Electron beam-irradiated donor cornea for on-demand lenticule implantation to treat corneal diseases and refractive error.

The cornea is the major contributor to the refractive power of the eye, and corneal diseases are a leading cause of reversible blindness. The main treatment for advanced corneal disease is keratoplasty: allograft transplantation of the cornea. Examples include lenticule implantation to treat corneal disorders (e.g. keratoconus) or correct refractive errors. These procedures are limited by the shelf-life of the corneal tissue, which must be discarded within 2-4 weeks. Electron-beam irradiation is an emerging sterilisation technique, which extends this shelf life to 2 years. Here, we produced lenticules from fresh and electron-beam (E-beam) irradiated corneas to establish a new source of tissue for lenticule implantation. In vitro, in vivo, and ex vivo experiments were conducted to compare fresh and E-beam-irradiated lenticules. Results were similar in terms of cutting accuracy, ultrastructure, optical transparency, ease of extraction and transplantation, resilience to mechanical handling, biocompatibility, and post-transplant wound healing process. Two main differences were noted. First, ∼59% reduction of glycosaminoglycans resulted in greater compression of E-beam-irradiated lenticules post-transplant, likely due to reduced corneal hydration-this appeared to affect keratometry after implantation. Cutting a thicker lenticule would be required to ameliorate the difference in refraction. Second, E-beam-sterilised lenticules exhibited lower Young's modulus which may indicate greater care with handling, although no damage or perforation was caused in our procedures. In summary, E-beam-irradiated corneas are a viable source of tissue for stromal lenticules, and may facilitate on-demand lenticule implantation to treat a wide range of corneal diseases. Our study suggested that its applications in human patients are warranted. STATEMENT OF SIGNIFICANCE: Corneal blindness affects over six million patients worldwide. For patients requiring corneal transplantation, current cadaver-based procedures are limited by the short shelf-life of donor tissue. Electron-beam (E-beam) sterilisation extends this shelf-life from weeks to years but there are few published studies of its use. We demonstrated that E-beam-irradiated corneas are a viable source of lenticules for implantation. We conducted in vitro, in vivo, and ex vivo comparisons of E-beam and fresh corneal lenticules. The only differences exhibited by E-beam-treated lenticules were reduced expression of glycosaminoglycans, resulting in greater tissue compression and lower refraction suggesting that a thicker cut is required to achieve the same optical and refractive outcome; and lower Young's modulus indicating extra care with handling.

A Highly Conducting Polymer for Self-Healable, Printable, and Stretchable Organic Electrochemical Transistor Arrays and Near Hysteresis-Free Soft Tactile Sensors.

A stretchable and self-healable conductive material with high conductivity is critical to high-performance wearable electronics and integrated devices for applications where large mechanical deformation is involved. While there has been great progress in developing stretchable and self-healable conducting materials, it remains challenging to concurrently maintain and recover such functionalities before and after healing. Here, a highly stretchable and autonomic self-healable conducting film consisting of a conducting polymer (poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS) and a soft-polymer (poly(2-acrylamido-2-methyl-1-propanesulfonic acid), PAAMPSA) is reported. The optimal film exhibits outstanding stretchability as high as 630% and high electrical conductivity of 320 S cm-1 , while possessing the ability to repair both mechanical and electrical breakdowns when undergoing severe damage at ambient conditions. This polymer composite film is further utilized in a tactile sensor, which exhibits good pressure sensitivity of 164.5 kPa-1 , near hysteresis-free, an ultrafast response time of 19 ms, and excellent endurance over 1500 consecutive presses. Additionally, an integrated 5 × 4 stretchable and self-healable organic electrochemical transistor (OECT) array with great device performance is successfully demonstrated. The developed stretchable and autonomic self-healable conducting film significantly increases the practicality and shelf life of wearable electronics, which in turn, reduces maintenance costs and build-up of electronic waste.

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa.

Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains.IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

Targeting efficiency of nanoliposomes on atherosclerotic foam cells: polyethylene glycol-to-ligand ratio effects.

BACKGROUND: Nanoparticles that actively target tissues, with ligands attached at the extremity of polyethylene glycol (PEG) spacer, are a promising strategy to enhance target cell specificity and internalization. However, the interplay between the targeting ligands and the adjacent ligand-free PEG remains poorly understood. RESEARCH DESIGN AND METHODS: Experimentally, liposomes containing active folate ligands were firstly formulated and the optimum amount of ligand that yields the highest foam cell uptake was determined. Subsequently, ligand-free PEG was incorporated, and the effects of PEG lengths and concentrations on foam cell uptake were evaluated after the nanoparticles were incubated in human serum for 90 min. RESULTS: It was demonstrated that the targeting efficiency progressively decreased and was eventually annulled as PEG-to-ligand ratio was increased, with loss of targeting effect occurring at PEG-to-ligand ratio of >2 for PEG 750, >0.5 for PEG 2000 and <0.5 for PEG 5000. CONCLUSIONS: This work demonstrates that PEG-to-ligand ratio and serum coating on nanoparticle surface are both important features to be considered in the design of active targeting nanocarriers. This work also supports the development of novel active targeting nanotherapies for atherosclerosis.

Liposomal Nanotherapy for Treatment of Atherosclerosis.

Atherosclerosis is a chronic disease that can lead to life-threatening events such as myocardial infarction and stroke, is characterized by the build-up of lipids and immune cells within the arterial wall. It is understood that inflammation is a hallmark of atherosclerosis and can be a target for therapy. In support of this concept, an injectable nanoliposomal formulation encapsulating fluocinolone acetonide (FA), a corticosteroid, is developed that allows for drug delivery to atherosclerotic plaques while reducing the systemic exposure to off-target tissues. In this study, FA is successfully incorporated into liposomal nanocarriers of around 100 nm in size with loading efficiency of 90% and the formulation exhibits sustained release up to 25 d. The anti-inflammatory effect and cholesterol efflux capability of FA-liposomes are demonstrated in vitro. In vivo studies carried out with an apolipoprotein E-knockout (Apoe-/- ) mouse model of atherosclerosis show accumulation of liposomes in atherosclerotic plaques, colocalization with plaque macrophages and anti-atherogenic effect over 3 weeks of treatment. This FA-liposomal-based nanocarrier represents a novel potent nanotherapeutic option for atherosclerosis.

Nanocarriers for Stroke Therapy: Advances and Obstacles in Translating Animal Studies.

The technology of drug delivery systems (DDS) has expanded into many applications, such as for treating neurological disorders. Nanoparticle DDS offer a unique strategy for targeted transport and improved outcomes of therapeutics. Stroke is likely to benefit from the emergence of this technology though clinical breakthroughs are yet to manifest. This review explores the recent advances in this field and provides insight on the trends, prospects and challenges of translating this technology to clinical application. Carriers of diverse material compositions are presented, with special focus on the surface properties and emphasis on the similarities and inconsistencies among in vivo experimental paradigms. Research attention is scattered among various nanoparticle DDS and various routes of drug administration, which expresses the lack of consistency among studies. Analysis of current literature reveals lipid- and polymer-based DDS as forerunners of DDS for stroke; however, cell membrane-derived vesicles (CMVs) possess the competitive edge due to their innate biocompatibility and superior efficacy. Conversely, inorganic and carbon-based DDS offer different functionalities as well as varied capacity for loading but suffer mainly from poor safety and general lack of investigation in this area. This review supports the existing literature by systematizing presently available data and accounting for the differences in drugs of choice, carrier types, animal models, intervention strategies and outcome parameters.

Theranostic Probes for Targeting Tumor Microenvironment: An Overview.

Long gone is the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues, and immune cells in their environment, which is now known as the tumor microenvironment (TME). It has been found that the interactions between tumors and their surrounds promote tumor growth, invasion, and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design, and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME such as tumor vasculature, ECM, stromal cells, and the lymphatic system. This review explores how these significant factors in the TME, supply tumors with the required growth factors and signaling molecules to proliferate, invade, and metastasize. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis, and anticancer drug delivery systems. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT)).

The Advents of Hybrid Imaging Modalities: A New Era in Neuroimaging Applications.

Hybrid Imaging modalities have shown great potential in medical imaging and diagnosis. A more comprehensive and targeted view of neurological disorders can be achieved by blending the anatomical and functional perspectives through hybridization. With consistently improving technologies, there have been many developments in fused imaging techniques over the past few decades. This article provides an overview of various bimodal and trimodal hybrid imaging techniques being developed and explored for neuroimaging applications. Recent advancements and potentials are discussed for single photon emission computed tomography-computed tomography (SPECT-CT), positron emission tomography-CT (PET-CT), PET-magnetic resonance imaging (PET-MRI), electroencephalography-functional magnetic resonance imaging (EEG-fMRI), magnetoencephalography-fMRI (MEG-fMRI), EEG-near-infrared spectroscopy (EEG-NIRS), magnetic resonance-PET-EEG (MR-PET-EEG) and MR-PET-CT in the perspective of neuroimaging. A comparison of these hybrid approaches is provided on a single platform to analyze their performance on the basis of several common factors essential for imaging and analyzing neurological disorders and in vivo molecular processes. This article also provides an overview of recently developed advanced imaging technologies that are being hybridized with other imaging modalities and being explored as potential techniques for neuroscience. Novel approaches and clinical applications of hybrid neuroimaging are anticipated with inclusion of new technologies, better sensing capabilities, multimodal probes, and improved hybridization.