Activities of Clinical Expertise and Research in a Rare Disease Referral Centre: A Place for Telemedicine beyond the COVID-19 Pandemic?

INTRODUCTION: Rare disease referral centres are entrusted with missions of clinical expertise and research, two activities that have to contend with numerous obstacles. Providing specialist opinions is time-consuming, uncompensated and limited by difficulties in exchanging medical data. Clinical research is constrained by the need for frequent research protocol visits. Our objective was to determine whether telemedicine (TLM) can overcome these difficulties. METHODS: To better characterise the activity of clinical expertise provided by our French centre, each opinion delivered by our team was reported on a standardised form. To investigate our clinical research activity, investigators and patients were asked to complete a questionnaire on the acceptability of research protocol teleconsultations. RESULTS: Regarding clinical expertise, our team delivered 120 opinions per week (representing a total of 21 h), of which 29% were delivered to patients and 69% to medical practitioners. If these were delivered using TLM, it would represent a potential weekly income of EUR 500 (tele-expertise) and EUR 775 (teleconsultations). Regarding the research activity, 70% of investigators considered the frequency of visits to be a limiting factor for patient inclusions; nearly half of the patients surveyed would be in favour of having teleconsultations in place of (40%) or in addition to (56%) in-person visits. CONCLUSION: Whereas TLM has become widely used as a back-up procedure to in-person consultations during the COVID-19 pandemic, the solutions it provides to the problems encountered in performing expertise and research activities have made it a new conventional follow-up modality for patients with rare diseases.

Efficacy of Intra-Articular Injection of Botulinum Toxin Type A (IncobotulinumtoxinA) in Temporomandibular Joint Osteoarthritis: A Three-Arm Controlled Trial in Rats.

Temporomandibular disorders (TMD) are complex pathologies responsible for chronic orofacial pain. Intramuscular injection of botulinum toxin A (BoNT/A) has shown effectiveness in knee and shoulder osteoarthritis, as well as in some TMDs such as masticatory myofascial pain, but its use remains controversial. This study aimed to evaluate the effect of intra-articular BoNT/A injection in an animal model of temporomandibular joint osteoarthritis. A rat model of temporomandibular osteoarthritis was used to compare the effects of intra-articular injection of BoNT/A, placebo (saline), and hyaluronic acid (HA). Efficacy was compared by pain assessment (head withdrawal test), histological analysis, and imaging performed in each group at different time points until day 30. Compared with the rats receiving placebo, those receiving intra-articular BoNT/A and HA had a significant decrease in pain at day 14. The analgesic effect of BoNT/A was evident as early as day 7, and lasted until day 21. Histological and radiographic analyses showed decrease in joint inflammation in the BoNT/A and HA groups. The osteoarthritis histological score at day 30 was significantly lower in the BoNT/A group than in the other two groups (p = 0.016). Intra-articular injection of BoNT/A appeared to reduce pain and inflammation in experimentally induced temporomandibular osteoarthritis in rats.

Injectable Chitosan-Based Hydrogels for Trans-Cinnamaldehyde Delivery in the Treatment of Diabetic Foot Ulcer Infections.

Diabetic foot ulcers (DFU) are among the most common complications in diabetic patients and affect 6.8% of people worldwide. Challenges in the management of this disease are decreased blood diffusion, sclerotic tissues, infection, and antibiotic resistance. Hydrogels are now being used as a new treatment option since they can be used for drug delivery and to improve wound healing. This project aims to combine the properties of hydrogels based on chitosan (CHT) and the polymer of ß cyclodextrin (PCD) for local delivery of cinnamaldehyde (CN) in diabetic foot ulcers. This work consisted of the development and characterisation of the hydrogel, the evaluation of the CN release kinetics and cell viability (on a MC3T3 pre-osteoblast cell line), and the evaluation of the antimicrobial and antibiofilm activity (S. aureus and P. aeruginosa). The results demonstrated the successful development of a cytocompatible (ISO 10993-5) injectable hydrogel with antibacterial (99.99% bacterial reduction) and antibiofilm activity. Furthermore, a partial active molecule release and an increase in hydrogel elasticity were observed in the presence of CN. This leads us to hypothesise that a reaction between CHT and CN (a Schiff base) can occur and that CN could act as a physical crosslinker, thus improving the viscoelastic properties of the hydrogel and limiting CN release.

Evaluation of a Medical Grade Thermoplastic Polyurethane for the Manufacture of an Implantable Medical Device: The Impact of FDM 3D-Printing and Gamma Sterilization.

Three-dimensional printing (3DP) of thermoplastic polyurethane (TPU) is gaining interest in the medical industry thanks to the combination of tunable properties that TPU exhibits and the possibilities that 3DP processes offer concerning precision, time, and cost of fabrication. We investigated the implementation of a medical grade TPU by fused deposition modelling (FDM) for the manufacturing of an implantable medical device from the raw pellets to the gamma (γ) sterilized 3DP constructs. To the authors' knowledge, there is no such guide/study implicating TPU, FDM 3D-printing and gamma sterilization. Thermal properties analyzed by differential scanning calorimetry (DSC) and molecular weights measured by size exclusion chromatography (SEC) were used as monitoring indicators through the fabrication process. After gamma sterilization, surface chemistry was assessed by water contact angle (WCA) measurement and infrared spectroscopy (ATR-FTIR). Mechanical properties were investigated by tensile testing. Biocompatibility was assessed by means of cytotoxicity (ISO 10993-5) and hemocompatibility assays (ISO 10993-4). Results showed that TPU underwent degradation through the fabrication process as both the number-averaged (Mn) and weight-averaged (Mw) molecular weights decreased (7% Mn loss, 30% Mw loss, p < 0.05). After gamma sterilization, Mw increased by 8% (p < 0.05) indicating that crosslinking may have occurred. However, tensile properties were not impacted by irradiation. Cytotoxicity (ISO 10993-5) and hemocompatibility (ISO 10993-4) assessments after sterilization showed vitality of cells (132% ± 3%, p < 0.05) and no red blood cell lysis. We concluded that gamma sterilization does not highly impact TPU regarding our application. Our study demonstrates the processability of TPU by FDM followed by gamma sterilization and can be used as a guide for the preliminary evaluation of a polymeric raw material in the manufacturing of a blood contacting implantable medical device.

Comparison of chemical-induced temporomandibular osteoarthritis rat models (monosodium iodoacetate versus collagenase type II) for the study of prolonged drug delivery systems.

OBJECTIVE: To compare two agents that can induce a rat model of temporomandibular joint osteoarthritis (TMJOA) by chemical induction: monosodium iodoacetate (MIA) and collagenase type 2 (Col-2). We wished to ascertain the best agent for assessing drug-delivery systems (DDSs). METHOD: Male Wistar rats underwent intra-articular injection with MIA or Col-2. They were manipulated for 30 days. The head withdrawal threshold (HWT), immunohistological assessment, and positron emission tomography (PET) were used to evaluate the relevance of our models. RESULTS: For both the MIA and Col-2 groups, pain persisted for 30 days after injection. Change in the HWT showed that Col-2 elicited a strong action initially that decreased progressively. MIA had a constant action upon pain behavior. Histology of TMJ tissue from both groups showed progressive degradation of TMJ components. CONCLUSIONS: MIA and Col-2 induced orofacial pain by their local chemical action on TMJs. However, based on a prolonged and greater sustained effect on the pain threshold, persistent histological changes, and imaging results, MIA appeared to be more suitable for creation of a rat model of TMJOA for the study of DDSs.

Systematic review of studies on drug-delivery systems for management of temporomandibular-joint osteoarthritis.

INTRODUCTION: Temporomandibular-joint osteoarthritis (TMJOA) management is a major challenge. Minimally invasive therapies (based mainly on injections) have been developed to increase local efficacy and limit adverse systemic effects. However, the requirement for repeat injections due to a short duration of action and expensive healthcare costs have pushed researchers to develop, via tissue engineering, drug-delivery systems (DDSs). In this literature systematic review, we aim to provide an overview of studies that tested DDSs on a TMJOA model. MATERIAL AND METHODS: We searched on PubMed for articles published from November 1965 to March 2021 on DDSs using a TMJOA model. We highlighted the different DDSs and the active molecule employed. Route of drug administration, model type, test duration, and efficacy duration were assessed. To evaluate the quality of each study, a protocol bias was tested using QUADAS-2™. RESULTS: Of the 10 studies that were full text-screened, four used a poly(lactic-co-glycolic acid)-based delivery system. The other DDSs employed chitosan-based hydrogels, microneedles patches, nanostructured lipid carriers, or poloxamer micelles. Hyaluronic acid, nonsteroidal anti-inflammatory drugs, and analgesics were used as active molecules in five studies. The main way to administer DDSs was intra-articular injection and the most used model was the rat. DISCUSSION: Various DDSs and active molecules have been studied on a TMJOA model that could aid TMJOA management. Further works using longer test durations are necessary to validate these advances.

In Vitro Microbiological and Drug Release of Silver/Ibuprofen Loaded Wound Dressing Designed for the Treatment of Chronically Infected Painful Wounds.

This study consisted of developing a dressing loaded with silver (Ag) and ibuprofen (IBU) that provides a dual therapy, antibacterial and antalgic, intended for infected painful wounds. Therefore, non-woven polyethyleneterephtalate (PET) textiles nonwovens were pre-treated by cyclodextrin crosslinked with citric acid by a pad/dry/cure process. Then, textiles were impregnated in silver solution followed by a thermal treatment and were then coated by Layer-by-Layer (L-b-L) deposition of a polyelectrolyte multilayer (PEM) system consisting of anionic water-soluble poly(betacyclodextrin citrate) (PCD) and cationic chitosan. Finally, ibuprofen lysinate (IBU-L) was loaded on the PEM coating. We demonstrated the complexation of IBU with native ßCD and PCD by phase solubility diagram and 1H NMR. PEM system allowed complete IBU-L release in 6 h in PBS pH 7.4 batch (USP IV). On the other hand, microbiological tests demonstrated that loaded silver induced bacterial reduction of 4 Log10 against S. aureus and E. coli and tests revealed that ibuprofen lysinate loading did not interfere with the antibacterial properties of the dressing.

A Systematic Review of Rat Models With Temporomandibular Osteoarthritis Suitable for the Study of Emerging Prolonged Intra-Articular Drug Delivery Systems.

PURPOSE: Development of minimally invasive therapies for temporomandibular joint osteoarthritis (TMJOA) has focused on drug intra-articular injections to avoid the systemic adverse effects experienced when these substances are administered orally. Therefore, we performed a systematic review to answer the question "Which method of induction of a TMJOA-related pain model in rats leads to prolonged painful symptoms, allowing the best assessment of a sustained drug delivery system?" MATERIALS AND METHODS: Following the PRISMA guidelines, we searched MEDLINE for papers published from 1994 to July 2020 on a TMJ arthritis model using rats. We identified the means of pain induction and of nociception assessment. We assessed protocol bias using an adaptation of the QUADAS-2 tool. Animal selection, the reference standard method of pain assessment, applicability of a statistical assessment, and flow and timing were assessed. RESULTS: Of the 59 full papers we reviewed, 41 performed no pain assessment after the first 7 days following induction of the TMJ-related pain model. We eventually identified 18 long-term TMJOA-related pain models. Pain was induced by injection of toxic substances, most commonly Freund's complete adjuvant (50 µg per 50 µl), formalin at various concentrations, or monosodium iodoacetate (0,5 mg per 50 µl), into the TMJ, or by physical methods. Few studies reported data on pain after 21 days of follow-up. Heterogeneity of induction methods, pain assessment methods, and flow and timing biases precluded a meta-analysis. CONCLUSIONS: Given that pain is 1 of the main symptoms of TMJOA, experimental study protocols should include long-term pain assessment.

New multifunctional pharmaceutical excipient in tablet formulation based on citric acid-cyclodextrin polymer.

A ß-cyclodextrin (ß-CD) polymer obtained by crosslinking ß-CD with citric acid in its water-insoluble (PCD-I) and soluble (PCD-S) forms was used as a multifunctional direct compression excipient for tablet designing. PCD-I powder was obtained after grinding the solid fraction through a 200µm grid. PCD-S powder was recovered after lyophilization or spray drying of the PCD-S aqueous solutions, eventually followed by a wet granulation step. Both PCD-I and PCD-S powders were characterized, separately and mixed in variable ratios, based on dynamic water vapor sorption, SEM, particle size distribution, tapped density, compressibility, and flowability. PCD-I and spray dried and lyophilized/wet granulated PCD-S, as well as the mixture PCD-I/PCD-S=90/10, presented optimal free flowing characteristics. Then, PCD-I or PCD-S powders - separately or mixed in variable ratios - were used for tablets preparation by direct compression without adding any other excipient (e.g. binder, lubricant, disintegrant etc). As PCD-I decreased, tablets resistance to crushing and disintegration time increased from 15s to 15min (against 30min for ß-CD), showing the improved disintegrant functionality of PCD-I, that rapidly swelled once in contact with water. Finally, PCD was force-fed to Sprague-Dawley rats (2g/kg) which were then observed during 14days for any clinical signs of toxicity.

Determination of the glass transition temperature of cyclodextrin polymers.

The aim of this work was to determine the main physical characteristics of ß-cyclodextrin polymers, well known for improving complexation capacities and providing enhanced and sustained release of a large panel of drugs. Two polymers were investigated: a polymer of ß-cyclodextrin (polyß-CD) and a polymer of partially methylated (DS=0.57) ß-cyclodextrin (polyMe-ß-CD). The physical characterizations were performed by powder X-ray diffraction and differential scanning calorimetry. The results indicate that these polymers are amorphous and that their glass transition is located above the thermal degradation point of the materials preventing their direct observation and thus their full characterization. We could however estimate the virtual glass transition temperatures by mixing the polymers with different plasticizers (trehalose and mannitol) which decreases Tg sufficiently to make the glass transition observable. Extrapolation to zero plasticizer concentration then yield the following Tg values: Tg (polyMe-ß-CD)=317°C±5°C and Tg (polyß-CD)=418°C±6°C.

Dressings Loaded with Cyclodextrin-Hamamelitannin Complexes Increase Staphylococcus aureus Susceptibility Toward Antibiotics Both in Single as well as in Mixed Biofilm Communities.

Bacteria reside within biofilms at the infection site, making them extremely difficult to eradicate with conventional wound care products. Bacteria use quorum sensing (QS) systems to regulate biofilm formation, and QS inhibitors (QSIs) have been proposed as promising antibiofilm agents. Despite this, few antimicrobial therapies that interfere with QS exist. Nontoxic hydroxypropyl-ß-cyclodextrin-functionalized cellulose gauzes releasing a burst of the antibiotic vancomycin and the QSI hamamelitannin are developed, followed by a sustained release of both. The gauzes affect QS and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of chronic wound infection and can be considered as candidates to be used to prevent wound infection as well as treat infected wounds.

[Evaluation of process of an educational web-based and mobile phone-based program for encouraging healthy behaviours among Spanish and Mexican students]. / Evaluación del proceso de un programa realizado a través de Internet y de la telefonía móvil para promover conductas saludables en estudiantes de educación secundaria de España y México.

BACKGROUND: Current communication technologies can be used in health education. The aim was to assess the process of an online program designed to prevent cancer risk behaviours using an educational website and mobile phones. METHODS: High school students from Spain and Mexico were recruited during 3 academic years (2009-12) to participate in a web-based program supplemented with mobile phone messages (SMS) which aim was to prevent cancer risk behaviours. The program was designed as a randomized trial, with control and experimental group (EG). Recruitment and adherence were analyzed using data of the Web management platform and Google Analytics. RESULTS: 3,855 students started the logging on the program of which 2,001 (51.9%) completed the questionnaire.77.5% were Mexicans, 13 years old (40.6%), with good academic level (68.7%) and with parents (49.6%) and mothers (53.9%) having university degree. 56.4% recorded a phone number to receive SMS. The EG consisted of 1,014 students and the averages of their visits to the website were 31.6 in the first year, 21.8 in the second and 21.9 in the third. Each adolescent of the EG was able to incorporate 1.16 adults (total 1,172) and other 1,076 were recorded spontaneously. Retention rate at the end of follow-up was 41.5% and was higher among those who were best students (OR: 12,5), Mexicans (OR: 4.4), 12 years old (OR: 3.1) and have been incorporated in the first three months of the implementation (OR: 2.8). CONCLUSION: Students' recruitment and retention was scarce, mainly in Spain. However students involved visited the program website with sufficient amount of time to achieve good results.

Evaluación del proceso de un programa realizado a través de internet y de la telefonía para promover conductas saludables en estudiantes de educación secundaria de España y México / Evaluation of process of an educational web-based and mobile phone-based program for encouraging healthy behaviours among spanish and mexican students

Fundamentos: Internet y la telefonía móvil forman parte de la tecnología más reciente que puede utilizarse en la educación para la salud. El objetivo fue evaluar el proceso de un programa para prevenir conductas de riesgo de cáncer implementado a través de internet y telefonía móvil. Métodos: Durante tres cursos académicos del período 2009-12 se seleccionó a estudiantes de secundaria de España y México para participar en un programa en línea suplementado con el envío de mensajes al teléfono móvil (SMS) cuyo objetivo era prevenir conductas de riesgo de cáncer. La intervención fue diseñada como un ensayo aleatorizado, con un grupo experimental (GE) y un grupo control. Se midieron el reclutamiento y la retención utilizando las herramientas de la plataforma de gestión de la web y de Google Analytics. Resultados: 3.855 estudiantes iniciaron el registro en el programa de los cuales 2.001 (51,9%) completaron el cuestionario. 77,5% fueron mexicanos, de 13 años (40,6%), de buen nivel académico (68,7%) y con padres (49,6%) y madres (53,9%) universitarios. El 56,4% registró un número de teléfono para recibir SMS. El GE estuvo formado por 1.014 estudiantes y la media de sus visitas a la web fue 31,6 en el primer curso, 21,8 en el segundo y 21,9 en el tercero. Las duraciones medias fueron, respectivamente, 11:02, 8:07 y 12:55 minutos. Cada adolescente del GE logró incorporar a 1,16 adultos (total1.172) y otros 1.076 se registraron espontáneamente. La tasa de retención de los estudiantes del GE fue 41,5% al final del seguimiento y fue mayor entre quienes tenían mejor nivel académico (OR:12,5), eran mexicanos (OR:4,4), tenían 12 años (OR: 3,1) y habían sido incorporados durante el primer trimestre del curso (OR: 2,8). Conclusión: El reclutamiento y la retención de estudiantes fueron escasos, especialmente en España. No obstante, los estudiantes que participaron visitaron la web del programa, en teoría durante un tiempo suficiente para lograr buenos resultados preventivos(AU)

Background: Current communication technologies can be used in health education. The aim was to assess the process of an online program designed to prevent cancer risk behaviours using an educational website and mobile phones. Methods: High school students from Spain and Mexico were recruited during 3 academic years (2009-12) to participate in a web-based program supplemented with mobile phone messages (SMS) which aim was to prevent cancer risk behaviours. The program was designed as a randomized trial, with control and experimental group (EG). Recruitment and adherence were analyzed using data of the Web management platform and Google Analytics. Results: 3,855 students started the logging on the program of which 2,001 (51.9%) completed the questionnaire.77.5% were Mexicans, 13 years old (40.6%), with good academic level (68.7%) and with parents (49.6%) and mothers (53.9%) having university degree. 56.4% recorded a phone number to receive SMS. The EG consisted of 1,014 students and the averages of their visits to the website were 31.6 in the first year, 21.8 in the second and 21.9 in the third. Each adolescent of the EG was able to incorporate 1.16 adults (total 1,172) and other 1,076 were recorded spontaneously. Retention rate at the end of follow-up was 41.5% and was higher among those who were best students (OR: 12,5), Mexicans (OR: 4.4), 12 years old (OR: 3.1) and have been incorporated in the first three months of the implementation (OR: 2.8). Conclusion: Students’ recruitment and retention was scarce, mainly in Spain. However students involved visited the program website with sufficient amount of time to achieve good results(AU)

Antiseptic cyclodextrin-functionalized hydrogels and gauzes for loading and delivery of benzalkonium chloride.

Prevention and management of wound infections receive a lot of attention, since the presence of micro-organisms interferes with the wound-healing process. The aim of this work was to use cyclodextrins (CDs) to endow hydrogels and gauzes with the ability to take up antiseptics and sustain their delivery for several hours. Benzalkonium chloride (BzCl) can form inclusion complexes with cross-linked CDs that regulate the release through an affinity-driven mechanism. Grafting of CDs to cotton gauzes using citric acid as the linker, at 190 °C and for 15 min, led to grafting yields of about 148%, much larger than those obtained at 180 °C or with shorter reaction times. Microbiological tests revealed that the BzCl-loaded networks can inhibit the growth of Staphylococcus epidermidis and Escherichia coli both on agar plates and in liquid medium. Furthermore, the antiseptic-loaded gauzes were able to inhibit biofilm formation by Staphylococcus aureus RN1HG pMV158GFP when applied in early stages of biofilm formation and could reduce the number of living cells in preformed biofilms grown in a chronic wound biofilm model. These findings highlight the role of CDs as main components of hydrogels and gauzes for the efficient delivery of antiseptics.