In vivo study to assess fat embolism resulting from the Reamer-Irrigator-Aspirator 2 system compared to a novel aspirator-based concept for intramedullary bone graft harvesting.

INTRODUCTION: Fat embolism (FE) following intramedullary (IM) reaming can cause severe pulmonary complications and sudden death. Recently, a new harvesting concept was introduced in which a novel aspirator is used first for bone marrow (BM) aspiration and then for subsequent aspiration of morselized endosteal bone during sequential reaming (A + R + A). In contrast to the established Reamer-Irrigator-Aspirator (RIA) 2 system, the new A + R + A concept allows for the evacuation of fatty BM prior to reaming. In this study, we hypothesized that the risk of FE, associated coagulopathic reactions and pulmonary FE would be comparable between the RIA 2 system and the A + R + A concept. MATERIALS AND METHODS: Intramedullary bone graft was harvested from intact femora of 16 Merino sheep (age: 1-2 years) with either the RIA 2 system (n = 8) or the A + R + A concept (n = 8). Fat intravasation was monitored with the Gurd test, coagulopathic response with D-dimer blood level concentration and pulmonary FE with histological evaluation of the lungs. RESULTS: The total number and average size of intravasated fat particles was similar between groups (p = 0.13 and p = 0.98, respectively). D-dimer concentration did not significantly increase within 4 h after completion of surgery (RIA 2: p = 0.82; A + R + A: p = 0.23), with an interaction effect similar between groups (p = 0.65). The average lung area covered with fat globules was similar between groups (p = 0.17). CONCLUSIONS: The use of the RIA 2 system and the novel A + R + A harvesting concept which consists of BM evacuation followed by sequential IM reaming and aspiration of endosteal bone, resulted in only minor fat intravasation, coagulopathic reactions and pulmonary FE, with no significant differences between the groups. Our results, therefore, suggest that both the RIA 2 system and the new A + R + A concept are comparable technologies in terms of FE-related complications.

Controlled release vaccine implants for delivery of booster immunisations.

Most current animal vaccine regimes involve a primary vaccination followed sometime later by a booster vaccination. This presents challenges when vaccinating difficult to access animals such as livestock. Mustering livestock to deliver a vaccine boost is costly and stressful for animals. Thus, we have produced a platform system that can be administered at the same time as the priming immunisation and delivers payload after an appropriate delay time to boost the immune response, without need for further handling of animals. A 30 × 2 mm osmotically triggered polymer implant device with burst-release characteristics delivered the booster dose of a tetanus vaccine. Blood samples were collected from an experimental group that received the priming vaccine and implant on day 0 and control group that received the initial vaccine (tetanus toxoid) and then a bolus dose 28 days later via subcutaneous injection. The two groups showed identical weight gain curves. T cell proliferation following in vitro stimulation with antigen was identical between the two groups at all time points. However, serum IgG antibody responses to the tetanus toxoid antigen were significantly higher in the control group at weeks 8 and 12. The implant capsules stayed at the site of implantation and at week 12 there was evidence of tissue integration. No local reactions at the implant site were observed, other than mild thickening of the skin in half of the experimental group animals and no other adverse health events were recorded in either group.

In vivo evaluation of skin integration with ventricular assist device drivelines.

BACKGROUND: Ventricular assist device (VAD) driveline exit site infection is a common complication. 3D scaffolds manufactured with highly homogeneous pores via melt electro-writing (MEW) may generate an improved skin-driveline interface which permits cellular in-growth and creates a barrier to prevent bacterial migration along the driveline tissue tunnel. This study investigated skin integration on segments of Heartmate 3 driveline: smooth polyurethane, velour, and on a custom MEW scaffold in a small animal model. METHODS: Drivelines with surfaces consisting of smooth polyurethane, velour bonded to smooth polyurethane, and smooth polyurethane with a MEW scaffold sleeve were implanted percutaneously in the dorsum of 42 rats. Each rat was implanted with 2 pieces of driveline of 2 cm in length. Skin integration was assessed after 7 and 14 days. RESULTS: Macroscopically, velour and MEW scaffold surfaces were anchored at the driveline-skin interface while smooth polyurethane samples were not attached. The histology analyses showed epidermal migration throughout the thickness of the velour and MEW scaffold groups. Evident tissue growth around single MEW scaffold fibers resulted in full coverage of the pores, while areas of compacted fibers were apparent in the velour group. Tissue ingrowth was significantly higher in the MEW group compared to the velour group after 7 (p < 0.0001) and 14 days (p < 0.0001). Marsupialization was observed in the smooth polyurethane samples. Mechanical pull-out forces were similar between velour and MEW scaffold groups at 7 and 14 days (p > 0.05). CONCLUSIONS: Velour and MEW scaffolds promoted epidermal integration while smooth polyurethane drivelines did not. Fine control of MEW scaffold structure production resulted in full cellular coverage and may reduce driveline infection.

Regulatory aspects and evidences of melatonin use for sleep disorders and insomnia: an integrative review.

BACKGROUND: Insomnia is a sleep disorder characterized by difficulty of falling asleep or maintaining sleep, which affects different age groups. Currently, melatonin is used as a therapeutic treatment in cases of insomnia in children, adults, and elderly people. OBJECTIVE: To evaluate the effectiveness of melatonin in sleep disorders, its dosage, potential adverse effects, as well as labeling laws and regulations in Brazil. METHODS: This integrative review was carried out using the Cochrane Library, Medline (Pubmed), and Science Direct databases. Twenty-five articles and three documents available on the Brazilian Society of Endocrinology and Metabology (SBEM) and National Health Surveillance Agency (ANVISA) websites published between 2015 and 2020 were selected to be evaluated in full. RESULTS: It was found that in most of the selected articles the use of melatonin reduces sleep latency. The effective melatonin doses varied according to each age group, from 0.5 to 3 mg in children, 3 to 5 mg in adolescents, 1 to 5 mg in adults, and 1 to 6 mg in elderly people. Side effects are mild when taking usual doses. In Brazil, no registered drug and current regulation on the use and marketing of melatonin has been identified. CONCLUSION: The use of melatonin is an alternative therapy that can be used for sleeping disorders. According to the evidences found, it did not demonstrate toxicity or severe side effects, nor dependence even when administered at high doses, suggesting that it is a safe medication to treat patients of different ages suffering from sleeping disorders.

Regulatory aspects and evidences of melatonin use for sleep disorders and insomnia: an integrative review / Aspectos regulatórios e evidências do uso de melatonina em distúrbio do sono e insônia: uma revisão integrativa

ABSTRACT Background: Insomnia is a sleep disorder characterized by difficulty of falling asleep or maintaining sleep, which affects different age groups. Currently, melatonin is used as a therapeutic treatment in cases of insomnia in children, adults, and elderly people. Objective: To evaluate the effectiveness of melatonin in sleep disorders, its dosage, potential adverse effects, as well as labeling laws and regulations in Brazil. Methods: This integrative review was carried out using the Cochrane Library, Medline (Pubmed), and Science Direct databases. Twenty-five articles and three documents available on the Brazilian Society of Endocrinology and Metabology (SBEM) and National Health Surveillance Agency (ANVISA) websites published between 2015 and 2020 were selected to be evaluated in full. Results: It was found that in most of the selected articles the use of melatonin reduces sleep latency. The effective melatonin doses varied according to each age group, from 0.5 to 3 mg in children, 3 to 5 mg in adolescents, 1 to 5 mg in adults, and 1 to 6 mg in elderly people. Side effects are mild when taking usual doses. In Brazil, no registered drug and current regulation on the use and marketing of melatonin has been identified. Conclusion: The use of melatonin is an alternative therapy that can be used for sleeping disorders. According to the evidences found, it did not demonstrate toxicity or severe side effects, nor dependence even when administered at high doses, suggesting that it is a safe medication to treat patients of different ages suffering from sleeping disorders.

RESUMO Antecedentes: Insônia é um distúrbio do sono caracterizado por dificuldade de iniciar e manter o sono, afetando diferentes faixas etárias. Atualmente, a melatonina é utilizada no tratamento de insônia em crianças, adultos e idosos. Objetivo: Avaliar a eficácia da melatonina nos distúrbios do sono, posologia e potenciais efeitos adversos, bem como a regulamentação vigente no Brasil. Métodos: Trata-se de uma revisão integrativa, os artigos foram identificados nas bases de dados Cochrane Library, Medline (Pubmed) e Science Direct, totalizando 25 artigos, e foram selecionados três materiais disponíveis no site da Sociedade Brasileira de Endocrinologia e Metabologia e Agência Nacional de Vigilância Sanitária, publicados entre 2015 e 2020. Resultados: Verificou-se na maioria dos artigos selecionados que a melatonina reduz a latência do sono. Quanto as dosagens de melatonina identificou-se variação em cada faixa etária, para crianças de 0,5 a 3mg; adolescentes de 3 a 5mg; adultos de 1 a 5mg e idosos 1 mg a 6 mg demostraram serem eficazes. Em doses habituais os efeitos colaterais são leves. No Brasil, não foi identificado medicamento registrado e regulamentação vigente sobre o uso e comercialização de melatonina. Conclusão: A utilização da melatonina é uma alternativa que pode ser utilizada em distúrbios do sono. De acordo com as evidências encontradas, não demonstrou toxicidade ou efeitos colaterais severos, nem dependência mesmo em doses elevadas, sendo, portanto, segura para tratamento de pacientes desde crianças a idosos que sofrem de distúrbios do sono.

Poly(2-allylamidopropyl-2-oxazoline)-Based Hydrogels: From Accelerated Gelation Kinetics to In Vivo Compatibility in a Murine Subdermal Implant Model.

A rapid photo-curing system based on poly(2-ethyl-2-oxazoline-co-2-allylamidopropyl-2-oxazoline) and its in vivo compatibility are presented. The base polymer was synthesized from the copolymerization of 2-ethyl-2-oxazoline (EtOx) and the methyl ester containing 2-methoxycarboxypropyl-2-oxazoline (C3MestOx) followed by amidation with allylamine to yield a highly water-soluble macromer. We showed that spherical hydrogels can be obtained by a simple water-in-oil gelation method using thiol-ene coupling and investigated the in vivo biocompatibility of these hydrogel spheres in a 28-day murine subdermal model. For comparison, hydrogel spheres prepared from poly(ethylene glycol) were also implanted. Both materials displayed mild, yet typical foreign body responses with little signs of fibrosis. This is the first report on the foreign body response of a poly(2-oxazoline) hydrogel, which paves the way for future investigations into how this highly tailorable class of materials can be used for implantable hydrogel devices.

A patent review of antibiofilm fungal drugs (2002-present).

Fungal biofilms, such as Candida albicans biofilms, are capable of surviving in hostile environments owing to their remarkable ability to adhere to surfaces and their tolerance to chemical interventions. Currently, therapeutic treatment options are few, making these biofilm-based infections problematic particularly due to their great tolerance to conventional antimicrobial drugs, thus causing serious health and economic problems. Therefore, the development of new drugs and antibiofilm specific therapies for the prevention and treatment of antifungal to eradicate biofilms are needed. This study was aimed at carrying out a patent review analysis to identify the innovation trends, and to explore the latest antifungal drugs and the specific therapeutic strategies available for the treatment of fungal biofilms. The present patent review was carried out using the Espacenet database, using the key words "biofilm and antifungal," from 2002 to December 2019. Through this review, it was possible to identify that most of the patent contents refer to new synthetic drugs derived from natural products and associations thereof with existing antifungal drugs. Methods and biomaterials for the treatment and prevention of fungal biofilms, mainly for C. albicans biofilms, which is the most isolated and studied fungal species, were also disclosed. The lack of scientific and technical information on the biofilm eradication subject is remarkable and further confirmed by the small number of patents identified in this survey.

A preclinical large-animal model for the assessment of critical-size load-bearing bone defect reconstruction.

Critical-size bone defects, which require large-volume tissue reconstruction, remain a clinical challenge. Bone engineering has the potential to provide new treatment concepts, yet clinical translation requires anatomically and physiologically relevant preclinical models. The ovine critical-size long-bone defect model has been validated in numerous studies as a preclinical tool for evaluating both conventional and novel bone-engineering concepts. With sufficient training and experience in large-animal studies, it is a technically feasible procedure with a high level of reproducibility when appropriate preoperative and postoperative management protocols are followed. The model can be established by following a procedure that includes the following stages: (i) preoperative planning and preparation, (ii) the surgical approach, (iii) postoperative management, and (iv) postmortem analysis. Using this model, full results for peer-reviewed publication can be attained within 2 years. In this protocol, we comprehensively describe how to establish proficiency using the preclinical model for the evaluation of a range of bone defect reconstruction options.

The Patenting and Technological Trends in Candidiasis Treatment: A Systematic Review (2014-2018).

BACKGROUND: In the last few decades, mycoses caused by opportunistic fungi namely Candida species has gained significant attention. Such infections are very common and present high mortality rates, especially in immunocompromised patients. Currently, a limited number of antifungal drugs are available for the treatment of these infections and are also often related to severe adverse side effects. Therefore, new drugs and innovative technologies for the treatment of this infection are necessary. OBJECTIVE: The aim of this study was to evaluate the development of new drugs, formulations, as well as patents for the treatment of infections caused by Candida spp. METHODS: The present patent review was carried out through a specialized search database Espacenet. The patent selection was based on the following inclusion criteria: Recent patents published in English or Spanish containing candidiasis as the keyword in the title, abstract or full text. This survey was conducted in October and November 2018. RESULTS: As a result of that, 22 patents were selected to the final selection, the most common routes of application were oral (n = 6), vaginal (n = 6), topical (n = 5) and others (n = 5). This fact is related to the clinical manifestations of candidiasis. CONCLUSION: Through this review, it was possible to identify significant improvements and advances in the area of antifungal therapeutic innovation research. In addition, we demonstrated the growing interest of academic and industrial groups in pharmaceutical development and novel formulations for the treatment of candidiasis. New therapeutic options can contribute to improve the quality of patient's life, prevent infections and promote the search for an innovative and effective treatment of Candida infections.

Histomorphometric Evaluation of Critical-Sized Bone Defects Using Osteomeasure and Aperio Image Analysis Systems.

Most histological evaluations of critical-sized bone defects are limited to the analysis of a few regions of interest at a time. Manual and semiautomated histomorphometric approaches often have intra- and interobserver subjectivity, as well as variability in image analysis methods. Moreover, the production of large image data sets makes histological assessment and histomorphometric analysis labor intensive and time consuming. Herein, we tested and compared two image segmentation methods: thresholding (automated) and region-based (manual) modes, for quantifying complete image sets across entire critical-sized bone defects, using the widely used Osteomeasure system and the freely downloadable Aperio Image Scope software. A comparison of bone histomorphometric data showed strong agreement between the automated segmentation mode of the Osteomeasure software with the manual segmentation mode of Aperio Image Scope analysis (bone formation R2 = 0.9615 and fibrous tissue formation R2 = 0.8734). These results indicate that Aperio is capable of handling large histological images, with excellent speed performance in producing highly consistent histomorphometric evaluations compared with the Osteomeasure image analysis system. The statistical evaluation of these two major bone parameters demonstrated that Aperio Image Scope is as capable as Osteomeasure. This study developed a protocol to improve the quality of results and reduce analysis time, while also promoting the standardization of image analysis protocols for the histomorphometric analysis of critical-sized bone defect samples. Impact Statement Despite bone tissue engineering innovations increasing over the last decade, histomorphometric analysis of large bone defects used to study such approaches continues to pose a challenge for pathological assessment. This is due to the resulting large image data set, and the lack of a gold standard image analysis protocol to quantify histological outcomes. Herein, we present a standardized protocol for the image analysis of critical-sized bone defect samples stained with Goldner's Trichrome using the Osteomeasure and Aperio Image Scope image analysis systems. The results were critically examined to determine their reproducibility and accuracy for analyzing large bone defects.

Convergence of Scaffold-Guided Bone Reconstruction and Surgical Vascularization Strategies-A Quest for Regenerative Matching Axial Vascularization.

The prevalent challenge facing tissue engineering today is the lack of adequate vascularization to support the growth, function, and viability of tissue engineered constructs (TECs) that require blood vessel supply. The research and clinical community rely on the increasing knowledge of angiogenic and vasculogenic processes to stimulate a clinically-relevant vascular network formation within TECs. The regenerative matching axial vascularization approach presented in this manuscript incorporates the advantages of flap-based techniques for neo-vascularization yet also harnesses the in vivo bioreactor principle in a more directed "like for like" approach to further assist regeneration of the specific tissue type that is lost, such as a corticoperiosteal flap in critical sized bone defect reconstruction.