Contactless Resolution of Inflammatory Signals in Tailored Macrophage-Based Cell Therapeutics.

In recent years, nanotechnology-based microRNA (miR) therapeutic platforms have shown great promise for immunotherapy and tissue regeneration, despite the unmet challenge of achieving efficient and safe delivery of miRs. The transport of miRs offers precision and regulatory value for a myriad of biological processes and pathways, including the control of macrophage (Mφ) functions and, consequently, the inflammatory cascades Mφ are involved in. Thus, enforcement of Mφ can boost the regenerative process and provide new solutions for diverse chronic pathologies. In this study, we sought to develop a magnetically guided transporter to deliver an miR-155 antagonist to M1-primed Mφ. Furthermore, we determined its modulatory effect in reprogramming Mφ from inflammatory to pro-regenerative phenotypes, with the aim of tissue healing and regenerative medicine approaches. This strategy combines contactless and high-precision control of Mφ, anticipating new functional miR carriers for targeted strategies controlled by extracorporeal action. The magnetoplexes SPION@PEI-miR were efficiently delivered into Mφ without compromising cell viability and successfully induced miR-mediated gene silencing by enhancing the expression of anti-inflammatory markers (IL4 and IL10) and the production of M2φ-related markers (CD206 and IL4). Given its multimodal features, SPION@PEI-miR represents a simple, safe, and nonviral theranostic platform that enables imaging, tracking, and miR delivery with modulatory effects on immune cells.

Prospects of magnetically based approaches addressing inflammation in tendon tissues.

Tendon afflictions constitute a significant share of musculoskeletal diseases and represent a primary cause of incapacity worldwide. Unresolved/chronic inflammatory states have been associated with the onset and progression of tendon disorders, contributing to undesirable immune stimulation and detrimental tissue effects. Thus, targeting persistent inflammatory events could assist important developments to solve pathophysiological processes and innovative therapeutics to address impaired healing and accomplish complete tendon regeneration. This review overviews the impact of inflammation and inflammatory mediators in tendon niches, unveiling the importance of tendon cell populations and their signature features, and the influence of microenvironmental factors on inflamed and injured tendons. The demand for non-invasive instructive strategies to manage persistent inflammatory mediators, guide inflammatory pathways, and modulate cellular responses will also be approached by exploring the role of pulsed electromagnetic field (PEMF). PEMF alone or combined with more sophisticated systems triggered by magnetic fields will be considered in the design of successful therapies to control inflammation in tendinopathic conditions.

Controlling Macrophage Polarization to Modulate Inflammatory Cues Using Immune-Switch Nanoparticles.

The persistence of inflammatory mediators in tissue niches significantly impacts regenerative outcomes and contributes to chronic diseases. Interleukin-4 (IL4) boosts pro-healing phenotypes in macrophages (Mφ) and triggers the activation of signal transducer and activator of transcription 6 (STAT6). Since the IL4/STAT6 pathway reduces Mφ responsiveness to inflammation in a targeted and precise manner, IL4 delivery offers personalized possibilities to overcome inflammatory events. Despite its therapeutic potential, the limited success of IL4-targeted delivery is hampered by inefficient vehicles. Magnetically assisted technologies offer precise and tunable nanodevices for the delivery of cytokines by combining contactless modulation, high tissue penetration, imaging features, and low interference with the biological environment. Although superparamagnetic iron oxide nanoparticles (SPION) have shown clinical applicability in imaging, SPION-based approaches have rarely been explored for targeted delivery and cell programming. Herein, we hypothesized that SPION-based carriers assist in efficient IL4 delivery to Mφ, favoring a pro-regenerative phenotype (M2φ). Our results confirmed the efficiency of SPION-IL4 and Mφ responsiveness to SPION-IL4 with evidence of STAT6-mediated polarization. SPION-IL4-treated Mφ showed increased expression of M2φ associated-mediators (IL10, ARG1, CCL2, IL1Ra) when compared to the well-established soluble IL4. The ability of SPION-IL4 to direct Mφ polarization using sophisticated magnetic nanotools is valuable for resolving inflammation and assisting innovative strategies for chronic inflammatory conditions.

Magnetic Micellar Nanovehicles: Prospects of Multifunctional Hybrid Systems for Precision Theranostics.

Hybrid nanoarchitectures such as magnetic polymeric micelles (MPMs) are among the most promising nanotechnology-enabled materials for biomedical applications combining the benefits of polymeric micelles and magnetic nanoparticles within a single bioinstructive system. MPMs are formed by the self-assembly of polymer amphiphiles above the critical micelle concentration, generating a colloidal structure with a hydrophobic core and a hydrophilic shell incorporating magnetic particles (MNPs) in one of the segments. MPMs have been investigated most prominently as contrast agents for magnetic resonance imaging (MRI), as heat generators in hyperthermia treatments, and as magnetic-susceptible nanocarriers for the delivery and release of therapeutic agents. The versatility of MPMs constitutes a powerful route to ultrasensitive, precise, and multifunctional diagnostic and therapeutic vehicles for the treatment of a wide range of pathologies. Although MPMs have been significantly explored for MRI and cancer therapy, MPMs are multipurpose functional units, widening their applicability into less expected fields of research such as bioengineering and regenerative medicine. Herein, we aim to review published reports of the last five years about MPMs concerning their structure and fabrication methods as well as their current and foreseen expectations for advanced biomedical applications.

Targeting Lysosomes in Colorectal Cancer: Exploring the Anticancer Activity of a New Benzo[a]phenoxazine Derivative.

Colorectal cancer (CRC) has been ranked as one of the cancer types with a higher incidence and one of the most mortal. There are limited therapies available for CRC, which urges the finding of intracellular targets and the discovery of new drugs for innovative therapeutic approaches. In addition to the limited number of effective anticancer agents approved for use in humans, CRC resistance and secondary effects stemming from classical chemotherapy remain a major clinical problem, reinforcing the need for the development of novel drugs. In the recent years, the phenoxazines derivatives, Nile Blue analogues, have been shown to possess anticancer activity, which has created interest in exploring the potential of these compounds as anticancer drugs. In this context, we have synthetized and evaluated the anticancer activity of different benzo[a]phenoxazine derivatives for CRC therapy. Our results revealed that one particular compound, BaP1, displayed promising anticancer activity against CRC cells. We found that BaP1 is selective for CRC cells and reduces cell proliferation, cell survival, and cell migration. We observed that the compound is associated with reactive oxygen species (ROS) generation, accumulates in the lysosomes, and leads to lysosomal membrane permeabilization, cytosolic acidification, and apoptotic cell death. In vivo results using a chicken embryo choriollantoic membrane (CAM) assay showed that BaP1 inhibits tumor growth, angiogenesis, and tumor proliferation. These observations highlight that BaP1 as a very interesting agent to disturb and counteract the important roles of lysosomes in cancer and suggests BaP1 as a promising candidate to be exploited as new anticancer lysosomal-targeted agent, which uses lysosome membrane permeabilization (LMP) as a therapeutic approach in CRC.

Magnetic triggers in biomedical applications - prospects for contact free cell sensing and guidance.

In recent years, the inputs from magnetically assisted strategies have been contributing to the development of more sensitive screening methods and precise means of diagnosis to overcome existing and emerging treatment challenges. The features of magnetic materials enabling in vivo traceability, specific targeting and space- and time-controlled delivery of nanomedicines have highlighted the resourcefulness of the magnetic toolbox for biomedical applications and theranostic strategies. The breakthroughs in magnetically assisted technologies for contact-free control of cell and tissue fate opens new perspectives to improve healing and instruct regeneration reaching a wide range of diseases and disorders. In this review, the contribution of magnetic nanoparticles (MNPs) will be explored as sophisticated and versatile nanotriggers, evidencing their unique cues to probe and control cell function. As cells detect and engage external magnetic features, these approaches will be overviewed considering molecular engineering and cell programming perspectives as well as cell and tissue targeting modalities. The therapeutic relevance of MNPs will be also emphasized as key components of nanostructured systems to control the release of nanomedicines and in the context of new therapy technologies.

Magnetic Stimulation Drives Macrophage Polarization in Cell to-Cell Communication with IL-1ß Primed Tendon Cells.

Inflammation is part of the natural healing response, but it has been simultaneously associated with tendon disorders, as persistent inflammatory events contribute to physiological changes that compromise tendon functions. The cellular interactions within a niche are extremely important for healing. While human tendon cells (hTDCs) are responsible for the maintenance of tendon matrix and turnover, macrophages regulate healing switching their functional phenotype to environmental stimuli. Thus, insights on the hTDCs and macrophages interactions can provide fundamental contributions on tendon repair mechanisms and on the inflammatory inputs in tendon disorders. We explored the crosstalk between macrophages and hTDCs using co-culture approaches in which hTDCs were previously stimulated with IL-1ß. The potential modulatory effect of the pulsed electromagnetic field (PEMF) in macrophage-hTDCs communication was also investigated using the magnetic parameters identified in a previous work. The PEMF influences a macrophage pro-regenerative phenotype and favors the synthesis of anti-inflammatory mediators. These outcomes observed in cell contact co-cultures may be mediated by FAK signaling. The impact of the PEMF overcomes the effect of IL-1ß-treated-hTDCs, supporting PEMF immunomodulatory actions on macrophages. This work highlights the relevance of intercellular communication in tendon healing and the beneficial role of the PEMF in guiding inflammatory responses toward regenerative strategies.

Methodological Quality of Manuscripts Reporting on the Usability of Mobile Applications for Pain Assessment and Management: A Systematic Review.

BACKGROUND: There has been increasing use of mobile mHealth applications, including pain assessment and pain self-management apps. The usability of mHealth applications has vital importance as it affects the quality of apps. Thus, usability assessment with methodological rigor is essential to minimize errors and undesirable consequences, as well as to increase user acceptance. OBJECTIVE: this study aimed to synthesize and evaluate existing studies on the assessment of the usability of pain-related apps using a newly developed scale. METHODS: an electronic search was conducted in several databases, combining relevant keywords. Then titles and abstracts were screened against inclusion and exclusion criteria. The eligible studies were retrieved and independently screened for inclusion by two authors. Disagreements were resolved by discussion until consensus was reached. RESULTS: a total of 31 articles were eligible for inclusion. Quality assessment revealed that most manuscripts did not assess usability using valid instruments or triangulation of methods of usability assessment. Most manuscripts also failed to assess the three domains of usability (effectiveness, efficiency and satisfaction). CONCLUSIONS: future studies should consider existing guidelines on usability assessment design, development and assessment of pain-related apps.

Haemophilus influenzae type b meningitis in a vaccinated and immunocompetent child.

Invasive Haemophilus influenzae type b (Hib) disease decreased dramatically after the introduction of conjugate vaccine in routine immunization schedules. We report a case of a fifteen-months-old girl, previously healthy and vaccinated, admitted in the emergency room with fever and vomiting. She was irritable and the Brudzinski's sign was positive. The cerebrospinal fluid (CSF) analysis showed pleocytosis and high protein level. Empiric intravenous antibiotics (ceftriaxone and vancomycin) were administered for suspected bacterial meningitis during 10 days. Serotyping of the Haemophilus influenzae strain found in CSF revealed a serotype b. After one year of follow-up no Hib meningitis sequelae were noted. Despite vaccination compliance and absence of risk factors, invasive Hib disease can occur due to vaccine failure. Efforts to keep the low incidence of invasive Hib disease should be directed to the maintenance of high vaccination coverage rates, combined with the notification and surveillance strategies already implemented in each country.