Polymeric Nanoparticles for Wound Healing.

Skin injury is one of the most prevalent lesions in humans, and many such wounds, including deep burns and chronic skin wounds, are notoriously difficult to heal. It has been established by medical practitioners that current wound therapies are not perfectly effective and are far from satisfactory. Meanwhile, nanotechnologies have made it possible to develop pharmaceutical formulations that can elevate the effectiveness of conventional pharmacotherapies to entirely new heights. Most nanostructured biomaterials used to treat wounds, including those that have helped establish this fascinating subject, have been polymeric. The bibliographic analysis presented here shows a steady growth in the research output of studies on the use of polymeric nanoparticles in wound healing therapies. This article provides an overview of polymeric nanoparticles for the treatment of wounds with an emphasis on different chemistries and polymer-drug combinations that have been proven the most effective. The wound age, pathophysiology, wound healing treatments of the present and past, as well as the physicochemical nature and methods for the synthesis of polymeric nanoparticles, are all covered in the opening parts of the review. The existing polymeric nano-drug delivery systems with the greatest promise for wound healing and skin regeneration are subsequently addressed and their potentials summarized.

Polymeric nanotechnologies for the treatment of periodontitis: A chronological review.

Periodontitis is a chronic infectious and inflammatory disease of periodontal tissues estimated to affect 70-80 % of all adults. At the same time, periodontium, the site of periodontal pathologies, is an extraordinarily complex plexus of soft and hard tissues, the regeneration of which using even the most advanced forms of tissue engineering continues to be a challenge. Nanotechnologies, meanwhile, have provided exquisite tools for producing biomaterials and pharmaceutical formulations capable of elevating the efficacies of standard pharmacotherapies and surgical approaches to whole new levels. A bibliographic analysis provided here demonstrates a continuously increasing research output of studies on the use of nanotechnologies in the management of periodontal disease, even when they are normalized to the total output of studies on periodontitis. The great majority of biomaterials used to tackle periodontitis, including those that pioneered this interesting field, have been polymeric. In this article, a chronological review of polymeric nanotechnologies for the treatment of periodontitis is provided, focusing on the major conceptual innovations since the late 1990s, when the first nanostructures for the treatment of periodontal diseases were fabricated. In the opening sections, the etiology and pathogenesis of periodontitis and the anatomical and histological characteristics of the periodontium are being described, along with the general clinical manifestations of the disease and the standard means of its therapy. The most prospective chemistries in the design of polymers for these applications are also elaborated. It is concluded that the amount of innovation in this field is on the rise, despite the fact that most studies are focused on the refinement of already established paradigms in tissue engineering rather than on the development of revolutionary new concepts.

Metabolic Syndrome and Breast Cancer Molecular Subtypes: An Observational Patient Study.

Background: Breast cancer molecular subtypes share various prognostic profiles, and luminal A molecular subtypes have a better prognosis compared with other molecular subtypes. However, whether metabolic syndrome or individual risk factors of metabolic syndrome influence on the development of molecular subtype remains elusive. We aimed to assess the association between metabolic syndrome risk factors and breast cancer molecular subtypes among patients with metabolic syndrome in a clinical setting. Methods: In total, 101 breast cancer patients with mean age, 58.4 ± 8.5 years, and overt metabolic syndrome prospectively were recruited. Immunohistochemistry procedure was used to determine molecular subtypes. Assessment of clinical, biochemical, and anthropometric parameters was performed. Logistic regression analysis was used to assess the relationship between risk factors and breast cancer molecular subtypes categories. A similar approach was used to assess the relation between breast cancer molecular subtypes and menopause. Results: Comparison of metabolic syndrome individual risk factors according to breast cancer molecular subtypes no statistical difference was found for systolic (P = .33) and diastolic blood pressure (P = .17), fasting glucose (P = .77), triglycerides (P = .62), high-density lipoprotein (P = .33), body mass index (P = .87), and waist circumference (P = .81). A positive trend was found between high-density lipoprotein and HER2+. No association was found with other risk factors. Moreover, an association was found between HER2+ categories and menopause. Conclusion: In breast cancer patients with metabolic syndrome, we observed an increased trend between high-density lipoprotein and HER2+ molecular subtype, suggesting that underlying dyslipidemia may favor poor prognosis. HER2+ was associated with menopause which may influence further expression of HER2+ .

Application of Design of Expert software for evaluating the influence of formulation variables on the encapsulation efficacy, drug content and particle size of PEO-PPO-PEO/Poly (DL-lactide-co-caprolactone) nanoparticles as carriers for SN-38.

Background and aims: Hydrophobic substances are mainly encapsulated into polymer nanocarriers in order to improve their solubility, enable their administration, at the same time to empower targeted tissue or cell specific delivery of the drug using the encapsulating vehicle as targeting and controlled release platform. 7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of Irinotecan, showing 100-fold to 1000-fold higher effect than Irinotecan, but its clinical use is limited because of its extreme hydrophobicity, as it is practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. Method: In order to fully exploit the potential of the nanoprecipitation as a method for preparation of Poly(DL-lactide-co-caprolactone)-poly(ethylene oxide) - poly(propylene oxide) - poly(ethylene oxide) (P(DL)LCL/PEO-PPO-PEO) nanoparticles and evaluate the influence of the polymer P(DL)LCL, stabilizing agent PEO-PPO-PEO copolymer (Lutrol F127) and the drug concentration (SN-38) upon drug entrapment efficiency, size and drug content, a D-optimal experimental design for response surface using Design Expert Version 9.0.4.1. software investigation was created and statistically analyzed. Results: We have observed that at higher SN-38 concentration during the preparation procedure (nanoprecipitation, solvent diffusion method), and due to its extremely low water solubility, the drug will start to precipitate as unprotected crystals at a faster pace compared to polymer aggregation, leading to extremely low encapsulation efficacy and waste of the active compound. The most desirable combination of factor settings are SN-38 = 0.5 mg, Polymer = 5 mg and F127 = 4%. Conclusion: This investigation utilizes the design of experiment approach and extends the primary understanding of impact of formulation development of P(DL)LCL/PEO-PPO-PEO nanoparticles as carriers for SN-38.

A review of the current understanding of nanoparticles protein corona composition.

Upon entering into the biological environments, the surface of the nanoparticles is immediately coated with proteins and form the so-called a protein corona due to which a nanoparticle changes its "synthetic" identity to a new "biological" identity. Different types of nanoparticles have different protein binding profiles, which is why they have different protein corona composition and therefore it cannot be said that there is a universal protein corona. The composition and amount of protein in the corona depends on the physical and chemical characteristics of the nanoparticles, the type of biological medium and the exposure time. Protein corona increases the diameter but also changes the composition of the surface of the nanoparticles and these changes affect biodistribution, efficacy, and toxicity of the nanoparticles.

Efficacy assessment of self-assembled PLGA-PEG-PLGA nanoparticles: Correlation of nano-bio interface interactions, biodistribution, internalization and gene expression studies.

The aim of our study was to develop and compare the biological performance of two types of biodegradable SN-38 loaded nanoparticles (NPs) with various surface properties, composed of low and high Mw triblock PLGA-PEG-PLGA copolymers, applying rational quality and safety by design approach. Therefore, along with the optimization of crucial physico-chemical properties and in order to evaluate the therapeutical potential and biocompatibility of prepared polymeric nanoparticles, analysis of nano-bio interactions, cell internalization, gene expression and biodistribution studies were performed. The optimized formulations, one of low Mw and one composed of high Mw PLGA-PEG-PLGA copolymer, exhibited different characteristics in terms of surface properties, particle size, zeta potential, drug loading, protein adsorption and biodistribution, which may be attributed to the variations in nano-bio interface interactions due to different NP building blocks length and Mw. On the contrary to protein adsorption and biodistribution studies, both types of NPs exhibited similar results during cell internalization and gene expression studies performed in cell culture medium containing serum proteins. This pool of useful data for internalization and efficacy as well as the notable advance in the circulation time of low Mw NPs may be further employed for shaping the potential of the designed nanocarriers.

PEO-PPO-PEO/Poly(DL-lactide-co-caprolactone) Nanoparticles as Carriers for SN-38: Design, Optimization and Nano-Bio Interface Interactions.

Encapsulation of extremely hydrophobic substances such as SN-38 into nanoparticles, is a promising approach to solve the solubility issue and enable drug administration. Moreover, nanocarriers' tumor homing behavior, targeted and controlled release at the site of action will optimize therapeutic potency and decrease toxicity of the incorporated drug substance. However, the enormous drug hydrophobicity might limit the capacity for encapsulation as the premature drug precipitation will contribute to fast free drug crystal growth, low drug incorporation and huge waste of the active material. In this article we defined the optimal region for manufacturing of SN-38 loaded PEO-PPO-PEO/P(DL)LCL nanoparticles (NPs) with high efficacy of encapsulation, suitable particle size and different surface properties, using D-optimal design and nanoprecipitation as production method. Further we made an approach to investigate the interactions with macromolecules at the nano-bio interface which are predetermined by the physico-chemical and surface properties of the NPs, and are important determinants for the biological identity of the nanoparticles, the potential for evasion of the physiological barriers and the efficacy of localization at the site of action. Here we present in depth analysis of the behavior of two types of nanoparticles with different surface properties through structured protein interaction and bioreactivity experiments in order to presuppose NP performance and toxicological profile in biological environment.

Prevalence of Side Effects Treatment with Carbamazepine and Other Antiepileptics in Patients with Epilepsy.

OBJECTIVE: This paper reveals the studies of carbamazepine monitoring in the manifestation of side effects during clinical use. It is important to realize that these ranges are derived statistically, with most patients who have high levels suffering side effects and some with poor control having low levels. Broadly, the newer agents have advantages of lower risk of side effects and less drug interaction. At the presence they are more expensive than the, than "older" agents. Current recommendations and practice are to use newer agents as second line drugs, although in some countries there are gaining favour as potential first line agents. METHODS: In the study 91 patients with epilepsy were involved from which 53 or 58.2% were female and 38 or 41.8% were male with no great significant difference between two genders (X(2)=2.47, P=0.116). However, according to the study results female patients had slightly greater prevalence of epilepsy than man. Average age of epileptic patients was 23.2 years (SD ± 16.4 years), in the range 1-66 years. Patient distribution was present within all age-groups, but 59.4% of all patients were up to 20 years old. The highest prevalence of epilepsy was in the group age 6-15 years old: 33.0%. There were also children 1 - 5 years old with 7 or 7.7% of the patients, and the patients older than 60 years with 4 or 4.4% of the patients. Patient distribution according to the age and gender results with no female patient over 60 year old and more female patients in the age group 1-5 years. However statistically this did not produce a highly significant difference (T-test= 0.72, P=0.437) between average age according to the gender. The average age of the female gender was 22.1 year (SD ± 14.2 years), with the range 2-55 years, while the average age of the male patients was 24.6 year (SD ±19.2 years), with the range 1-66 years. CONCLUSION: Unwanted side effects of antiepileptic drugs analyzed in the study are frequent, but not so severe as to be life threatening. Treatment of epilepsy with these three drugs (carbamazepine, ac.valproic and phenobarbitone) would be the first choice of treatment, with the best safety and efficacy. Application of this therapy is rarely compromised because of the appearance of unwanted side effects. Replacement or termination of therapy may be applied if actual therapy is not adequate for the management of epileptic attacks.

In vitro examination of degenerative evolution of adrenergic nerve endings in pulmonary inflammatory [corrected] processes in newborns.

Morphological aspect of tracheal preparations and pulmonary tissue was studied in vitro. The material was obtained from autopsy of newborns that died from different causes. Examinations were made in different gestational periods (immature 23-29 weeks; premature 30-37 weeks; mature >38 weeks). Material for examination was obtained up to 6 hours after death. Pulmonary and tracheal tissue was incubated for fixation in buffered formalin (10%). Special histochemical and histoenzymatic methods were used for coloring of pulmonary and tracheal tissue and the activity of ATP-ase and dopaoxidase was monitored. Cut out models were made in series of 7 micro, 10 micro and 20 micro. In peripheral axons of tracheobronchial pathways, degenerative alterations of adrenergic nerve endings in lung inflammatory processes were documented. These morphologic neuronal changes were described: Walerians degeneration, neuro-axonal degeneration and segment demyelinisation. These changes are well seen with argentafine coloring (Sevier-Munger modification for nerve endings) and with dopaoxidase reaction. In mature newborns that died from respiratory distress syndrome, we found different forms of metabolic and toxic degenerative damage in peripheral axons, such as: segment demyelinisation, neurotubular fragmentation, Schwann cell proliferation, fragmentation and bulging out of axonal neurotubules and neurofilaments. In tracheo-bronchial tissue, chromafine granules are homogeneously distributed on Lamina propria layer and through glandular structures. This gives as a contradiction, according to some authors, that adrenergic nerve fibers for muscle tissue are absent and that adrenaline and noradrenaline diffuse in muscle tissue from interstice.

In vitro examination of ontogenesis of developing neuronal cells in vagal nuclei in medulla oblongata in newborns.

The development of neuron cells in vagal nerve nuclei in medulla oblongata was studied in vitro in live newborns and stillborns from different cases. Morphological changes were studied in respiratory nuclei of dorsal motor centre (DMNV) and nucleus tractus solitarius (NTS) in medulla oblongata. The material from medulla oblongata was fixated in 10 micro buffered formalin solution. Fixated material was cut in series of 10mu thickness, with starting point from obex in +/- 4 mm thickness. Special histochemical and histoenzymatic methods for central nervous system were used: cresyl echt violet coloring, tolyidin blue, Sevier-Munger modification and Grimelius coloring. In immature newborns (abortions and immature) in dorsal motor nucleus of the vagus (DMNV) population stages S1, S2, S3 are dominant. In neuron population in vagal sensory nuclei (NTS) stages S1, S2 are dominant. In more advanced stages of development of newborns (premature), in DMNV stages S3 and S4 are seen and in NTS stages S2 and S3 are dominant. In mature phase of newborns (maturity) in vagal nucleus DMNV stages S5 and S6 are dominant, while in sensory nucleus NTS stages S4 and S5 are dominant. These data suggest that neuron population in dorsal motor nucleus of the vagus (DMNV) are more advanced in neuronal maturity in comparison with sensory neuron population of vagal sensory nucleus NTS. This occurrence shows that phylogenetic development of motor complex is more advanced than the sensory one, which is expected to take new information's from the extra uterine life after birth (extra uterine vagal phenotype).

Examination of ontogenetic-morphologic growth of adrenergic receptor system in the isolated preparation of trachea in vitro.

Morphological development of the bronchial respiratory system of the living newborns and dead newborns was studied. Tracheal smooth musculature was studied in 19 experimental preparations which were obtained from autopsy of newborns that died from different causes. Based on the morphological research of the isolated preparation of human trachea the following was stated: numerical density of the tracheal ganglions is higher in the premature. Decrease of ganglion cells number is noticed in mature newborns. This can be explained with the fact that in the phase of intensive ramification, ganglions penetrate from the serous layers in the deeper layers of the trachea--in the direction of epithelium. Main diameter of tracheal ganglions is bigger in premature; this is proportional with the developmental phase of newborns. Based on histological, histochemical and hystoenzymatic analyses, three types of synaptic-axonal neurotransmitter vesicles are visualized in our material: small granularvesicles (SGV), large granular vesicles (LGV) and aminoacid vesicles, with gamma-amino butyric acid and glycine (GABA). Vesicles give positive reaction with argentaffin, argyrophilin and dopa-oxidase. Argentaffin and argyrophile reactions are positive in synapses, hydrocyte cartilage, epithelium, smooth musculature, SGV, LGV, GABA of the tracheal-bronchial pathways. ATP is positive in hydrocyte cartilages and tracheobronchial mucus glands. On airways most of the nerve endings are vesicular (motor) type. Non-vesicular (sensory) types of nerve endings are present in perichondrial localization. These morphological data indicate interaction between adrenergic, cholinergic and third nonadrenergic-noncholinergic system in airways.