Restoring Endogenous Repair Mechanisms to Heal Chronic Wounds with a Multifunctional Wound Dressing.

Current treatment of chronic wounds has been critically limited by various factors, including bacterial infection, biofilm formation, impaired angiogenesis, and prolonged inflammation. Addressing these challenges, we developed a multifunctional wound dressing-based three-pronged approach for accelerating wound healing. The multifunctional wound dressing, composed of nanofibers, functional nanoparticles, natural biopolymers, and selected protein and peptide, can target multiple endogenous repair mechanisms and represents a promising alternative to current wound healing products.

Nanoscale Technologies for Prevention and Treatment of Heart Failure: Challenges and Opportunities.

The adult myocardium has a limited regenerative capacity following heart injury, and the lost cells are primarily replaced by fibrotic scar tissue. Suboptimal efficiency of current clinical therapies to resurrect the infarcted heart results in injured heart enlargement and remodeling to maintain its physiological functions. These remodeling processes ultimately leads to ischemic cardiomyopathy and heart failure (HF). Recent therapeutic approaches (e.g., regenerative and nanomedicine) have shown promise to prevent HF postmyocardial infarction in animal models. However, these preclinical, clinical, and technological advancements have yet to yield substantial enhancements in the survival rate and quality of life of patients with severe ischemic injuries. This could be attributed largely to the considerable gap in knowledge between clinicians and nanobioengineers. Development of highly effective cardiac regenerative therapies requires connecting and coordinating multiple fields, including cardiology, cellular and molecular biology, biochemistry and chemistry, and mechanical and materials sciences, among others. This review is particularly intended to bridge the knowledge gap between cardiologists and regenerative nanomedicine experts. Establishing this multidisciplinary knowledge base may help pave the way for developing novel, safer, and more effective approaches that will enable the medical community to reduce morbidity and mortality in HF patients.

Poly(diethylene glycol methylether methacrylate) Brush-Functionalized Anodic Alumina Nanopores: Curvature-Dependent Polymerization Kinetics and Nanopore Filling.

We report on the synthesis and characterization of poly(diethylene glycol methylether methacrylate) (PDEGMA) brushes by surface-initiated atom transfer radical polymerization inside ordered cylindrical nanopores of anodic aluminum oxide with different pore radii between 20 and 185 nm. In particular, the dependence of polymerization kinetics and the degree of pore filling on the interfacial curvature were analyzed. On the basis of field emission scanning electron microscopy data and thermal gravimetric analysis (TGA), it was concluded that the polymerization rate was faster at the pore orifice compared to the pore interior and also as compared to the analogous reaction carried out on flat aluminum oxide substrates. The apparent steady-state polymerization rate near the orifice increased with decreasing pore size. Likewise, the overall apparent polymerization rate estimated from TGA data indicated stronger confinement for pores with increased curvature as well as increased mass transport limitations due to the blockage of the pore orifice. Only for pores with a diameter to length ratio of ∼1, PDEGMA brushes were concluded to grow uniformly with constant thickness. However, because of mass transport limitations in longer pores, incomplete pore filling was observed, which leads presumably to a PDEGMA gradient brush. This study contributes to a better understanding of polymer brush-functionalized nanopores and the impact of confinement, in which the control of polymer brush thickness together with grafting density along the nanopores is key for applications of PDEGMA brushes confined inside nanopores.

In Situ Study of Layer-by-Layer Polyelectrolyte Deposition in Nanopores of Anodic Aluminum Oxide by Reflectometric Interference Spectroscopy.

The modification of cylindrical anodic aluminum oxide (AAO) nanopores by alternating layer-by-layer (LBL) deposition of poly(sodium-4-styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) was studied in situ by reflectometric interference spectroscopy (RIfS). In particular, the kinetics of polyelectrolyte deposition inside the pores with a diameter of 37 ± 3 nm and a length of 3.7 ± 0.3 µm were unraveled, and potential differences in the LBL multilayer growth compared to flat silicon substrates as well as the effect of different ionic strengths and different types of ions were investigated. RIfS measures the effective optical thicknesses, which is-for a constant pore length-proportional to the effective refractive index of the AAO sample, from which, in turn, the deposited mass of the polymer or the corresponding layer thickness can be estimated. Compared to the multilayer growth by the LBL deposition on the flat aminosilane-primed silicon wafers, which was assessed by spectroscopic ellipsometry, the thickness increment per deposited bilayer, as well as the dependence of this increment on the ionic strength (0.01-0.15) and the counterion type (Na+ vs Ca2+) inside the aminosilane-primed nanopores, was for the first bilayers to within the experimental error identical. For thicker multilayers, the pore diameter became smaller, which led to reduced thickness increments and eventually virtually completely filled the pores. The observed kinetics is consistent with the mass-transport-limited adsorption of the polyelectrolyte to the charged surface according to a Langmuir isotherm with a negligible desorption rate. In addition to fundamental insights into the buildup of polyelectrolyte multilayers inside the AAO nanopores, our results highlight the sensitivity of RIfS and its use as an analytical tool for probing processes inside the nanopores and for the development of biosensors.

Fabrication of unconventional inertial microfluidic channels using wax 3D printing.

Inertial microfluidics has emerged over the past decade as a powerful tool to accurately control cells and microparticles for diverse biological and medical applications. Many approaches have been proposed to date in order to increase the efficiency and accuracy of inertial microfluidic systems. However, the effects of channel cross-section and solution properties (Newtonian or non-Newtonian) have not been fully explored, primarily due to limitations in current microfabrication methods. In this study, we overcome many of these limitations using wax 3D printing technology and soft lithography through a novel workflow, which eliminates the need for the use of silicon lithography and polydimethylsiloxane (PDMS) bonding. We have shown that by adding dummy structures to reinforce the main channels, optimizing the gap between the dummy and main structures, and dissolving the support wax on a PDMS slab to minimize the additional handling steps, one can make various non-conventional microchannels. These substantially improve upon previous wax printed microfluidic devices where the working area falls into the realm of macrofluidics rather than microfluidics. Results revealed a surface roughness of 1.75 µm for the printed channels, which does not affect the performance of inertial microfluidic devices used in this study. Channels with complex cross-sections were fabricated and then analyzed to investigate the effects of viscoelasticity and superposition on the lateral migration of the particles. Finally, as a proof of concept, microcarriers were separated from human mesenchymal stem cells using an optimized channel with maximum cell-holding capacity, demonstrating the suitability of these microchannels in the bioprocessing industry.

Targeting non-apoptotic cell death in cancer treatment by nanomaterials: Recent advances and future outlook.

Many tumors develop resistance to most of the apoptosis-based cancer therapies. In this sense targeting non-apoptotic forms of cell death including necroptosis, autophagy and ferroptosis may have therapeutic benefits in apoptosis-defective cancer cells. Nanomaterials have shown great advantages in cancer treatment owing to their unique characteristics. Besides, the capability of nanomaterials to induce different forms of cell death has gained widespread attention in cancer treatment. Reports in this field reflect the therapeutic potential of necroptotic cell death induced by nanomaterials in cancer. Also, autophagic cell death induced by nanomaterials alone and as a part of chemo-, radio- and photothermal therapy holds great promise as anticancer therapeutic option. Besides, ferroptosis induction by iron-based nanomaterials in drug delivery, immunotherapy, hyperthermia and imaging systems shows promising results in malignancies. Hence, this review is devoted to the latest efforts and the challenges in this field of research and its clinical merits.

Novel therapeutic strategies for Alzheimer's disease: Implications from cell-based therapy and nanotherapy.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which leads to progressive dysfunction of cognition, memory and learning in elderly people. Common therapeutic agents are not only inadequate to suppress the progression of AD pathogenesis but also produce deleterious side effects; hence, development of alternative therapies is required to specifically suppress complications of AD. The current review provides a commentary on conventional as well as novel therapeutic approaches with an emphasis on stem cell and nano-based therapies for improvement and management of AD pathogenesis. According to our overview of the current literature, AD is a multi-factorial disorder with various pathogenic trajectories; hence, a multifunctional strategy to create effective neuroprotective agents is required to treat this disorder.

Targeted superparamagnetic iron oxide nanoparticles for early detection of cancer: Possibilities and challenges.

Nanomedicine, the integration of nanotechnological tools in medicine demonstrated promising potential to revolutionize the diagnosis and treatment of various human health conditions. Nanoparticles (NPs) have shown much promise in diagnostics of cancer, especially since they can accommodate targeting molecules on their surface, which search for specific tumor cell receptors upon injection into the blood stream. This concentrates the NPs in the desired tumor location. Furthermore, such receptor-specific targeting may be exploited for detection of potential metastases in an early stage. Some NPs, such as superparamagnetic iron oxide NPs (SPIONs), are also compatible with magnetic resonance imaging (MRI), which makes their clinical translation and application rather easy and accessible for tumor imaging purposes. Furthermore, multifunctional and/or theranostic NPs can be used for simultaneous imaging of cancer and drug delivery. In this review article, we will specifically focus on the application of SPIONs in early detection and imaging of major cancer types. FROM THE CLINICAL EDITOR: Super-paramagnetic iron oxide nanoparticles (SPIONs) have been reported by many to be useful as an MRI contrast agent in the detection of tumors. To further enhance the tumor imaging, SPIONs can be coupled with tumor targeting motifs. In this article, the authors performed a comprehensive review on the current status of using targeted SPIONS in tumor detection and also the potential hurdles to overcome.

Nanopore Diameters Tune Strain in Extruded Fibronectin Fibers.

Fibronectin is present in the extracellular matrix and can be assembled into nanofibers in vivo by undergoing conformational changes. Here, we present a novel approach to prepare fibronectin nanofibers under physiological conditions using an extrusion approach through nanoporous aluminum oxide membranes. This one-step process can prepare nanofiber bundles up to a millimeter in length and with uniform fiber diameters in the nanometer range. Most importantly, by using different pore diameters and protein concentrations in the extrusion process, we could induce varying lasting structural changes in the fibers, which were monitored by Förster resonance energy transfer and should impose different physiological functions.

Enzyme degradable polymersomes from hyaluronic acid-block-poly(ε-caprolactone) copolymers for the detection of enzymes of pathogenic bacteria.

We introduce a new hyaluronidase-responsive amphiphilic block copolymer system, based on hyaluronic acid (HYA) and polycaprolactone (PCL), that can be assembled into polymersomes by an inversed solvent shift method. By exploiting the triggered release of encapsulated dye molecules, these HYA-block-PCL polymersomes lend themselves as an autonomous sensing system for the detection of the presence of hyaluronidase, which is produced among others by the pathogenic bacterium Staphylococcus aureus. The synthesis of the enzyme-responsive HYA-block-PCL block copolymers was carried out by copper-catalyzed Huisgen 1,3-dipolar cycloaddition of ω-azide-terminated PCL and ω-alkyne-functionalized HYA. The structure of the HYA-block-PCL assemblies and their enzyme-triggered degradation and concomitant cargo release were investigated by dynamic light scattering, fluorescence spectroscopy, confocal laser-scanning microscopy, scanning and transmission electron, and atomic force microscopy. As shown, a wide range of reporter dye molecules as well as antimicrobials can be encapsulated into the vesicles during formation and are released upon the addition of hyaluronidase.

Fabrication of complex free-standing nanostructures with concave and convex curvature via the layer-by-layer approach.

We report on the fabrication of unprecedented free-standing complex polymeric nanoobjects, which possess both concave and convex curvatures, by exploiting the layer-by-layer (LBL) deposition of polyelectrolytes. In a combined top-down/bottom-up replication approach pore diameter-modulated anodic aluminum oxide (AAO) templates, fabricated by temperature modulation hard anodization (TMHA), were replicated with multilayers of poly(styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) to yield open nanotubes with diameters in the wide and narrow segments of 210 and 150 nm, respectively. To obtain stable pore diameter-modulated nanopores, which possess segment lengths between 1 and 5 µm and 5 and 10 µm in the narrow and wide pore portion, respectively, conventional hard anodization of aluminum was followed by a subsequent temperature-modulated anodization. After removing the backside aluminum electrode, silanizing the aluminum oxide, and passivating the exposed membrane surface with a thin layer of gold, PSS and PAH were deposited alternatingly to yield LBL multilayers. For optimized LBL multilayer thicknesses and compactness, established in separate experiments on silicon substrates and nanoporous AAO with straight pores, free-standing polymeric nanoobjects with concave and convex curvatures, were obtained. These were stable for wall thickness to pore diameter ratios of ≥0.08.

PEI-based functional materials: Fabrication techniques, properties, and biomedical applications.

Cationic polymers have recently attracted considerable interest as research breakthroughs for various industrial and biomedical applications. They are particularly interesting due to their highly positive charges, acceptable physicochemical properties, and ability to undergo further modifications, making them attractive candidates for biomedical applications. Polyethyleneimines (PEIs), as the most extensively utilized polymers, are one of the valuable and prominent classes of polycations. Owing to their flexible polymeric chains, broad molecular weight (MW) distribution, and repetitive structural units, their customization for functional composites is more feasible. The specific beneficial attributes of PEIs could be introduced by purposeful functionalization or modification, long service life, biocompatibility, and distinct geometry. Therefore, PEIs have significant potential in biotechnology, medicine, and bioscience. In this review, we present the advances in PEI-based nanomaterials, their transfection efficiency, and their toxicity over the past few years. Furthermore, the potential and suitability of PEIs for various applications are highlighted and discussed in detail. This review aims to inspire readers to investigate innovative approaches for the design and development of next-generation PEI-based nanomaterials possessing cutting-edge functionalities and appealing characteristics.

A review on inertial microfluidic fabrication methods.

In recent decades, there has been significant interest in inertial microfluidics due to its high throughput, ease of fabrication, and no need for external forces. The focusing efficiency of inertial microfluidic systems relies entirely on the geometrical features of microchannels because hydrodynamic forces (inertial lift forces and Dean drag forces) are the main driving forces in inertial microfluidic devices. In the past few years, novel microchannel structures have been propounded to improve particle manipulation efficiency. However, the fabrication of these unconventional structures has remained a serious challenge. Although researchers have pushed forward the frontiers of microfabrication technologies, the fabrication techniques employed for inertial microfluidics have not been discussed comprehensively. This review introduces the microfabrication approaches used for creating inertial microchannels, including photolithography, xurography, laser cutting, micromachining, microwire technique, etching, hot embossing, 3D printing, and injection molding. The advantages and disadvantages of these methods have also been discussed. Then, the techniques are reviewed regarding resolution, structures, cost, and materials. This review provides a thorough insight into the manufacturing methods of inertial microchannels, which could be helpful for future studies to improve the harvesting yield and resolution by choosing a proper fabrication technique.

Feasibility and preliminary accuracy of high-resolution imaging of the liver and pancreas using FNA compatible microendoscopy (with video).

BACKGROUND: EUS-guided FNA is one of the few techniques that can obtain cells and tissue from the liver and pancreas. However, the technique remains vulnerable to poor specimen quality and sampling error. OBJECTIVE: To evaluate the ability of a high-resolution microendoscope (HRME) to visualize the cellular and architectural features of normal and malignant liver and pancreatic tissue ex vivo, to assess the ability of endosonographers to identify normal and neoplastic tissue by using HRME images, and to demonstrate preliminary technical feasibility of in vivo HRME imaging via EUS fine-needle puncture (FNP). DESIGN: Ex vivo pilot feasibility study in human tissue; in vivo swine model. SETTING: Two academic medical centers. PATIENTS: Co-registered HRME images and biopsies were obtained from surgically resected hepatic and pancreatic tissues from 44 patients. INTERVENTION: Images were divided into training (12 images) and test (80 images) sets containing a range of normal and pathologic conditions for each organ. After viewing the training sets, 9 endosonographers attempted to distinguish malignant tissue from normal or benign lesions in the test sets, each of which contained 40 unique images with individual diagnoses from pathology. MAIN OUTCOME MEASUREMENTS: Image acquisition feasibility, ex vivo and in vivo. Ability of endosonographers to recognize features of normal/benign or malignant tissue from the liver and pancreas. RESULTS: Overall, the 9 endosonographers achieved median accuracy figures of 85% in the liver and 90% in the pancreas. The endosonographers with prior experience in reading HRME images achieved accuracy rates between 90% and 95%. Technical feasibility of HRME imaging through a 19-gauge EUS-FNP needle was demonstrated in an in vivo swine model. LIMITATIONS: Ex vivo study. CONCLUSION: High-resolution microendoscopy allows real-time imaging of cellular-level morphology and tissue architecture in the liver and pancreas. The technique appears to have a short learning curve, after which endosonographers achieved high accuracy rates in distinguishing malignant tissue from normal and benign pathology in both organs. Translating this imaging platform to the in vivo setting appears technically feasible.

Pushing the size limits in the replication of nanopores in anodized aluminum oxide via the layer-by-layer deposition of polyelectrolytes.

We report on the successful replication of the smallest pores in anodized aluminum oxide (AAO) via the layer-by-layer (LBL) deposition of polyelectrolytes to date to yield free-standing, open nanotubes with inner and outer diameters (±2σ) down to 37 ± 4 and 52 ± 19 nm, respectively. This work is based on the fabrication of defined arrays of highly regular nanopores by anodic oxidation of aluminum. Pores with pore diameters between 53 ± 9 and 356 ± 14 nm and interpore distances between 110 ± 3 and 500 ± 17 nm were obtained using an optimized two-step anodization procedure. 3-(Ethoxydimethylsilyl)propylamine-coated pores were replicated by alternating LBL deposition of poly(styrenesulfonate) and poly(allylamine). The detrimental adsorption of polyelectrolyte on the top surface of the template that typically results in partial pore blocking was eliminated by controlling the surface energy of the top surface via deposition of an ultrathin gold layer. The thickness of the deposited LBL multilayer assembly at the pore orifice agreed to within the experimental error with the thicknesses measured by variable angle spectroscopic ellipsometry and atomic force microscopy (AFM) for layers assembled on flat substrates. The selective dissolution of the alumina template afforded free-standing, open polymer nanotubes that were stable without any cross-linking procedure. The nanotubes thus obtained possessed mean outer diameters as small as 52 nm, limited by the size of the AAO template.

Matrixyl Patch vs Matrixyl Cream: A Comparative In Vivo Investigation of Matrixyl (MTI) Effect on Wound Healing.

Wound healing is one of the most complex biological processes. Studies show that Matrixyl (MTI), known as a cosmetic peptide, can lead to a faster healing process. The contribution of MTI to collagen formation during wound healing also depends on its mode of delivery and its release over time. Here, we investigate two modes of MTI-delivery system, the influence of MTI patch for wound healing application in comparison with MTI cream. In this study, animals were randomly divided into seven groups and studied for 21 days: patches containing two different concentrations of MTI (P-MTI-0.1 mg and P-MTI-1 mg), a cream containing MTI (C-MTI-1 mg), a patch (P-MTI-0), a cream with no MTI (C-MTI-0), a positive control (Comfeel), and a negative control (sham) group. To study the wound healing process, the change in collagen density, angiogenesis, epitheliogenesis, histopathology, immunohistochemical analysis, and wound area through imaging was monitored and measured. The macroscopic results showed that wound healing was improved from 63.5 up to 81.81% in treatment groups compared to that in the negative control group (P < 0.05 and P < 0.001). In addition, C-MTI-1 and P-MTI-1 had a larger impact on wound healing compared to that in the positive control group (Comfeel, P < 0.05). In hematoxylin and eosin (H&E) staining analysis, the rejuvenation of skin appendage was visible in both groups of cream and patches with MTI. According to the obtained results, the re-epithelialization had a higher range for the patch with MTI in comparison with cream containing MTI and positive control.

Polysaccharide-based hydrogels containing herbal extracts for wound healing applications.

Development of an ideal wound dressing with effective function for healing various types of wounds is the ultimate desire of the researchers. Natural-based compounds such as polysaccharides and phytochemicals offer useful properties making them perfect candidates for wound management. Polysaccharides-based hydrogels with an interconnected three-dimensional network, and desired properties have great potential as a carrier for delivery of different herbal extracts for oral and topical applications. Herbal extracts are extensively used for wound healing purposes, individually or in combination with other active agents. This study summarizes the current knowledge acquired on the preparation, functionalizing, and application of different kinds of polysaccharide-based hydrogels enriched by herbal extracts for different wound healing applications. The structural, biological, and functional impact of the polysaccharides and herbal extracts on the final hydrogel characteristics, as well as their influence on the different phases of the wound healing process have been discussed.

Cigarette smoke-induced toxicity consequences of intracellular iron dysregulation and ferroptosis.

Despite numerous studies on the mechanisms of cigarette smoking toxicity over the past three decades, some aspects remain obscure. Recent developments have drawn attention to some hopeful indicators that allow us to advance our awareness of cigarette-induced cell death. Ferroptosis is considered a type of governed death of cells distinguished by the iron-dependent lipid hydroperoxide deposition to fatal concentrations. Ferroptosis has been linked with pathological settings such as neurodegenerative diseases, cancer, heart attack, hemorrhagic stroke, traumatic brain injury, ischemia-reperfusion injury, and renal dysfunction. This review tries to explain the causal role of ferroptosis cascade in cigarette smoke-mediated toxicity and cell death, highlighting associations on potential action mechanisms and proposing suggestions for its detoxifying and therapeutic interventions.

Mantle Cell Lymphoma Presenting as Diarrhea in a Liver Transplant Recipient.

We present a 63-year-old man with a medical history of hepatocellular carcinoma who underwent orthotopic liver transplant 10 years prior on long-term immunosuppressive therapy. The patient presented to the clinic with diarrhea, and the workup revealed mantle cell lymphoma. Mantle cell lymphoma is an extremely rare finding in transplanted livers. It is essential to include mantle cell lymphoma, along with a broad differential, during the workup of diarrhea in post-transplant patients.

Enzyme-Responsive Biopolymeric Nanogel Fibers by Extrusion: Engineering of High-Surface-Area Hydrogels and Application in Bacterial Enzyme Detection.

The fabrication of covalently cross-linked high-surface-area biopolymeric nanogel fibers by nanopore extrusion is reported for the first time. The biopolymer pullulan was functionalized with tert-butyl acetoacetate via a transesterification reaction to synthesize the water-soluble ketone-rich precursor pullulan acetoacetate (PUAA). PUAA and carbonic dihydrazide (CDH) as cross-linker were extruded through anodic aluminum oxide (AAO) nanoporous membranes, which possessed an average pore diameter of 61 ± 2 nm. By changing the concentration of PUAA, the flow rate, and extrusion time, the step polymerization cross-linking reaction was controlled so that the polymer can be extruded gradually during cross-linking through the membrane, avoiding the formation of macroscopic bulk hydrogels and rupture of the AAO membrane. Fibers with diameters on the order of 250 nm were obtained. This approach was also expanded to functionalized PUAA derivatives together with the fluorogenic substrate 4-methylumbelliferyl-ß-d-glucuronide MUGlcU in (PUAA-MUGlcU), which exhibited a mean equilibrium swelling ratio of 5.7 and 9.0 in Milli-Q water and in phosphate-buffered saline, respectively. ß-Glucuronidase was sensitively detected via fluorescence of 4-methylumbelliferone, which was liberated in the enzymatic hydrolysis reaction of PUAA-MUGlcU. Compared to hydrogel slabs, the rate of the hydrolysis was >20% higher in the nanogel fibers, facilitating the rapid detection of ß-glucuronidase-producing Escherichia coli (E. coli Mach1-T1). Nanopore extruded nanogel fibers are therefore considered a viable approach to enhance the functionality of hydrogels in surface-dominated processes.