Mesoporous Silica Particles Retain Their Structure and Function while Passing through the Gastrointestinal Tracts of Mice and Humans.

Mesoporous silica particles (MSPs) can be used as food additives, clinically for therapeutic applications, or as oral delivery vehicles. It has also been discussed to be used for a number of novel applications including treatment for diabetes and obesity. However, a major question for their possible usage has been if these particles persist structurally and retain their effect when passing through the gastrointestinal tract (GIT). A substantial breaking down of the particles could reduce function and be clinically problematic for safety issues. Hence, we investigated the biostability of MSPs of the SBA-15 kind prepared at large scales (100 and 1000 L). The MSPs were orally administered in a murine model and clinically in humans. A joint extraction and calcination method was developed to recover the MSPs from fecal mass, and the MSPs were characterized physically, structurally, morphologically, and functionally before and after GIT passage. Analyses with N2 adsorption, X-ray diffraction, electron microscopy, and as a proxy for general function, adsorption of the enzyme α-amylase, were conducted. The adsorption capacity of α-amylase on extracted MSPs was not reduced as compared to the pristine and control MSPs, and adsorption of up to 17% (w/w) was measured. It was demonstrated that the particles did not break down to any substantial degree and retained their function after passing through the GITs of the murine model and in humans. The fact the particles were not absorbed into the body was ascribed to that they were micron-sized and ingested as agglomerates and too big to pass the intestinal barrier. The results strongly suggest that orally ingested MSPs can be used for a number of clinical applications.

Towards mesoporous silica as a pharmaceutical treatment for obesity - impact on lipid digestion and absorption.

Mesoporous silica particles (MSPs) are emerging as an interesting option to reduce calorific uptake as a treatment for obesity and other metabolic conditions. However, their further development under the pharmaceutical regulatory framework is hindered by poor understanding of the mechanisms by which they exert their effects. In the current study the interaction of MSPs with the lipid digestion process is investigated, specifically interactions with lipase enzymes and lipid digestion products as a key contributing factor to lipid absorption and calorific intake. The impact of exposing lipase to MSPs on the enzyme activity was assessed directly using the tributyrin digestion test. The extent of interaction of digestion products with MSPs was studied using selectively radiolabeled bile components and lipids, while the impact on in vivo absorption of lipids was studied by incorporation of radiolabelled lipid (triolein) into milk and administration with and without particles. The studies showed that particles that inhibited lipase activity also tended to interact more extensively with lipid digestion products. In vitro X-ray scattering studies revealed the interaction of some MSPs with lipid digestion products through changes in lipid self-assembly during digestion. The MSPs led to reduced lipid absorption in vivo compared to the control particles and MSP-free milk. While the specific properties of the MSPs that drive the differences between the behavior of MSPs during lipid digestion remain elusive, the studies highlight that interactions with the lipid digestion and absorption pathways are a likely mechanism for reducing calorific uptake.

Engineered mesoporous silica reduces long-term blood glucose, HbA1c, and improves metabolic parameters in prediabetics.

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15®, on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Lay abstract Prediabetes is a health condition in which blood sugar levels are higher than normal but below diabetes diagnosis level. Without intervention, prediabetic adults and children are most likely to progress to Type 2 diabetes. To try and prevent this progression, the authors of this article are proposing an innovative solution with an engineered material called SiPore15^®. SiPore15 is classified as a medical device, and is made up entirely of porous silica particles. It has been proven to be safe to take orally. The effects of SiPore15 were investigated in people with prediabetes and newly diagnosed Type 2 diabetes. SiPore15 was taken three times a day for 12 weeks. It significantly reduced long-term blood glucose levels and improved other factors related to the disease with minimal side effects. The results from this study show that SiPore15 has the potential to be used as a treatment for prediabetes. This may help to delay or prevent the onset of Type 2 diabetes. Clinical Trial Registration: NCT03823027 (ClinicalTrials.gov).

Entrapping Digestive Enzymes with Engineered Mesoporous Silica Particles Reduces Metabolic Risk Factors in Humans.

Engineered mesoporous silica particles (MSP) are thermally and chemically stable porous materials composed of pure silica and have attracted attention for their potential biomedical applications. Oral intake of engineered MSP is shown to reduce body weight and adipose tissue in mice. Here, clinical data from a first-in-humans study in ten healthy individuals with obesity are reported, demonstrating a reduction in glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol, which are well-established metabolic and cardiovascular risk factors. In vitro investigations demonstrate sequestration of pancreatic  α-amylase and lipase in an MSP pore-size dependent manner. Subsequent ex vivo experiments in conditions mimicking intestinal conditions and in vivo experiments in mice show a decrease in enzyme activity upon exposure to the engineered MSP, presumably by the same mechanism. Therefore, it is suggested that tailored MSP act by lowering the digestive enzyme availability in the small intestine, resulting in decreased digestion of macronutrient and leading to reduced caloric uptake. This novel MSP based mechanism-of-action, combined with its excellent safety in man, makes it a promising future agent for prevention and treatment of metabolic diseases.

Mesoporous silica with precisely controlled pores reduces food efficiency and suppresses weight gain in mice.

Aim: Obesity is a risk factor for cardiovascular disease and diabetes. We aimed to elucidate the effects of distinct mesoporous silica particles (MSPs) supplemented in food on metabolic parameters in obesity. Materials & methods: MSPs with precisely controlled pore size were synthesized, characterized and compared with a control in a C57Bl/6 mouse diet-induced obesity model, studying weight, adiposity, metabolic regulation and food efficiency. Results: The most effective MSPs reduced adipose tissue formation to 6.5 ± 0.5 g compared with 9.4 ± 1.2 g, leptin levels nearly halved from 32.8 ± 7.4 to 16.9 ± 1.9 ng/ml and a 33% reduction of food efficiency. Control MSP showed no effects. Conclusion: Results demonstrate potential of distinct MSPs to improve metabolic risk factors. Further studies investigating mechanism of action and confirming human safety are needed.

Quantitative descriptors for the effect of nature/mechanical properties of solid substrates on fibroblast morphology.

PURPOSE: Cell shape is a powerful indicator of cell activity. This study aimed to validate the use of numeric descriptors for the assessment of the effect of substrate mechanical properties on the morphology of 2D cultured fibroblasts. METHODS: Two fibroblast cell types, the 3T3 murine cell line and primary Human Dermal Fibroblasts (HDF) were cultured on substrates (fibrin, silicone, Tissue Culture PolyStyrene) with modulus values spanning more than six orders of magnitude (<1kPa - > 1 GPa), using cell area, circularity, aspect ratio and solidity (ratio between actual and convex area) as morphologic descriptors of cell shape. In order to reduce differences in chemical composition, silicones and TCPS were pre-treated with fibrinogen. RESULTS: Cell area and solidity appeared to be the most sensitive indicators of the differential dependency of the cell morphology on the nature of the substrate. They highlighted complex behavior, where the increase in modulus did not correspond to clear trends in cell shape over the complete range of moduli investigated. CONCLUSIONS: The analysis of cell shape descriptors appears to indicate that chemical differences may overwhelm mechanical effects in 2D culture. These indications are partial and purely phenomenologic, but suggest that specific care should be paid to also consider the role of substrate chemistry in the analysis of the dependency of cell behavior on substrate mechanical properties.