New paradigm to design micro and nano-patterned membranes

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2010.Cataloged from PDF version of thesis.Includes bibliographical references.Access to drinking water is a growing issue and one of the key challenging of the twenty first century. The rapid depletion of current supply sources (aquifers, rivers, lake...) urges to find solutions, especially cost and energy efficient processes to desalinate seawater. Reverse osmosis is a membrane process for purification of seawater, invented in 1940's, which has evolved ever since, to become nowadays the most efficient process for desalination. We discuss the shortcomings of this technology, and identify bio-fouling to be the main cause of irreversibility (thus costs) in this process. After observation of solutions developed by Nature to deter bio-fouling (especially for marine species), surface micro-topography and chemistry have been identified as the two effective anti-fouling strategies. We introduce a brand new technology to create micro- and nano-patterned surfaces that is compatible with a wide variety of chemical compounds. A proof of concept is introduced with the first prototypes of wrinkled surfaces created with Initiated Chemical Vapor Deposition; Stiff polymeric coatings form wrinkles when deposited on pre-stretched soft elastomeric substrates. We are showing, both theoretically and experimentally, that the characteristics of these wrinkles can be tuned very easily. Mimicking Nature requires creating more complicated micro-topographies than the sinusoid-like pattern obtained with uniform coatings and substrates. We are showing with a numerical model that local stiffening of the substrate can be used to direct and control the buckling of the coating. In order to gain the full control of this design strategy, an inverse method is needed to establish how to treat the substrate in order to obtain a desired micro-topography. We set up the foundations of this inverse mechanical model, and develop an algorithm for a simple case.by Damien Eggenspieler.S.M

Application for primary endpoint qualification of the 95th centile of stride velocity (SV95C) in Duchenne muscular dystrophy

peer reviewe

First regulatory qualification of a digital primary endpoint to measure treatment efficacy in DMD.

peer reviewe

Normative data on spontaneous stride velocity, stride length, and walking activity in a non-controlled environment.

Background: Normative data are necessary for validation of new outcome measures. Recently, the 95th centile of stride speed was qualified by the European Medicines Agency as a valid secondary outcome for clinical trials in subjects with Duchenne muscular dystrophy. This study aims to obtain normative data on spontaneous stride velocity and length in a non-controlled environment and their evolution after 12 months. Method: Ninety-one healthy volunteers (50 females, 41 males), with a mean age of 16 years and 2 months, were recruited and assessed at baseline and 12 months later. The 4-stair climb, 6-min walk test, 10-m walk test and rise from floor assessments were performed. Stride length, stride velocity, and the distance walked per hour were studied in an everyday setting for one month after each evaluation. Results: Of the 91 subjects assessed, 82 provided more than 50 h of recordings at baseline; and 73 subjects provided the same at the end of the year. We observed significant positive correlations of the stride length with age and height of participants, and a significant increase of the median stride length in children after the period. In this group, the 95th centile stride velocity was not correlated with age and was stable after one year. All measures but the 10MWT were stable in adults after a one-year period. Conclusion: This study provides with data on the influence of age, height, and gender on stride velocity and length as well as accounting for natural changes after one year in controls.Actilièg

First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases.

BACKGROUND: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. SUMMARY: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development

Qualitative Insights into Key Angelman Syndrome Motor Related Concepts Reported by Caregivers—A Thematic Analysis of Semi-Structured Interviews

Previous patient-centered concept models of Angelman syndrome (AS) are integral in developing our understanding of the symptoms and impact of this condition with a holistic perspective and have highlighted the importance of motor function. We aimed to develop the motor and movement aspects of the concept models, to support research regarding motor-related digital outcomes aligned with patients’ and caregivers’ perspectives. We conducted a qualitative analysis of semi-structured interviews of 24 caregivers to explore AS motor-related features, factors influencing them and their impact on patients and caregivers.The most impacted motor features were gait, walking and stair-climbing. Half of caregivers ranked motor symptoms as one of the most burdensome symptoms of AS. Caregivers frequently reported physical therapy, motivation, medical management and age as factors influencing motor function in AS and reported that impaired motor function affected both patients and caregivers. Measures of lower-limb motor function were identified as relevant to monitor drug effectiveness in AS. Caregivers discussed expected benefits of a digital outcome and potential issues with wearable technology in the context of AS. We propose a new motor function patient-centered concept model, providing insights for the development of relevant, motor-related, digital outcomes in AS

First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases.

BACKGROUND: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. SUMMARY: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development

Evolving regulatory perspectives on digital health technologies for medicinal product development

Abstract Digital health technology tools (DHTTs) present real opportunities for accelerating innovation, improving patient care, reducing clinical trial duration and minimising risk in medicines development. This review is comprised of four case studies of DHTTs used throughout the lifecycle of medicinal products, starting from their development. These cases illustrate how the regulatory requirements of DHTTs used in medicines development are based on two European regulatory frameworks (medical device and the medicinal product regulations) and highlight the need for increased collaboration between various stakeholders, including regulators (medicines regulators and device bodies), pharmaceutical sponsors, manufacturers of devices and software, and academia. As illustrated in the examples, the complexity of the interactions is further increased by unique challenges related to DHTTs. These case studies are the main examples of DHTTs with a regulatory assessment thus far, providing an insight into the applicable current regulatory approach; they were selected by a group of authors, including regulatory specialists from pharmaceutical sponsors, technology experts, academic researchers and employees of the European Medicines Agency. For each case study, the challenges faced by sponsors and proposed potential solutions are discussed, and the benefit of a structured interaction among the different stakeholders is also highlighted

E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

peer reviewedBy definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases

Isolated tricuspid valve surgery: impact of aetiology and clinical presentation on outcomes

International audienceAims: The aim of this study was to identify determinants of in-hospital and mid-term outcomes after isolated tricuspid valve surgery (ITVS) and more specifically the impact of tricuspid regurgitation (TR) mechanism and clinical presentation.Methods and results: Among 5661 consecutive adult patients who underwent a tricuspid valve (TV) surgery at 12 French tertiary centres in 2007-2017 collected from a mandatory administrative database, we identified 466 patients (8% of all tricuspid surgeries) who underwent an ITVS. Most patients presented with advanced disease [47% in New York Heart Association (NYHA) III/IV, 57% with right-sided heart failure (HF) signs]. Tricuspid regurgitation was functional in 49% (22% with prior left-sided heart valve surgery and 27% isolated) and organic in 51% (infective endocarditis in 31% and other causes in 20%). In-hospital mortality and major complications rates were 10% and 31%, respectively. Rates of survival and survival free of HF readmission were 75% and 62% at 5 years. Patients with functional TR incurred a worse in-hospital mortality than those with organic TR (14% vs. 6%, P = 0.004), but presentation was more severe. Independent determinants of outcomes were NYHA Class III/IV [odd ratios (OR) = 2.7 (1.2-6.1), P = 0.01], moderate/severe right ventricular dysfunction [OR = 2.6 (1.2-5.8), P = 0.02], lower prothrombin time [OR = 0.98 (0.96-0.99), P = 0.008], and with borderline statistical significance, right-sided HF signs [OR = 2.4 (0.9-6.5), P = 0.06] while TR mechanism was not [OR = 0.7 (0.3-1.8), P = 0.88].Conclusion: Isolated TV surgery was associated with high mortality and morbidity, both in hospital and during follow-up, predicted by the severity of the presentation but not by TR mechanism. Our results suggest that TV intervention should be performed earlier in the course of the disease