In situ Tissue Regeneration in the Cornea from Bench to Bedside.

Corneal blindness accounts for 5.1% of visual deficiency and is the fourth leading cause of blindness globally. An additional 1.5-2 million people develop corneal blindness each year, including many children born with or who later develop corneal infections. Over 90% of corneal blind people globally live in low- and middle-income regions (LMIRs), where corneal ulcers are approximately 10-fold higher compared to high-income countries. While corneal transplantation is an effective option for patients in high-income countries, there is a considerable global shortage of corneal graft tissue and limited corneal transplant programs in many LMIRs. In situ tissue regeneration aims to restore diseases or damaged tissues by inducing organ regeneration. This can be achieved in the cornea using biomaterials based on extracellular matrix (ECM) components like collagen, hyaluronic acid, and silk. Solid corneal implants based on recombinant human collagen type III were successfully implanted into patients resulting in regeneration of the corneal epithelium, stroma, and sub-basal nerve plexus. As ECM crosslinking and manufacturing methods improve, the focus of biomaterial development has shifted to injectable, in situ gelling formulations. Collagen, collagen-mimetic, and gelatin-based in situ gelling formulas have shown the ability to repair corneal wounds, surgical incisions, and perforations in in-vivo models. Biomaterial approaches may not be sufficient to treat inflammatory conditions, so other cell-free therapies such as treatment with tolerogenic exosomes and extracellular vesicles may improve treatment outcomes. Overall, many of the technologies described here show promise as future medical devices or combination products with cell or drug-based therapies. In situ tissue regeneration, particularly with liquid formulas, offers the ability to triage and treat corneal injuries and disease with a single regenerative solution, providing alternatives to organ transplantation and improving patient outcomes.

Do genetic mutations and genotypes contribute to onychomycosis?

BACKGROUND: The variability in susceptibility to onychomycosis for individuals exposed to the same environmental risk factors raises the possibility that there may be individuals with a genetic predisposition to dermatophyte infection. OBJECTIVE: To determine whether there are genetic mutations or genotypes which contribute to onychomycosis. METHODS: The PubMed database was searched for examples of immune deficiencies resulting in dermatophyte infections. RESULTS: There are mutations in the innate immune receptors Dectin-1 and its adaptor protein CARD9 which result in familial mucocutaneous infections. There are also specific human leukocyte antigen genotypes that are more common in individuals and families with a high prevalence of onychomycosis. In addition, some patients have been reported with insufficient levels of CD4+CD25+ regulatory T cells. These deficits impair a full innate and adaptive immune response and may result in chronic or recurrent infections. CONCLUSIONS: There are documented mutations and genotypes that contribute to familial and individual susceptibility to onychomycosis.

Efinaconazole: a new topical treatment for onychomycosis.

Efinaconazole is an emerging antifungal therapy for the topical treatment of onychomycosis. Efinaconazole is an inhibitor of sterol 14α-demethylase and is more effective in vitro than terbinafine, itraconazole, ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds. Phase II studies indicate that efinaconazole 10% nail solution is more effective than either the 5% strength or 10% solution with semi-occlusion. In duplicate Phase III clinical trials, complete cure rates of 17.8% and 15.2% were demonstrated. The mean mycological cure rate for efinaconazole is similar to the oral antifungal itraconazole and exceeds the efficacy of topical ciclopirox. Efinaconazole showed minimal localized adverse events, which ceased upon stopping treatment. Overall, efinaconazole 10% nail solution is an effective topical monotherapy for distal and lateral subungual onychomycosis (<65% nail involvement, excluding the matrix) that shows further potential use as an adjunct to oral and device-based therapies.

Medical devices for the treatment of onychomycosis.

Device-based therapies are the most rapidly expanding area of onychomycosis treatment. Traditional pharmacotherapy of onychomycosis has a low to moderate efficacy and is associated with adverse reactions and drug interactions that limit its use in many patients. These new therapies include laser systems, photodynamic therapy, iontophoresis, and ultrasound. Device-based therapies are procedures conducted in the clinic by a trained professional, which mitigates the requirement for long-term patient compliance. In addition, the drug component of these therapies is topical, preventing the adverse events associated with systemic antifungal administration, and potentially allowing for the treatment of individuals who were previously excluded due to drug interactions. Device-based therapy is a nascent field, so clinical data is still in an emergent stage; however, preliminary clinical trials of laser, photodynamic therapy, and iontophoresis suggest that some devices may have a degree of efficacy. More studies are required to better determine their ability to treat onychomycosis.

Electron-Beam Irradiated Recombinant Human Collagen-Phosphorylcholine Corneal Implants Retain Pro-Regeneration Capacity.

Sterilization of biodegradable, collagen-based implants is challenging as irradiation sterilization methods can alter their mechanical properties. Electron beam (EB) irradiation is a terminal sterilization method that has been used for biologically-derived implants. Here, recombinant human collagen type III-phosphorylcholine (RHCIII-MPC) hydrogels were irradiated with EB doses of 17, 19, or 21 kGy and their subsequent biocompatibility and ability to promote regeneration in rabbit corneas was evaluated. Unirradiated hydrogels stored in 1% chloroform in phosphate-buffered saline (C-PBS) were the controls. There were no significant differences between irradiated and non-irradiated samples in optical or physical properties (tensile strength, modulus, elasticity), or the ability to support cell growth. However, irradiated implants were more sensitive to high levels of collagenase than unirradiated controls and the C-PBS implants had increased cell growth compared to EB and controls at 72 h. Corneal implants e-beamed at 17 kGy or e-beamed and subsequently frozen (EB-F) to increase shelf-life showed no adverse biological effects of the irradiation. EB, EB-F, and C-PBS implanted corneas all rapidly re-epithelialized but showed mild neovascularization that resolved over 6 months. The regenerated neo-corneas were transparent at 6 months post-operation. In vivo confocal microscopy confirmed normal morphology for the epithelium, stroma, sub-basal nerves and unoperated endothelium. Histology showed that all the regenerated corneas were morphologically similar to the normal. Immunohistochemistry indicated the presence of a differentiated corneal epithelium and functional tear film. In conclusion, the e-beamed corneal implants performed as well as non-irradiated control implants, resulting in fully regenerated neo-corneas with new nerves and without blood vessels or inflammation that may impede vision or corneal function. Therefore, a complete validation study to establish EB irradiation as an effective means for corneal implant sterilization prior to clinical application is necessary as a next step.

Collagen analogs with phosphorylcholine are inflammation-suppressing scaffolds for corneal regeneration from alkali burns in mini-pigs.

The long-term survival of biomaterial implants is often hampered by surgery-induced inflammation that can lead to graft failure. Considering that most corneas receiving grafts are either pathological or inflamed before implantation, the risk of rejection is heightened. Here, we show that bioengineered, fully synthetic, and robust corneal implants can be manufactured from a collagen analog (collagen-like peptide-polyethylene glycol hybrid, CLP-PEG) and inflammation-suppressing polymeric 2-methacryloyloxyethyl phosphorylcholine (MPC) when stabilized with the triazine-based crosslinker 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The resulting CLP-PEG-MPC implants led to reduced corneal swelling, haze, and neovascularization in comparison to CLP-PEG only implants when grafted into a mini-pig cornea alkali burn model of inflammation over 12 months. Implants incorporating MPC allowed for faster nerve regeneration and recovery of corneal sensation. CLP-PEG-MPC implants appear to be at a more advanced stage of regeneration than the CLP-PEG only implants, as evidenced by the presence of higher amounts of cornea-specific type V collagen, and a corresponding decrease in the presence of extracellular vesicles and exosomes in the corneal stroma, in keeping with the amounts present in healthy, unoperated corneas.

LiQD Cornea: Pro-regeneration collagen mimetics as patches and alternatives to corneal transplantation.

Transplantation with donor corneas is the mainstay for treating corneal blindness, but a severe worldwide shortage necessitates the development of other treatment options. Corneal perforation from infection or inflammation is sealed with cyanoacrylate glue. However, the resulting cytotoxicity requires transplantation. LiQD Cornea is an alternative to conventional corneal transplantation and sealants. It is a cell-free, liquid hydrogel matrix for corneal regeneration, comprising short collagen-like peptides conjugated with polyethylene glycol and mixed with fibrinogen to promote adhesion within tissue defects. Gelation occurs spontaneously at body temperature within 5 min. Light exposure is not required-particularly advantageous because patients with corneal inflammation are typically photophobic. The self-assembling, fully defined, synthetic collagen analog is much less costly than human recombinant collagen and reduces the risk of immune rejection associated with xenogeneic materials. In situ gelation potentially allows for clinical application in outpatient clinics instead of operating theaters, maximizing practicality, and minimizing health care costs.

Obstructive sleep apnea and dermatologic disorders.

Obstructive sleep apnea (OSA) is present in at least 2% of women and 4% of men, and its prevalence is increasing, because a major predisposing factor for OSA is a high body mass index. Psoriasis has the most strongly substantiated link with OSA, where the relationship may be bidirectional. Dermatologic disorders may be comorbid with OSA due to several factors: (i) the heightened proinflammatory state in OSA, which can occur independent of body mass index, and may exacerbate inflammatory dermatoses; (ii) intermittent hypoxemia may promote neovascularization and tumor growth in certain cancers, such as melanoma; (iii) obesity, present in majority of OSA patients, can be associated with a heightened proinflammatory state; (iv) upper airway obstruction due to local tumors or soft tissue swelling due to physical urticaria or angioedema; (v) acute nasal congestion in the atopic patient with allergic rhinitis; (vi) dermatologic disorders associated with other OSA risk factors (eg, acanthosis nigricans and metabolic syndrome); and (vii) a high sympathetic tone (eg, in atopic dermatitis) and resultant sleep fragmentation contributing to upper airway instability during sleep. In many instances, the dermatology patient with OSA may have other medical and psychiatric comorbidities that are also associated with increased OSA risk.

Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis.

The route of antifungal drug entry into the nail plate and the underlying nail bed plays an important role in determining the efficacy of therapy. Oral antifungal agents reach the nail bed and nail plate by being ingested and achieving antifungal levels in the blood stream that are well in excess of the minimum inhibitory concentration. The reticular circulation at the distal end of the digit enables the drug to reach the nail bed, the proximal matrix and the lateral nail folds. The drug then diffuses into the proximal, ventral and lateral nail plate. The primary route of drug delivery for topical lacquers is transungual, with drug applied to the dorsal aspect of the nail plate and penetrating to the underlying nail bed. The new topical agents approved in the US for the treatment of onychomycosis are solutions with lower viscosity and increased nail penetration characteristics; therefore, these agents penetrate through the transungual route, but also through the space between the nail plate and the nail bed. This subungual route is an important method of drug delivery and is able to in part circumvent the thickness of the nail plate.

Psoriasis and sleep disorders: A systematic review.

Psoriasis is an immune-mediated chronic inflammatory disorder which manifests as dermatologic lesions, and psoriatic arthritis (PsA) in about 30% of cases. Psoriasis is associated with multiple comorbidities including metabolic syndrome, hypertension, diabetes, cardiovascular events, obesity and psychiatric disorders, which can all affect the course of sleep disorders. A systematic review of the literature on the relationship between psoriasis, PsA, and formal sleep disorders identified 33 studies. There is an increased prevalence of obstructive sleep apnea (OSA) with 36%-81.8% prevalence in psoriasis versus 2%-4% in the general population. There was also an increase in the prevalence of restless legs syndrome of 15.1%-18% in psoriasis versus 5%-10% in European and North American samples. The wide variety of insomnia criteria used in studies resulted in an insomnia prevalence of 5.9%-44.8% in psoriasis, which is insufficient to show an elevated prevalence when the general population has a 10% prevalence of chronic insomnia and 30-35% prevalence of transient insomnia. There is evidence that symptoms of insomnia in psoriasis are directly mediated by pruritus and pain. Treatments that decrease the cutaneous symptoms in psoriasis were successful in mitigating insomnia, but did not show improvements in OSA where the relationship with psoriasis is multifactorial.

The effect of treating obstructive sleep apnea with positive airway pressure on depression and other subjective symptoms: A systematic review and meta-analysis.

Patients with obstructive sleep apnea (OSA) frequently present with symptoms of depression and anxiety. The objective of this study is to determine if treatment with positive airway pressure (PAP) improves symptoms of depression and anxiety. A systematic review was conducted to identify clinical trials of PAP that contained a validated measure of depression severity. Meta-analysis was conducted for depression, anxiety, excessive daytime sleepiness (EDS), quality of life (QoL) and respiratory variables. The systematic review included 33 reports. Pre-post-test analysis of PAP showed a moderate effect size (Hedge's g, 95% CI) for depression 0.524 [0.401-0.647], but a low effect size compared to oral placebo (0.355 [0.187-0.524]) and no effect when compared to dental appliances (0.107 [-0.72-0.287]) and sham PAP (-0.049 [-0.292-0.194]). Anxiety, EDS, and QoL showed similar improvement in pre-post-test analysis, but a lack of superiority to dental appliances and sham PAP. PAP was superior to all comparators for respiratory variables. PAP has a moderate clinical effect on symptoms of depression and anxiety in OSA, but it is not superior to dental appliances or sham PAP. The improvement in subjective symptoms, such as depression and anxiety, may be mediated by patient expectations and contact with healthcare providers.

Obstructive sleep apnea and psychiatric disorders: a systematic review.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with psychiatric pathology. Psychiatric comorbidity in OSA may affect patient quality of life and adherence to CPAP. A focused evaluation of OSA in highly selected groups of primarily psychiatric patients may provide further insights into the factors contributing to comorbidity of OSA and psychopathology. The goal of this study is to examine the prevalence and treatment of OSA in psychiatric populations. METHODS: A systematic review following the PRISMA guidelines was conducted to determine the prevalence of OSA in schizophrenia and other psychotic disorders, mood disorders, and anxiety disorders, and to examine potential interventions. The PubMed, EMBASE, and PsycINFO databases were searched (last search April 26, 2014) using keywords based on the ICD-9-CM coding for OSA and the DSM-IV-TR diagnostic groups. RESULTS: The search retrieved 47 records concerning studies of OSA in the selected disorders. The prevalence studies indicate that there may be an increased prevalence of OSA in individuals with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), despite considerable heterogeneity and a high risk of bias. There was insufficient evidence to support increased OSA in schizophrenia and psychotic disorders, bipolar and related disorders, and anxiety disorders other than PTSD. Studies of treatment of OSA indicate an improvement in both OSA and psychiatric symptoms. CPAP adherence was reduced in veterans with PTSD. CONCLUSIONS: OSA prevalence may be increased in MDD and PTSD. In individuals with OSA and psychiatric illness, treatment of both disorders should be considered for optimal treatment outcomes.

New pharmacotherapy for the treatment of onychomycosis: an update.

INTRODUCTION: Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions. AREAS COVERED: This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development. EXPERT OPINION: The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis.

Efinaconazole (Jublia) for the treatment of onychomycosis.

Efinaconazole 10% nail solution (Jublia(®)) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14α-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease.

Investigational drugs for onychomycosis.

INTRODUCTION: Onychomycosis is the fungal infection of the nail plate by dermatophytes, yeasts and nondermatophyte molds. The treatment of onychomycosis poses many challenges due to low initial cure rates and a high rate of relapse and recurrence. Oral therapy is limited by adverse events and drug-drug interactions, whereas topical therapy has limited penetrance through the nail plate. AREAS COVERED: New and reformulated drugs are in development for the treatment of onychomycosis. Experimental molecules include both oral and topical azole molecules, topical reformulations of terbinafine, the benzoxaboroles tavaborole and AN2718, the aganocide NVC-422 and the photosensitizer Sylsens B. These drugs are in varying stages of development so results from in vitro studies to Phase III clinical trials are discussed to present a complete picture of the current development pipeline for onychomycosis. EXPERT OPINION: The development of new molecules from familiar and novel classes for both oral and topical administration is encouraging. It is clear that there is currently more emphasis on the development of topical drugs than orals, due to their lower potential for adverse events and drug-drug interactions. The emergence of novel molecular targets is encouraging for the possibility of combination therapy and any future drug-resistant strains of fungi.

Laser therapy for onychomycosis.

BACKGROUND: Laser therapy is a rapidly expanding new treatment modality for onychomycosis. OBJECTIVE: To review current and prospective laser systems for the treatment of onychomycosis. METHOD: We searched the PubMed database, the Food and Drug Administration 510(k) database, ClinicalTrials.gov, and Google Scholar for in vitro studies, peer-reviewed clinical trials, manufacturers' white papers, and registered clinical trials of laser systems indicated for the treatment of onychomycosis. All published clinical trials were assessed on a 20-point methodological quality scale. RESULTS: We identified three basic science articles, five peer-reviewed articles, three white papers, and four pending clinical trials, as well as numerous gray literature documents. The overall methodological score for the clinical trials was 9.1 ± 1.1, with peer-reviewed studies showing a higher score (9.8 ± 1.5) than white papers (7.5 ± 0.7). We also identified 11 commercial laser device systems of varying global availability. CONCLUSION: Laser therapy has been tested and approved as a cosmetic treatment only for onychomycosis. It cannot be recommended as a therapeutic intervention to eradicate fungal infection at this time as more rigorous randomized, controlled trials are required to determine if laser therapy is efficacious on par with oral and topical interventions.

Diagnosing onychomycosis.

The diagnosis of onychomycosis may require the use of mycological diagnostic testing to supplement the clinical presentation. In order to verify that onychomycosis is present, the viability, penetrance, and species of the fungal infection should be determined. The most common diagnostic tests are mycological culture, direct microscopic examination, histopathologic study, and polymerase chain reaction (PCR)-based tests. Each of these tests has individual strengths in satisfying the three criteria, with a minimum of two positive diagnostic tests being the gold standard for confirming all three diagnostic criteria.

Therapies for the treatment of onychomycosis.

Onychomycosis treatments include nail avulsion and debridement by chemical or surgical procedures, topical and oral antifungals, and device-based therapies. The advantages, disadvantages, and limitations of the different types of treatments--including the most commonly prescribed topical (ciclopirox) and oral (terbinafine, itraconazole, and fluconazole) treatments for onychomycosis caused by dermatophytes, non-dermatophyte molds, and yeasts--are reviewed. Safety and efficacy data for the healthy adult population and for special populations such as children and diabetic patients have confirmed the importance of proper mycological diagnosis before the initiation of therapy as well as the evaluation of the risks and benefits of the different treatments.