Low-dose nano-gel incorporated with bile acids enhanced pharmacology of surgical implants.

Aim: Major challenges to islet transplantation in Type 1 diabetes include host-inflammation, which results in failure to maintain survival and functions of transplanted islets. Therefore, this study investigated the applications of encapsulating the bile acid ursodeoxycholic acid (UDCA) with transplanted islets within improved nano-gel systems for Type 1 diabetes treatment. Materials & methods: Islets were harvested from healthy mice, encapsulated using UDCA-nano gel and transplanted into the diabetic mice, while the control group was transplanted encapsulated islets without UDCA. The two groups' survival plot, blood glucose, and inflammation and bile acid profiles were analyzed. Results & conclusion: UDCA-nano gel enhanced survival, glycemia and normalized bile acids' profile, which suggests improved islets functions and potential adjunct treatment for insulin therapy.

In this study, we explore the delivery of insulin producing cells that may benefit those with Type 1 diabetes. Cells were delivered to mice in a protective matrix. The matrix contained unique components, such as bile acids, that allowed for sustained reduction in glucose levels. This process may represent a novel diabetes treatment that could be an alternative to traditional insulin therapies.

Reduced Cytokine Tumour Necrosis Factor by Pharmacological Intervention in a Preclinical Study.

Recent preclinical studies in our laboratory have shown that the bile acid profile is altered during diabetes development and such alteration has been linked to the diabetes-associated inflammatory profile. Hence, this study aimed to investigate if the first-line antidiabetic drug metformin will alter the bile acid profile and diabetes-associated inflammation in a murine model of pre-type 2 diabetes. C57 mice were randomly allocated into three equal groups of eight. Group One was given a low-fat diet (LFD), Group Two was given a high-fat diet (HFD), and Group Three was given an HFD and, upon prediabetes confirmation, daily oral metformin for one month. Blood glucose, glycated haemoglobin, drug concentrations in tissues and faeces, and the inflammatory and bile acid profiles were measured. Metformin showed wide tissue distribution and was also present in faeces. The bile acid profile showed significant alteration due to prediabetes, and although metformin did not completely normalize it, it did exert significant effects on both the bile acid and the inflammatory profiles, suggesting a direct and, to some extent, positive impact, particularly on the diabetes-associated inflammatory profile.

The emerging role of bile acids as critical components in nanotechnology and bioengineering: Pharmacology, formulation optimizers and hydrogel-biomaterial applications.

The role of endogenous bile acids as lipid stabilizers aiding uptake of lipophilic nutrients via micelle formation and saponification effects is well documented and precedes their growing applications in pharmaceutical sciences. Their utility stems from their unique physico-chemical profile and ability to modulate immune cell signalling pathways. It has been shown that bile acids alter specific receptor-mediated pathways of cellular respiration and metabolism, providing potential clinical therapies for cardio-metabolic disorders such as diabetes mellitus, hypercholesterolemia, and heart disease. Additionally, some bile acids exert profound anti-oxidant, anti-inflammatory and immunosuppressant properties, and are effective at reducing blood pressure and alleviating hypertension. Their unique amphoteric properties and proven ability as permeability enhancers make them a desirable pharmaceutical excipient. When incorporated with various carbohydrates, polymers, hydrogels and/or polyelectrolytes to form micro- or nano-capsules, they provide enhanced thermodynamic, osmotic and structural stability, and cater for controlled delivery via specific tissue targeting, pH dependant release and temperature guided sol-gel complexation. Additionally, due to their immunosuppressant properties, they enhance the immunogenicity of encapsulated cells, increasing the feasibility of bioartificial organs as transplantable therapeutics. This review explores existing and future applications of bile acids and provides a synopsis of their role in advanced, novel therapeutic delivery systems.

Pharmacological Dose-Effect Profiles of Various Concentrations of Humanised Primary Bile Acid in Encapsulated Cells.

Bile acids (BA)s are known surfactants and well-documented to play a major role in food digestion and absorption. Recently, potential endocrinological and formulation-stabilisation effects of BAs have been explored and their pharmacological effects on supporting cell survival and functions have gained wide interest. Hence, this study aimed to explore the hyper-glycaemic dependent dose-effect of the BA chenodeoxycholic acid (CDCA) when encapsulated with pancreatic ß-cells, allowing assessment of CDCA's impacts when encapsulated. Four different concentrations of the BA were prepared, and viable cells were encapsulated and incubated for 2 days. Multiple analyses were carried out including confocal imaging, glucose-induced cellular mitochondrial viability indices, insulin production, inflammatory biomarker analyses and cellular bioenergetics measurements. There was a significant dose-effect with different concentrations of the BA, affecting cellular viability and antioxidant activities, cell functions and insulin release, inflammatory biomarkers, and cellular-bioenergetics at different oxidative stress levels. The results demonstrate that, when encapsulated, the BA CDCA exerts positive pharmacological effects at the cellular level, and such effects are concentration dependent.

Taurine Grafted Micro-Implants Improved Functions without Direct Dependency between Interleukin-6 and the Bile Acid Lithocholic Acid in Plasma.

A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA.

Single-Cellular Biological Effects of Cholesterol-Catabolic Bile Acid-Based Nano/Micro Capsules as Anti-Inflammatory Cell Protective Systems.

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic ß-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules' images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules' thermal and chemical stability assays were also assessed to ascertain an association between capsules' stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.

Biguanide Pharmaceutical Formulations and the Applications of Bile Acid-Based Nano Delivery in Chronic Medical Conditions.

Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems. Such studies have demonstrated significantly enhanced delivery and safety of biguanides using nanocapsules. Enhanced delivery and safety have widened the potential applications of biguanides not only in diabetes but also in other disorders. Hence, this review aimed to explore biguanides' pharmacokinetics, pharmacodynamics, and pharmaceutical applications in diabetes, as well as in other disorders.

Pharmaceutical formulation and polymer chemistry for cell encapsulation applied to the creation of a lab-on-a-chip bio-microsystem.

Microencapsulation of formulation designs further expands the field and offers the potential for use in developing bioartificial organs via cell encapsulation. Combining formulation design and encapsulation requires ideal excipients to be determined. In terms of cell encapsulation, an environment which allows growth and functionality is paramount to ensuring cell survival and incorporation into a bioartificial organ. Hence, excipients are examined for both individual properties and benefits, and compatibility with encapsulated active materials. Polymers are commonly used in microencapsulation, offering protection from the immune system. Bile acids are emerging as a tool to enhance delivery, both biologically and pharmaceutically. Therefore, this review will focus on bile acids and polymers in formulation design via microencapsulation, in the field of bioartificial organ development.

Artificial Cell Encapsulation for Biomaterials and Tissue Bio-Nanoengineering: History, Achievements, Limitations, and Future Work for Potential Clinical Applications and Transplantation.

Pancreatic ß-cell loss and failure with subsequent deficiency of insulin production is the hallmark of type 1 diabetes (T1D) and late-stage type 2 diabetes (T2D). Despite the availability of parental insulin, serious complications of both types are profound and endemic. One approach to therapy and a potential cure is the immunoisolation of ß cells via artificial cell microencapsulation (ACM), with ongoing promising results in human and animal studies that do not depend on immunosuppressive regimens. However, significant challenges remain in the formulation and delivery platforms and potential immunogenicity issues. Additionally, the level of impact on key metabolic and disease biomarkers and long-term benefits from human and animal studies stemming from the encapsulation and delivery of these cells is a subject of continuing debate. The purpose of this review is to summarise key advances in this field of islet transplantation using ACM and to explore future strategies, limitations, and hurdles as well as upcoming developments utilising bioengineering and current clinical trials.

The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications.

INTRODUCTION: In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs. METHODS: Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug's main target being pancreatic beta-cells, the formulations' effects on cell viability, functions and inflammatory profiles were also investigated. RESULTS AND CONCLUSIONS: CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.

The Effects of Accelerated Temperature-Controlled Stability Systems on the Release Profile of Primary Bile Acid-Based Delivery Microcapsules.

INTRODUCTION: Bile acid-based drug encapsulation for oral delivery has been recently explored in our laboratory and has shown to be beneficial in terms of drug-targeted delivery and release profile, but stability at various temperatures has not previously been examined; hence, this is the aim of this study. METHODS: Various types of bile acid-based microcapsules containing the drug metformin were produced and tested for accelerated temperature-controlled profiles, as well as morphology, elemental composition, drug content, resilience, floatability, wettability and release profiles at various pH values. RESULTS: Accelerated temperature-controlled analysis showed negligible effects on morphology, size, or shape at very low temperatures (below 0 °C), while higher temperatures (above 25 °C) caused alterations. Drug contents, morphology and elemental composition remained similar, while wettability and the release profiles showed formulation-dependent effects. DISCUSSION AND CONCLUSION: Results suggest that bile acid-based microcapsules containing metformin are affected by temperature; hence, their shelf life is likely to be affected by storage temperature, all of which have a direct impact on drug release and stability profiles.

Polyelectrolytes Formulated with Primary Unconjugated Bile Acid Optimised Pharmacology of Bio-Engineered Implant.

INTRODUCTION: Several studies have shown that different biomaterials and hydrogels comprising various bile acids such as chenodeoxycholic acid (CDCA), as well as excipients such as poly-(styrene)-sulphonate (PSS) and poly-(allyl)-amine (PAA), exhibited positive biological effects on encapsulated viable pancreatic ß-cells. Hence, this study aimed to investigate whether incorporating CDCA with PSS and PAA will optimise the functions of encapsulated pancreatic islets post-transplantation in Type 1 diabetes (T1D). METHODS: Mice were made T1D, divided into two equal groups, and transplanted with encapsulated islets in PSS-PAA (control) or with CDCA-PSS-PAA (treatment) microcapsules. The effects of transplanted microcapsules on blood glucose, inflammation and the bile acid profile were measured post-transplantation. RESULTS AND CONCLUSION: Compared with control, the treatment group showed better survival rate, improved glycaemic control, and lower inflammatory profile, illustrated by ↓ interleukin 1-ß, interleukin-6, interleukin-12, and tumour-necrosis factor-α, and ↓ levels of the bile acid, as well as lithocholic acid in the plasma, liver, large intestine and faeces. The results suggest that CDCA incorporation with PSS-PAA microcapsules exerted beneficial effects on encapsulated islets and resulted in enhanced diabetes treatment, post-transplantation, at the local and systemic levels.

Chenodeoxycholic Acid Pharmacology in Biotechnology and Transplantable Pharmaceutical Applications for Tissue Delivery: An Acute Preclinical Study.

INTRODUCTION: Primary bile acids (PBAs) are produced and released into human gut as a result of cholesterol catabolism in the liver. A predominant PBA is chenodeoxycholic acid (CDCA), which in a recent study in our laboratory, showed significant excipient-stabilizing effects on microcapsules carrying insulinoma ß-cells, in vitro, resulting in improved cell functions and insulin release, in the hyperglycemic state. Hence, this study aimed to investigate the applications of CDCA in bio-encapsulation and transplantation of primary healthy viable islets, preclinically, in type 1 diabetes. METHODS: Healthy islets were harvested from balb/c mice, encapsulated in CDCA microcapsules, and transplanted into the epididymal tissues of 6 syngeneic diabetic mice, post diabetes confirmation. Pre-transplantation, the microcapsules' morphology, size, CDCA-deep layer distribution, and physical features such as swelling ratio and mechanical strength were analyzed. Post-transplantation, animals' weight, bile acids', and proinflammatory biomarkers' concentrations were analyzed. The control group was diabetic mice that were transplanted encapsulated islets (without PBA). RESULTS AND CONCLUSION: Islet encapsulation by PBA microcapsules did not compromise the microcapsules' morphology or features. Furthermore, the PBA-graft performed better in terms of glycemic control and resulted in modulation of the bile acid profile in the brain. This is suggestive that the improved glycemic control was mediated via brain-related effects. However, the improvement in graft insulin delivery and glycemic control was short-term.

Enhanced Bilosomal Properties Resulted in Optimum Pharmacological Effects by Increased Acidification Pathways.

INTRODUCTION: Recent studies in our laboratory have shown that some bile acids, such as chenodeoxycholic acid (CDCA), can exert cellular protective effects when encapsulated with viable ß-cells via anti-inflammatory and anti-oxidative stress mechanisms. However, to explore their full potential, formulating such bile acids (that are intrinsically lipophilic) can be challenging, particularly if larger doses are required for optimal pharmacological effects. One promising approach is the development of nano gels. Accordingly, this study aimed to examine biological effects of various concentrations of CDCA using various solubilising nano gel systems on encapsulated ß-cells. METHODS: Using our established cellular encapsulation system, the Ionic Gelation Vibrational Jet Flow technology, a wide range of CDCA ß-cell capsules were produced and examined for morphological, biological, and inflammatory profiles. RESULTS AND CONCLUSION: Capsules' morphology and topographic characteristics remained similar, regardless of CDCA or nano gel concentrations. The best pharmacological, anti-inflammatory, and cellular respiration, metabolism, and energy production effects were observed at high CDCA and nano gel concentrations, suggesting dose-dependent cellular protective and positive effects of CDCA when incorporated with high loading nano gel.

Probucol Pharmacological and Bio-Nanotechnological Effects on Surgically Transplanted Graft Due to Powerful Anti-Inflammatory, Anti-Fibrotic and Potential Bile Acid Modulatory Actions.

INTRODUCTION: A major obstacle in islet transplantation and graft survival pre and post transplantation is islet apoptosis due to mainly inflammatory bio molecules released during islet harvesting and post graft transplantation and hence, subsequent graft fibrosis and failure. This study aimed to investigate if incorporation of the anti-inflammatory anti-hyperlipidaemic drug probucol (PB) would improve islet-graft survival and function, post transplantation in Type 1 diabetes (T1D). METHODS: T1D was induced in mice, and biological profiles of the diabetic mice transplanted PB-microencapsulated islets harvested from healthy syngeneic mice were measured. RESULTS AND CONCLUSION: Compared with sham (no PB), the treated group showed significant reduction in serum levels of interleukin-1ß, interleukin-6, interleukin-12, interleukin-17, and tumour necrosis factor-α, accompanied by a 3-fold increase in survival duration, which suggests PB islet-protective effects, post transplantation.

A Review on Recent Advancement on Age-Related Hearing Loss: The Applications of Nanotechnology, Drug Pharmacology, and Biotechnology.

Aging is considered a contributing factor to many diseases such as cardiovascular disease, Alzheimer's disease, and hearing loss. Age-related hearing loss, also termed presbycusis, is one of the most common sensory impairments worldwide, affecting one in five people over 50 years of age, and this prevalence is growing annually. Associations have emerged between presbycusis and detrimental health outcomes, including social isolation and mental health. It remains largely untreatable apart from hearing aids, and with no globally established prevention strategies in the clinical setting. Hence, this review aims to explore the pathophysiology of presbycusis and potential therapies, based on a recent advancement in bile acid-based bio-nanotechnologies. A comprehensive online search was carried out using the following keywords: presbycusis, drugs, hearing loss, bile acids, nanotechnology, and more than 150 publications were considered directly relevant. Evidence of the multifaceted oxidative stress and chronic inflammation involvement in cellular damage and apoptosis that is associated with a loss of hair cells, damaged and inflamed stria vascularis, and neuronal signalling loss and apoptosis continues to emerge. New robust and effective therapies require drug delivery deeper into the various layers of the cochlea. Bile acid-based nanotechnology has gained wide interest in its permeation-enhancing ability and potential for numerous applications in treating presbycusis.

Advancements in Assessments of Bio-Tissue Engineering and Viable Cell Delivery Matrices Using Bile Acid-Based Pharmacological Biotechnologies.

The utilisation of bioartificial organs is of significant interest to many due to their versatility in treating a wide range of disorders. Microencapsulation has a potentially significant role in such organs. In order to utilise microcapsules, accurate characterisation and analysis is required to assess their properties and suitability. Bioartificial organs or transplantable microdevices must also account for immunogenic considerations, which will be discussed in detail. One of the most characterized cases is the investigation into a bioartificial pancreas, including using microencapsulation of islets or other cells, and will be the focus subject of this review. Overall, this review will discuss the traditional and modern technologies which are necessary for the characterisation of properties for transplantable microdevices or organs, summarizing analysis of the microcapsule itself, cells and finally a working organ. Furthermore, immunogenic considerations of such organs are another important aspect which is addressed within this review. The various techniques, methodologies, advantages, and disadvantages will all be discussed. Hence, the purpose of this review is providing an updated examination of all processes for the analysis of a working, biocompatible artificial organ.