Popularity and Harms of Aural Foreign Bodies: A Descriptive Study of Patients in Baqiyatallah University Hospital, Tehran, Iran.

OBJECTIVE: To evaluate the prevalence of external ear complications among Iranian aural foreign body users attending to otolaryngology clinic of our hospital. METHODS: In this cross-sectional study patients attending to Otolaryngology clinics of Baqiyatallah hospital were enrolled regardless of their age, gender and reason of attending. Patients between 15 and 60 years of age were included in the present study. Those with positive history of chronic ear diseases, ear surgery, congenital ear disorders, trauma to ear or head and neck region or shock wave trauma were excluded from the study. Demographic information as well as data on chief complaint, educational level, frequency and type of used foreign body and findings of physical examination and Otoscopy by a single otolaryngologist were recorded in a predesigned checklist. RESULTS: Eventually 362 patients (232 male and 130 female) with a mean age of 40.32 ± 16.90 years underwent analysis. Of all patients 244 (67.2%) were using a kind of aural foreign body frequently and Cotton bud was the most popular (63.5%) used foreign body among patients. Drying ear canal was the most common (54.9%) reason of using AFBs among study individuals followed by itching (29.5%) and pyorrhea (11.06%). Also 11 (4.5%) patients were using AFBs as a habit with no specific reason. Itching was the most prevalent symptom reported by both aural foreign body users (78%) and non-users (45.5%); however it was significantly higher among AFB users (p = 0.026). Also hearing loss was significantly more reported by AFB users (p = 0.033). A majority of patients had normal physical examination in both AFB users and non-users group. Inflammation of ear canal was significantly more detected in AFB users (p = 0.004). In addition, rate of right ear wax impaction was higher among AFB users (p = 0.016). CONCLUSION: In conclusion we realized that 67.2% of patients attending to Otolaryngology clinic of our hospital were using a kind of aural foreign bodies and itching was the most common chief complaint of these patients.

Moisture soft sensor for agitated pan dryers using a hybrid modeling approach.

A hybrid soft sensor model is developed to provide real-time estimations of the moisture content in the Active Pharmaceutical Ingredient (API) wet cake for an agitated pan drying process. The soft sensor is calibrated using data from 5 batches. The estimation accuracy of the soft sensor is demonstrated with additional 21 commercial scale batches. Dynamic global sensitivity analysis has been performed to investigate the significance of input process parameters on the variability of soft sensor estimations over the whole drying process. The results indicate that the soft sensor acts as a powerful tool for real-time estimation of the moisture content, which can consequently be used to monitor and control the API drying process and enable Quality by Design (QbD) approach for this important pharmaceutical process.

Application of Raman spectroscopy in monoclonal antibody producing continuous systems for downstream process intensification.

Monoclonal antibodies (mAbs) are biopharmaceuticals produced by mammalian cell lines in bioreactors at a variety of scales. Cell engineering, media optimization, process monitoring, and control strategies for in vitro production have become crucial subjects to meet increasing demand for these high value pharmaceuticals. Raman Spectroscopy has gained great attention in the pharmaceutical industry for process monitoring and control to maintain quality assurance. For the first time, this article demonstrated the possibility of subclass independent quantitative mAb prediction by Raman spectroscopy in real time. The developed model estimated the concentrations of different mAb isotypes with average prediction errors of 0.2 (g/L) over the course of cell culture. In situ Raman spectroscopy combined with chemometric methods showed to be a useful predictive tool for monitoring of real time mAb concentrations in a permeate stream without sample removal. Raman spectroscopy can, therefore, be considered as a reliable process analytical technology tool for process monitor, control, and intensification of downstream continuous manufacturing. The presented results provide useful information for pharmaceutical industries to choose the most appropriate spectroscopic technology for their continuous processes.

In-line monitoring of amino acids in mammalian cell cultures using raman spectroscopy and multivariate chemometrics models.

The application of PAT for in-line monitoring of biopharmaceutical manufacturing operations has a central role in developing more robust and consistent processes. Various spectroscopic techniques have been applied for collecting real-time data from cell culture processes. Among these, Raman spectroscopy has been shown to have advantages over other spectroscopic techniques, especially in aqueous culture solutions. Measurements of several process parameters such as glucose, lactate, glutamine, glutamate, ammonium, osmolality and VCD using Raman-based chemometrics models have been reported in literature. The application of Raman spectroscopy, coupled with calibration models for amino acid measurement in cell cultures, has been assessed. The developed models cover four amino acids important for cell growth and production: tyrosine, tryptophan, phenylalanine and methionine. The chemometrics models based on Raman spectroscopy data demonstrate the significant potential for the quantification of tyrosine, tryptophan and phenylalanine. The model for methionine would have to be further refined to improve quantification.

Suppurative appendicitis presenting acute scrotal pain: a rare condition may confuse surgeons.

Scrotal pain presentation has many differential diagnoses such as testicular torsion is surgical emergency. For this reason, it is necessary for surgeons to differentiate between diseases for choosing the best treatment approach. We have reported a rare condition of 19-year-old male case had an atypical scrotal pain presentation of appendicitis. He was admitted to emergency service with 4 days history of pain in abdomen and testis. In physical examination, there is tenderness in right lower quadrant, right inguinal region and scrotum. Testicular torsion and appendicitis were roll-out in sonography. Because of low sensitivity of sonography in diagnose of appendicitis and high suspicious of surgeons, the case was candidate for an open appendectomy surgery. Acute suppurative appendicitis that presenting testicular pain is rare for making the best diagnosis and prevents multiple surgeries in such cases, cooperation of urology, general surgery and radiology specialists with high index of suspicion is required.

Generic Raman-based calibration models enabling real-time monitoring of cell culture bioreactors.

Raman-based multivariate calibration models have been developed for real-time in situ monitoring of multiple process parameters within cell culture bioreactors. Developed models are generic, in the sense that they are applicable to various products, media, and cell lines based on Chinese Hamster Ovarian (CHO) host cells, and are scalable to large pilot and manufacturing scales. Several batches using different CHO-based cell lines and corresponding proprietary media and process conditions have been used to generate calibration datasets, and models have been validated using independent datasets from separate batch runs. All models have been validated to be generic and capable of predicting process parameters with acceptable accuracy. The developed models allow monitoring multiple key bioprocess metabolic variables, and hence can be utilized as an important enabling tool for Quality by Design approaches which are strongly supported by the U.S. Food and Drug Administration.

Pore Interconnectivity Influences Growth Factor-Mediated Vascularization in Sphere-Templated Hydrogels.

Rapid and controlled vascularization within biomaterials is essential for many applications in regenerative medicine. The extent of vascularization is influenced by a number of factors, including scaffold architecture. While properties such as pore size and total porosity have been studied extensively, the importance of controlling the interconnectivity of pores has received less attention. A sintering method was used to generate hydrogel scaffolds with controlled pore interconnectivity. Poly(methyl methacrylate) microspheres were used as a sacrificial agent to generate porous poly(ethylene glycol) diacrylate hydrogels with interconnectivity varying based on microsphere sintering conditions. Interconnectivity levels increased with sintering time and temperature with resultant hydrogel structure showing agreement with template structure. Porous hydrogels with a narrow pore size distribution (130-150 µm) and varying interconnectivity were investigated for their ability to influence vascularization in response to gradients of platelet-derived growth factor-BB (PDGF-BB). A rodent subcutaneous model was used to evaluate vascularized tissue formation in the hydrogels in vivo. Vascularized tissue invasion varied with interconnectivity. At week 3, higher interconnectivity hydrogels had completely vascularized with twice as much invasion. Interconnectivity also influenced PDGF-BB transport within the scaffolds. An agent-based model was used to explore the relative roles of steric and transport effects on the observed results. In conclusion, a technique for the preparation of hydrogels with controlled pore interconnectivity has been developed and evaluated. This method has been used to show that pore interconnectivity can independently influence vascularization of biomaterials.

Agent-based modeling of porous scaffold degradation and vascularization: Optimal scaffold design based on architecture and degradation dynamics.

A multi-layer agent-based model (ABM) of biomaterial scaffold vascularization is extended to consider the effects of scaffold degradation kinetics on blood vessel formation. A degradation model describing the bulk disintegration of porous hydrogels is incorporated into the ABM. The combined degradation-angiogenesis model is used to investigate growing blood vessel networks in the presence of a degradable scaffold structure. Simulation results indicate that higher porosity, larger mean pore size, and rapid degradation allow faster vascularization when not considering the structural support of the scaffold. However, premature loss of structural support results in failure for the material. A strategy using multi-layer scaffold with different degradation rates in each layer was investigated as a way to address this issue. Vascularization was improved with the multi-layered scaffold model compared to the single-layer model. The ABM developed provides insight into the characteristics that influence the selection of optimal geometric parameters and degradation behavior of scaffolds, and enables easy refinement of the model as new knowledge about the underlying biological phenomena becomes available. STATEMENT OF SIGNIFICANCE: This paper proposes a multi-layer agent-based model (ABM) of biomaterial scaffold vascularization integrated with a structural-kinetic model describing bulk degradation of porous hydrogels to consider the effects of scaffold degradation kinetics on blood vessel formation. This enables the assessment of scaffold characteristics and in particular the disintegration characteristics of the scaffold on angiogenesis. Simulation results indicate that higher porosity, larger mean pore size, and rapid degradation allow faster vascularization when not considering the structural support of the scaffold. However, premature loss of structural support by scaffold disintegration results in failure of the material and disruption of angiogenesis. A strategy using multi-layer scaffold with different degradation rates in each layer was investigated as away to address this issue. Vascularization was improved with the multi-layered scaffold model compared to the single-layer model. The ABM developed provides insight into the characteristics that influence the selection of optimal geometric and degradation characteristics of tissue engineering scaffolds.

Evaluating 3D-printed biomaterials as scaffolds for vascularized bone tissue engineering.

There is an unmet need for a consistent set of tools for the evaluation of 3D-printed constructs. A toolbox developed to design, characterize, and evaluate 3D-printed poly(propylene fumarate) scaffolds is proposed for vascularized engineered tissues. This toolbox combines modular design and non-destructive fabricated design evaluation, evaluates biocompatibility and mechanical properties, and models angiogenesis.

Agent-based modeling of osteogenic differentiation of mesenchymal stem cells in porous biomaterials.

Mesenchymal stem cells (MSC) have shown promise in tissue engineering applications due to their potential for differentiating into mesenchymal tissues such as osteocytes, chondrocytes, and adipocytes and releasing proteins to promote tissue regeneration. One application involves seeding MSCs in biomaterial scaffolds to promote osteogenesis in the repair of bone defects following implantation. However, predicting in vivo survival and differentiation of MSCs in biomaterials is challenging. Rapid and stable vascularization of scaffolds is required to supply nutrients and oxygen that MSCs need to survive as well as to go through osteogenic differentiation. The objective of this study is to develop an agent-based model and simulator that can be used to investigate the effects of using gradient growth factors on survival and differentiation of MSCs seeded in scaffolds. An agent-based model is developed to simulate the MSC behavior. The effect of vascular endothelial growth factor (VEGF) and bone morphogenic protein-2 (BMP-2) on both survival and osteogenic differentiation is studied. Results showed that the survival ratio of MSCs can be enhanced by increasing VEGF concentration. BMP-2 caused a slight increase on survival ratio. Osteogenesis strongly depends on the VEGF concentration as well because of its effect on vascularization. BMP-2 increased the osteogenic differentiation of MSCs.

Three-dimensional modeling of angiogenesis in porous biomaterial scaffolds.

Vascularization of biomaterial scaffolds is essential for the successful clinical application of engineered tissues. Experimental studies are often performed to investigate the role of scaffold architecture on vascularized tissue formation. However, experiments are expensive and time-consuming and synthesis protocols often do not allow for independent investigation of specific scaffold properties. Computational models allow for rapid screening of potential material designs with control over scaffold properties that is difficult in laboratory settings. We have developed and tested a three-dimensional agent-based framework for investigating the effect of scaffold pore architecture on angiogenesis. Software agents represent endothelial cells, interacting together and with their micro-environment, leading to the invasion of blood vessels into the scaffold. A rule base, driven by experimental findings, governs the behavior of individual agents. 3D scaffold models with well-defined homogeneous and heterogeneous pore architectures were simulated to investigate the impact of various design parameters. Simulation results indicate that pores of larger size with higher interconnectivity and porosity support rapid and extensive angiogenesis. The developed framework can be used to screen biomaterial scaffold designs for optimal vascularization and investigate complex interactions among invading blood vessels and their micro-environment.

An agent-based model for the investigation of neovascularization within porous scaffolds.

The ability to control blood vessel assembly in polymer scaffolds is important for clinical success in tissue engineering. A mathematical and computational representation of the relationship between scaffold properties and neovascularization may provide a better understanding of the fundamental process itself and help guide the design of new therapeutic approaches. This article proposes a multilayered, multiagent framework to model sprouting angiogenesis in porous scaffolds and examines the impact of pore structure on vessel invasion and network structure. We have defined the speed of vessel sprouting in the agent-based model based on in vivo results in the absence of a polymer scaffold. A number of cases were run to investigate the effect of scaffold pore size on angiogenesis. The simulation results indicate that the rate of scaffold vascularization increases with pore size. Pores of larger size (160-270 µm) support rapid and extensive angiogenesis throughout the scaffold. Model predictions were compared to experimental results of vascularization in porous poly(ethylene glycol) hydrogels to validate the results. This model can be used to provide insight into optimal scaffold properties that support vascularization of engineered tissues.