Archimedean Spirals Form at Low Flow Rates in Confined Chemical Gardens.

We describe and study the formation of confined chemical garden patterns. At low flow rates of injection of cobalt chloride solution into a Hele-Shaw cell filled with sodium silicate, the precipitate forms with a thin filament wrapping around an expanding "candy floss" structure. The result is the formation of an Archimedean spiral structure. We model the growth of the structure mathematically. We estimate the effective density of the precipitate and calculate the membrane permeability. We set the results within the context of recent experimental and modeling work on confined chemical garden filaments.

Filament dynamics in vertical confined chemical gardens.

When confined to a Hele-Shaw cell, chemical gardens can grow as filaments, narrow structures with an erratic and tortuous trajectory. In this work, the methodology applied to studies with horizontal Hele-Shaw cells is adapted to a vertical configuration, thus introducing the effect of buoyancy into the system. The motion of a single filament tip is modeled by taking into account its internal pressure and the variation of the concentration of precipitate that constitutes the chemical garden membrane. While the model shows good agreement with the results, it also suggests that the concentration of the host solution of sodium silicate also plays a role in the growth of the structures despite being in stoichiometric excess.

Filament dynamics in planar chemical gardens.

Filaments in a planar chemical garden grow following tortuous, erratic paths. We show from statistical mechanics that this scaling results from a self-organized dispersion mechanism. Effective diffusivities as high as 10-5 m2 s-1 are measured in 2D laboratory experiments. This efficient transport is four orders of magnitude larger than molecular diffusion in a liquid, and ensures widespread contact and exchange between fluids in the chemical-garden structure and its surrounding environment.

High-Resolution Seismocardiogram Acquisition and Analysis System.

Several devices and measurement approaches have recently been developed to perform ballistocardiogram (BCG) and seismocardiogram (SCG) measurements. The development of a wireless acquisition system (hardware and software), incorporating a novel high-resolution micro-electro-mechanical system (MEMS) accelerometer for SCG and BCG signals acquisition and data treatment is presented in this paper. A small accelerometer, with a sensitivity of up to 0.164 µs/µg and a noise density below 6.5 µg/ Hz is presented and used in a wireless acquisition system for BCG and SCG measurement applications. The wireless acquisition system also incorporates electrocardiogram (ECG) signals acquisition, and the developed software enables the real-time acquisition and visualization of SCG and ECG signals (sensor positioned on chest). It then calculates metrics related to cardiac performance as well as the correlation of data from previously performed sessions with echocardiogram (ECHO) parameters. A preliminarily clinical study of over 22 subjects (including healthy subjects and cardiovascular patients) was performed to test the capability of the developed system. Data correlation between this measurement system and echocardiogram exams is also performed. The high resolution of the MEMS accelerometer used provides a better signal for SCG wave recognition, enabling a more consistent study of the diagnostic capability of this technique in clinical analysis.

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol.

Introduction: The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed. Methods: In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues. Results: We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-ß1 (M(IL-10+TGF-ß1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-ß1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-ß1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-ß1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation. Discussion: Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

Exploring Suspected Diagnoses in Elderly Patients: A Case Study of Potential Necrotizing Otitis Externa.

Necrotizing otitis externa (NOE) is a rare invasive infection affecting the EAC and the base of the skull. This condition is more prevalent in the elderly, diabetics, and immunocompromised individuals, often attributed to the bacterium Pseudomonas aeruginosa. In this case report, we present the clinical scenario of a 90-year-old woman with a history of diabetes and epilepsy. Initially admitted with acute pyelonephritis, fever, and prostration, she subsequently developed left facial paralysis during treatment. Cranial computed tomography (CT) revealed inflammation in the middle ear and bone erosion of the facial nerve canal. The examination by the Department of Ear, Nose, and Throat (ENT) describes that NOE would be the most likely diagnosis. Given the patient's comorbidities and the severity of the disease, the treatment was initiated empirically and later adjusted based on the culture and sensitivity results with ceftazidime. NOE is a critical condition requiring early diagnosis and interdisciplinary collaboration due to the associated risk of complications. Adequate glycemic control is imperative, and the judicious use of antibiotics is crucial in light of escalating resistance.

Meningococcal Septic Oligoarthritis: An Unusual Presentation Revealing Concurrent Multiple Myeloma.

Meningococcal invasive disease is rare in immunocompetent hosts but may occur in patients with risk factors. Septic arthritis is an uncommon form of presentation and is usually due to surgical colonization or hematogenous dissemination. We present a case of a 73-year-old woman, who recently underwent knee replacement surgery, presenting with right knee and left shoulder pain, swelling, and reduced range of motion. Antibiotic therapy was promptly initiated, and the identification of invasive meningococcal disease with septic arthritis was possible through blood cultures and synovial fluid analysis.

Titanium dioxide nanoparticles affect osteoblast-derived exosome cargos and impair osteogenic differentiation of human mesenchymal stem cells.

Titanium (Ti) and its alloys are the most widely used metallic biomaterials in total joint replacement; however, increasing evidence supports the degradation of its surface due to corrosion and wear processes releasing debris (ions, and micro and nanoparticles) and contribute to particle-induced osteolysis and implant loosening. Cell-to-cell communication involving several cell types is one of the major biological processes occurring during bone healing and regeneration at the implant-bone interface. In addition to the internal response of cells to the uptake and intracellular localization of wear debris, a red flag is the ability of titanium dioxide nanoparticles (mimicking wear debris) to alter cellular communication with the tissue background, disturbing the balance between osseous tissue integrity and bone regenerative processes. This study aims to understand whether titanium dioxide nanoparticles (TiO2 NPs) alter osteoblast-derived exosome (Exo) biogenesis and whether exosomal protein cargos affect the communication of osteoblasts with human mesenchymal stem/stromal cells (HMSCs). Osteoblasts are derived from mesenchymal stem cells coexisting in the bone microenvironment during development and remodelling. We observed that TiO2 NPs stimulate immature osteoblast- and mature osteoblast-derived Exo secretion that present a distinct proteomic cargo. Functional tests confirmed that Exos derived from both osteoblasts decrease the osteogenic differentiation of HMSCs. These findings are clinically relevant since wear debris alter extracellular communication in the bone periprosthetic niche, contributing to particle-induced osteolysis and consequent prosthetic joint failure.

An enhanced reservation-based MAC protocol for IEEE 802.15.4 networks.

The IEEE 802.15.4 Medium Access Control (MAC) protocol is an enabling standard for wireless sensor networks. In order to support applications requiring dedicated bandwidth or bounded delay, it provides a reservation-based scheme named Guaranteed Time Slot (GTS). However, the GTS scheme presents some drawbacks, such as inefficient bandwidth utilization and support to a maximum of only seven devices. This paper presents eLPRT (enhanced Low Power Real Time), a new reservation-based MAC protocol that introduces several performance enhancing features in comparison to the GTS scheme. This MAC protocol builds on top of LPRT (Low Power Real Time) and includes various mechanisms designed to increase data transmission reliability against channel errors, improve bandwidth utilization and increase the number of supported devices. A motion capture system based on inertial and magnetic sensors has been used to validate the protocol. The effectiveness of the performance enhancements introduced by each of the new features is demonstrated through the provision of both simulation and experimental results.

Levetiracetam treatment leads to functional recovery after thoracic or cervical injuries of the spinal cord.

Spinal cord injury (SCI) leads to dramatic impairments of motor, sensory, and autonomic functions of affected individuals. Following the primary injury, there is an increased release of glutamate that leads to excitotoxicity and further neuronal death. Therefore, modulating glutamate excitotoxicity seems to be a promising target to promote neuroprotection during the acute phase of the injury. In this study, we evaluated the therapeutic effect of a FDA approved antiepileptic drug (levetiracetam-LEV), known for binding to the synaptic vesicle protein SV2A in the brain and spinal cord. LEV therapy was tested in two models of SCI-one affecting the cervical and other the thoracic level of the spinal cord. The treatment was effective on both SCI models. Treated animals presented significant improvements on gross and fine motor functions. The histological assessment revealed a significant decrease of cavity size, as well as higher neuronal and oligodendrocyte survival on treated animals. Molecular analysis revealed that LEV acts by stabilizing the astrocytes allowing an effective uptake of the excess glutamate from the extracellular space. Overall, our results demonstrate that Levetiracetam may be a promising drug for acute management of SCI.

In vitro Evaluation of ASCs and HUVECs Co-cultures in 3D Biodegradable Hydrogels on Neurite Outgrowth and Vascular Organization.

Vascular disruption following spinal cord injury (SCI) decisively contributes to the poor functional recovery prognosis facing patients with the condition. Using a previously developed gellan gum hydrogel to which the adhesion motif GRGDS was grafted (GG-GRGDS), this work aimed to understand the ability of adipose-derived stem cells (ASCs) to impact vascular organization of human umbilical vein endothelial cells (HUVECs), and how this in turn affects neurite outgrowth of dorsal root ganglia (DRG) explants. Our data shows that culturing these cells together lead to a synergistic effect as showed by increased stimulation of neuritogenesis on DRG. Importantly, HUVECs were only able to assemble into vascular-like structures when cultured in the presence of ASCs, which shows the capacity of these cells in reorganizing the vascular milieu. Analysis of selected neuroregulatory molecules showed that the co-culture upregulated the secretion of several neurotrophic factors. On the other hand, ASCs, and ASCs + HUVECs presented a similar profile regarding the presence of angiotrophic molecules herein analyzed. Finally, the implantation of GG-GRGDS hydrogels encapsulating ASCs in the chick chorioallantoic membrane (CAM) lead to increases in vascular recruitment toward the hydrogels in comparison to GG-GRGDS alone. This indicates that the combination of ASCs with GG-GRGDS hydrogels could promote re-vascularization in trauma-related injuries in the central nervous system and thus control disease progression and induce functional recovery.

Logic of Selecting Suitable Dissolution Parameters in New Drug Formulations Based on A BCS Approach.

Since the biopharmaceutical quality of generic drug formulations depends on the quality of the reference products and also information about the in-vitro release performance of drugs under different conditions is scarce in the literature, a dissolution study of four reference tablets was performed. Each drug was representative of one Class of the Biopharmaceutical Classification System. The in-vitro release performance of propranolol-HCl, carbamazepine, ranitidine-HCl, and metronidazole was evaluated using a USP basket and paddle apparatus at different agitation rates (50, 75, and 100 rpm) with two doses of each drug. In all experiments, pharmacopeial dissolution media was used and the samples were taken with automatic equipment at specific times up to 60 min, except for propranolol-HCl, for which the samples were taken up to 30 min. The dissolution profiles were compared by model-independent, model-dependent, and ANOVA-based comparisons. The three methods of data comparison showed that low vs. high doses were significantly different (P < 0.05), which may influence cases in which biowaivers of propranolol-HCl and ranitidine-HCl are requested. Additionally, the results showed that despite different hydrodynamic environments produced by the basket and paddle apparatus, under certain conditions, both types of equipment generated comparable in-vitro results. Variables such as the dose, agitation rate, and type of dissolution apparatus are important factors to consider in designing dissolution tests for drug products. This information can be used to test a new dosage when there is no pharmacopeial method available to perform a dissolution study. Further researches on the in-vitro release performance of reference drug products are required.

Vanadium ionic species from degradation of Ti-6Al-4V metallic implants: In vitro cytotoxicity and speciation evaluation.

Among the metallic materials used in biomedical industry, the most common choice for orthopedics and dental implants is titanium (Ti) and its alloys, mainly due to their superior corrosion and tribocorrosion resistance and biocompatibility. Under different conditions in vivo, such as different pH levels, composition of body fluid and mechanical loads, metallic materials may suffer from degradation, resulting in the release of undesired wear particles and ions. In particular, the Ti-6Al-4V system represents almost half of the production of Ti as a biomaterial and many concerns have been raised about titanium, aluminum and vanadium ions releasing. This work evaluates the cytotoxic effects of vanadium ionic species generated from Ti-6Al-4V surfaces regarding mouse pre-osteoblasts and fibroblasts. In our cell viability tests, we noticed a significant decrease in the fibroblasts' cell viability with vanadium concentrations (23 µM) close to those previously reported to be observed in vivo in patients with poor functioning of their medical devices based on Ti-6Al-4V (30 µM). Speciation modelling was carried-out, for the first time, to this system. Results of the modelling reveal that vanadates(V), namely H2VO4- and HVO42-, are the main species present in cell culture media. Otherwise, in synovial fluids of individuals with poorly functioning implants, wherein the concentration of vanadium may go up to ca. 30 µM, the tentative theoretical speciation data indicates a high occurrence probability for VV- and VIV-species bound to albumin and hyaluronic acid. In conclusion, even though relatively low concentrations of vanadium may be released from Ti-6Al-4V implants in vivo, the continuous contact with peri-implant cells for long periods of time may represent a potentially hazardous situation.

Exposure effects of endotoxin-free titanium-based wear particles to human osteoblasts.

Titanium-based materials are widely employed by the biomedical industry in orthopedic and dental implants. However, when placed into the human body, these materials are highly susceptible to degradation processes, such as corrosion, wear, and tribocorrosion. As a consequence, metallic ions or particles (debris) may be released, and although several studies have been conducted in recent years to better understand the effects of their exposure to living cells, a consensual opinion has not yet been obtained. In this work, we produced metallic-based wear particles by tribological tests carried out on Ti-6Al-4V and Ti-15Zr-15Mo alloys. They were posteriorly physicochemically characterized according to their crystal structure, size, morphology, and chemical composition and compared to Ti-6Al-4V commercially available particles. Finally, adsorbed endotoxins were removed (by applying a specific thermal treatment) and endotoxin-free particles were used in cell experiments to evaluate effects of their exposure to human osteoblasts (MG-63 and HOb), namely cell viability/metabolism, proinflammatory cytokine production (IL-6 and PGE2), and susceptibility to internalization processes. Our results indicate that tribologically-obtained wear particles exhibit fundamental differences in terms of size (smaller) and morphology (irregular shapes and rough surfaces) when compared to the commercial ones. Consequently, both Ti-6Al-4V and Ti-15Zr-15Mo particles were able to induce more pronounced effects on cell viability (decrease) and cytokine production (increase) than did Ti-6Al-4V commercial particles. Furthermore, both types of wear particles penetrated osteoblast membranes and were internalized by the cells. Influences on cytokine production by endotoxins were also demonstrated.

αvß3 and α5ß1 integrin-specific ligands: From tumor angiogenesis inhibitors to vascularization promoters in regenerative medicine?

Integrins are cell adhesion receptors predominantly important during normal and tumor angiogenesis. A sequence present on several extracellular matrix proteins composed of Arg-Gly-Asp (RGD) has attracted attention due to its role in cell adhesion mediated by integrins. The development of ligands that can bind to integrins involved in tumor angiogenesis and brake disease progression has resulted in new investigational drug entities reaching the clinical trial phase in humans. The use of integrin-specific ligands can be useful for the vascularization of regenerative medicine constructs, which remains a major limitation for translation into clinical practice. In order to enhance vascularization, immobilization of integrin-specific RGD peptidomimetics within constructs is a recommended approach, due to their high specificity and selectivity towards certain desired integrins. This review endeavours to address the potential of peptidomimetic-coated biomaterials as vascular network promoters for regenerative medicine purposes. Clinical studies involving molecules tracking active integrins in cancer angiogenesis and reasons for their failure are also addressed.

The Role of Biomaterials as Angiogenic Modulators of Spinal Cord Injury: Mimetics of the Spinal Cord, Cell and Angiogenic Factor Delivery Agents.

Spinal cord injury (SCI) represents an extremely debilitating condition for which no efficacious treatment is available. One of the main contributors to the inhospitable environment found in SCI is the vascular disruption that happens at the moment of injury that compromises the blood-spinal cord barrier (BSCB) and triggers a cascade of events that includes infiltration of inflammatory cells, ischemia and intraparenchymal hemorrhage. Due to the unsatisfactory nature of revascularization following SCI, restoring vascular perfusion and the BSCB seems an interesting way of modulating the lesion environment into a regenerative phenotype, with a potential increase in functional recovery. Certain biomaterials possess interesting features to enhance SCI therapies, and in fact have been applied as angiogenic promoters in other pathologies. The present mini-review intends to highlight the contribution that biomaterials could make in the development of novel therapeutic solutions able to restore proper vascularization and the BSCB.

Improved tribocorrosion performance of bio-functionalized TiO2 nanotubes under two-cycle sliding actions in artificial saliva.

After insertion into bone, dental implants may be subjected to tribocorrosive conditions resulting in the release of metallic ions and solid wear debris, which can induce to peri-implant inflammatory reactions accompanied by bone loss, and ultimately implant loosening. Despite the promising ability of TiO2 nanotubes (NTs) to improve osseointegration and avoid infection-related failures, the understanding of their degradation under the simultaneous action of wear and corrosion (tribocorrosion) is still very limited. This study aims, for the first time, to study the tribocorrosion behavior of bio-functionalized TiO2 NTs submitted to two-cycle sliding actions, and compare it with conventional TiO2 NTs. TiO2 NTs grown by anodization were doped with bioactive elements, namely calcium (Ca), phosphorous (P), and zinc (Zn), through reverse polarization anodization treatments. Characterization techniques such as scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and scanning transmission electron microscopy (STEM), were used to characterize the films. Tribocorrosion tests were carried out in artificial saliva (AS) by applying two cycles of reciprocating sliding actions. The open circuit potential (OCP) was monitored before, during, and after both cycles of sliding, during which the coefficient of friction (COF) was calculated. The resulting wear scars were analyzed by SEM and EDS, and wear volume measurements were performed by 2D profilometry. Finally, the mechanical features of TiO2 NTs were accessed by nanoindentation. The results show that bio-functionalized TiO2 NTs display an enhanced tribocorrosion performance, ascribed to the growth of a nano-thick oxide film at Ti/TiO2 NTs interface, which significantly increased their adhesion strength to the substrate and consequently their hardness. Furthermore, it was discovered that during tribo-electrochemical solicitations, the formation of a P-rich tribofilm takes place, which grants both electrochemical protection and resistance to mechanical wear. This study provides fundamental and new insights for the development of multifunctional TiO2 NTs with long-term biomechanical stability and improved clinical outcomes.

Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats.

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R² > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action.

Bio-camouflage of anatase nanoparticles explored by in situ high-resolution electron microscopy.

While titanium is the metal of choice for most prosthetics and inner body devices due to its superior biocompatibility, the discovery of Ti-containing species in the adjacent tissue as a result of wear and corrosion has been associated with autoimmune diseases and premature implant failures. Here, we utilize the in situ liquid cell transmission electron microscopy (TEM) in a liquid flow holder and graphene liquid cells (GLCs) to investigate, for the first time, the in situ nano-bio interactions between titanium dioxide nanoparticles and biological medium. This imaging and spectroscopy methodology showed the process of formation of an ionic and proteic bio-camouflage surrounding Ti dioxide (anatase) nanoparticles that facilitates their internalization by bone cells. The in situ understanding of the mechanisms of the formation of the bio-camouflage of anatase nanoparticles may contribute to the definition of strategies aimed at the manipulation of these NPs for bone regenerative purposes.

Implantable flexible pressure measurement system based on inductive coupling.

One of the currently available treatments for aortic aneurysms is endovascular aneurysm repair (EVAR). In spite of major advances in the operating techniques, complications still occur and lifelong surveillance is recommended. In order to reduce and even eliminate the commonly used surveillance imaging exams, as well as to reduce follow-up costs, new technological solutions are being pursued. In this paper, we describe the development, including design and performance characterization, of a flexible remote pressure measurement system based on inductive-coupling for post-EVAR monitoring purposes. The telemetry system architecture and operation are described and main performance characteristics discussed. The implantable sensor details are provided and its model is presented. Simulations with the reading circuit and the sensor's model were performed and compared with measurements carried out with air and a phantom as media, in order to characterize the telemetry system and validate the models. The transfer characteristic curve (pressure versus frequency) of the monitoring system was obtained with measurements performed with the sensor inside a controlled pressure vacuum chamber. Additional experimental results which proof the system functionality were obtained within a hydraulic test bench that emulates the aorta. Several innovative aspects, when compared to the state of the art, both in the sensor and in the telemetry system were achieved.