Microfluidic Generation of Nanomaterials for Biomedical Applications.

As nanomaterials (NMs) possess attractive physicochemical properties that are strongly related to their specific sizes and morphologies, they are becoming one of the most desirable components in the fields of drug delivery, biosensing, bioimaging, and tissue engineering. By choosing an appropriate methodology that allows for accurate control over the reaction conditions, not only can NMs with high quality and rapid production rate be generated, but also designing composite and efficient products for therapy and diagnosis in nanomedicine can be realized. Recent evidence implies that microfluidic technology offers a promising platform for the synthesis of NMs by easy manipulation of fluids in microscale channels. In this Review, a comprehensive set of developments in the field of microfluidics for generating two main classes of NMs, including nanoparticles and nanofibers, and their various potentials in biomedical applications are summarized. Furthermore, the major challenges in this area and opinions on its future developments are proposed.

Recent Advances in Microfluidics for the Preparation of Drug and Gene Delivery Systems.

Drug delivery systems (DDSs) have great potential for improving the treatment of several diseases, especially microbial infections and cancers. However, the formulation procedures of DDSs remain challenging, especially at the nanoscale. Reducing batch-to-batch variation and enhancing production rate are some of the essential requirements for accelerating the translation of DDSs from a small scale to an industrial level. Microfluidic technologies have emerged as an alternative to the conventional bench methods to address these issues. By providing precise control over the fluid flows and rapid mixing, microfluidic systems can be used to fabricate and engineer different types of DDSs with specific properties for efficient delivery of a wide range of drugs and genetic materials. This review discusses the principles of controlled rapid mixing that have been employed in different microfluidic strategies for producing DDSs. Moreover, the impact of the microfluidic device design and parameters on the type and properties of DDS formulations was assessed, and recent applications in drug and gene delivery were also considered.

A DNA Nanodevice Simultaneously Activating the EGFR and Integrin for Enhancing Cytoskeletal Activity and Cancer Cell Treatment.

Cell-surface receptors (e.g., EGFR and integrin) and their interactions play determining roles in signal transduction and cytoskeletal activation, which affect cell attachment/detachment, invasion, motility, metastasis (intracellular), and cell-cell signaling. For instance, the interactions between the EGFR and integrin (α6ß4) may cause increased mechanical force and shear stress via enhanced cytoskeleton activation. Here, we design a DNA nanodevice (DNA-ND) that can simultaneously target the EGFR and integrin receptors on the caveolae. The piconewton (pN) forces in response to the EGFR-integrin coactivation can be sensed upon the unfolding of the DNA hairpin structure on the side arm of the device via changes of the fluorescence and plasmonic signals. We find that simultaneous activation of EGFR-integrin receptors causes enhanced signal transduction, contractions of the cells, and initiation of the biochemical pathways, thus resulting in a change of the cell division and endocytosis/exocytosis processes that affect the cell proliferation/apoptosis. The DNA-ND further enables us to visualize the cointernalization and degradation of the receptors by lysosomes, providing a novel approach toward bioimaging and mechano-pharmacology.

Rational Design of Semiconductor Nanostructures for Functional Subcellular Interfaces.

One of the fundamental questions guiding research in the biological sciences is how cellular systems process complex physical and environmental cues and communicate with each other across multiple length scales. Importantly, aberrant signal processing in these systems can lead to diseases that can have devastating impacts on human lives. Biophysical studies in the past several decades have demonstrated that cells can respond to not only biochemical cues but also mechanical and electrical ones. Thus, the development of new materials that can both sense and modulate all of these pathways is necessary. Semiconducting nanostructures are an emerging class of discovery platforms and tools that can push the limits of our ability to modulate and sense biological behaviors for both fundamental research and clinical applications. These materials are of particular interest for interfacing with cellular systems due to their matched dimension with subcellular components (e.g., cytoskeletal filaments), and easily tunable properties in the electrical, optical and mechanical regimes. Rational design via traditional or new approaches, such as nanocasting and mesoscale chemical lithography, can allow us to control micro- and nanoscale features in nanowires to achieve new biointerfaces. Both processes endogenous to the target cell and properties of the material surface dictate the character of these interfaces. In this Account, we focus on (1) approaches for the rational design of semiconducting nanowires that exhibit unique structures for biointerfaces, (2) recent fundamental discoveries that yield robust biointerfaces at the subcellular level, (3) intracellular electrical and mechanical sensing, and (4) modulation of cellular behaviors through material topography and remote physical stimuli. In the first section, we discuss new approaches for the synthetic control of micro- and nanoscale features of these materials. In the second section, we focus on achieving biointerfaces with these rationally designed materials either intra- or extracellularly. We last delve into the use of these materials in sensing mechanical forces and electrical signals in various cellular systems as well as in instructing cellular behaviors. Future research in this area may shift the paradigm in fundamental biophysical research and biomedical applications through (1) the design and synthesis of new semiconductor-based materials and devices that interact specifically with targeted cells, (2) the clarification of many developmental, physiological, and anatomical aspects of cellular communications, (3) an understanding of how signaling between cells regulates synaptic development (e.g., information like this would offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases), (4) and the creation of new cellular materials that have the potential to open up completely new areas of application, such as in hybrid information processing systems.

Design of nanorobots for exposing cancer cells.

We discuss in detail, the design of a nanorobot that can navigate, detect cancer cells in the blood and actuate the exposure of drugs. The nanorobot is designed with blood energy harvesting capability and the accumulation of electricity in a capacitor, which forms the main body of the nanorobot. Glucose hunger-based cancer detectors immobilized on a carbon nanotube sensor, reduces its electrical resistance when attached to a cancer cell. This mechanism in turn allows electric current to activate a nano-electrical-mechanical relay (mechanical transistor) to break the chamber ceiling exposing a drug identified by the immune system for cell elimination. This concept is in line with the effort to design an autonomous computational nanorobot for in vivo medical diagnosis and treatment. We present this facile approach to design a collective system to visualize the programmability in nanorobots. The calculations and simulation results provide a proof-of-concept towards a plausible implementation. Through this work, we present an overall picture towards an inorganic autonomous computational nanorobot for cancer diagnosis and treatment.

Nanomaterial-based devices for point-of-care diagnostic applications.

In this review, we have discussed the capabilities of nanomaterials for point-of-care (PoC) diagnostics and explained how these materials can help to strengthen, miniaturize and improve the quality of diagnostic devices. Since the optical, electrochemical and other physical properties of nanomaterials are dictated by their composition, size and shape, these factors are critical in the design and function of nanomaterial-based PoC diagnostics.

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases.

There is a huge demand for pro-/anti-angiogenic nanomedicines to treat conditions such as ischemic strokes, brain tumors, and neurodegenerative diseases such as Alzheimer's and Parkinson's. Nanomedicines are therapeutic particles in the size range of 10-1000 nm, where the drug is encapsulated into nano-capsules or adsorbed onto nano-scaffolds. They have good blood-brain barrier permeability, stability and shelf life, and able to rapidly target different sites in the brain. However, the relationship between the nanomedicines' physical and chemical properties and its ability to travel across the brain remains incompletely understood. The main challenge is the lack of a reliable drug testing model for brain angiogenesis. Recently, microfluidic platforms (known as "lab-on-a-chip" or LOCs) have been developed to mimic the brain micro-vasculature related events, such as vasculogenesis, angiogenesis, inflammation, etc. The LOCs are able to closely replicate the dynamic conditions of the human brain and could be reliable platforms for drug screening applications. There are still many technical difficulties in establishing uniform and reproducible conditions, mainly due to the extreme complexity of the human brain. In this paper, we review the prospective of LOCs in the development of nanomedicines for brain angiogenesis-related conditions.

Tumor-on-a-chip platforms for assessing nanoparticle-based cancer therapy.

Cancer has become the most prevalent cause of deaths, placing a huge economic and healthcare burden worldwide. Nanoparticles (NPs), as a key component of nanomedicine, provide alternative options for promoting the efficacy of cancer therapy. Current conventional cancer models have limitations in predicting the effects of various cancer treatments. To overcome these limitations, biomimetic and novel 'tumor-on-a-chip' platforms have emerged with other innovative biomedical engineering methods that enable the evaluation of NP-based cancer therapy. In this review, we first describe cancer models for evaluation of NP-based cancer therapy techniques, and then present the latest advances in 'tumor-on-a-chip' platforms that can potentially facilitate clinical translation of NP-based cancer therapies.

Nanomedicines for developing cancer nanotherapeutics: from benchtop to bedside and beyond.

Cancer is a devastating disease and remains a significant cause of mortality and morbidity in both developed and developing countries. Although there are large number of drugs that can be used for the treatment of cancer, the problem is selective and specific killing of cancerous cells without harming the normal cells. There are some biological barriers to potential drug delivery in cancer cells like hepatic, renal, abnormal vasculature, dense extracellular matrix, and high interstitial fluid pressure. The physicochemical characteristics of nanoparticles (NPs) such as size, shape, and surface charge may also have significant effects on tumor penetration. NPs coated with drug can be used to overcome these biological barriers to enhance targeted delivery. This literature survey encompasses the biological barriers to potential drug delivery in cancer cells, elaborate on designing strategies to enhance NPs penetration and distribution inside the tumor interstitium. Scientists are now doing great efforts to design next-generation of nanomedicines (NMs) that need to be better targeted with high specificity and efficacy to kill cancer cells. These challenges need to be overcome through collaborations among academia, pharmaceutical industries, and regulatory agencies to eradicate this global menace. Furthermore, this review article has critically discussed the recent developments, controversies, challenges, emerging concepts, and future perspectives in cancer NMs.

Deformable Discoidal Polymeric Nanoconstructs for the Precise Delivery of Therapeutic and Imaging Agents.

Over the last 15 years, a plethora of materials and different formulations have been proposed for the realization of nanomedicines. Yet drug-loading efficiency, sequestration by phagocytic cells, and tumor accumulation are sub-optimal. This would imply that radically new design approaches are needed to propel the clinical integration of nanomedicines, overcoming well-accepted clichés. This work briefly reviews the use of deformable discoidal nanoconstructs as a novel delivery strategy for therapeutic and imaging agents. Inspired by blood cell behavior, these nanoconstructs are designed to efficiently navigate the circulatory system, minimize sequestration by phagocytic cells, and recognize the tortuous angiogenic microvasculature of neoplastic masses. This article discusses the notion of nanoparticle margination and vascular adhesion, as well as advantages associated with deformable particles. Finally, details on the synthesis, physico-chemical properties, and in vivo characterization of discoidal polymeric nanoconstructs are provided, with particular emphasis on their ability to independently control size, shape, surface properties, and mechanical stiffness. These nanoconstructs could help in gaining a deeper understanding of the mechanisms regulating the behavior of nanomedicines and identifying optimal delivery strategies for patient-specific therapeutic interventions.

Stem Cell Smart Technology, where are we now and how far we have to go?

Approximately eight million people in the United States have peripheral arterial disease, which increases exponentially with age. There have been a plethora of available treatments including surgery, angioplasty, atherectomy, laser technology, and cell-based therapies. Cell-based therapies were developed in the hope of translating laboratory-based technology into clinical successes. However, clinical results have been disappointing. Infusion or injection for stem cell therapy is still considered experimental and investigational, and major questions on safety and durability have arisen. In no option patients, how can they be treated safely and successfully? In this article, we review contemporary practice for cell therapy, its pitfalls and breakthroughs, and look at the future ahead. We introduce a novel smart system for minimally invasive delivery of cell therapies, which exemplifies the next generation of endovascular solutions to stem cell technology and promises safety, efficacy, and reliability.

Carbon nanotubes: a novel material for multifaceted applications in human healthcare.

Remarkable advances have been achieved in modern material technology, especially in device fabrication, and these have facilitated the use of diverse materials in various applications. Carbon nanotubes (CNTs) are being successfully implemented in drug delivery, sensing, water purification, composite materials, and bone scaffolds. Thus, CNTs must meet a wide range of criteria such as surface modification, high aspect ratio, desired conductivity, high porosity and loading, non-toxicity, specificity, and selectivity, and compatibility for device fabrication. The main focus of this review is to explore the maximum applications of CNTs for human health, and we particularly focus on nanocarrier and biomedical applications. The scope of this review initially covers the basic aspects of CNTs and is also extended further to describe their synthesis strategies as well as various challenges encountered in their functionalization, dispersion, and toxicity. Our discussion also emphasizes future directions for these emerging fields of research.

Design of virus-based nanomaterials for medicine, biotechnology, and energy.

This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.

Microneedles: A New Frontier in Nanomedicine Delivery.

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN.

Hyperbranched polymer vesicles: from self-assembly, characterization, mechanisms, and properties to applications.

Vesicles, including lipid vesicles, surfactant vesicles, as well as polymer vesicles, have been extensively investigated over the past fifty years. Among them, polymer vesicles have attracted more and more attention because of their low permeability, superior stability and toughness, in addition to the numerous possibilities for tailoring physical, chemical and biological properties. Polymer vesicles are generally fabricated through the self-assembly of amphiphilic polymers with a linear architecture. Recently, as representative polymers with a highly branched three-dimensional architecture, hyperbranched polymers have also exhibited great potential for preparing vesicles. The resultant hyperbranched polymer vesicles, defined as branched-polymersomes (BPs), have shown unique properties, such as giant and easily tuned vesicle sizes, facile functionalization, a special formation mechanism, and appealing solution behaviours. In this tutorial review, ten years of advances in BPs have been summarized since their first discovery in the year 2004, including the syntheses of vesicle-forming hyperbranched polymers, self-assembly methods, self-assembly mechanisms, as well as the special properties. In addition, the cytomimetic, biomedical and other initiatory applications of BPs are also included.

Time-Resolved Fluorescence Spectroscopy and Fluorescence Lifetime Imaging Microscopy for Characterization of Dendritic Polymer Nanoparticles and Applications in Nanomedicine.

The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research.

A nanostructured genosensor for the early diagnosis of systemic arterial hypertension.

The rapid progress of nanomedicine, especially in areas related to medical imaging and diagnostics, has motivated the development of new nanomaterials that can be combined with biological materials for specific medical applications. One such area of research involves the detection of specific DNA sequences for the early diagnosis of genetic diseases, using nanoparticles-containing genosensors. Typical genosensors devices are based on the use of sensing electrodes - biorecognition platforms - containing immobilized capture DNA probes capable of hybridizing with specific target DNA sequences. In this paper we show that upon an appropriate design of the biorecognition platform, efficient sandwich-type genosensors based upon DNA-AuNPs nanocomplexes can be efficiently applied to the detection of a Systemic Arterial Hypertension (SAH) polymorphism located in intron 16 of the Angiotensin-converter enzyme (ACE) gene. Since SAH is intimately related to heart diseases, especially blood hypertension, its early detection is of great biomedical interest. The biorecognition platforms were assembled using mixed self-assembled monolayers (SAMmix), which provided the immobilization of organized architectures with molecular control. Detection of the DNA target sequence at concentrations down to 1 nM was carried out using electrochemical impedance spectroscopy (EIS). We show that the use of EIS combined with specific nanobiocomplexes represents an efficient method for the unambiguous detection of complementary DNA hybridization for preventative nanomedicine applications.

Fabrication of a nanofibrous mat with a human skin pattern.

A number of studies on skin tissue regeneration and wound healing have been conducted. Electrospun nanofibers have numerous advantages for use in wound healing dressings. Here, we present an electrospinning method for alteration of the surface morphological properties of electrospun mats because most previous studies focused on the materials used or the introduction of bioactive healing agents. In this study, a micromachined human skin pattern mold was used as a collector in an electrospinning setup to replicate the pattern onto the surface of the electrospun mat. We demonstrated the successful fabrication of a nanofibrous mat with a human skin pattern. To verify its suitability for wound healing, a 14-day in vitro cell culture was carried out. The results indicated that the fabricated mat not only induces equivalent cell viability to the conventional electrospun mat, but also exhibits guidance of cells along the skin pattern without significant deterioration of pattern geometry.