Alzheimer's Disease: Treatment Strategies and Their Limitations.

Alzheimer's disease (AD) is the most frequent case of neurodegenerative disease and is becoming a major public health problem all over the world. Many therapeutic strategies have been explored for several decades; however, there is still no curative treatment, and the priority remains prevention. In this review, we present an update on the clinical and physiological phase of the AD spectrum, modifiable and non-modifiable risk factors for AD treatment with a focus on prevention strategies, then research models used in AD, followed by a discussion of treatment limitations. The prevention methods can significantly slow AD evolution and are currently the best strategy possible before the advanced stages of the disease. Indeed, current drug treatments have only symptomatic effects, and disease-modifying treatments are not yet available. Drug delivery to the central nervous system remains a complex process and represents a challenge for developing therapeutic and preventive strategies. Studies are underway to test new techniques to facilitate the bioavailability of molecules to the brain. After a deep study of the literature, we find the use of soft nanoparticles, in particular nanoliposomes and exosomes, as an innovative approach for preventive and therapeutic strategies in reducing the risk of AD and solving problems of brain bioavailability. Studies show the promising role of nanoliposomes and exosomes as smart drug delivery systems able to penetrate the blood-brain barrier and target brain tissues. Finally, the different drug administration techniques for neurological disorders are discussed. One of the promising therapeutic methods is the intranasal administration strategy which should be used for preclinical and clinical studies of neurodegenerative diseases.

Macrophages enhance contractile force in iPSC-derived human engineered cardiac tissue.

Resident cardiac macrophages are critical mediators of cardiac function. Despite their known importance to cardiac electrophysiology and tissue maintenance, there are currently no stem-cell-derived models of human engineered cardiac tissues (hECTs) that include resident macrophages. In this study, we made an induced pluripotent stem cell (iPSC)-derived hECT model with a resident population of macrophages (iM0) to better recapitulate the native myocardium and characterized their impact on tissue function. Macrophage retention within the hECTs was confirmed via immunofluorescence after 28 days of cultivation. The inclusion of iM0s significantly impacted hECT function, increasing contractile force production. A potential mechanism underlying these changes was revealed by the interrogation of calcium signaling, which demonstrated the modulation of ß-adrenergic signaling in +iM0 hECTs. Collectively, these findings demonstrate that macrophages significantly enhance cardiac function in iPSC-derived hECT models, emphasizing the need to further explore their contributions not only in healthy hECT models but also in the contexts of disease and injury.

An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms of myocardial injury in SLE remain poorly understood. In this study, we engineered human cardiac tissues and cultured them with IgG from patients with SLE, with and without myocardial involvement. IgG from patients with elevated myocardial inflammation exhibited increased binding to apoptotic cells within cardiac tissues subjected to stress, whereas IgG from patients with systolic dysfunction exhibited enhanced binding to the surface of live cardiomyocytes. Functional assays and RNA sequencing revealed that, in the absence of immune cells, IgG from patients with systolic dysfunction altered cellular composition, respiration and calcium handling. Phage immunoprecipitation sequencing (PhIP-seq) confirmed distinctive IgG profiles between patient subgroups. Coupling IgG profiling with cell surfaceome analysis identified four potential pathogenic autoantibodies that may directly affect the myocardium. Overall, these insights may improve patient risk stratification and inform the development of new therapeutic strategies.

An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury.

Systemic lupus erythematosus (SLE) is a highly heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms by which myocardial injury develops in SLE, however, remain poorly understood. Here we engineered human cardiac tissues and cultured them with IgG fractions containing autoantibodies from SLE patients with and without myocardial involvement. We observed unique binding patterns of IgG from two patient subgroups: (i) patients with severe myocardial inflammation exhibited enhanced binding to apoptotic cells within cardiac tissues subjected to stress, and (ii) patients with systolic dysfunction exhibited enhanced binding to the surfaces of viable cardiomyocytes. Functional assays and RNA sequencing (RNA-seq) revealed that IgGs from patients with systolic dysfunction exerted direct effects on engineered tissues in the absence of immune cells, altering tissue cellular composition, respiration and calcium handling. Autoantibody target characterization by phage immunoprecipitation sequencing (PhIP-seq) confirmed distinctive IgG profiles between patient subgroups. By coupling IgG profiling with cell surface protein analyses, we identified four pathogenic autoantibody candidates that may directly alter the function of cells within the myocardium. Taken together, these observations provide insights into the cellular processes of myocardial injury in SLE that have the potential to improve patient risk stratification and inform the development of novel therapeutic strategies.

Directed differentiation of human iPSCs into mesenchymal lineages by optogenetic control of TGF-ß signaling.

In tissue development and homeostasis, transforming growth factor (TGF)-ß signaling is finely coordinated by latent forms and matrix sequestration. Optogenetics can offer precise and dynamic control of cell signaling. We report the development of an optogenetic human induced pluripotent stem cell system for TGF-ß signaling and demonstrate its utility in directing differentiation into the smooth muscle, tenogenic, and chondrogenic lineages. Light-activated TGF-ß signaling resulted in expression of differentiation markers at levels close to those in soluble factor-treated cultures, with minimal phototoxicity. In a cartilage-bone model, light-patterned TGF-ß gradients allowed the establishment of hyaline-like layer of cartilage tissue at the articular surface while attenuating with depth to enable hypertrophic induction at the osteochondral interface. By selectively activating TGF-ß signaling in co-cultures of light-responsive and non-responsive cells, undifferentiated and differentiated cells were simultaneously maintained in a single culture with shared medium. This platform can enable patient-specific and spatiotemporally precise studies of cellular decision making.

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery.

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.

Effects of electrically conductive nano-biomaterials on regulating cardiomyocyte behavior for cardiac repair and regeneration.

Myocardial infarction (MI) represents one of the most prevalent cardiovascular diseases, with a highly relevant and impactful role in public health. Despite the therapeutic advances of the last decades, MI still begets extensive death rates around the world. The pathophysiology of the disease correlates with cardiomyocyte necrosis, caused by an imbalance in the demand of oxygen to cardiac tissues, resulting from obstruction of the coronary flow. To alleviate the severe effects of MI, the use of various biomaterials exhibit vast potential in cardiac repair and regeneration, acting as native extracellular matrices. These hydrogels have been combined with nano sized or functional materials which possess unique electrical, mechanical, and topographical properties that play important roles in regulating phenotypes and the contractile function of cardiomyocytes even in adverse microenvironments. These nano-biomaterials' differential properties have led to substantial healing on in vivo cardiac injury models by promoting fibrotic scar reduction, hemodynamic function preservation, and benign cardiac remodeling. In this review, we discuss the interplay of the unique physical properties of electrically conductive nano-biomaterials, are able to manipulate the phenotypes and the electrophysiological behavior of cardiomyocytes in vitro, and can enhance heart regeneration in vivo. Consequently, the understanding of the decisive roles of the nano-biomaterials discussed in this review could be useful for designing novel nano-biomaterials in future research for cardiac tissue engineering and regeneration. STATEMENT OF SIGNIFICANCE: This study introduced and deciphered the understanding of the role of multimodal cues in recent advances of electrically conductive nano-biomaterials on cardiac tissue engineering. Compared with other review papers, which mainly describe these studies based on various types of electrically conductive nano-biomaterials, in this review paper we mainly discussed the interplay of the unique physical properties (electrical conductivity, mechanical properties, and topography) of electrically conductive nano-biomaterials, which would allow them to manipulate phenotypes and the electrophysiological behavior of cardiomyocytes in vitro and to enhance heart regeneration in vivo. Consequently, understanding the decisive roles of the nano-biomaterials discussed in the review could help design novel nano-biomaterials in future research for cardiac tissue engineering and regeneration.

Biofabrication of natural hydrogels for cardiac, neural, and bone Tissue engineering Applications.

Natural hydrogels are one of the most promising biomaterials for tissue engineering applications, due to their biocompatibility, biodegradability, and extracellular matrix mimicking ability. To surpass the limitations of conventional fabrication techniques and to recapitulate the complex architecture of native tissue structure, natural hydrogels are being constructed using novel biofabrication strategies, such as textile techniques and three-dimensional bioprinting. These innovative techniques play an enormous role in the development of advanced scaffolds for various tissue engineering applications. The progress, advantages, and shortcomings of the emerging biofabrication techniques are highlighted in this review. Additionally, the novel applications of biofabricated natural hydrogels in cardiac, neural, and bone tissue engineering are discussed as well.

Synthesis and characterization of C2C12-laden gelatin methacryloyl (GelMA) from marine and mammalian sources.

Gelatin methacryloyl (GelMA) is widely used for tissue engineering applications as an extracellular matrix (ECM) mimicking scaffold due to its cost-effectiveness, ease of synthesis, and high biocompatibility. GelMA is widely synthesized from porcine skin gelatin, which labors under clinical, religious, and economical restrictions. In order to overcome these limitations, GelMA can be produced from fish skin gelatin, which is eco-friendly as well. Here, we present a comparative study of the physicochemical (structural, thermal, water uptake, swelling, rheological, and mechanical) and biological (cell viability, proliferation, and spreading) properties of porcine and fish skin GelMA with low and high methacrylation degrees, before and after crosslinking, to check whether fish skin can replace porcine skin as the source of GelMA. Porcine and fish skin GelMA presented similar structural, thermal, and water uptake properties prior to crosslinking. However, subsequent to crosslinking, fish skin GelMA hydrogels exhibited a higher mass swelling ratio and a lower elastic and compressive Young's moduli than porcine skin GelMA hydrogels of similar methacrylation level. Both types of GelMA hydrogels showed great biocompatibility toward encapsulated mouse myoblast cells (C2C12), however, improved cell spreading was observed in fish skin GelMA hydrogels, and cell proliferation was only induced in low methacrylated GelMA. These results suggest that fish skin GelMA is a promising substitute for porcine skin GelMA for biomedical applications and that low methacrylated fish skin GelMA can be used as a potential scaffold for skeletal muscle tissue engineering.

New Trends in Drug Delivery Systems for Veterinary Applications.

BACKGROUND: The veterinary pharmaceutical industry has shown significant growth in recent decades. Several factors contribute to this increase as the demand for the improvement of the quality of life of both domestic and wild animals, together with the need to improve the quality, productivity, and safety of foodstuffs of animal origin. METHODS: The goal of this work was to identify the most suitable medicines for animals that focus on drug delivery routes as those for humans, although they may have different devices, such as collars and ear tags. RESULTS: Recent advances in drug delivery systems for veterinary use are discussed, both from academic research and the global market. The administration routes commonly used for veterinary medicines are also explored, while special attention is given to the latest technological trends to improve the drug performance, reducing the number of doses, animal stress, and side effects. CONCLUSION: Drug delivery system in veterinary decreased the number of doses, side effects, and animal stress that are a small fraction of the benefits of veterinary drug delivery systems and represent a significant increase in profit for the industry; also, it demands investments in research regarding the quality, safety, and efficacy of the drug and the drug delivery systems.

Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications.

Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system's function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed.