Association of serum osteocalcin levels with glucose metabolism in trauma patients.

Osteocalcin (OC) is an endocrine hormone that regulates glucose metabolism.The aim of this study was to investigate the relationship between serum OC levels and glucose metabolism after trauma.This was a retrospective study of trauma patients admitted to the Department of Emergency Medicine between October 2017 and April 2019. Age, height, weight, injury severity score, and previous medical history were recorded. Serum N-terminal mid-fragment of OC (N-MID OC), hemoglobin Alc (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, and other biochemical indicators were measured. Differences between the HbA1c-L (HbA1c <6.5%) and HbA1c-H (HbA1c ≥6.5%) groups were compared. The association of N-MID OC with indicators of glucose metabolism was analyzed.Out of 394 trauma patients, leukocyte and FPG levels in the HbA1c-H group (n = 93) were higher (P < .05), while N-MID OC levels were lower (P = .011) than the HbA1c-L group (n = 301). N-MID OC was negatively correlated with HbA1c in the total population (r = -0.273, P < .001) as well as in the HbA1c-L (r = -0.289, P < .001) and HbA1c-H (r = -0.390, P < 0.001) groups, and was positively correlated with C-peptide in the HbA1c-H group (r = 0.395, P < .001). The different quartiles in the HbA1c-L showed that N-MID OC declined with increasing HbA1c, which was higher than N-MID OC levels in the HbA1c-H group. Multiple linear regression analysis revealed that serum HbA1c was independently associated with serum OC levels after trauma (ß=-1.608, P < .001).This study strongly suggests the importance of serum OC on glucose metabolism in trauma patients. HbA1c is independently associated with serum OC levels.

Mucus-Penetrating Nanosuspensions for Enhanced Delivery of Poorly Soluble Drugs to Mucosal Surfaces.

Mucus-penetrating nanosuspensions, consisting of pure hydrophobic therapeutics with dense muco-inert coatings that enable particles to effectively bypass the mucus barrier, demonstrate superior drug distribution and absorption at mucosal surfaces. With significantly increased drug load compared to polymeric systems and established clinical translation of nanosuspensions-based products, mucus-penetrating nanosuspensions are a promising vehicle for improving mucosal delivery of poorly soluble drugs.

Nanoparticle penetration of human cervicovaginal mucus: the effect of polyvinyl alcohol.

Therapeutic nanoparticles must rapidly penetrate the mucus secretions lining the surfaces of the respiratory, gastrointestinal and cervicovaginal tracts to efficiently reach the underlying tissues. Whereas most polymeric nanoparticles are highly mucoadhesive, we previously discovered that a dense layer of low MW polyethylene glycol (PEG) conferred a sufficiently hydrophilic and uncharged surface to effectively minimize mucin-nanoparticle adhesive interactions, allowing well-coated particles to rapidly diffuse through human mucus. Here, we sought to investigate the influence of surface coating by polyvinyl alcohol (PVA), a relatively hydrophilic and uncharged polymer routinely used as a surfactant to formulate drug carriers, on the transport of nanoparticles in fresh human cervicovaginal mucus. We found that PVA-coated polystyrene (PS) particles were immobilized, with speeds at least 4000-fold lower in mucus than in water, regardless of the PVA molecular weight or incubation concentration tested. Nanoparticles composed of poly(lactide-co-glycolide) (PLGA) or diblock copolymers of PEG-PLGA were similarly immobilized when coated with PVA (slowed 29,000- and 2500-fold, respectively). PVA coatings could not be adequately removed upon washing, and the residual PVA prevented sufficient coating with Pluronic F127 capable of reducing particle mucoadhesion. In contrast to PVA-coated particles, the similar sized PEG-coated formulations were slowed only ~6- to 10-fold in mucus compared to in water. Our results suggest that incorporating PVA in the particle formulation process may lead to the formation of mucoadhesive particles for many nanoparticulate systems. Thus, alternative methods for particle formulation, based on novel surfactants or changes in the formulation process, should be identified and developed in order to produce mucus-penetrating particles for mucosal applications.

The microstructure and bulk rheology of human cervicovaginal mucus are remarkably resistant to changes in pH.

The protective barrier, lubricant, and clearance functions of mucus are intimately coupled to its microstructure and bulk rheology. Mucus gels consist of a network of mucin biopolymers along with lipids, salts, and other proteins and exhibit similar biochemical and physical properties across diverse mucosal surfaces. Nevertheless, mucus is exposed to a broad range of pH values throughout the human body. Protein functions are typically sensitive to small changes in pH, and prior investigations using reconstituted, purified mucin gels suggested mucus undergoes a transition from a low-viscosity liquid at neutral pH to a highly viscoelastic solid at low pH. We sought to determine whether those observations hold for fresh, minimally perturbed human mucus ex vivo by using different-sized muco-inert nanoparticles to probe microstructure and cone-and-plate rheometry to measure bulk rheology. We demonstrate that both the microstructure and bulk rheology of fresh, undiluted, and minimally perturbed cervicovaginal mucus exhibit relatively minor changes from pH 1-2 to 8-9, in marked contrast with the pH sensitivity of purified mucin gels. Our work also suggests additional components in mucus secretions, typically eliminated during mucin purification and reconstitution, may play an important role in maintaining the protective properties of mucus.

Biodegradable mucus-penetrating nanoparticles composed of diblock copolymers of polyethylene glycol and poly(lactic-co-glycolic acid).

Mucus secretions coating entry points to the human body that are not covered by skin efficiently trap and clear conventional drug carriers, limiting controlled drug delivery at mucosal surfaces. To overcome this challenge, we recently engineered nanoparticles that readily penetrate a variety of human mucus secretions, which we termed mucus-penetrating particles (MPP). Here, we report a new biodegradable MPP formulation based on diblock copolymers of poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA-PEG). PLGA-PEG nanoparticles prepared by a solvent diffusion method rapidly diffused through fresh, undiluted human cervicovaginal mucus (CVM) with an average speed only eightfold lower than their theoretical speed in water. In contrast, PLGA nanoparticles were slowed more than 12,000-fold in the same CVM secretions. Based on the measured diffusivities, as much as 75% of the PLGA-PEG nanoparticles are expected to penetrate a 10-µm-thick mucus layer within 30 min, whereas virtually no PLGA nanoparticles are expected to do so over the same duration. These results encourage further development of PLGA-PEG nanoparticles as mucus-penetrating drug carriers for improved drug and gene delivery to mucosal surfaces.