Search

Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers are limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(-lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of 16 aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically crosslinked methacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels, and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in the proximity of the implanted gel surface. Copyright (c) 2016 John Wiley & Sons, Ltd., This work was mainly supported by the EC FP7 project Disc Regeneration (Contract no. NMP3-LA-2008-213904). This study was also funded by the EC FP7 Programme contract agreement no. REGPOT-CT2012-316331-POLARIS., info:eu-repo/semantics/publishedVersion

Introduction and hypothesisMixed urinary incontinence (MUI) can be a challenging condition to manage. We describe the protocol design and rationale for the Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) trial, designed to compare a combined conservative and surgical treatment approach versus surgery alone for improving patient-centered MUI outcomes at 12months.MethodsESTEEM is a multisite, prospective, randomized trial of female participants with MUI randomized to a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone. We describe our methods and four challenges encountered during the design phase: defining the study population, selecting relevant patient-centered outcomes, determining sample size estimates using a patient-reported outcome measure, and designing an analysis plan that accommodates MUI failure rates. A central theme in the design was patient centeredness, which guided many key decisions. Our primary outcome is patient-reported MUI symptoms measured using the Urogenital Distress Inventory (UDI) score at 12months. Secondary outcomes include quality of life, sexual function, cost-effectiveness, time to failure, and need for additional treatment.ResultsThe final study design was implemented in November 2013 across eight clinical sites in the Pelvic Floor Disorders Network. As of 27 February 2016, 433 total/472 targeted participants had been randomized.ConclusionsWe describe the ESTEEM protocol and our methods for reaching consensus for methodological challenges in designing a trial for MUI by maintaining the patient perspective at the core of key decisions. This trial will provide information that can directly impact patient care and clinical decision making.

© 2015 Elsevier Inc. The goals of this trial are to determine the efficacy and safety of two treatments for women experiencing fecal incontinence. First, we aim to compare the use of loperamide to placebo and second, to compare the use of anal sphincter exercises with biofeedback to usual care. The primary outcome is the change from baseline in the St. Mark's (Vaizey) Score 24. weeks after treatment initiation. As a Pelvic Floor Disorders Network (PFDN) trial, subjects are enrolling from eight PFDN clinical centers across the United States. A centralized data coordinating center supervises data collection and analysis. These two first-line treatments for fecal incontinence are being investigated simultaneously using a two-by-two randomized factorial design: a medication intervention (loperamide versus placebo) and a pelvic floor strength and sensory training intervention (anal sphincter exercises with manometry-assisted biofeedback versus usual care using an educational pamphlet). Interventionists providing the anal sphincter exercise training with biofeedback have received standardized training and assessment. Symptom severity, diary, standardized anorectal manometry and health-related quality of life outcomes are assessed using validated instruments administered by researchers masked to randomized interventions. Cost effectiveness analyses will be performed using prospectively collected data on care costs and resource utilization. This article describes the rationale and design of this randomized trial, focusing on specific research concepts of interest to researchers in the field of female pelvic floor disorders and all other providers who care for patients with fecal incontinence.

The regeneration of cartilage in the intervertebral disc nucleus pulposus and joints is impaired by the formation of fibrocartilage that is caused by the invasion of the tissue by blood vessels. Peptides have been identified by phage display technique which are able to bind VEGF thus inhibiting angiogenesis. The present works focusses on the synthesis of poly(epsilon-lysine) dendrons of three branching generations in which the molecular root of the dendron bears a di-phenylalanine sequence to promote hydrophobic interactions with material surfaces and the uppermost molecular branches are functionalised with the amino acid sequenceWHLPFKC that is known to block VEGF. These biofunctionalised dendrons were entrapped in methacrylated Gellan Gum (GG-MA) hydrogels and tested for their ability to inhibit endothelial cell sprouting by both a 3D in vitro cell models and an in ovo model. The results show that when GG-MA is functionalised with the dendronised VEGF blockers, a regression of angiogenesis takes place around the hydrogel boundary. The in ovo study supports these findings as the GG-MA functionalised with the dendronised VEGF blockers did not elicit any acute inflammatory response, and decrease the number of converging macroscopic blood vessels as compared to positive controls. Moreover, the hydrogels prevented the infiltration of blood vessels, after 4 days of implantation., Fundação para a Ciência e Tecnologia, EU 7th Framework Programme, MICINN, Junta de Castilla y León, CIBER-BBN, Fundo Social Europeu, Programa Operacional Potencial Humano