Micro and Nanoscale Technologies for Diagnosis of Viral Infections.

Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID-19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost-effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip-based integrated platforms, and nano- and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip-based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted.

Advances in Controlled Oxygen Generating Biomaterials for Tissue Engineering and Regenerative Therapy.

Oxygen (O2) generating biomaterials are emerging as important compositions to improve our capabilities in supporting tissue engineering and regenerative therapeutics. Several in vitro studies demonstrated the usefulness of O2 releasing biomaterials in enhancing cell survival and differentiation. However, more efforts are needed to develop materials that can provide sustained O2 release for the long-term. In this paper, we present different O2 generating sources, including hydrogen peroxide, sodium percarbonate, calcium peroxide and magnesium peroxide, and also cover types of carriers and relevant methods of fabricating O2 generating systems. Then, the applications of O2 generating materials in supporting engineered constructs, supplying high O2 demanding cell transplants, and supporting ischemic tissues are discussed. Moreover, the challenges and future perspectives are highlighted.

Spine Intervention-An Update on Injectable Biomaterials.

Back pain is the second most common reason for primary-care physician visits after the common cold. New understanding of the spine pathophysiology and biomechanics led to the development of novel injectable biomaterials to treat those pain generators. Although not all biomaterials are currently ready for common use, there is significant interest by the medical community to invest time, resources, and energy to optimize these injectables. This review introduces basic concepts and advancements in the field of bioinjectables tailored for the vertebral body. Also, we highlight advances in injectable biomaterials which were presented at the Groupe de Recherche Interdisciplinaire sur les Biomatériaux Ostéoarticulaires Injectables (GRIBOI) (Interdisciplinary Research Society for Injectable Osteoarticular Biomaterials) meeting in March 2018 in Los Angeles, CA. Indeed, multidisciplinary translational research and international meetings such as GRIBOI bring together scientists and clinicians with different backgrounds/expertise to discuss injectable biomaterials innovations tailored for the interventional pain management field.

Enhanced Maturation of 3D Bioprinted Skeletal Muscle Tissue Constructs Encapsulating Soluble Factor-Releasing Microparticles.

Several microfabrication technologies have been used to engineer native-like skeletal muscle tissues. However, the successful development of muscle remains a significant challenge in the tissue engineering field. Muscle tissue engineering aims to combine muscle precursor cells aligned within a highly organized 3D structure and biological factors crucial to support cell differentiation and maturation into functional myotubes and myofibers. In this study, the use of 3D bioprinting is proposed for the fabrication of muscle tissues using gelatin methacryloyl (GelMA) incorporating sustained insulin-like growth factor-1 (IGF-1)-releasing microparticles and myoblast cells. This study hypothesizes that functional and mature myotubes will be obtained more efficiently using a bioink that can release IGF-1 sustainably for in vitro muscle engineering. Synthesized microfluidic-assisted polymeric microparticles demonstrate successful adsorption of IGF-1 and sustained release of IGF-1 at physiological pH for at least 21 days. Incorporating the IGF-1-releasing microparticles in the GelMA bioink assisted in promoting the alignment of myoblasts and differentiation into myotubes. Furthermore, the myotubes show spontaneous contraction in the muscle constructs bioprinted with IGF-1-releasing bioink. The proposed bioprinting strategy aims to improve the development of new therapies applied to the regeneration and maturation of muscle tissues.

Droplet-based microfluidics in biomedical applications.

Droplet-based microfluidic systems have been employed to manipulate discrete fluid volumes with immiscible phases. Creating the fluid droplets at microscale has led to a paradigm shift in mixing, sorting, encapsulation, sensing, and designing high throughput devices for biomedical applications. Droplet microfluidics has opened many opportunities in microparticle synthesis, molecular detection, diagnostics, drug delivery, and cell biology. In the present review, we first introduce standard methods for droplet generation (i.e. passive and active methods) and discuss the latest examples of emulsification and particle synthesis approaches enabled by microfluidic platforms. Then, the applications of droplet-based microfluidics in different biomedical applications are detailed. Finally, a general overview of the latest trends along with the perspectives and future potentials in the field are provided.

Healthy and diseased in vitro models of vascular systems.

Irregular hemodynamics affects the progression of various vascular diseases, such atherosclerosis or aneurysms. Despite the extensive hemodynamics studies on animal models, the inter-species differences between humans and animals hamper the translation of such findings. Recent advances in vascular tissue engineering and the suitability of in vitro models for interim analysis have increased the use of in vitro human vascular tissue models. Although the effect of flow on endothelial cell (EC) pathophysiology and EC-flow interactions have been vastly studied in two-dimensional systems, they cannot be used to understand the effect of other micro- and macro-environmental parameters associated with vessel wall diseases. To generate an ideal in vitro model of the vascular system, essential criteria should be included: 1) the presence of smooth muscle cells or perivascular cells underneath an EC monolayer, 2) an elastic mechanical response of tissue to pulsatile flow pressure, 3) flow conditions that accurately mimic the hemodynamics of diseases, and 4) geometrical features required for pathophysiological flow. In this paper, we review currently available in vitro models that include flow dynamics and discuss studies that have tried to address the criteria mentioned above. Finally, we critically review in vitro fluidic models of atherosclerosis, aneurysm, and thrombosis.

Multimaterial bioprinting and combination of processing techniques towards the fabrication of biomimetic tissues and organs.

Tissue reconstruction requires the utilization of multiple biomaterials and cell types to replicate the delicate and complex structure of native tissues. Various three-dimensional (3D) bioprinting techniques have been developed to fabricate customized tissue structures; however, there are still significant challenges, such as vascularization, mechanical stability of printed constructs, and fabrication of gradient structures to be addressed for the creation of biomimetic and complex tissue constructs. One approach to address these challenges is to develop multimaterial 3D bioprinting techniques that can integrate various types of biomaterials and bioprinting capabilities towards the fabrication of more complex structures. Notable examples include multi-nozzle, coaxial, and microfluidics-assisted multimaterial 3D bioprinting techniques. More advanced multimaterial 3D printing techniques are emerging, and new areas in this niche technology are rapidly evolving. In this review, we briefly introduce the basics of individual 3D bioprinting techniques and then discuss the multimaterial 3D printing techniques that can be developed based on combination of these techniques for the engineering of complex and biomimetic tissue constructs. We also discuss the perspectives and future directions to develop state-of-the-art multimaterial 3D bioprinting techniques for engineering tissues and organs.

An Alkaline Based Method for Generating Crystalline, Strong, and Shape Memory Polyvinyl Alcohol Biomaterials.

Strong, stretchable, and durable biomaterials with shape memory properties can be useful in different biomedical devices, tissue engineering, and soft robotics. However, it is challenging to combine these features. Semi-crystalline polyvinyl alcohol (PVA) has been used to make hydrogels by conventional methods such as freeze-thaw and chemical crosslinking, but it is formidable to produce strong materials with adjustable properties. Herein, a method to induce crystallinity and produce physically crosslinked PVA hydrogels via applying high-concentration sodium hydroxide into dense PVA polymer is introduced. Such a strategy enables the production of physically crosslinked PVA biomaterial with high mechanical properties, low water content, resistance to injury, and shape memory properties. It is also found that the developed PVA hydrogel can recover 90% of plastic deformation due to extension upon supplying water, providing a strong contraction force sufficiently to lift objects 1100 times more than their weight. Cytocompatibility, antifouling property, hemocompatibility, and biocompatibility are also demonstrated in vitro and in vivo. The fabrication methods of PVA-based catheters, injectable electronics, and microfluidic devices are demonstrated. This gelation approach enables both layer-by-layer and 3D printing fabrications.

Microphysiological Systems: Next Generation Systems for Assessing Toxicity and Therapeutic Effects of Nanomaterials.

Microphysiological systems, also known as organ-on-a-chip platforms, show promise for the development of new testing methods that can be more accurate than both conventional two-dimensional cultures and costly animal studies. The development of more intricate microphysiological systems can help to better mimic the human physiology and highlight the systemic effects of different drugs and materials. Nanomaterials are among a technologically important class of materials used for diagnostic, therapeutic, and monitoring purposes; all of which and can be tested using new organ-on-a-chip systems. In addition, the toxicity of nanomaterials which have entered the body from ambient air or diet can have deleterious effects on various body systems. This in turn can be studied in newly developed microphysiological systems. While organ-on-a-chip models can be useful, they cannot pick up secondary and systemic toxicity. Thus, the utilization of multi-organ-on-a-chip systems for advancing nanotechnology will largely be reflected in the future of drug development, toxicology studies and precision medicine. Various aspects of related studies, current challenges, and future perspectives are discussed in this paper.

3D Bioprinting of Oxygenated Cell-Laden Gelatin Methacryloyl Constructs.

Cell survival during the early stages of transplantation and before new blood vessels formation is a major challenge in translational applications of 3D bioprinted tissues. Supplementing oxygen (O2 ) to transplanted cells via an O2 generating source such as calcium peroxide (CPO) is an attractive approach to ensure cell viability. Calcium peroxide also produces calcium hydroxide that reduces the viscosity of bioinks, which is a limiting factor for bioprinting. Therefore, adapting this solution into 3D bioprinting is of significant importance. In this study, a gelatin methacryloyl (GelMA) bioink that is optimized in terms of pH and viscosity is developed. The improved rheological properties lead to the production of a robust bioink suitable for 3D bioprinting and controlled O2 release. In addition, O2 release, bioprinting conditions, and mechanical performance of hydrogels having different CPO concentrations are characterized. As a proof of concept study, fibroblasts and cardiomyocytes are bioprinted using CPO containing GelMA bioink. Viability and metabolic activity of printed cells are checked after 7 days of culture under hypoxic condition. The results show that the addition of CPO improves the metabolic activity and viability of cells in bioprinted constructs under hypoxic condition.

Non-transdermal microneedles for advanced drug delivery.

Microneedles (MNs) have been used to deliver drugs for over two decades. These platforms have been proven to increase transdermal drug delivery efficiency dramatically by penetrating restrictive tissue barriers in a minimally invasive manner. While much of the early development of MNs focused on transdermal drug delivery, this technology can be applied to a variety of other non-transdermal biomedical applications. Several variations, such as multi-layer or hollow MNs, have been developed to cater to the needs of specific applications. The heterogeneity in the design of MNs has demanded similar variety in their fabrication methods; the most common methods include micromolding and drawing lithography. Numerous materials have been explored for MN fabrication which range from biocompatible ceramics and metals to natural and synthetic biodegradable polymers. Recent advances in MN engineering have diversified MNs to include unique shapes, materials, and mechanical properties that can be tailored for organ-specific applications. In this review, we discuss the design and creation of modern MNs that aim to surpass the biological barriers of non-transdermal drug delivery in ocular, vascular, oral, and mucosal tissue.

An injectable conductive Gelatin-PANI hydrogel system serves as a promising carrier to deliver BMSCs for Parkinson's disease treatment.

Parkinson's disease (PD) is a long-term neurodegenerative disorders that characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNc). Bone marrow stromal cells (BMSCs) are promising therapeutic agents for neurodegenerative disease due to their multipotent capacity. To promote the potential therapeutic effect of BMSCs on PD, we developed an injectable Gelatin-PANI hydrogels as a novel carrier for delivering BMSCs to the SNc region in mice with PD by stereotactic injection. Histology results showed that the BMSCs-loaded hydrogels lead to increased numbers of tyrosine hydroxylase positive (TH+) dopaminergic neurons and fibers in the SNc and striatum, and increased expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the SNc. Meanwhile, rotarod and open field evaluation demonstrated BMSCs-loaded hydrogels significantly improved the behavioral performance of PD mice. Importantly, BMSCs-loaded hydrogels imparted more sustained protective effects than BMSCs alone in PD mice. Overall, the current data indicate that the hydrogel serves as a promising carrier to deliver BMSCs to the SNc for the treatment of PD.

Minimally Invasive and Regenerative Therapeutics.

Advances in biomaterial synthesis and fabrication, stem cell biology, bioimaging, microsurgery procedures, and microscale technologies have made minimally invasive therapeutics a viable tool in regenerative medicine. Therapeutics, herein defined as cells, biomaterials, biomolecules, and their combinations, can be delivered in a minimally invasive way to regenerate different tissues in the body, such as bone, cartilage, pancreas, cardiac, skeletal muscle, liver, skin, and neural tissues. Sophisticated methods of tracking, sensing, and stimulation of therapeutics in vivo using nano-biomaterials and soft bioelectronic devices provide great opportunities to further develop minimally invasive and regenerative therapeutics (MIRET). In general, minimally invasive delivery methods offer high yield with low risk of complications and reduced costs compared to conventional delivery methods. Here, minimally invasive approaches for delivering regenerative therapeutics into the body are reviewed. The use of MIRET to treat different tissues and organs is described. Although some clinical trials have been performed using MIRET, it is hoped that such therapeutics find wider applications to treat patients. Finally, some future perspective and challenges for this emerging field are highlighted.

Skin-Inspired Multifunctional Autonomic-Intrinsic Conductive Self-Healing Hydrogels with Pressure Sensitivity, Stretchability, and 3D Printability.

The advent of conductive self-healing (CSH) hydrogels, a class of novel materials mimicking human skin, may change the trajectory of the industrial process because of their potential applications in soft robots, biomimetic prostheses, and health-monitoring systems. Here, the development of a mechanically and electrically self-healing hydrogel based on physically and chemically cross-linked networks is reported. The autonomous intrinsic self-healing of the hydrogel is attained through dynamic ionic interactions between carboxylic groups of poly(acrylic acid) and ferric ions. A covalent cross-linking is used to support the mechanical structure of the hydrogel. Establishing a fair balance between the chemical and physical cross-linking networks together with the conductive nanostructure of polypyrrole networks leads to a double network hydrogel with bulk conductivity, mechanical and electrical self-healing properties (100% mechanical recovery in 2 min), ultrastretchability (1500%), and pressure sensitivity. The practical potential of CSH hydrogels is further revealed by their application in human motion detection and their 3D-printing performance.

Flexible Electrode Design: Fabrication of Freestanding Polyaniline-Based Composite Films for High-Performance Supercapacitors.

Polyaniline (PANI) is a promising pseudocapacitance electrode material. However, its structural instability leads to low cyclic stability and limited rate capability which hinders its practical applications. In view of the limitations, flexible PANI-based composite films are developed to improve the electrochemical performance of electrode materials. We report in the research a facile and cost-effective approach for fabrication of a high-performance supercapacitor (SC) with excellent cyclic stability and tunable energy and power densities. SC electrode containing a very high mass loading of active materials is a flexible film of PANI, tissue wiper-based cellulose, graphite-based exfoliated graphite (ExG), and silver nanoparticles with potential applications in wearable electronics. The optimum preparation weight ratios of silver nitrate/aniline and ExG/aniline used in the research are estimated to be 0.18 and 0.65 (or higher), respectively. Our results show that an ultrahigh capacitance of 3.84 F/cm(2) (240.10 F/g) at a discharge rate of 5 mA can be achieved. In addition, our study shows that the power density can be increased from 1531.3 to 3000 W/kg by selecting the weight ratio of ExG/aniline to be more than 0.65, with a sacrifice in the energy density. The obtained promising electrochemical properties are found to be mainly attributed to an effective combination of PANI, ExG, cushiony cellulose scaffold, and silver as well as the porosity of the composite.

Mussel-inspired alginate gel promoting the osteogenic differentiation of mesenchymal stem cells and anti-infection.

Alginate hydrogels have been used in cell encapsulation for many years but a prevalent issue with pure alginates is that they are unable to provide enough bioactive properties to interact with mammalian cells. This paper discusses the modification of alginate with mussel-inspired dopamine for cell loading and anti-infection. Mouse bone marrow stem cells were immobilized into alginate and alginate-dopamine beads and fibers. Through live-dead and MTT assay, alginates modified by dopamine promoted cell viability and proliferation. In vitro cell differentiation results showed that such an alginate-dopamine gel can promote the osteogenic differentiation of mesenchymal stem cell after PCR and ALP assays. In addition to that, the adhesive prosperities of dopamine allowed for coating the surface of alginate-dopamine gel with silver nanoparticles, which provided the gel with significant antibacterial characteristics. Overall, these results demonstrate that a dopamine-modified alginate gel can be a great tool for cell encapsulation to promote cell proliferation and can be applied to bone regeneration, especially in contaminated bone defects.

Fast and safe fabrication of a free-standing chitosan/alginate nanomembrane to promote stem cell delivery and wound healing.

Polymeric ultrathin membranes that are compatible with cells offer tremendous advantages for tissue engineering. In this article, we report a free-standing nanomembrane that was developed using a layer-by-layer self-assembly technique with a safe and sacrificial substrate method. After ionization, two oppositely charged polyelectrolytes, alginate and chitosan, were alternately deposited on a substrate of a solidified gelatin block to form an ultrathin nanomembrane. The space between the two adjacent layers was ∼200 nm. The thickness of the nanomembrane was proportional to the number of layers. The temperature-sensitive gelatin gel served as a sacrificial template at 37°C. The free-standing nanomembrane promoted bone marrow stem cell adhesion and proliferation. Fluorescence-activated cell sorting was used to analyze green-fluorescent-protein-positive mesenchymal stem cells from the wounds, which showed a significantly high survival and proliferation from the nanomembrane when cells were transplanted to mouse dorsal skin that had a full-thickness burn. The bone-marrow-stem-cell-loaded nanomembrane also accelerated wound contraction and epidermalization. Therefore, this methodology provides a fast and facile approach to construct free-standing ultrathin scaffolds for tissue engineering. The biocompatibility and free-standing nature of the fabricated nanomembrane may be particularly useful for stem cell delivery and wound healing.

Highly Flexible and Resilient Elastin Hybrid Cryogels with Shape Memory, Injectability, Conductivity, and Magnetic Responsive Properties.

A strategy utilizing elastin peptide macroporous cryogels to build highly flexible scaffolds to load carbon nanotubes, polypyrrole, and iron oxide magnetic nanoparticles, is presented. This combines high elasticity, flexibility, shape memory property, and injectable property together with conductivity and/or magnetic responsive property. The network can afford 97.5% compressive strain with an excellent conductivity of 50.1 ± 2.9 S cm(-1) at 90% strain.

Cytokine loaded layer-by-layer ultrathin matrices to deliver single dermal papilla cells for spot-by-spot hair follicle regeneration.

The dermal papilla cell (DPC) is a type of highly specialized mesenchymal cells located in hair follicles (HF). Due to the primary role in the epithelial-mesenchymal interaction that enables hair-follicle morphogenesis and hair cycling, DPC has become an attractive cell source for hair regeneration to treat alopecia patients. However, DPCs tend to lose their function during in vitro culture. Hence, there exists a clear need to develop a microenvironment that can recapitulate the interactions within the native milieu of DPCs. Since layer-by-layer (LBL) nano-coating with biocompatible materials on the cell surface displays the versatility with tunable loading and release properties, which can provide a remodeled microenvironment for regulating cell function. Here, we developed a LBL self-assembly technique to single DPCs to create a nano-scale ultrathin extracellular matrix (ECM). We studied that the single cell-based LBL-encapsulation would not impact the viability, morphology, proliferation and intrinsic properties of DPCs using Western blot and mRNA expressions of ß-catenin, ALP and α-SMA. We then included fibroblast growth factor-2 (FGF-2) into the LBL nano-structure to regulate the DPC function. Finally, we performed in vivo hair reconstitution assays using LBL-encapsulated DPCs combined with freshly isolated epidermal cells (EPCs) and found this strategy can treat hair loss.