Search results for: patent foramen ovale

Authors: Mansur Agzamov, Valery Bersnev, Natalia Ivanova, Istam Agzamov, Timur Khayrullaev, Yulduz Agzamova

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Objectives. Treatment of hypertensive intracerebral hematoma (ICH) is controversial. Advantage of one surgical method on other has not been established. Recent reports suggest a favorable effect of minimally invasive surgery. We conducted a small comparative study of different surgical methods. Methods. We analyzed the result of surgical treatment of 176 patients with intracerebral hematomas at the age from 41 to 78 years. Men were been113 (64.2%), women - 63 (35.8%). Level of consciousness: conscious -18, lethargy -63, stupor –55, moderate coma - 40. All patients on admission and in the dynamics underwent computer tomography (CT) of the brain. ICH was located in the putamen in 87 cases, thalamus in 19, in the mix area in 50, in the lobar area in 20. Ninety seven patients of them had an intraventricular hemorrhage component. The baseline volume of the ICH was measured according to a bedside method of measuring CT intracerebral hematomas volume. Depending on the intervention of the patients were divided into three groups. Group 1 patients, 90 patients, operated open craniotomy. Level of consciousness: conscious-11, lethargy-33, stupor–18, moderate coma -18. The hemorrhage was located in the putamen in 51, thalamus in 3, in the mix area in 25, in the lobar area in 11. Group 2 patients, 22 patients, underwent smaller craniotomy with endoscopic-assisted evacuation. Level of consciousness: conscious-4, lethargy-9, stupor–5, moderate coma -4. The hemorrhage was located in the putamen in 5, thalamus in 15, in the mix area in 2. Group 3 patients, 64 patients, was conducted minimally invasive removal of intracerebral hematomas using the original device (patent of Russian Federation № 65382). The device - funnel cannula - which after the special markings introduced into the hematoma cavity. Level of consciousness: conscious-3, lethargy-21, stupor–22, moderate coma -18. The hemorrhage was located in the putamen in 31, in the mix area in 23, thalamus in 1, in the lobar area in 9. Results of treatment were evaluated by Glasgow outcome scale. Results. The study showed that the results of surgical treatment in three groups depending on the degree of consciousness, the volume and localization of hematoma. In group 1, good recovery observed in 8 cases (8.9%), moderate disability in 22 (24.4%), severe disability - 17 (18.9%), death-43 (47.8%). In group 2, good recovery observed in 7 cases (31.8%), moderate disability in 7 (31.8%), severe disability - 5 (29.7%), death-7 (31.8%). In group 3, good recovery was observed in 9 cases (14.1%), moderate disability-17 (26.5%), severe disability-19 (29.7%), death-19 (29.7%). Conclusions. The method of using cannulae allowed to abandon from open craniotomy of the majority of patients with putaminal hematomas. Minimally invasive technique reduced the postoperative mortality and improves treatment outcomes of these patients.

Keywords: nontraumatic intracerebral hematoma, minimal invasive surgical technique, funnel canula, differentiated surcical treatment

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Authors: Weixing Tan

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Production of nutraceuticals from microalgae—a virtually untapped natural phyto-based source of which there are 200,000 to 1,000,000 species—offers a sustainable and healthy alternative to conventionally sourced nutraceuticals for the market. Microalgae can be grown organically using only natural sunlight, water and nutrients at an extremely fast rate, e.g. 10-100 times more efficiently than crops or trees. However, the commercial success of microalgae products at scale remains limited largely due to the lack of economically viable technologies. There are two major microalgae production systems or technologies currently available: 1) the open system as represented by open pond technology and 2) the closed system such as photobioreactors (PBR). Each carries its own unique features and challenges. Although an open system requires a lower initial capital investment relative to a PBR, it conveys many unavoidable drawbacks; for example, much lower productivity, difficulty in contamination control/cleaning, inconsistent product quality, inconvenience in automation, restriction in location selection, and unsuitability for cold areas – all directly linked to the system openness and flat underground design. On the other hand, a PBR system has characteristics almost entirely opposite to the open system, such as higher initial capital investment, better productivity, better contamination and environmental control, wider suitability in different climates, ease in automation, higher and consistent product quality, higher energy demand (particularly if using artificial lights), and variable operational expenses if not automated. Although closed systems like PBRs are not highly competitive yet in current nutraceutical supply market, technological advances can be made, in particular for the PBR technology, to narrow the gap significantly. One example is a readily scalable P2P Microalgae PBR Technology at Grande Prairie Regional College, Canada, developed over 11 years considering return on investment (ROI) for key production processes. The P2P PBR system is approaching economic viability at a pre-commercial stage due to five ROI-integrated major components. They include: (1) optimum use of free sunlight through attenuation (patented); (2) simple, economical, and chemical-free harvesting (patent ready to file); (3) optimum pH- and nutrient-balanced culture medium (published), (4) reliable water and nutrient recycling system (trade secret); and (5) low-cost automated system design (trade secret). These innovations have allowed P2P Microalgae Technology to increase daily yield to 106 g/m2/day of Chlorella vulgaris, which contains 50% proteins and 2-3% omega-3. Based on the current market prices and scale-up factors, this P2P PBR system presents as a promising microalgae technology for market competitive nutraceutical supply.

Keywords: microalgae technology, nutraceuticals, open pond, photobioreactor PBR, return on investment ROI, technological advances

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Authors: Akmez Nabeerasool, Michaelis Massaros, Nigel Brown, David Sanderson, David Parocki, Charlotte Thompson, Mike Lodge, Mikael Khan

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The provision of clean and safe drinking water is of paramount importance and is a basic human need. Water scarcity coupled with tightening of regulations and the inability of current treatment technologies to deal with emerging contaminants and Pharmaceuticals and personal care products means that alternative treatment technologies that are viable and cost effective are required in order to meet demand and regulations for clean water supplies. Logistically, the application of water treatment in rural areas presents unique challenges due to the decentralisation of abstraction points arising from low population density and the resultant lack of infrastructure as well as the need to treat water at the site of use. This makes it costly to centralise treatment facilities and hence provide potable water direct to the consumer. Furthermore, across the UK there are segments of the population that rely on a private water supply which means that the owner or user(s) of these supplies, which can serve one household to hundreds, are responsible for the maintenance. The treatment of these private water supply falls on the private owners, and it is imperative that a chemical free technological solution that can operate unattended and does not produce any waste is employed. Arvia’s patented advanced oxidation technology combines the advantages of adsorption and electrochemical regeneration within a single unit; the Organics Destruction Cell (ODC). The ODC uniquely uses a combination of adsorption and electrochemical regeneration to destroy organics. Key to this innovative process is an alternative approach to adsorption. The conventional approach is to use high capacity adsorbents (e.g. activated carbons with high porosities and surface areas) that are excellent adsorbents, but require complex and costly regeneration. Arvia’s technology uses a patent protected adsorbent, Nyex™, which is a non-porous, highly conductive, graphite based adsorbent material that enables it to act as both the adsorbent and as a 3D electrode. Adsorbed organics are oxidised and the surface of the Nyex™ is regenerated in-situ for further adsorption without interruption or replacement. Treated water flows from the bottom of the cell where it can either be re-used or safely discharged. Arvia™ Technology Ltd. has trialled the application of its tertiary water treatment technology in treating reservoir water abstracted near Glasgow, Scotland, with promising results. Several other pilot plants have also been successfully deployed at various locations in the UK showing the suitability and effectiveness of the technology in removing recalcitrant organics (including pharmaceuticals, steroids and hormones), COD and colour.

Keywords: Arvia™ process, adsorption, water treatment, electrochemical oxidation

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Authors: Aarti M. Shetty, Estela Davoodi, Subrata Gangooly, Anita Rao-Coppisetty

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Background: Testing Patency of Fallopian Tubes is among one of the several protocols for investigating Subfertile Couples. Both, Hysterosalpingogram (HSG) and Laparoscopy and dye test have been used as Tubal patency test for several years, with well-known limitation. Hysterosalpingo Contrast Sonography (HyCoSy) can be used as an alternative tool to HSG, to screen patency of Fallopian tubes, with an advantage of being non-ionising, and also, use of transvaginal scan to diagnose pelvic pathology. Aim: To determine the indication and analyse the performance of transvaginal scan and HyCoSy in Broomfield Hospital. Methods: We retrospectively analysed fertility workup of 282 women, who attended HyCoSy clinic at our institution from January 2015 to June 2016. An Audit proforma was designed, to aid data collection. Data was collected from patient notes and electronic records, which included patient demographics; age, parity, type of subfertility (primary or secondary), duration of subfertility, past medical history and base line investigation (hormone profile and semen analysis). Findings of the transvaginal scan, HyCoSy and Laparoscopy were also noted. Results: The most common indication for referral were as a part of primary fertility workup on couples who had failure to conceive despite intercourse for a year, other indication for referral were recurrent miscarriage, history of ectopic pregnancy, post reversal of sterilization(vasectomy and tuboplasty), Post Gynaecology surgery(Loop excision, cone biopsy) and amenorrhea. Basic Fertility workup showed 34% men had abnormal semen analysis. HyCoSy was successfully completed in 270 (95%) women using ExEm foam and Transvaginal Scan. Of the 270 patients, 535 tubes were examined in total. 495/535 (93%) tubes were reported as patent, 40/535 (7.5%) tubes were reported as blocked. A total of 17 (6.3%) patients required laparoscopy and dye test after HyCoSy. In these 17 patients, 32 tubes were examined under laparoscopy, and 21 tubes had findings similar to HyCoSy, with a concordance rate of 65%. In addition to this, 41 patients had some form of pelvic pathology (endometrial polyp, fibroid, cervical polyp, fibroid, bicornuate uterus) detected during transvaginal scan, who referred to corrective surgeries after attending HyCoSy Clinic. Conclusion: Our audit shows that HyCoSy and Transvaginal scan can be a reliable screening test for low risk women. Furthermore, it has competitive diagnostic accuracy to HSG in identifying tubal patency, with an additional advantage of screening for pelvic pathology. With addition of 3D Scan, pulse Doppler and other non-invasive imaging modality, HyCoSy may potentially replace Laparoscopy and chromopertubation in near future.

Keywords: hysterosalpingo contrast sonography (HyCoSy), transvaginal scan, tubal infertility, tubal patency test

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Authors: Arnesh Vijay

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Ever since its early introduction in the late 1980s, the mobile industry has been rapidly evolving with each passing year. The development witnessed is not just in its ability to support diverse applications, but also its extension into diverse technological means to access and offer various services to users. Amongst the various technologies present, radio systems have clearly emerged as a strong contender, due to its fine attributes of accessibility, reachability, interactiveness, and cost efficiency. These advancements have no doubt guaranteed unprecedented ease, utility and sophistication to the cell phone users, but caused uncertainty due to the interdependence of various systems, making it extremely complicated to exactly map concepts on to 3GPP (3rd Generation Partnership Project) standards. Although the close interrelation and interdependence of intellectual property rights and mobile standard specifications have been widely acknowledged by the technical and legal community; there, however, is a requirement for clear distinction between the scope and future-proof of inventions to influence standards and its market place adoptability. For this, collaborative work is required between intellectual property professionals, researchers, standardization specialists and country specific legal experts. With the evolution into next generation mobile technology, i.e., to 5G systems, there is a need for further work to be done in this field, which has been felt now more than ever before. Based on these lines, this poster will briefly describe the importance of intellectual property rights in the European market. More specifically, will analyse the role played by intellectual property in various standardization institutes, such as 3GPP (3rd generation partnership project) and ITU (International Telecommunications Union). The main intention: to ensure the scope and purpose is well defined, and concerned parties on all four sides are well informed on the clear significance of good proposals which not only bring economic revenue to the company but those that are capable of improving the technology and offer better services to mankind. The poster will comprise different sections. The first segment begins with a background on the rapidly evolving mobile technology, with a brief insight on the industrial impact of standards and its relation to intellectual property rights. Next, section two will succinctly outline the interplay between patents and standards; explicitly discussing the ever changing and rapidly evolving relationship between the two sectors. Then the remaining sections will examine ITU and its role played in international standards development, touching upon the various standardization process and the common patent policies and related guidelines. Finally, it proposes ways to improve the collaboration amongst various sectors for a more evolved and sophisticated next generation mobile telecommunication system. The sole purpose here is to discuss methods to reduce the gap and enhance the exchange of information between the two sectors to offer advanced technologies and services to mankind.

Keywords: mobile technology, mobile standards, intellectual property rights, 3GPP

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Authors: A. Delimitsou, C. Gouedard, E. Konstanta, A. Koletis, S. Patera, E. Manou, K. Spaho, S. Murray

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Background: There remains a lack of International Standard Control Reference materials for Next Generation Sequencing-based approaches or device calibration. We have designed and validated dsDNA biomimetic reference materials for targeted such approaches incorporating proprietary motifs (patent pending) for device/test calibration. They enable internal single-sample calibration, alleviating sample comparisons to pooled historical population-based data assembly or statistical modelling approaches. We have validated such an approach for BRCA Copy Number Variation analytics using iQRS™-CNVSUITE versus Mixed Ligation-dependent Probe Amplification. Methods: Standard BRCA Copy Number Variation analysis was compared between mixed ligation-dependent probe amplification and next generation sequencing using a cohort of 198 breast/ovarian cancer patients. Next generation sequencing based copy number variation analysis of samples spiked with iQRS™ dsDNA biomimetics were analysed using proprietary CNVSUITE software. Mixed ligation-dependent probe amplification analyses were performed on an ABI-3130 Sequencer and analysed with Coffalyser software. Results: Concordance of BRCA – copy number variation events for mixed ligation-dependent probe amplification and CNVSUITE indicated an overall sensitivity of 99.88% and specificity of 100% for iQRS™-CNVSUITE. The negative predictive value of iQRS-CNVSUITE™ for BRCA was 100%, allowing for accurate exclusion of any event. The positive predictive value was 99.88%, with no discrepancy between mixed ligation-dependent probe amplification and iQRS™-CNVSUITE. For device calibration purposes, precision was 100%, spiking of patient DNA demonstrated linearity to 1% (±2.5%) and range from 100 copies. Traditional training was supplemented by predefining the calibrator to sample cut-off (lock-down) for amplicon gain or loss based upon a relative ratio threshold, following training of iQRS™-CNVSUITE using spiked iQRS™ calibrator and control mocks. BRCA copy number variation analysis using iQRS™-CNVSUITE™ was successfully validated and ISO15189 accredited and now enters CE-IVD performance evaluation. Conclusions: The inclusion of a reference control competitor (iQRS™ dsDNA mimetic) to next generation sequencing-based sequencing offers a more robust sample-independent approach for the assessment of copy number variation events compared to mixed ligation-dependent probe amplification. The approach simplifies data analyses, improves independent sample data analyses, and allows for direct comparison to an internal reference control for sample-specific quantification. Our iQRS™ biomimetic reference materials allow for single sample copy number variation analytics and further decentralisation of diagnostics to single patient sample assessment.

Keywords: validation, diagnostics, oncology, copy number variation, reference material, calibration

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Authors: Jianli Jiang, Bai-Chen Xie

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The climate issue has aroused global concern. Achieving sustainable development is a good path for countries to mitigate environmental and climatic pressures, although there are many difficulties. The first step towards sustainable development is to evaluate the environmental efficiency of the energy industry with proper methods. The power sector is a major source of CO2, SO2, and NOx emissions. Evaluating the environmental efficiency (EE) of power systems is the premise to alleviate the terrible situation of energy and the environment. Data Envelopment Analysis (DEA) has been widely used in efficiency studies. However, measuring the efficiency of a system (be it a nation, region, sector, or business) is a challenging task. The classic DEA takes the decision-making units (DMUs) as independent, which neglects the interaction between DMUs. While ignoring these inter-regional links may result in a systematic bias in the efficiency analysis; for instance, the renewable power generated in a certain region may benefit the adjacent regions while the SO2 and CO2 emissions act oppositely. This study proposes a spatial network DEA (SNDEA) with a slack measure that can capture the spatial spillover effects of inputs/outputs among DMUs to measure efficiency. This approach is used to study the EE of China's power system, which consists of generation, transmission, and distribution departments, using a panel dataset from 2014 to 2020. In the empirical example, the energy and patent inputs, the undesirable CO2 output, and the renewable energy (RE) power variables are tested for a significant spatial spillover effect. Compared with the classic network DEA, the SNDEA result shows an obvious difference tested by the global Moran' I index. From a dynamic perspective, the EE of the power system experiences a visible surge from 2015, then a sharp downtrend from 2019, which keeps the same trend with the power transmission department. This phenomenon benefits from the market-oriented reform in the Chinese power grid enacted in 2015. The rapid decline in the environmental efficiency of the transmission department in 2020 was mainly due to the Covid-19 epidemic, which hinders economic development seriously. While the EE of the power generation department witnesses a declining trend overall, this is reasonable, taking the RE power into consideration. The installed capacity of RE power in 2020 is 4.40 times that in 2014, while the power generation is 3.97 times; in other words, the power generation per installed capacity shrank. In addition, the consumption cost of renewable power increases rapidly with the increase of RE power generation. These two aspects make the EE of the power generation department show a declining trend. Incorporation of the interactions among inputs/outputs into the DEA model, this paper proposes an efficiency evaluation method on the basis of the DEA framework, which sheds some light on efficiency evaluation in regional studies. Furthermore, the SNDEA model and the spatial DEA concept can be extended to other fields, such as industry, country, and so on.

Keywords: spatial network DEA, environmental efficiency, sustainable development, power system

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Authors: Elena Parmentier, Henrik Endeman

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Introduction: Large mediastinal masses often present with diagnostic and clinical challenges due to compression of the respiratory and hemodynamic system. We present a case of a mediastinal mass with symptomatic mechanical compression of the trachea, resulting in challenging airway management. Methods: We present a case of 66-year-old male, complaining of progressive dysphagia. Initial esophagogastroscopy revealed a stenosis secondary to external compression, biopsies were inconclusive. Additional CT scan showed a large mediastinal mass of unknown origin, situated between the vertebrae and esophagus. Symptoms progressed and patient developed dyspnea and stridor. A new CT showed quick growth of the mass with compression of the trachea, subglottic to just above the carina. A tracheal covered stent was successfully placed. Endobronchial ultrasound revealed a large irregular mass without tracheal invasion, biopsies were taken. 4 days after stent placement, the patients’ condition deteriorated with worsening of stridor, dyspnea and desaturation. Migration of the tracheal stent into the right main bronchus was seen on chest X ray, with obstruction of the left main bronchus and secondary atelectasis. Different methods have been described in the literature for tracheobronchial stent removal (surgical, endoscopic, fluoroscopyguided), our first choice in this case was flexible bronchoscopy. However, this revealed tracheal compression above the migrated stent and passage of the scope occurred impossible. Patient was admitted to the ICU, high-flow nasal oxygen therapy was started and the situation stabilized, giving time for extensive assessment and preparation of the airway management approach. Close cooperation between the intensivist, pulmonologist, anesthesiologist and otorhinolaryngologist was essential. Results: In case of sudden deterioration, a protocol for emergency situations was made. Given the increased risk of additional tracheal compression after administration of neuromuscular blocking agents, an approach with awake fiberoptic intubation maintaining spontaneous ventilation was proposed. However, intubation without retrieval of the tracheal stent was found undesirable due to expected massive shunting over the left atelectatic lung. As rescue option, assistance of extracorporeal circulation was considered and perfusionist was kept on standby. The patient stayed stable and was transferred to the operating theatre. High frequency jet ventilation under general anesthesia resulted in desaturations up to 50%, making rigid bronchoscopy impossible. Subsequently an endotracheal tube size 8 could be placed successfully and the stent could be retrieved via bronchoscopy over (and with) the tube, after which the patient was reintubated. Finally, a tracheostomy (Shiley™ Tracheostomy Tube With Cuff, size 8) was placed, fiberoptic control showed a patent airway. Patient was readmitted to the ICU and could be quickly weaned of the ventilator. Pathology was positive for rhabdomyosarcoma, without indication for systemic therapy. Extensive surgery (laryngectomy, esophagectomy) was suggested, but patient refused and palliative care was started. Conclusion: Due to meticulous planning in an interdisciplinary team, we showed a successful airway management approach in this complicated case of critical airway compression secondary to a rare rhabdomyosarcoma, complicated by tracheal stent migration. Besides presenting our thoughts and considerations, we support exploring other possible approaches of this specific clinical problem.

Keywords: airway management, rhabdomyosarcoma, stent displacement, tracheal stenosis

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Authors: Loretta Ichim, Dan Popescu, Grigore Stamatescu

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The paper reports the collaboration between a top university from Romania and three companies for the implementation of a research project in a multidisciplinary domain, focusing on the impact and benefits both for the education and industry. The joint activities were developed under the Space Technology and Advanced Research Program (STAR), funded by the Romanian Space Agency (ROSA) for a university-industry partnership. The context was defined by linking the European Space Agency optional programs, with the development and promotion national research, with the educational and industrial capabilities in the aeronautics, security and related areas by increasing the collaboration between academic and industrial entities as well as by realizing high-level scientific production. The project name is Multisensory Robotic System for Aerial Monitoring of Critical Infrastructure Systems (MUROS), which was carried 2013-2016. The project included the University POLITEHNICA of Bucharest (coordinator) and three companies, which manufacture and market unmanned aerial systems. The project had as main objective the development of an integrated system for combined ground wireless sensor networks and UAV monitoring in various application scenarios for critical infrastructure surveillance. This included specific activities related to fundamental and applied research, technology transfer, prototype implementation and result dissemination. The core area of the contributions laid in distributed data processing and communication mechanisms, advanced image processing and embedded system development. Special focus is given by the paper to analyzing the impact the project implementation in the educational process, directly or indirectly, through the faculty members (professors and students) involved in the research team. Three main directions are discussed: a) enabling students to carry out internships at the partner companies, b) handling advanced topics and industry requirements at the master's level, c) experiments and concept validation for doctoral thesis. The impact of the research work (as the educational component) developed by the faculty members on the increasing performances of the companies’ products is highlighted. The collaboration between university and companies was well balanced both for contributions and results. The paper also presents the outcomes of the project which reveals the efficient collaboration between high education and industry: master thesis, doctoral thesis, conference papers, journal papers, technical documentation for technology transfer, prototype, and patent. The experience can provide useful practices of blending research and education within an academia-industry cooperation framework while the lessons learned represent a starting point in debating the new role of advanced research and development performing companies in association with higher education. This partnership, promoted at UE level, has a broad impact beyond the constrained scope of a single project and can develop into long-lasting collaboration while benefiting all stakeholders: students, universities and the surrounding knowledge-based economic and industrial ecosystem. Due to the exchange of experiences between the university (UPB) and the manufacturing company (AFT Design), a new project, SIMUL, under the Bridge Grant Program (Romanian executive agency UEFISCDI) was started (2016 – 2017). This project will continue the educational research for innovation on master and doctoral studies in MUROS thematic (collaborative multi-UAV application for flood detection).

Keywords: education process, multisensory robotic system, research and innovation project, technology transfer, university-industry partnership

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Authors: Z. S. Haidar

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Millions of teeth are removed annually, and dental extraction is one of the most commonly performed surgical procedures globally. Whether due to caries, periodontal disease, or trauma, exodontia and the ensuing wound healing and bone remodeling processes of the resultant socket (hole in the jaw bone) usually result in serious deformities of the residual alveolar osseous ridge and surrounding soft tissues (reduced height/width). Such voluminous changes render the placement of a proper conventional bridge, denture, or even an implant-supported prosthesis extremely challenging. Further, most extractions continue to be performed with no regard for preventing the onset of alveolar osteitis (also known as dry socket, a painful and difficult-to-treat/-manage condition post-exodontia). Hence, such serious resorptive morphological changes often result in significant facial deformities and a negative impact on the overall Quality of Life (QoL) of patients (and oral health-related QoL); alarming, particularly for the geriatric with compromised healing and in light of the thriving longevity statistics. Despite advances in tissue/wound grafting, serious limitations continue to exist, including efficacy and clinical outcome predictability, cost, treatment time, expertise, and risk of immune reactions. For cases of dry socket, specifically, the commercially available and often-prescribed home remedies are highly-lacking. Indeed, most are not recommended for use anymore. Alveogyl is a fine example. Hence, there is a great market demand and need for alternative solutions. Herein, SockGEL/PLUG (patent pending), an innovative, all-natural, drug-free, and injectable thermo-responsive hydrogel, was designed, formulated, characterized, and evaluated as an osteogenic, angiogenic, anti-microbial, and pain-soothing suture-free intra-alveolar dressing, safe and efficacious for use in fresh extraction sockets, immediately post-exodontia. It is composed of FDA-approved, biocompatible and biodegradable polymers, self-assembled electro-statically to formulate a scaffolding matrix to (1) prevent the on-set of alveolar osteitis via securing the fibrin-clot in situ and protecting/sealing the socket from contamination/infection; and (2) endogenously promote/accelerate wound healing and bone remodeling to preserve the volume of the alveolus. The intrinsic properties of the SockGEL/PLUG hydrogel were evaluated physical-chemical-mechanically for safety (cell viability), viscosity, rheology, bio-distribution, and essentially, capacity to induce wound healing and osteogenesis (small defect, in vivo) without any signaling cues from exogenous cells, growth factors or drugs. The proposed animal model of cranial critical-sized and non-vascularized bone defects shall provide new and critical insights into the role and mechanism of the employed natural bio-polymer blend and gel product in endogenous reparative regeneration of soft tissues and bone morphogenesis. Alongside, the fine-tuning of our modified formulation method will further tackle appropriateness, reproducibility, scalability, ease, and speed in producing stable, biodegradable, and sterilizable thermo-sensitive matrices (3-dimensional interpenetrating yet porous polymeric network) suitable for the intra-socket application. Findings are anticipated to provide sufficient evidence to translate into pilot clinical trials and validate the innovation before engaging the market for feasibility, acceptance, and cost-effectiveness studies.

Keywords: hydrogel, nanotechnology, bioengineering, bone regeneration, nanogel, drug delivery

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Authors: Ziyad S. Haidar

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Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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