefficient of >0.99. The accuracy ranged from 100.00% to 110.22% across the quality control range. The mean absolute recovery from matrix samples for LUR and the internal standard was found to be 68.46% and 67.25%, respectively, and the relative recovery was found to be 73.89% and 77.44%, respectively. This method can determine LUR concentrations in rat plasma samples up to 12 h after oral administration, aiding in LUR pharmacokinetic (PK) investigations in rats. The method's reproducibility on a conventional LC-MS/MS system and a shorter run time of 3.0 min make it an appealing bioanalytical method for quantifying LUR in PK studies.

Development, validation and application of a liquid chromatography-tandem mass spectrometry method for quantifying lurasidone in dried blood spot samples.

Background: A liquid chromatography-tandem mass spectrometry method for quantifying lurasidone in rat dried blood spot (DBS) samples was developed. Method: The analyte was extracted from DBSs using the liquid-liquid extraction method. Chromatographic separation was achieved using a C18, Phenomenex, 150 × 4.6 mm, 3.0 µm column. The mobile phase composed of methanol, acetonitrile and water (70:10:20 v/v/v) with 0.1% heptafluorobutyric acid performed well in terms of reducing the matrix effect and achieving shorter retention time. Result: The method was validated over a concentration range of 5.0 to 1200.0 ng/ml and supported by the evaluation of various validation parameters. Conclusion: This simple, sensitive and specific method proved to be a viable alternative sampling method with reduced logistics and blood sample storage expenses despite analytical challenges.

Nose-to-brain delivery of hesperidin nanoparticles loaded in-situ gel for neuroprotective action.

OBJECTIVE: Major depressive disorder (also known as depression) is a serious mental health condition that has a detrimental impact on a person's mood, thoughts, and behaviour. The presence of oxidative stress is associated with an increased risk of developing depression. A flavonoid called hesperidin (HSP) has been proven to be helpful in experimental depression because of its powerful antioxidant properties. However, due to its limited bioavailability, gastro-intestinal degradation, inadequate permeability, and low water solubility, the clinical development of HSP has been impeded. The objective of the present research was to develop HSP nanoparticles (NPs) loaded in-situ gel for nose-to-brain delivery to provide neuroprotective action. MATERIAL AND METHODS: HSP NPs were prepared by nanoprecipitation technique and were tailored to the size by using ultrasonication technique. Optimisation of NPs was conducted using the central composite design. Prepared particles were analysed by Fourier transformed infrared spectroscopy (FTIR), DSC, and UV technique. Forced swim test was conducted as a behavioural assessment to gauze the neuroprotective antidepressant activity of the prepared formulation. RESULTS: The particle size was found to be in the range of 76.5±0.86nm to 239.2+0.31nm, zeta potential in the range of -8.37±0.6mV to 22.4±1.37mV, and entrapment efficiency in the range of 54.92±1.36% to 74.53±1.28%. Pharmacodynamic study showed formulation significantly decreased the immobility time in experimental animals. CONCLUSION: This study showed the potential of HSP NPs to be an effective neuroprotective agent.

Zein-maltodextrin nanocomplex based dissolving microneedle: A promising approach for Paliperidone palmitate delivery.

Researchers are looking at microneedle devices as a possible solution to the problems with poor patient compliance and severe gastrointestinal side effects associated with conventional oral or injectable techniques for treating schizophrenia. Microneedles (MNs) may be an effective approach for transdermal drug delivery of antipsychotic drugs. We fabricated polyvinyl alcohol (PVA) microneedles loaded with paliperidone palmitate (PLDN) nanocomplex and studied their therapeutic potency for schizophrenia. We demonstrated that PLDN nanocomplex-loaded MNs had a pyramidal shape with high mechanical strength, which allowed us to successfully deliver PLDN into the skin and improve permeation behavior ex-vivo. Microneedling enhanced the concentration of PLDN in plasma and brain tissue as compared with the plain drug as observed. In addition, the therapeutic effectiveness was significantly improved by MNs with the capability of extended release. According to the findings of our study, the nanocomplex-loaded microneedle-mediated transdermal delivery of PLDN has the potential to be a novel treatment for schizophrenia.

Improved oral bioavailability of febuxostat by liquid self-micro emulsifying drug delivery system in capsule shells.

PURPOSE: Febuxostat is a non-purine xanthine oxidase inhibitor which belongs to the BCS class II. Main aim of this study is to enhance dissolution and bioavailability of a drug by formulating a liquid self-micro emulsifying drug delivery system (SMEDDS) in different capsule shells. METHOD: Compatability of gelatin and cellulose capsule shells was checked with different oils, surfactants and co-surfactants. Solubility studies were then carried out in selected excipients. Capryol 90, labrasol, and PEG 400 were used in a liquid SMEDDS formulation based on phase diagram and the drug loading. Further SMEDDS was characterized for zeta potential, globule size and shape, thermal stability and in vitro release. Based on the in vitro release, pharmacokinetic study was carried out using SMEDDS in gelatin capsule shells. RESULT: The diluted SMEDDS had globule size of 157.9±1.5d.nm, zeta potential of -16.2±0.4mV and they were thermodynamically stable. The formulation was found stable for 12 months in capsule shells. When tested in different media (0.1N HCl and pH 4.5 acetate buffer), the in vitro release of newly produced formulations differed substantially from that of commercially available tablets, while the release rate in alkaline medium (pH 6.8) was comparable and the highest. According to in vivo findings in rats, a threefold increase in plasma concentration, a fourfold increase in AUC0-t, and a reduction in oral clearance increased fuxostat's oral bioavailability. CONCLUSION: This investigation revealed that the novel liquid SMEDDS formulation sealed in capsules has considerable potential as a vehicle for enhancing the bioavailability of febuxostat.

The Rise of Extracellular Vesicles as New Age Biomarkers in Cancer Diagnosis: Promises and Pitfalls.

Cell-to-cell interactions in the intricate microenvironment of tissue have a significant impact on the progression of cancer at every stage. Both cancer cells and stromal cells are responsible for the secretion of soluble chemical compounds as well as membrane-encased components, which both influence and govern the cell-to-cell interactions within the micro-environment of tumor cells. These membrane structures are identified as extracellular vesicles (EVs), which include exosomes and microvesicles. These nanosized vesicles are made up of bilayered proteolipids and have dimensions ranging from 50 to 1000 nm. It has been speculated that extracellular vesicles that originate from cancer cells perform a variety of functions in the development and progression of cancer which may involve the transport of regulatory materials, such as oncogenic proteins between nearby cells and to distant biological locations. In addition, their level in the serum of cancer patients is noticeably higher than those of healthy controls. The release of extracellular vesicles into the extracellular space is a continual process in both healthy and diseased cells. These extracellular vesicles hold molecular signatures that are defining features of health as well as disease. And hence, the EVs present in biological fluids provide unparalleled and noninvasive access to the necessary molecular details about the health status of the cells. Recent discoveries about these complex extracellular organelles have accelerated the discovery of cancer-specific biological markers as well as the development of unique diagnostic tools based on extracellular vesicles. In this mini-review, we aim to highlight the hopes and hypes associated with the applications of extracellular vesicles as biomarkers for cancer diagnosis.

A comparison of dissolving microneedles and transdermal film with solid microneedles for iloperidone in vivo: a proof of concept.

Iloperidone (ILO) is a poorly soluble and bioavailable WHO-approved schizophrenia drug. Microneedles are a revolutionary delivery technology that overcomes many of the issues associated with traditional drug administration. The current research aimed to compare the antipsychotic activity and pharmacokinetics of ILO-loaded dissolving microneedles (DMNs) and transdermal film with a solid microneedle (STF). The DMNs were fabricated using the micromolding process, while the transdermal film was created using the solvent casting approach. Furthermore, an in vivo pharmacokinetic, pharmacodynamic, and skin irritation study was performed on Wistar rats. Studies were compared with transdermal film (TF) on untreated skin as a passive control. STF and DMNs had considerably greater AUC and Cmax (p ≤ 0.001) than transdermal film. In pharmacodynamic tests, STF and DMNs demonstrated significant (p ≤ 0.001) forelimb retraction time (FRT) and hindlimb retraction time (HRT) delay responses as compared to control and TF. In the skin irritation test, no adverse effects such as erythema or edema were observed at the end of the 48 h. Thus, antipsychotic activity (paw test) and pharmacokinetics studies revealed sustained action of DMN and STF. This research revealed that improved efficacy of DMN and STF for antipsychotic drug delivery may be an alternative to the existing dosage form.

Polysaccharide-based hydrogels for drug delivery and wound management: a review.

INTRODUCTION: Polysaccharide-based hydrogels (PBHs) offer several advantages over their synthetic counterparts. Their natural origin contributes to their nontoxicity, high biocompatibility, and in vivo biodegradability. Their properties can be tuned finely to obtain hydrogels with desired mechanical, structural, and chemical properties. AREAS COVERED: Such versatile characteristics have potentiated the use of PBHs for the delivery of drugs, vaccines, protein and peptide therapeutics, genes, cells, probiotics, bacteriophages, and other therapeutic agents. Recent advances in hydrogel-based formulations such as nanogels, microgels, microneedles, hydrogel beads, nanocarrier-loaded hydrogels, and complexation hydrogels have enabled the precise delivery of a wide range of therapeutics. This review aims to give a holistic overview of hydrogels in the delivery of a variety of therapeutics through different routes. EXPERT OPINION: PBHs have been used to enable the oral delivery of vaccines and other biologicals, thereby allowing self-administration of life-saving vaccines during public health emergencies. There is a lack of commercialized wound dressings for the treatment of chronic wounds. PBH-based wound dressings, especially those based on chitosan and loaded with actives and growth factors, have the potential to help in the long-term treatment of such wounds. Recent developments in the 3D printing of hydrogels can enable the quick and large-scale production of drug-loaded hydrogels.

A systematic review of carbohydrate-based microneedles: current status and future prospects.

Microneedles (MNs) are minimally invasive tridimensional biomedical devices that bypass the skin barrier resulting in systemic and localized pharmacological effects. Historically, biomaterials such as carbohydrates, due to their physicochemical properties, have been used widely to fabricate MNs. Owing to their broad spectrum of functional groups, carbohydrates permit designing and engineering with tunable properties and functionalities. This has led the carbohydrate-based microarrays possessing the great potential to take a futuristic step in detecting, drug delivery, and retorting to biologicals. In this review, the crucial and extensive summary of carbohydrates such as hyaluronic acid, chitin, chitosan, chondroitin sulfate, cellulose, and starch has been discussed systematically, using PRISMA guidelines. It also discusses different approaches for drug delivery and the mechanical properties of biomaterial-based MNs, till date, progress has been achieved in clinical translation of carbohydrate-based MNs, and regulatory requirements for their commercialization. In conclusion, it describes a brief perspective on the future prospects of carbohydrate-based MNs referred to as the new class of topical drug delivery systems.

Microsampling: A role to play in Covid-19 diagnosis, surveillance, treatment and clinical trials.

The outbreak of the new coronavirus disease changed the world upside down. Every day, millions of people were subjected to diagnostic testing for Covid-19, all over the world. Molecular tests helped in the diagnosis of current infection by detecting the presence of viral genome whereas serological tests helped in detecting the presence of antibody in blood as well as contributed to vaccine development. This testing helped in understanding the immunogenicity, community prevalence, geographical spread and conditions post-infection. However, with the contagious nature of the virus, biological specimen sampling involved the risk of transmission and spread of infection. Clinic or pathology visit was the most concerning part. Trained personnel and resources was another barrier. In this scenario, microsampling played an important role due to its most important advantage of remote, contactless, small volume and self-sampling. Minimum requirements for sample storage and ease of shipment added value in this situation. The highly sensitive instruments and validated assay formats assured the accuracy of results and stability of samples. Microsampling techniques are contributing effectively to the Covid-19 pandemic by reducing the demand for clinical staff in population-level testing. The validated and established applications supported the use of microsampling in diagnosis, therapeutic drug monitoring, development of treatment or vaccines and clinical trials for Covid-19.

Exosome as a Natural Gene Delivery Vector for Cancer Treatment.

BACKGROUND: Current gene therapy vectors such as viral, non-viral, and bacterial vectors, which are used for cancer treatment, but there are certain safety concerns and stability issues of these conventional vectors. Exosomes are the vesicles of size 40-100 nm secreted from multivesicular bodies into the extracellular environment by most of the cell types in-vivo and in-vitro. As a natural nanocarrier, exosomes are immunologically inert, biocompatible, and can cross biological barriers like the blood-brain barrier, intestinal barrier, and placental barrier. OBJECTIVE: This review focusses on the role of exosome as a carrier to efficiently deliver a gene for cancer treatment and diagnosis. The methods for loading of nucleic acids onto the exosomes, advantages of exosomes as a smart intercellular shuttle for gene delivery and therapeutic applications as a gene delivery vector for siRNA, miRNA and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and also the limitations of exosomes as a gene carrier are all reviewed in this article. METHODS: Mostly, electroporation and chemical transfection are used to prepare gene loaded exosomes. RESULTS: Exosome-mediated delivery is highly promising and advantageous in comparison to the current delivery methods for systemic gene therapy. Targeted exosomes, loaded with therapeutic nucleic acids, can efficiently promote the reduction of tumor proliferation without any adverse effects. CONCLUSION: In the near future, exosomes can become an efficient gene carrier for delivery and a biomarker for the diagnosis and treatment of cancer.

Unfolding the future: Self-controlled catalytic nanomotor in healthcare system.

Nanomotors, multimetallic systems are biologically inspired self-propelled tiny engines able to perform difficult tasks of transporting cargos from one end to another in presence of hydrogen peroxide fuel. Nanomotors can revolutionize the drug delivery system at the desired target by converting chemical energy into mechanical energy. Nanomotors exhibit unique properties like moving at higher speed, self-propulsion and drilling into the complex cellular environment. The review focuses on fuel dependent and fuel-free nanomotors with their propulsion mechanism. Further, the review highlights the method of fabrication, biohybrid nanomotors, toxicities along with their application in the field of active drug delivery, diabetes, precise surgery, ischemic stroke therapy, diagnosis and treatment of coronavirus, microwave hyperthermia, zika virus detection, anti-bacterial activity, water treatment and sensing and challenges lying at the forefront in the development of these tiny nanomachines. Hydrogen peroxide is toxic to mankind; biohybrid motors give an extra edge of eliminating hydrogen peroxide as fuel for self-propulsion, this can be used for smart drug delivery by reducing toxicities as compared to artificial nanomotors. Cost-effective fabrication of nanomotors will extend their applications in commercial sector overcoming limitations like scale-up and regulatory approval. In near future, nanomotors will diversify in fields of restoring conductivity of electronic medical devices, 3D printing and theranostics.

Widespread applications of host-guest interactive cyclodextrin functionalized polymer nanocomposites: Its meta-analysis and review.

Cyclodextrins are cyclic oligosaccharides, having tyroid shape of the molecule which has a hydrophobic cavity and outer hydrophilic surface. This characteristic feature of the dextrins allows it to function as a functionalizing as well as a stabilizing agent. Polymer nanocomposites are nanoscale composites of polymers with enhanced and synergized properties of its components and have been known to have applications in various fields of chemistry, biomedical, pharmaceutical and environmental purposes to name a few. To impart specificity, thermal, mechanical stability, resistance to solvents and biodegradability to the polymers, cyclodextrins have been incorporated in the nanocomposites. The utilization of the aforementioned properties of cyclodextrins to the polymer nanocomposites, implications of the incorporation of cyclodextrins to polymer nanocomposites and their subsequent applications in various fields have been discussed in this review systematically, using PRISMA guidelines.

Improved anti-arthritic activity of ginger extract, a traditional medicine, using novel drug delivery approach.

BACKGROUND: Ginger and castor oil, both are used in traditional medicine to treat arthritis, the latter is also commonly used as a vehicle in these systems of medicine. The study was designed to prepare a nanostructured lipid carrier (NLC) of ginger extract using castor oil as a novel liquid lipid and evaluate its safety and efficacy in rheumatoid arthritis in experimental animals. METHODS: Ginger extract was standardized using High performance liquid chromatography (HPLC). The optimized NLC formulation was characterized and its therapeutic efficacy was evaluated in Chronic Freund's adjuvant (CFA) induced arthritis in experimental animals. RESULTS: Ginger extract contained 38.76 ± 3.01%w/w of 6-gingerol. The optimized NLC formulation showed a particle size of around 205 nm, a zeta potential of -33.7 and %entrapment efficiency of 76.59 ± 0.83%. Reduction in primary inflammation was significantly higher with NLC when compared with ginger extract and castor oil alone (p<0.001). The formulation also improved hyperalgesia in rats. CONCLUSION: Castor oil can be used as a novel lipid in the preparation of NLC. The NLC effectively enhanced the therapeutic value of poorly bioavailable ginger extract.

Personalized neoantigen vaccines: a glimmer of hope for glioblastoma.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor. In spite of the rigorous multimodal treatment involving surgery and radiochemotherapy, GBM has a dismal prognosis and rapid relapsing potential. Hence, search for novel therapeutic agents still continues. Neoantigens are the tumor-specific antigens which arise due to somatic mutations in the tumor genome. In recent years, personalized vaccine approach targeting neoantigens has been explored widely in cancer immunotherapy and several efforts have also been made to revolutionize the immunotherapy of cold tumors such as GBM using neoantigen targeted vaccines. AREAS COVERED: In this review, we discuss the clinical application of personalized neoantigen targeted vaccine strategy in GBM immunotherapy. While discussing this strategy, we brief about the current challenges faced in GBM treatment by the novel immunotherapeutics. EXPERT OPINION: To date, very few vaccines developed for GBM have reached till phase III clinical development. Early-phase clinical trials of GBM neoantigen vaccines have shown promising clinical outcomes and therefore, its rapid clinical development is warranted. Advent of newer and faster techniques such as next-generation sequencing will drive the faster clinical development of multiplex neoantigen vaccines and hence, increase in the clinical trials is expected.

Opportunities and obstacles for microsampling techniques in bioanalysis: Special focus on DBS and VAMS.

Microsampling, a reduced volume (< 50 µl) sampling method has successfully gained attention at the International Conference on Harmonization (ICH) level. It has been reflected in a few guidelines like ICH SA3, S11 and M10. The established benefits of microsampling support its use in Toxicokinetic (TK) and Pharmacokinetic (PK) studies, clinical studies, neonate sampling and remote sampling. When designing the TK component of a juvenile animal study, microsampling and sparse sampling (if justified) are strongly encouraged from the view of 3Rs (Replace, Refine, and Reduce). The novel sampling techniques arose with benefits over conventional sampling in terms of ease of sampling, storage, and shipment. These improved sampling techniques are less invasive and preferred by patients and trial participants. For the acceptance of these techniques in regulated bioanalysis, it is essential to prove its suitability with a robust and reliable method. Though there are many opportunities for the newer and smarter microsampling devices, the major obstacles are hematocrit influence, homogeneity of samples, repeats, incurred samples reanalysis and regulatory acceptance. With the advancement in techniques, opportunities are marching ahead of obstacles. The two microsampling techniques Dried Blood Spot (DBS) and Volumetric Absorption Microsampling (VAMS) are studied and elaborated in this article with respect to bioanalytical consideration, method validation and regulatory perspectives on its acceptance in regulated bioanalysis.

Bio-tactics for neuroprotection of retinal ganglion cells in the treatment of glaucoma.

Glaucoma, a neurodegenerative disorder is characterized by damage of ganglion cells of retina and also its axons. The manner of progression of disease and retinal ganglion cells death in glaucoma still remains unknown and hence many mechanisms are put forward to understand the disease. Clinical developments have suggested that in every single patient decreasing intraocular pressure (IOP) is not the solution to prevent glaucoma which suggests on the fact that there are other risk factors affecting the disease. The demand for substitute unconventional treatments gives rise to the need to understand the biologically based tactics (bio-tactics) for stopping the progression of disease. Pragmatic findings of past years have supported novelty of inventive molecules with hallmark of neuroprotection in gene therapy. On the other hand, transformation of the latest drugs to clinic has not been of much fruitful substantially for the reason that it lacked dependability while measuring in vivo retinal injury. This as a consequence thwarted the high quality healing possibility of neuroprotectants whether administered single-handedly or given complimentary with other IOP reducing agents. Advancement in research is crucial to grasp the underlying mechanisms concerned with glaucoma and apply it in clinical field to develop neuroprotective agents. In this context, the present review is to bring forth an update on up to date progress in the domain of neuroprotection of retinal ganglion cells for treating glaucoma.

Transdermal lipid vesicular delivery of iloperidone: Formulation, in vitro and in vivo evaluation.

The objective of present study was to develop and evaluate lipid vesicular transdermal system of iloperidone. Liposomes were prepared successfully using thin film hydration method. With aim of enhancing permeation, cholesterol from liposomes was replaced with transcutol to give PEVs. Liposomes and PEVs were evaluated for particle size, shape, entrapment efficiency, viscosity and release study. The vesicles were incorporated in 0.5% of Carbopol gel and evaluated. Particle size of liposomes and PEVs was found between 200-300 nm and entrapment efficiency was found 80-90%w/w. The transdermal gels were homogeneous, spreadable having acceptable pH and drug content between 90-100%.In ex vivo studies, both liposomes and PEVs showed relatively higher skin deposition and permeation of Iloperidone than the plain drug without vesicles. The in vivo pharmacokinetics studies showed relative bioavailability of the PEV loaded gel as 62% and 166% when compared to the oral drug and gel without vesicles respectively. Pharmacodynamic studies showed FRT and HRT delay responses of the transdermal gel systems were significant[p < 0.05] as compared to control at the end of 24 hs. Thus, it can be concluded that transdermal delivery system can be a promising approach for sustained delivery of Iloperidone.