Implantable sustained-release drug delivery systems: a revolution for ocular therapeutics.

PURPOSE: Due to the inimitable anatomical structure of the eyeball and various physiological barriers, conventional ocular local administration is often complicated by apparent shortcomings, such as limited bioavailability and short drug retention. Thus, developing methods for sustainable, safe and efficient drug delivery to ocular target sites has long been an urgent need. This study briefly summarizes the barriers to ocular drug administration and various ocular drug delivery routes and highlights recent progress in ocular implantable sustained-release drug delivery systems (DDSs) to provide literature evidence for developing novel ocular implants for sustained drug delivery. METHODS: We conducted a comprehensive search of studies on ocular implantable sustained-release DDSs in PubMed and Web of Science using the following keywords: ocular, implantable and drug delivery system. More than 400 papers were extracted. Publications focused on sustained and controlled drug release were primarily considered. Experimental articles involving DDSs that cannot be implanted into the eye through surgeries and cannot be inserted into ocular tissues in solid form were excluded. Approximately 143 publications were reviewed to summarize the most current information on the subject. RESULTS: In recent years, numerous ocular sustained-release DDSs using lipids, nanoparticles and hydrogels as carriers have emerged. With unique properties and systematic design, ocular implantable sustained-release DDSs are able to continuously maintain drug release, effectively sustain the therapeutic concentration in target tissues, and substantially enhance the therapeutic efficacy. Nevertheless, few ocular implantable sustained-release DDSs have been available in clinical use. CONCLUSIONS: Ocular implantable sustained-release DDSs have become a new focus in the field of ocular drug development through unique designs and improvements in the materials of drug carriers, administration methods and dosage forms. With more ocular implantable sustained-release DDSs being commercialized, ocular therapeutics may be revolutionized.

The Molecular Mechanism of Retina Light Injury Focusing on Damage from Short Wavelength Light.

Natural visible light is an electromagnetic wave composed of a spectrum of monochromatic wavelengths, each with a characteristic color. Photons are the basic units of light, and their wavelength correlates to the energy of light; short-wavelength photons carry high energy. The retina is a fragile neuronal tissue that senses light and generates visual signals conducted to the brain. However, excessive and intensive light exposure will cause retinal light damage. Within the visible spectrum, short-wavelength light, such as blue light, carries higher energy, and thus the retinal injury, is more significant when exposed to these wavelengths. The damage mechanism triggered by different short-wavelength light varies due to photons carrying different energy and being absorbed by different photosensitive molecules in the retinal neurons. However, photooxidation might be a common molecular step to initiate cell death. Herein, we summarize the historical understanding of light, the key molecular steps related to retinal light injury, and the death pathways of photoreceptors to further decipher the molecular mechanism of retinal light injury and explore potential neuroprotective strategies.

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress.

Age-related macular degeneration (AMD) is a leading cause of severe visual loss and irreversible blindness in the elderly population worldwide. Retinal pigment epithelial (RPE) cells are the major site of pathological alterations in AMD. They are responsible for the phagocytosis of shed photoreceptor outer segments (POSs) and clearance of cellular waste under physiological conditions. Age-related, cumulative oxidative stimuli contribute to the pathogenesis of AMD. Excessive oxidative stress induces RPE cell degeneration and incomplete digestion of POSs, leading to the continuous accumulation of cellular waste (such as lipofuscin). Autophagy is a major system of degradation of damaged or unnecessary proteins. However, degenerative RPE cells in AMD patients cannot perform autophagy sufficiently to resist oxidative damage. Increasing evidence supports the idea that enhancing the autophagic process can properly alleviate oxidative injury in AMD and protect RPE and photoreceptor cells from degeneration and death, although overactivated autophagy may lead to cell death at early stages of retinal degenerative diseases. The crosstalk among the NFE2L2, PGC-1, p62, AMPK, and PI3K/Akt/mTOR pathways may play a crucial role in improving disturbed autophagy and mitigating the progression of AMD. In this review, we discuss how autophagy prevents oxidative damage in AMD, summarize potential neuroprotective strategies for therapeutic interventions, and provide an overview of these neuroprotective mechanisms.

A potentially new phase of the cardiac cycle: Pre-isovolumic contraction recognized by echocardiography.

Clinically the isovolumic contraction time (IVCT) can be measured by 3 echocardiographic methods of M-mode, pulse-wave Doppler (PWD), and tissue Doppler imaging (TDI). But IVCT can be clinically different by the 3 methods. This study is to investigate whether there is a potentially unidentified phase causing the discrepancies by analyzing electric mechanical delay time (EMD), IVCT, and pre-ejection period (PEP).A total of 30 healthy subjects were recruited for the study. EMD, IVCT, and PEP were obtained by the 3 methods, respectively. MCT (the interval from the onset of the QRS wave to the closure point of the mitral valve measured by TDI) and ICMC (the interval from the onset of IVC wave S1 to the closure point of the mitral valve measured by TDI) were both measured by color TDI.IVCTt (IVCT measured by TDI) was significantly longer than IVCTm or IVCTd (IVCT measured by M-mode or PWD) (both P < .0001), while EMDt (EMD measured by TDI) was significantly shorter than EMDm or EMDd (EMD measured by M-mode or PWD) (both P < .0001). But MCT was not significantly different from EMDm or EMDd (P > .05) and ICMC did not differ significantly from EMDm or EMDd minus EMDt or IVCTt minus IVCTm or IVCTd (P > .05), in other words, ICMC almost equaled to (EMDm or EMDd minus EMDt) or (IVCTt minus IVCTm or IVCTd).There may be an unidentified phase between the end of atrial contraction and the closure of mitral valve causing the discrepancies in IVCT, which is named as the pre-isovolumic contraction phase. It is a non-isovolumic phase and is included in the traditional isovolumic contraction phase.