Advanced 3D imaging and organoid bioprinting for biomedical research and therapeutic applications.

Organoid cultures offer a valuable platform for studying organ-level biology, allowing for a closer mimicry of human physiology compared to traditional two-dimensional cell culture systems or non-primate animal models. While many organoid cultures use cell aggregates or decellularized extracellular matrices as scaffolds, they often lack precise biochemical and biophysical microenvironments. In contrast, three-dimensional (3D) bioprinting allows precise placement of organoids or spheroids, providing enhanced spatial control and facilitating the direct fusion for the formation of large-scale functional tissues in vitro. In addition, 3D bioprinting enables fine tuning of biochemical and biophysical cues to support organoid development and maturation. With advances in the organoid technology and its potential applications across diverse research fields such as cell biology, developmental biology, disease pathology, precision medicine, drug toxicology, and tissue engineering, organoid imaging has become a crucial aspect of physiological and pathological studies. This review highlights the recent advancements in imaging technologies that have significantly contributed to organoid research. Additionally, we discuss various bioprinting techniques, emphasizing their applications in organoid bioprinting. Integrating 3D imaging tools into a bioprinting platform allows real-time visualization while facilitating quality control, optimization, and comprehensive bioprinting assessment. Similarly, combining imaging technologies with organoid bioprinting can provide valuable insights into tissue formation, maturation, functions, and therapeutic responses. This approach not only improves the reproducibility of physiologically relevant tissues but also enhances understanding of complex biological processes. Thus, careful selection of bioprinting modalities, coupled with appropriate imaging techniques, holds the potential to create a versatile platform capable of addressing existing challenges and harnessing opportunities in these rapidly evolving fields.

A proposal to reduce the amount of permethrin entering wastewater resultant from topical use to treat scabies.

The incidence of scabies is rising in the last years. Subsequently, the use of pharmaceuticals to treat the disease has also increased. Treatment with topical permethrin is usually recommended as a first line agent. This substance is also an aquatic contaminant that is toxic for many non-target organisms, and has been included as a priority substance in the recently published proposal of the European Water Framework Directive. Current guidelines neglect the potential environmental impact of this drug, recommending that the cream should be applied head to toe and "washed off after 8-12 h". Recently, a wiping procedure before hand washing after application of the topical treatment resulted in a 66 % reduction of the amount of diclofenac released in wastewater. The authors suggested that this method could be explored for other topical treatments. In the case of scabiosis, a protocol implicating the whole body needs to be designed. The absorption of topical permethrin is low. Considering the growing incidence of scabies, the amount of the pyrethroid reaching the environment may also be increasing. Therefore, we believe that applying the wiping procedure to the case of topical permethrin deserves consideration. Other measures to minimize the amount of permethrin residues reaching wastewater by washing clothes and bed linen such as wearing single-use pijamas should also be explored. In conclusion, we need to apply a One Health approach in the treatment with scabies, without neglecting the environmental impact of pharmaceuticals. It is not rational to forget drugs once they go down the drain.

Enhancing Diabetic Wound Healing Through Improved Angiogenesis: The Role of Emulsion-Based Core-Shell Micro/Nanofibrous Scaffold with Sustained CuO Nanoparticle Delivery.

Attempts are made to design a system for sustaining the delivery of copper ions into diabetic wounds and induce angiogenesis with minimal dose-dependent cytotoxicity. Here, a dual drug-delivery micro/nanofibrous core-shell system is engineered using polycaprolactone/sodium sulfated alginate-polyvinyl alcohol (PCL/SSA-PVA), as core/shell parts, by emulsion electrospinning technique to optimize sustained delivery of copper oxide nanoparticles (CuO NP). Herein, different concentrations of CuO NP (0.2, 0.4, 0.8, and 1.6%w/w) are loaded into the core part of the core-shell system. The morphological, biomechanical, and biocompatibility properties of the scaffolds are fully determined in vitro and in vivo. The 0.8%w/w CuO NP scaffold reveals the highest level of tube formation in HUVEC cells and also upregulates the pro-angiogenesis genes (VEGFA and bFGF) expression with no cytotoxicity effects. The presence of SSA and its interaction with CuO NP, and also core-shell structure sustain the release of the nanoparticles and provide a non-toxic microenvironment for cell adhesion and tube formation, with no sign of adverse immune response in vivo. The optimized scaffold significantly accelerates diabetic wound healing in a rat model. This study strongly suggests the 0.8%w/w CuO NP-loaded PCL/SSA-PVA as an excellent diabetic wound dressing with significantly improved angiogenesis and wound healing.

Pharmaceutical residues in stranded dolphins in the Bay of Biscay.

There is a growing concern about the presence of pharmaceuticals on the aquatic environment, while the marine environment has been much less investigated than in freshwater. Marine mammals are suitable sentinel species of the marine environment because they often feed at high trophic levels, have unique fat stores and long lifespan. Some small delphinids in particular serve as excellent sentinel species for contamination in the marine environment worldwide. To the best of our knowledge, no pharmaceuticals have been detected or reported in dolphins so far. In the present study, muscle, liver and blubber samples from three common dolphins (Delphinus delphis) and seven striped dolphins (Stenella coeruleoalba) stranded along the Basque Coast (northern Spain) were collected. A total of 95 pharmaceuticals based on detectability and predicted ability to bioaccumulate in fish were included in the liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. At least one pharmaceutical was found in 70 % of the individuals. Only three of the 95 monitored pharmaceuticals were detected in dolphin's tissues. Very low concentrations (<1 ng/g) of orphenadrine and pizotifen were found in liver and promethazine in blubber. Herein, the gap in the knowledge regarding the study organisms and marine environments with respect to pharmaceutical pollution, which demands further research to understand if pharmaceuticals are a threat for these apex predators, is highlighted and discussed.

Chitosan-functionalized bioplatforms and hydrogels in breast cancer: immunotherapy, phototherapy and clinical perspectives.

Breast cancer is the most common and malignant tumor among women. Chitosan (CS)-based nanoparticles have been introduced into breast cancer therapy as a way to increase the targeted delivery of drugs and genes to the tumor site. CS nanostructures suppress tumorigenesis by enhancing both the targeted delivery of cargo (drug and gene) and its accumulation in tumor cells. The tumor cells internalize CS-based nanoparticles through endocytosis. Moreover, chitosan nanocarriers can also induce phototherapy-mediated tumor ablation. Smart and multifunctional types of CS nanoparticles, including pH-, light- and redox-responsive nanoparticles, can be used to improve the potential for breast cancer removal. In addition, the acceleration of immunotherapy by CS nanoparticles has also been achieved, and there is potential to develop CS-nanoparticle hydrogels that can be used to suppress tumorigenesis.

4D Printing: The Development of Responsive Materials Using 3D-Printing Technology.

Additive manufacturing, widely known as 3D printing, has revolutionized the production of biomaterials. While conventional 3D-printed structures are perceived as static, 4D printing introduces the ability to fabricate materials capable of self-transforming their configuration or function over time in response to external stimuli such as temperature, light, or electric field. This transformative technology has garnered significant attention in the field of biomedical engineering due to its potential to address limitations associated with traditional therapies. Here, we delve into an in-depth review of 4D-printing systems, exploring their diverse biomedical applications and meticulously evaluating their advantages and disadvantages. We emphasize the novelty of this review paper by highlighting the latest advancements and emerging trends in 4D-printing technology, particularly in the context of biomedical applications.

Occurrence and ecological risk assessment of organic UV filters in coastal waters of the Iberian Peninsula.

This study aimed to assess the presence of 21 UVFs and metabolites in coastal regions of the Iberian Peninsula, to evaluate their environmental risk, and identify possible influential factors affecting their measured concentrations. Sampling was carried out in spring and summer to assess possible seasonal variations. UVFs were detected in 43 of the 46 sampling sites. Only 5 were found above LOD: BP4, OC, BP3 and metabolites BP1 and BP8. Samples collected in Mar Menor had the greatest variety of compounds per sample and the highest cumulative concentrations. The risk was characterized using Risk Quotients (RQ). BP1 showed a Low environmental Risk in 2 sites while for OC the RQ indicated a Moderate Risk in 22 points. The variables that contribute most to the variation are population density, sampling season, whether it was an open bay or not, and level of urbanization. The presence of WWTPs had a lower influence.

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Health financing policies during the COVID-19 pandemic and implications for universal health care: a case study of 15 countries.

BACKGROUND: The COVID-19 pandemic was a health emergency requiring rapid fiscal resource mobilisation to support national responses. The use of effective health financing mechanisms and policies, or lack thereof, affected the impact of the pandemic on the population, particularly vulnerable groups and individuals. We provide an overview and illustrative examples of health financing policies adopted in 15 countries during the pandemic, develop a framework for resilient health financing, and use this pandemic to argue a case to move towards universal health coverage (UHC). METHODS: In this case study, we examined the national health financing policy responses of 15 countries, which were purposefully selected countries to represent all WHO regions and have a range of income levels, UHC index scores, and health system typologies. We did a systematic literature review of peer-reviewed articles, policy documents, technical reports, and publicly available data on policy measures undertaken in response to the pandemic and complemented the data obtained with 61 in-depth interviews with health systems and health financing experts. We did a thematic analysis of our data and organised key themes into a conceptual framework for resilient health financing. FINDINGS: Resilient health financing for health emergencies is characterised by two main phases: (1) absorb and recover, where health systems are required to absorb the initial and subsequent shocks brought about by the pandemic and restabilise from them; and (2) sustain, where health systems need to expand and maintain fiscal space for health to move towards UHC while building on resilient health financing structures that can better prepare health systems for future health emergencies. We observed that five key financing policies were implemented across the countries-namely, use of extra-budgetary funds for a swift initial response, repurposing of existing funds, efficient fund disbursement mechanisms to ensure rapid channelisation to the intended personnel and general population, mobilisation of the private sector to mitigate the gaps in public settings, and expansion of service coverage to enhance the protection of vulnerable groups. Accountability and monitoring are needed at every stage to ensure efficient and accountable movement and use of funds, which can be achieved through strong governance and coordination, information technology, and community engagement. INTERPRETATION: Our findings suggest that health systems need to leverage the COVID-19 pandemic as a window of opportunity to make health financing policies robust and need to politically commit to public financing mechanisms that work to prepare for future emergencies and as a lever for UHC. FUNDING: Bill & Melinda Gates Foundation.

Design and Manufacture of Bone Cements Based on Calcium Sulfate Hemihydrate and Mg, Sr-Doped Bioactive Glass.

In the present study, a novel composite bone cement based on calcium sulfate hemihydrate (CSH) and Mg, Sr-containing bioactive glass (BG) as solid phase, and solution of chitosan as liquid phase were developed. The phase composition, morphology, setting time, injectability, viscosity, and cellular responses of the composites with various contents of BG (0, 10, 20, and 30 wt.%) were investigated. The pure calcium sulfate cement was set at approximately 180 min, whereas the setting time was drastically decreased to 6 min by replacing 30 wt.% glass powder for CSH in the cement solid phase. BG changed the microscopic morphology of the set cement and decreased the size and compaction of the precipitated gypsum phase. Replacing the CSH phase with BG increased injection force of the produced cement; however, all the cements were injected at a nearly constant force, lower than 20 N. The viscosity measurements in oscillatory mode determined the shear-thinning behavior of the pastes. Although the viscosity of the pastes increased with increasing BG content, it was influenced by the frequency extent. Pure calcium sulfate cement exhibited some transient cytotoxicity on human-derived bone mesenchymal stem cells and it was compensated by introducing BG phase. Moreover, BG improved the cell proliferation and mineralization of extracellular matrix as shown by calcein measurements. The results indicate the injectable composite cement comprising 70 wt.% CSH and 30 wt.% Mg, Sr-doped BG has better setting, mechanical and cellular behaviors and hence, is a potential candidate for bone repair, however more animal and human clinical evaluations are essential.

Nanomaterial-based drug delivery of immunomodulatory factors for bone and cartilage tissue engineering.

As life expectancy continues to increase, so do disorders related to the musculoskeletal system. Orthopedics-related impairments remain a challenge, with nearly 325 thousand and 120 thousand deaths recorded in 2019. Musculoskeletal system, including bone and cartilage tissue, is a living system in which cells constantly interact with the immune system, which plays a key role in the tissue repair process. An alternative to bridge the gap between these two systems is exploiting nanomaterials, as they have proven to serve as delivery agents of an array of molecules, including immunomodulatory agents (anti-inflammatory drugs, cytokines), as well as having the ability to mimic tissue by their nanoscopic structure and promote tissue repair per se. Therefore, this review outlooks nanomaterials and immunomodulatory factors widely employed in the area of bone and cartilage tissue engineering. Emerging developments in nanomaterials for delivery of immunomodulatory agents for bone and cartilage tissue engineering applications have also been discussed. It can be concluded that latest progress in nanotechnology have enabled to design intricate systems with the ability to deliver biologically active agents, promoting tissue repair and regeneration; thus, nanomaterials studied herein have shown great potential to serve as immunomodulatory agents in the area of tissue engineering.

Smart alginate inks for tissue engineering applications.

Amazing achievements have been made in the field of tissue engineering during the past decades. However, we have not yet seen fully functional human heart, liver, brain, or kidney tissue emerge from the clinics. The promise of tissue engineering is thus still not fully unleashed. This is mainly related to the challenges associated with producing tissue constructs with similar complexity as native tissue. Bioprinting is an innovative technology that has been used to obliterate these obstacles. Nevertheless, natural organs are highly dynamic and can change shape over time; this is part of their functional repertoire inside the body. 3D-bioprinted tissue constructs should likewise adapt to their surrounding environment and not remain static. For this reason, the new trend in the field is 4D bioprinting - a new method that delivers printed constructs that can evolve their shape and function over time. A key lack of methodology for printing approaches is the scalability, easy-to-print, and intelligent inks. Alginate plays a vital role in driving innovative progress in 3D and 4D bioprinting due to its exceptional properties, scalability, and versatility. Alginate's ability to support 3D and 4D printing methods positions it as a key material for fueling advancements in bioprinting across various applications, from tissue engineering to regenerative medicine and beyond. Here, we review the current progress in designing scalable alginate (Alg) bioinks for 3D and 4D bioprinting in a "dry"/air state. Our focus is primarily on tissue engineering, however, these next-generation materials could be used in the emerging fields of soft robotics, bioelectronics, and cyborganics.

Pharmaceuticals in hospital wastewaters: an analysis of the UBA's pharmaceutical database.

The presence of pharmaceuticals in hospital wastewaters (HWW) has been a focus of interest for researchers in the last decades. Certain therapeutic classes, such as X-ray contrast media, broad-spectrum antimicrobials and cytotoxics among others, are mainly used in hospitals-health care facilities. This study is focused on available studies monitoring the presence of pharmaceuticals in HWW around the world. To that end, the last available version (v3. 2021) of the "Pharmaceuticals in the Environment" database published by the Federal German Environment Agency (Umweltbundesamt) has been used. Almost half of all studies included (107) have been conducted in Europe. Pharmaceuticals have been monitored in HWW in 38 different countries across all five continents. The country with the greatest number of studies is Brazil (11), followed by Spain (8), China (7), and France (6). Our analysis revealed that 271 different pharmaceuticals have been detected at least once in HWW. The five drugs with more studies showing a positive detection are ciprofloxacin (38), sulfamethoxazole (36), diclofenac (34), ibuprofen (29), and trimethoprim (27). A total of 47 out of 271 drugs are considered in the NIOSH "Hazardous drug" list. However, monitoring data for some widely used drugs in hospital settings such as muscle relaxants, anesthetics, and antidotes is lacking. In conclusion, this study provides the first large-scale metadata analysis for the pharmaceuticals in HWW worldwide.

Sumecton reinforced gelatin-based scaffolds for cell-free bone regeneration.

Bone tissue engineering has risen to tackle the challenges of the current clinical need concerning bone fractures that is already considered a healthcare system problem. Scaffold systems for the repair of this tissue have yielded different combinations including biomaterials with nanotechnology or biological agents. Herein, three-dimensional porous hydrogels were engineered based on gelatin as a natural biomaterial and reinforced with synthetic saponite nanoclays. Scaffolds were biocompatible and shown to enhance the inherent properties of pristine ones, in particular, proved to withstand pressures similar to load-bearing tissues. Studies with murine mesenchymal stem cells found that scaffolds had the potential to proliferate and promote cell differentiation. In vivo experiments were conducted to gain insight about the ability of these cell-free scaffolds to regenerate bone, as well as to determine the role that these nanoparticles in the scaffold could play as a drug delivery system. SDF-1 loaded scaffolds showed the highest percentage of bone formation, which was corroborated by osteogenic markers and new blood vessels. Albeit a first attempt in the field of synthetic nanosilicates, these results suggest that the designed constructs may serve as delivery platforms for biomimetic agents to mend bony defects, circumventing high doses of therapeutics and cell-loading systems.

Molecularly Imprinted Polymer-Based Sensors for the Detection of Skeletal- and Cardiac-Muscle-Related Analytes.

Molecularly imprinted polymers (MIPs) are synthetic polymers with specific binding sites that present high affinity and spatial and chemical complementarities to a targeted analyte. They mimic the molecular recognition seen naturally in the antibody/antigen complementarity. Because of their specificity, MIPs can be included in sensors as a recognition element coupled to a transducer part that converts the interaction of MIP/analyte into a quantifiable signal. Such sensors have important applications in the biomedical field in diagnosis and drug discovery, and are a necessary complement of tissue engineering for analyzing the functionalities of the engineered tissues. Therefore, in this review, we provide an overview of MIP sensors that have been used for the detection of skeletal- and cardiac-muscle-related analytes. We organized this review by targeted analytes in alphabetical order. Thus, after an introduction to the fabrication of MIPs, we highlight different types of MIP sensors with an emphasis on recent works and show their great diversity, their fabrication, their linear range for a given analyte, their limit of detection (LOD), specificity, and reproducibility. We conclude the review with future developments and perspectives.

Injectable hydrogels for cartilage and bone tissue regeneration: A review.

Annually, millions of patients suffer from irreversible injury owing to the loss or failure of an organ or tissue caused by accident, aging, or disease. The combination of injectable hydrogels and the science of stem cells have emerged to address this persistent issue in society by generating minimally invasive treatments to augment tissue function. Hydrogels are composed of a cross-linked network of polymers that exhibit a high-water retention capacity, thereby mimicking the wet environment of native cells. Due to their inherent mechanical softness, hydrogels can be used as needle-injectable stem cell carrier materials to mend tissue defects. Hydrogels are made of different natural or synthetic polymers, displaying a broad portfolio of eligible properties, which include biocompatibility, low cytotoxicity, shear-thinning properties as well as tunable biological and physicochemical properties. Presently, novel ongoing developments and native-like hydrogels are increasingly being used broadly to improve the quality of life of those with disabling tissue-related diseases. The present review outlines various future and in-vitro applications of injectable hydrogel-based biomaterials, focusing on the newest ongoing developments of in-situ forming injectable hydrogels for bone and cartilage tissue engineering purposes.

3D-printed placental-derived bioinks for skin tissue regeneration with improved angiogenesis and wound healing properties.

Extracellular matrix (ECM)-based bioinks has attracted much attention in recent years for 3D printing of native-like tissue constructs. Due to organ unavailability, human placental ECM can be an alternative source for the construction of 3D print composite scaffolds for the treatment of deep wounds. In this study, we use different concentrations (1.5%, 3% and 5%w/v) of ECM derived from the placenta, sodium-alginate and gelatin to prepare a printable bioink biomimicking natural skin. The printed hydrogels' morphology, physical structure, mechanical behavior, biocompatibility, and angiogenic property are investigated. The optimized ECM (5%w/v) 3D printed scaffold is applied on full-thickness wounds created in a mouse model. Due to their unique native-like structure, the ECM-based scaffolds provide a non-cytotoxic microenvironment for cell adhesion, infiltration, angiogenesis, and proliferation. In contrast, they do not show any sign of immune response to the host. Notably, the biodegradation, swelling rate, mechanical property, cell adhesion and angiogenesis properties increase with the increase of ECM concentrations in the construct. The ECM 3D printed scaffold implanted into deep wounds increases granulation tissue formation, angiogenesis, and re-epithelialization due to the presence of ECM components in the construct, when compared with printed scaffold with no ECM and no treatment wound. Overall, our findings demonstrate that the 5% ECM 3D scaffold supports the best deep wound regeneration in vivo, produces a skin replacement with a cellular structure comparable to native skin.

Bioprinting and biomaterials for dental alveolar tissue regeneration.

Three dimensional (3D) bioprinting is a powerful tool, that was recently applied to tissue engineering. This technique allows the precise deposition of cells encapsulated in supportive bioinks to fabricate complex scaffolds, which are used to repair targeted tissues. Here, we review the recent developments in the application of 3D bioprinting to dental tissue engineering. These tissues, including teeth, periodontal ligament, alveolar bones, and dental pulp, present cell types and mechanical properties with great heterogeneity, which is challenging to reproduce in vitro. After highlighting the different bioprinting methods used in regenerative dentistry, we reviewed the great variety of bioink formulations and their effects on cells, which have been established to support the development of these tissues. We discussed the different advances achieved in the fabrication of each dental tissue to provide an overview of the current state of the methods. We conclude with the remaining challenges and future needs.