Fabrication and characterization of thin self-rolling film for anti-inflammatory drug delivery.

Thin films have been identified as an alternative approach for targeting sensitive site as drug delivery tool. In this work, the preparation of self-rolling thin films to form tubes for wound healing and easy placement (e.g. in the colon via colonoscopy) have been studied. We explored the use of thin films as a protective dressing combined to local release of an anti-inflammatory in order to improve drug efficacy and limit the side effects of the oral route. Non-cytotoxic poly(ethylene) glycol and poly(lactic acid) photo-crosslinkable star copolymers were used for rapid UV crosslinking of bilayered films loaded with prednisolone. The films, crosslinked under UV lamp without the need of photoinitiator, are optimized and compared in terms of water uptake, swelling ratio, final tube diameter and morphology, anti-inflammatory drug loading and release. Our studies showed the spontaneous rolling of bilayer constructs directly after immersion in water. Tubular geometry allows application of the patch through minimally invasive procedures such as colonoscopy. Moreover, the rolled-up bilayers highlighted efficient release of encapsulated drug following Fickian diffusion mechanism. We also confirmed the anti-inflammatory activity of the released anti-inflammatory drug that inhibits the pro-inflammatory cytokine IL-1ß in RAW 264.7 macrophages stimulated by Escherichia coli (E. coli).

Dynamic PEG-PLA/Hydroxyurethane Networks Based on Imine Bonds as Reprocessable Elastomeric Biomaterials.

The development of dynamic covalent chemistry opens the way to the design of materials able to be reprocessed by an internal exchange reaction under thermal stimulus. Imine exchange differs from other exchange reactions by its relatively low temperature of activation. In this study, amine-functionalized star-shaped PEG-PLA and an aldehyde-functionalized hydroxyurethane modifier were combined to produce PEG-PLA/hydroxyurethane networks incorporating imine bonds. The thermal and mechanical properties of these new materials were evaluated as a function of the initial ratio of amine/aldehyde used during synthesis. Rheological analyses highlighted the dynamic behavior of these vitrimers at moderate temperature (60-85 °C) and provided the flow activation energies. Additionally, the reprocessability of these PEG-PLA/hydroxyurethane vitrimers was assessed by comparing the material properties before reshaping and after three reprocessing cycles (1 ton, 1 h, 70 °C). Hence, these materials can easily be designed to satisfy a specific medical application without properties loss. This work opens the way to the development of a new generation of dynamic materials combining degradable PEG-PLA copolymers and hydroxyurethane modifiers, which could find applications in the shape of medical devices on-demand under mild conditions.

Dual-Crosslinked Degradable Elastomeric Networks With Self-Healing Properties: Bringing Multi(catechol) Star-Block Copolymers into Play.

In the biomedical field, degradable chemically crosslinked elastomers are interesting materials for tissue engineering applications, since they present rubber-like mechanical properties matching those of soft tissues and are able to preserve their three-dimensional (3D) structure over degradation. Their use in biomedical applications requires surgical handling and implantation that can be a source of accidental damages responsible for the loss of properties. Therefore, their inability to be healed after damage or breaking can be a major drawback. In this work, biodegradable dual-crosslinked networks that exhibit fast and efficient self-healing properties at 37 °C are designed. Self-healable dual-crosslinked (chemically and physically) elastomeric networks are prepared by two methods. The first approach is based on the mix of hydrophobic poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) star-shaped copolymers functionalized with either catechol or methacrylate moieties. In the second approach, hydrophobic bifunctional PEG-PLA star-shaped copolymers with both catechol and methacrylate on their structure are used. In the two systems, the supramolecular network is responsible for the self-healing properties, thanks to the dynamic dissociation/reassociation of the numerous hydrogen bonds between the catechol groups, whereas the covalent network ensures mechanical properties similar to pure methacrylate networks. The self-healable materials display mechanical properties that are compatible with soft tissues and exhibit linear degradation because of the chemical cross-links. The performances of networks from mixed copolymers versus bifunctional copolymers are compared and demonstrate the superiority of the latter. The biocompatibility of the materials is also demonstrated, confirming the potential of these degradable and self-healable elastomeric networks to be used for the design of temporary medical devices.

Degradable Bioadhesives Based on Star PEG-PLA Hydrogels for Soft Tissue Applications.

Tissue adhesives are interesting materials for wound treatment as they present numerous advantages compared to traditional methods of wound closure such as suturing and stapling. Nowadays, fibrin and cyanoacrylate glues are the most widespread commercial biomedical adhesives, but these systems display some drawbacks. In this study, degradable bioadhesives based on PEG-PLA star-shaped hydrogels are designed. Acrylate, methacrylate, and catechol functional copolymers are synthesized and used to design various bioadhesive hydrogels. Various types of mechanisms responsible for adhesion are investigated (physical entanglement and interlocking, physical interactions, chemical bonds), and the adhesive properties of the different systems are first studied on a gelatin model and compared to fibrin and cyanoacrylate references. Hydrogels based on acrylate and methacrylate reached adhesion strength close to cyanoacrylate (332 kPa) with values of 343 and 293 kPa, respectively, whereas catechol systems displayed higher values (11 and 19 kPa) compared to fibrin glue (7 kPa). Bioadhesives were then tested on mouse skin and human cadaveric colonic tissue. The results on mouse skin confirmed the potential of acrylate and methacrylate gels with adhesion strength close to commercial glues (15-30 kPa), whereas none of the systems led to high levels of adhesion on the colon. These data confirm that we designed a family of degradable bioadhesives with adhesion strength in the range of commercial glues. The low level of cytotoxicity of these materials is also demonstrated and confirm the potential of these hydrogels to be used as surgical adhesives.

Bioresorbable Bilayered Elastomer/Hydrogel Constructs with Gradual Interfaces for the Fast Actuation of Self-Rolling Tubes.

In the biomedical field, self-rolling materials provide interesting opportunities to develop medical devices suitable for drug or cell encapsulation. However, to date, a major limitation for medical applications is the use of non-biodegradable and non-biocompatible polymers that are often reported for such applications or the slow actuation witnessed with degradable systems. In this work, biodegradable self-rolling tubes that exhibit a spontaneous and rapid actuation when immersed in water are designed. Photo-crosslinkable hydrophilic and hydrophobic poly(ethylene glycol)-poly(lactide) (PEG-PLA) star-shaped copolymers are prepared and used to prepare bilayered constructs. Thanks to the discrete mechanical and swelling properties of each layer and the cohesive/gradual nature of the interface, the resulting bilayered films are able to self-roll in water in less than 30 s depending on the nature of the hydrophilic layer and on the shape of the sample. The cytocompatibility and degradability of the materials are demonstrated and confirm the potential of such self-rolling resorbable biomaterials in the field of temporary medical devices.

Characterisation of a Bioactive SiO2-CaO-CaF2-Na2O Glass Used in Composites.

OBJECTIVES: To characterise the ion release, pH changes and apatite formation of a phosphate free bioactive glass. METHODS: A SiO2-CaO-CaF2-Na2O glass was synthesized by a melt route with a composition close to the reactive glass in the commercial Cention N® composite. The glass was characterized after immersion in three media: Artificial Saliva pH4 (AS4) Artificial Saliva pH7 (AS7) and in a high phosphate artificial saliva at pH6.5 (AS6.5). The pH and fluoride release were measured using a pH meter and an ion selective electrode. The concentration of Ca, P, Na and Si were measured by ICP-OES. The glass powders after immersion were characterized by FTIR, X-ray powder diffraction and 19F MAS-NMR. RESULTS: The glass increased the pH in all three media. Fluoride was detected in all three media but was much higher in AS 6.5. Calcium fluoride formed in AS4 with a small amount of fluorapatite at long immersion times. Fluorapatite and calcium fluoride formed in AS7, whilst in AS6.5 fluorapatite formed. The ion concentrations in solution after immersion reflected the glass composition and the immersion media with fluorapatite being favoured by higher pHs and phosphate contents in the media. SIGNIFICANCE: The results demonstrated the ability of the glass to increase the pH and to form fluorapatite in phosphate containing media. This may explain the low incidence of secondary caries found in the commercial composite. Unlike the commercial composite evidence was found for the precipitation of fluorite, which will act to reduce the release of fluoride for preventing secondary caries.