Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These difficulties can be attributed to the diversity of cells involved, extreme complexity of the neural circuits, the limited capacity for tissue regeneration, and our incomplete understanding of the underlying pathological processes. Drug discovery is a complex and multidisciplinary process. The screening attrition rate in current drug discovery protocols mean that only one viable drug may arise from millions of screened compounds resulting in the need to improve discovery technologies and protocols to address the multiple causes of attrition. This has identified the need to screen larger libraries where the use of efficient high-throughput screening (HTS) becomes key in the discovery process. HTS can investigate hundreds of thousands of compounds per day. However, if fewer compounds could be screened without compromising the probability of success, the cost and time would be largely reduced. To that end, recent advances in computer-aided design, in silico libraries, and molecular docking software combined with the upscaling of cell-based platforms have evolved to improve screening efficiency with higher predictability and clinical applicability. We review, here, the increasing role of HTS in contemporary drug discovery processes, in particular for NDDs, and evaluate the criteria underlying its successful application. We also discuss the requirement of HTS for novel NDD therapies and examine the major current challenges in validating new drug targets and developing new treatments for NDDs.

https://www.mdpi.com/2306-5354/8/2/30/pdf

High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

In recent years, many promising nanotechnological approaches to biomedical research have been developed in order to increase implementation of regenerative medicine and tissue engineering in clinical practice. In the meantime, the use of nanomaterials for the regeneration of diseased or injured tissues is considered advantageous in most areas of medicine. In particular, for the treatment of cardiovascular, osteochondral and neurological defects, but also for the recovery of functions of other organs such as kidney, liver, pancreas, bladder, urethra and for wound healing, nanomaterials are increasingly being developed that serve as scaffolds, mimic the extracellular matrix and promote adhesion or differentiation of cells. This review focuses on the latest developments in regenerative medicine, in which iron oxide nanoparticles (IONPs) play a crucial role for tissue engineering and cell therapy. IONPs are not only enabling the use of non-invasive observation methods to monitor the therapy, but can also accelerate and enhance regeneration, either thanks to their inherent magnetic properties or by functionalization with bioactive or therapeutic compounds, such as drugs, enzymes and growth factors. In addition, the presence of magnetic fields can direct IONP-labeled cells specifically to the site of action or induce cell differentiation into a specific cell type through mechanotransduction.

/pdf/iron-oxide-nanoparticles-in-regenerative-medicine-and-tissue-2xxxoyc4k4.pdf

Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering.

Patient-derived tumor organoids (PDOs) are a highly promising preclinical model that recapitulates the histology, gene expression, and drug response of the donor patient tumor. Currently, PDO culture relies on basement-membrane extract (BME), which suffers from batch-to-batch variability, the presence of xenogeneic compounds and residual growth factors, and poor control of mechanical properties. Additionally, for the development of new organoid lines from patient-derived xenografts, contamination of murine host cells poses a problem. We propose a nanofibrillar hydrogel (EKGel) for the initiation and growth of breast cancer PDOs. PDOs grown in EKGel have histopathologic features, gene expression, and drug response that are similar to those of their parental tumors and PDOs in BME. In addition, EKGel offers reduced batch-to-batch variability, a range of mechanical properties, and suppressed contamination from murine cells. These results show that EKGel is an improved alternative to BME matrices for the initiation, growth, and maintenance of breast cancer PDOs. 

/pdf/biomimetic-hydrogel-supports-initiation-and-growth-of-17el7e8k.pdf

Biomimetic hydrogel supports initiation and growth of patient-derived breast tumor organoids

Inherited retinal diseases (IRDs) cause progressive loss of light-sensitive photoreceptors in the eye and can lead to blindness. Gene-based therapies for IRDs have shown remarkable progress in the past decade, but the vast majority of forms remain untreatable. In the era of personalised medicine, induced pluripotent stem cells (iPSCs) emerge as a valuable system for cell replacement and to model IRD because they retain the specific patient genome and can differentiate into any adult cell type. Three-dimensional (3D) iPSCs-derived retina-like tissue called retinal organoid contains all major retina-specific cell types: amacrine, bipolar, horizontal, retinal ganglion cells, Muller glia, as well as rod and cone photoreceptors. Here, we describe the main applications of retinal organoids and provide a comprehensive overview of the state-of-art analysis methods that apply to this model system. Finally, we will discuss the outlook for improvements that would bring the cellular model a step closer to become an established system in research and treatment development of IRDs.

/pdf/a-look-into-retinal-organoids-methods-analytical-techniques-43xmfeyp7n.pdf

A look into retinal organoids: methods, analytical techniques, and applications.

Environmental toxicology wars: Organ-on-a-chip for assessing the toxicity of environmental pollutants.

The development of novel 3D tissue culture systems has enabled the in vitro study of in vivo processes, thereby overcoming many of the limitations of previous 2D tissue culture systems. Advances in biomaterials, including the discovery of novel synthetic polymers has allowed for the generation of physiologically relevant in vitro 3D culture models. A large number of 3D culture systems, aided by novel organ-on-a-chip and bioreactor technologies have been developed to improve reproducibility and scalability of in vitro organ models. The discovery of induced pluripotent stem cells (iPSCs) and the increasing number of protocols to generate iPSC-derived cell types has allowed for the generation of novel 3D models with minimal ethical limitations. The production of iPSC-derived 3D cultures has revolutionized the field of developmental biology and in particular, the study of fetal brain development. Furthermore, physiologically relevant 3D cultures generated from PSCs or adult stem cells (ASCs) have greatly advanced in vitro disease modelling and drug discovery. This review focuses on advances in 3D culture systems over the past years to model fetal development, disease pathology and support drug discovery in vitro, with a specific focus on the enabling role of biomaterials.

Biomaterials and Culture Systems for Development of Organoid and Organ-on-a-Chip Models.

Tissue engineering has garnered significant attention for its potential to address the predominant modes of failure of small diameter vascular prostheses, namely mid-graft thrombosis and anastomotic intimal hyperplasia. In this review, we describe two main features underpinning the promise of tissue-engineered vascular grafts: the incorporation of an anti-thrombogenic endothelium, and the generation of a structurally and biomechanically mimetic extracellular matrix. From the early attempts at the in-vitro endothelialization of vascular prostheses in the 1970s through to the ongoing clinical trials of fully tissue-engineered vascular grafts, the historical advancements and unresolved challenges that characterize the current state-of-the-art are summarized in a manner that establishes a guide for the development of an effective vascular prosthesis for small diameter arterial reconstruction. The importance of endothelial cell purity and their arterial specification for the prevention of both diffuse neo-intimal hyperplasia and the accelerated development of atherosclerotic lesions is delineated. Additionally, the need for an extracellular matrix that recapitulates both the composition and structure of native elastic arteries to facilitate the protracted stability and patency of an engineered vaso-active conduit is described. Finally, the capacity of alternative sources of cells and mechanical conditioning to overcome these technical barriers to the clinical translation of an effective small diameter vascular prosthesis is discussed. In conclusion, this review provides an overview of the historical development of tissue-engineered vascular grafts, highlighting specific areas warranting further research, and commentating on the outlook of a clinically feasible and therapeutically efficacious vascular prosthesis for small diameter arterial reconstruction.

Katya A. D'''''Costa

Papers

Biomaterials and Culture Systems for Development of Organoid and Organ-on-a-Chip Models.

Advancing tissue-engineered vascular grafts via their endothelialization and mechanical conditioning.