Fibrin-based scaffolds for dental pulp regeneration: from biology to nanotherapeutics.

Tissue engineering-based endodontic therapies, designed to regenerate the dental pulp (DP) in the devitalised endodontic space, have been proposed to improve tooth longevity compared to conventional root-filling therapies. Their aim is to restore tooth vitality and major DP functions necessary to maintain tooth health such as immunosurveillance, sensitivity and healing/repair/regenerative capacities. Several formulations based on the use of fibrin, the main component of the blood clot matrix, recently gave valuable results in the regeneration of the human DP. This review describes recent fibrin-based scaffolds designed for that purpose. After having presented the various strategies for DP regeneration, the main fibrin-based scaffolds reported so far for clinical use in endodontics were reviewed. Particular emphasis was given to hydrogel devices that may be improved by incorporation of bioactive molecules that stimulate vascularisation and tissue neoformation or provide antibacterial properties. Data indicate that fibrin-based scaffolds constitute a highly favourable environment for mesenchymal stem cells, which is maintained upon functionalisation. Additional knowledge is needed to understand how fibrin and functionalising agents affect adhesion, survival, proliferation, migration and differentiation of cells incorporated in the scaffold or which will colonise it from neighbouring host tissues. This knowledge is needed to adapt the hydrogel formulation for various clinical conditions.

Dental pulp inflammatory/immune response to a chitosan-enriched fibrin hydrogel in the pulpotomised rat incisor.

Current pulpotomy is limited in its ability to induce regeneration of the dental-pulp (DP) complex. Hydrogels are reported to be well-suited for tissue engineering and are unlikely to induce an inflammatory response that might damage the remaining tissue. The present study investigated the molecular and cellular actors in the early inflammatory/immune response and deciphered M1/M2 macrophage polarisation to a chitosan-enriched fibrin hydrogel in pulpotomised rat incisors. Both fibrin and fibrin-chitosan hydrogels induced a strong increase in interleukin-6 (IL-6) transcript in the DP when compared to the DP of untreated teeth. Gene expression of other inflammatory mediators was not significantly modified after 3 h. In the viable DP cell population, the percentage of leukocytes assessed by flow cytometry was similar to fibrin and fibrin-chitosan hydrogels after 1 d. In this leukocyte population, the proportion of granulocytes increased beneath both hydrogels whereas the antigen-presenting cell, myeloid dendritic cells, T cells and B cells decreased. The natural killer (NK) cell population was significantly decreased only in DPs from teeth treated with fibrin-chitosan hydrogel. Immunolabeling analysis of the DP/hydrogel interface showed accumulation of neutrophil granulocytes in contact with both hydrogels 1 d after treatment. The DP close to this granulocyte area contained M2 but no M1 macrophages. These data collectively demonstrated that fibrin-chitosan hydrogels induced an inflammatory/immune response similar to that of the fibrin hydrogel. The results confirmed the potential clinical use of fibrin-chitosan hydrogel as a new scaffold for vital-pulp therapies.

Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study.

BACKGROUND: One million people worldwide benefit from chronic dialysis, with an increased rate in Western countries of 5% yearly. Owing to increased incidence of cancer in dialyzed patients, the management of these patients is challenging for oncologists/nephrologists. PATIENTS AND METHODS: The CANcer and DialYsis (CANDY) retrospective multicenter study included patients under chronic dialysis who subsequently had a cancer (T0). Patients were followed up for 2 years after T0. Prescriptions of anticancer drugs were studied with regard to their renal dosage adjustment/dialysability. RESULTS: A total of 178 patients from 12 institutions were included. The mean time between initiation of dialysis and T0 was 30.8 months. Fifty patients had received anticancer drug treatment. Among them, 72% and 82% received at least one drug needing dosage and one drug to be administered after dialysis sessions, respectively. Chemotherapy was omitted or prematurely stopped in many cases where systemic treatment was indicated or was often not adequately prescribed. CONCLUSIONS: Survival in dialysis patients with incident cancer was poor. It is crucial to consider anticancer drug treatment in these patients as for non-dialysis patients and to use current available specific drug management recommendations in order to (i) adjust the dose and (ii) avoid premature elimination of the drug during dialysis sessions.

Artificial Intelligence and Ethics in Dentistry: A Scoping Review.

Dentistry increasingly integrates artificial intelligence (AI) to help improve the current state of clinical dental practice. However, this revolutionary technological field raises various complex ethical challenges. The objective of this systematic scoping review is to document the current uses of AI in dentistry and the ethical concerns or challenges they imply. Three health care databases (MEDLINE [PubMed], SciVerse Scopus, and Cochrane Library) and 2 computer science databases (ArXiv, IEEE Xplore) were searched. After identifying 1,553 records, the documents were filtered, and a full-text screening was performed. In total, 178 studies were retained and analyzed by 8 researchers specialized in dentistry, AI, and ethics. The team used Covidence for data extraction and Dedoose for the identification of ethics-related information. PRISMA guidelines were followed. Among the included studies, 130 (73.0%) studies were published after 2016, and 93 (52.2%) were published in journals specialized in computer sciences. The technologies used were neural learning techniques for 75 (42.1%), traditional learning techniques for 76 (42.7%), or a combination of several technologies for 20 (11.2%). Overall, 7 countries contributed to 109 (61.2%) studies. A total of 53 different applications of AI in dentistry were identified, involving most dental specialties. The use of initial data sets for internal validation was reported in 152 (85.4%) studies. Forty-five ethical issues (related to the use AI in dentistry) were reported in 22 (12.4%) studies around 6 principles: prudence (10 times), equity (8), privacy (8), responsibility (6), democratic participation (4), and solidarity (4). The ratio of studies mentioning AI-related ethical issues has remained similar in the past years, showing that there is no increasing interest in the field of dentistry on this topic. This study confirms the growing presence of AI in dentistry and highlights a current lack of information on the ethical challenges surrounding its use. In addition, the scarcity of studies sharing their code could prevent future replications. The authors formulate recommendations to contribute to a more responsible use of AI technologies in dentistry.

Development of an antibacterial nanocomposite hydrogel for human dental pulp engineering.

Hydrogel-based regenerative endodontic procedures (REPs) are considered to be very promising therapeutic strategies to reconstruct the dental pulp (DP) tissue in devitalized human teeth. However, the success of the regeneration process is limited by residual bacteria that may persist in the endodontic space after the disinfection step and contaminate the biomaterial. The aim of this work was to develop an innovative fibrin hydrogel incorporating clindamycin (CLIN)-loaded Poly (d,l) Lactic Acid (PLA) nanoparticles (NPs) to provide the hydrogel with antibacterial properties. CLIN-PLA-NPs were synthesized by a surfactant-free nanoprecipitation method and their microphysical properties were assessed by dynamic light scattering, electrophoretic mobility and scanning electron microscopy. Their antimicrobial efficacy was evaluated on Enteroccocus fæcalis by the determination of the minimal inhibitory concentration (MIC) and the minimal biofilm inhibition and eradication concentrations (MBIC and MBEC). Antibacterial properties of the nanocomposite hydrogel were verified by agar diffusion assays. NP distribution into the hydrogel and release from it were evaluated using fluorescent PLA-NPs. NP cytotoxicity was assessed on DP mesenchymal stem cells (DP-MSCs) incorporated into the hydrogel. Type I collagen synthesis was investigated after 7 days of culture by immunohistochemistry. We found that CLIN-PLA-NPs displayed a drug loading of 10 ± 2 µg per mg of PLA polymer and an entrapment efficiency of 43 ± 7%. Antibiotic loading did not affect NP size, polydispersity index and zeta potential. The MIC for Enterococcus fæcalis was 32 µg mL-1. MBIC50 and MBEC50 were 4 and 16 µg mL-1, respectively. CLIN-PLA-NPs appeared homogenously distributed throughout the hydrogel. CLIN-PLA-NP-loaded hydrogels clearly inhibited E. faecalis growth. DP-MSC viability and type I collagen synthesis within the fibrin hydrogel were not affected by CLIN-PLA-NPs. In conclusion, CLIN-PLA-NP incorporation into the fibrin hydrogel gave the latter antibacterial and antibiofilm properties without affecting cell viability and function. This formulation could help establish an aseptic environment supporting DP reconstruction and, accordingly, might be a valuable tool for REPs.

A standardized procedure to obtain mesenchymal stem/stromal cells from minimally manipulated dental pulp and Wharton's jelly samples.

Transplantation of mesenchymal stem/stromalcells (MSCs) has emerged as an effectivemethod to treat diseased or damagedorgans and tissues, and hundreds of clinicaltrials using MSCs are currently under way todemonstrate the validity of such a therapeuticapproach. However, most MSCs used for clinicaltrials are prepared in research laboratorieswith insufficient manufacturing quality control.In particular, laboratories lack standardizedprocedures for in vitro isolation of MSCs fromtissue samples, resulting in heterogeneouspopulations of cells and variable experimentaland clinical results.MSCs are now referred to as Human CellularTissue-based Products or Advanced TherapyMedicinal Products, and guidelines fromthe American Code of Federal Regulation ofthe Food and Drug Administration (21 CFRPart 1271) and from the European MedicinesAgency (European Directive 1394/2007) definerequirements for appropriate production ofthese cells. These guidelines, commonly called"Good Manufacturing Practices" (GMP),include recommendations about laboratorycell culture procedures to ensure optimal reproducibility,efficacy and safety of the finalmedicinal product. In particular, the Food andDrug Administration divides ex vivo culturedcells into "minimally" and "more than minimally"manipulated samples, in function of theuse or not of procedures "that might alter thebiological features of the cells". Today, minimalmanipulation conditions have not beendefined for the collection and isolation ofMSCs (Torre et al. 2015)(Ducret et al. 2015).Most if not all culture protocols that have beenreported so far are unsatisfactory, becauseof the use of xeno- or allogeneic cell culturemedia, enzymatic treatment and long-termcell amplification that are known to alter thequality of MSCs.The aim of this study was to describe a standardizedprocedure for recovering MSCs withminimal handling from two promising sources,the dental pulp (DP) and the Wharton's jelly(WJ) of the umbilical cord. The quality and homogeneityof the expanded cell populationswere assessed by using flow cytometry withcriteria that go beyond the International Societyof Cellular Therapy (ISCT) guidelines forMSC characterization.

[Neurodevelopmental outcome of premature infants born at less than 33 weeks of gestational age and not cerebral palsy at the age of 5 years]. / Devenir neurodéveloppemental à cinq ans des prématurés nés avant 33 semaines d'aménorrhée et indemnes d'infirmité motrice d'origine cérébrale.

AIM: To appreciate the impact of prematurity, fetal hypotrophy and familial environment on the neurodevelopmental performances of very premature infants without cerebral palsy at the age of five years. POPULATION AND METHODS: We followed a regional cohort of 171 very premature infants (< or = 32 weeks of gestation) until they were five years of age. Cognitive functions were tested with the WPPSI test and the development quotient was assessed by the ability to draw a "bonhomme". Twenty-two premature infants suffered from cerebral palsy diagnosed before the age of two years. Another infant had a moderate diplegia at the five-year examination. We had no information for 16 prematures (9.3% of survivors). Twenty-eight premature infants were considered as having no severe disability on phone or mailed contact, and another child had a severe isolated mental retardation. We examined 104/148 infants, and 96/148 survivors without cerebral palsy passed the tests. The cognitive functions of these premature infants are compared to the performances of a control group made up of 108 children born at term > or = 37 weeks, matched for birthplace and single or twin characteristics of the pregnancy. RESULTS: The values of the different quotients are significantly decreased in the preterm group. The global IQ and the performance IQ are 0.8 SD, verbal IQ is 0.5 SD and the development quotient is 0.4 SD below the values observed in the control group. A performance IQ less than -2 SD for the mean of the control group is observed three times more than in the controls (13.5% vs 3.7%, P < 0.01). Multiple linear regression shows that prematurity explains, independent of hypotrophy and socioeconomic environment, 8% of the variation of the performance IQ (P < 0.01), 2% of the variation of the verbal IQ and 2% of the development quotient (P < 0.05). CONCLUSION: The five-year neurologic outcome of the children born prematurely in this regional study is similar to the results observed in regional studies conducted in Europe: 13.4% of the survivors have cerebral palsy, and the cognitive functions of the children with no cerebral palsy are significantly lower than the term control group. Other risk factors such as hypotrophy, which modulates the developmental quotient, and the socioeconomic status, which modulates the verbal IQ, are underlined.

[Instrumentalism and psychosocial rehabilitation. Development of methodological processes related to the "intermediate spaces"]. / Instrumentalisme et réadaptation psychosociale. Devenir des méthodes processuelles dans les "espaces intermédiaires".

In psychosocial rehabilitation, institutional actors which are not focused on the "intermediate space" (term coined by the authors to describe the time-space of interpersonal, solution-oriented communication filled by the actor and the patient) are faced with an identity crisis and other problems, some of which are linked to a instrumental vision of their practice. Such a vision leads to a discursive and theoretical approach, yet interferes with potential partnerships. Also, it traps open and solution-oriented relational situations by favouring that which is focused on acts of a prescriptive and normative nature. This state of affairs is encouraged by several factors linked to the actor's status, to health policies and to the evaluation of such policies. In future, effective work in this "intermediate space" will require that actors use other inductive models on which to base their practice which, incidentally, remains at the fringe of social care and support.

Effect of contrast media on whole blood filtrability. An in vitro comparative study of iohexol, iopamidol and ioxaglate on rat blood.

The effects of three contrast media, iohexol, iopamidol and ioxaglate, on rat erythrocytes were compared. Three parameters representative of the rheologic properties of blood were investigated: whole blood filtrability, red cell filtrability and morphology. Whole blood and red cell filtrabilities were both measured using an erythrometer and red cell morphology was observed with an optical microscope. Iohexol and iopamidol were found to cause a significant increase in filtrability indices and to modify the shape of red blood cells. Ioxaglate had less effect on these parameters than did the other two contrast media. The chemical structure seems to be a determining factor for red cell integrity. The study of blood rheology parameters in vitro may be useful as a model predictive of observations on human blood and of hemodynamic consequences.

Comparison of plasma and peritoneal concentrations of various categories of MRI blood pool agents in a murine experimental pharmacokinetic model.

The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation; low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation. Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t1/2=13.3 and 13.8 min, respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume: C(max) per dose decreased progressively (78.7, 51.2, 44.2, 33.5 1/l) and t(max) increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78.4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated.The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally.

Toxicologic profile of iobitridol, a new nonionic low-osmolality contrast medium.

PURPOSE: The toxicologic profile of iobitridol, a new nonionic low-osomolality contrast medium, was evaluated in compliance with the current regulatory requirements in Europe, the USA and Canada. MATERIAL AND METHODS: The toxicity of iobitridol was tested following acute or repeated i.v. administration in several different species (mouse, rat, dog); single oral administration in the mouse and intracisternal injection in the rat. Furthermore, teratogenicity and mutagenicity were evaluated in the rat and rabbit. Local perivenous toxicity was assessed in the rabbit. RESULTS: The acute toxicity of iobitridol in the mouse is equivalent to that of iohexol, a reference product tested under the same conditions. Chronic administration (daily injections i.v. injection over 4 weeks) in the rat and dog did not demonstrate any particular toxicity for iobitridol. It should be noted that, unlike iohexol, iobitridol did not provoke any vacuolization of the renal tubular cells in the rat following repeated injections. Furthermore, this contrast agent did not show any teratogenic or mutagenic potential. The typical local inflammatory signs observed following perivenous injection in the rabbit were low in intensity and reversible. CONCLUSION: The toxicologic profile of iobitridol appears to be favorable and does not show any particular risk for clinical use under the usual indications of water soluble iodinated contrast agents.