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Micro & Nano Polymer and diagnostics Polymers for medical imaging Polymers for in vitro diagnostics

Polymer and diagnostics

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Polymers for medical imaging

MRI visible polymers for coatings and theranostic applications

About the project:

This project aims at offering chemical strategies that can help making the polymeric implants visible by the clinically relevant MRI procedures.For that, we focus on novel macromolecular MRI contrast agents that can be used as coatings, or as micro- and nanoparticles, and we focus on surface modification to make existing polymers MRI-visible.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Xavier Garric
Xavier Garric
Jean Coudane
Jean Coudane
Vincent Darcos
Vincent Darcos
Audrey Bethry
Audrey Bethry

Students:

Anita Shulz
Mira Younis
Sarah El Habnouni

Collaborations:

Dr. Lemaire (MINT, Inserm 1066 – CNRS 6021), Dr. Franconi (platform PRISM), Prof. Letouzey (CHU Nîmes)

Funding:

Campus France, Post-doctoral program UM, MENRT grant (ED 459), Chercheur d’Avenir 2013

Controlled Anchoring of Iron Oxide Nanoparticles on Polymeric Nanofibers: Easy Access to Core@Shell Organic−Inorganic Nanocomposites for Magneto-Scaffolds

ACS Appl. Mater. Interfaces 11, 9519–9529 (2019)

Awada H., Al Samad A., Laurencin D., Gilbert R., Dumail X., El Jundi A., Bethry A., Pomrenke R., Johnson C., Lemaire L., Franconi F., Félix G., Larionova J., Guari Y., Nottelet B.

ABSTRACT

Composites combining superparamagnetic iron oxide nanoparticles (SPIONs) and polymers are largely present in modern (bio)materials. However, while SPIONs embedded in polymer matrices are classically reported, the mechanical and degradation properties of the polymer scaffold are impacted by the SPIONs. Therefore, the controlled anchoring of SPIONs onto polymer surfaces is still a major challenge. Herein, we propose an efficient strategy for the direct and uniform anchoring of SPIONs on the surface of functionalized-polylactide (PLA) nanofibers via a simple free ligand exchange procedure to design PLA@SPIONs core@shell nanocomposites. The resulting PLA@SPIONs hybrid biomaterials are characterized by electron microscopy (SEM and TEM) and EDXS analysis, to probe the morphology and detect elements present at the organic/inorganic interface, respectively. A monolayer of SPIONs with a complete and homogeneous coverage is observed on the surface of PLA nanofibers. Magnetization experiments show that magnetic properties of the nanoparticles are well-preserved after their grafting on the PLA fibers and that the size of the nanoparticles does not change. The absence of cytotoxicity, combined with a high sensitivity of detection in MRI both in vitro and in vivo make these hybrid nanocomposites attractive for the development of magnetic biomaterials for biomedical applications.

UV-triggered photoinsertion of contrast agent onto polymer surfaces for in vivo MRI-visible medical devices

Multifunct. Mater. 2 0240012019 (2019)

Schulz A., Lemaire L., Bethry A.; Allegre L., Cardoso M., Bernex F., Franconi F., Goze-Bac C., Taillades H., Garric X., Nottelet B.

ABSTRACT

Polymeric materials are largely employed for the manufacturing of implants for various reasons, but they are typically invisible by conventional imaging methods. To improve surgical procedure and postoperative implant follow-up though, biomaterials are needed which allow an accurate and efficient imaging. Here, we present a direct and versatile strategy that allows to covalently immobilize T1 magnetic resonance imaging (MRI) contrast agents at the surface of various clinically relevant polymeric biomaterials. An aryl-azide bearing complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and gadolinium (Gd) has been synthesized for easy photografting onto polymer surfaces. Polycaprolactone (PCL), polylactide (PLA), polyurethane (PU), polyetheretherketone (PEEK) and polypropylene (PP) have been selected as clinically relevant substrates and successfully functionalized with the photosensitive MRI probe DOTA/Gd. Following in vitro assessment of their biocompatibility and MRI visibility, commercial MRI-visible PP hernia repair meshes (MRI-meshes) have been prepared. MRI-meshes have been implanted in rats for in vivo evaluation of their imaging capacities over 1 month. Histological evaluation and Gd biodistribution studies have been carried out confirming the potential of this straightforward approach to simply yield imageable medical devices.

MRI-visible polymer based on poly(methyl methacrylate) for imaging applications

RSC Adv. 6, 5754–5760 (2016).

Younis, M., Darcos, V., Paniagua, C., Ronjat, P., Lemaire, L., Nottelet, B., Garric, X., Bakkour, Y., El Nakat, J. H. & Coudane, J.

 

ABSTRACT

Macromolecular contrast agents are very attractive to afford efficient magnetic resonance imaging (MRI) visualization of implantable medical devices. In this work, we report on the grafting of a Gd-based DTPA contrast agent onto a poly(methyl methacrylate) derivative backbone by combining free radical polymerization and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Using free radical polymerization, poly(methyl methacrylate-co-propargyl methacrylate) copolymers were prepared with a control of the ratio in propargyl methacrylate monomer units. The synthesis of a new azido mono-functionalized DTPA ligand was also reported and characterized by 1H NMR and mass spectroscopy. After complexation with gadolinium, this ligand has been grafted on the polymer backbone by click chemistry reaction. The obtained macromolecular contrast agent was then coated on a polypropylene mesh using the airbrushing technique and the mesh was assessed for MRI visualization at 7 teslas. The polymeric contrast agent was also tested for cytocompatibility and stability to assess its suitability for biomedical applications.

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MRI-visible nanoparticles from hydrophobic gadolinium poly(ε-caprolactone) conjugates

Polymer 56, 135–140 (2015)

Porsio, B., Lemaire, L., El Habnouni, S., Darcos, V., Franconi, F., Garric, X., Coudane, J. & Nottelet, B

 

ABSTRACT

In this work we report on the synthesis of two hydrophobic and degradable gadolinium poly(ε-caprolactone) conjugates and their use for the preparation of MRI-visible nanoparticles intended for diagnosis applications. Advantage has been taken from functional poly(ε-caprolactone)s (PCL) bearing propargyl (PCL-yne) or amine groups (P(CL-co-NH2VL)) to yield conjugates by following two strategies. In a first approach, an azido-chelate of gadolinium (Gd(III)) has been conjugated by CuAAC to PCL-yne to yield a polymeric chelate containing 2.6 wt% of Gd(III). In a second approach, a dianhydride Gd(III)-ligand was reacted with P(CL-co-NH2VL) to yield, after complexation with Gd(III) salts, a polymeric chelate containing 15.4 wt% of Gd(III). The polymers biocompatibility was assessed against L929 fibroblasts. In a second part, advantage was taken from the PCLs conjugates hydrophobicity to easily prepare by nanoprecipitation nanoparticles with diameters ranging from 120 to 170 nm. The nanoparticles MRI-visibility was then evaluated and confirmed under the spin-echo and the clinically relevant gradient-echo MRI sequences.

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X-ray visible polymers for implantable medical devices

About the project:

This project aims at offering chemical strategies that can help making the polymeric implants visible by the clinically relevant scanner procedures. For that, we focus on novel macromolecular MRI contrast agents that can be used as coatings, or as X-ray radiopaque agent to be formulated in medical devices.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Xavier Garric
Xavier Garric
Stéphane Dejean
Stéphane Dejean

Students:

Edouard Girard

Collaborations:

Dr. Rhiele (University of Glasgow)), Dr. Chagnon & Prof .Favier (TIMC-IMAG, UMR 5525)

Funding:

From in vitro evaluation to human post-mortem pre-validation of a radiopaque and resorbable internal biliary stent for liver transplantation applications

Acta Biomaterialia 106, 66-81, (2020)

Girard E., Chagnon G., Broisat A., Dejean S., Soubies A., Gil H., Sharkawi T., Boucher F. Roth G.S., Trilling B., Nottelet B.

 

Girard E. et al. Acta Biomaterialia 2020

ABSTRACT

The implantation of an internal biliary stent (IBS) during liver transplantation has recently been shown to reduce biliary complications. To avoid a potentially morbid ablation procedure, we developed a resorbable and radiopaque internal biliary stent (RIBS). We studied the mechanical and radiological properties of RIBS upon in vivo implantation in rats and we evaluated RIBS implantability in human anatomical specimens.

For this purpose, a blend of PLA50-PEG-PLA50 triblock copolymer, used as a polymer matrix, and of X-ray-visible triiodobenzoate-poly(e-caprolactone) copolymer (PCL-TIB), as a radiopaque additive, was used to design X-ray-visible RIBS. Samples were implanted in the peritoneal cavity of rats. The radiological, chemical, and biomechanical properties were evaluated during degradation. Further histological studies were carried out to evaluate the degradation and compatibility of the RIBS. A human cadaver implantability study was also performed.

The in vivo results revealed a decline in the RIBS mechanical properties within 3 months, whereas clear and stable X-ray visualization of the RIBS was possible for up to 6 months. Histological analyses confirmed compatibility and resorption of the RIBS, with a limited inflammatory response. The RIBS could be successfully implanted in human anatomic specimens. The results reported in this study will allow the development of trackable and degradable IBS to reduce biliary complications after liver transplantation.

Radiopaque poly(epsilon-caprolactone) as additive for X-ray imaging of temporary implantable medical devices

RSC Adv. 5, 84125–84133 (2015)

Samuel, R., Girard, E., Chagnon, G., Dejean, S., Favier, D., Coudane, J. & Nottelet, B

 

ABSTRACT

In this work we report on the synthesis of two hydrophobic and degradable gadolinium poly(ε-caprolactone) conjugates and their use for the preparation of MRI-visible nanoparticles intended for diagnosis applications. Advantage has been taken from functional poly(ε-caprolactone)s (PCL) bearing propargyl (PCL-yne) or amine groups (P(CL-co-NH2VL)) to yield conjugates by following two strategies. In a first approach, an azido-chelate of gadolinium (Gd(III)) has been conjugated by CuAAC to PCL-yne to yield a polymeric chelate containing 2.6 wt% of Gd(III). In a second approach, a dianhydride Gd(III)-ligand was reacted with P(CL-co-NH2VL) to yield, after complexation with Gd(III) salts, a polymeric chelate containing 15.4 wt% of Gd(III). The polymers biocompatibility was assessed against L929 fibroblasts. In a second part, advantage was taken from the PCLs conjugates hydrophobicity to easily prepare by nanoprecipitation nanoparticles with diameters ranging from 120 to 170 nm. The nanoparticles MRI-visibility was then evaluated and confirmed under the spin-echo and the clinically relevant gradient-echo MRI sequences.

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Aliphatic polyesters for medical imaging and theranostic applications

Eur. J. Pharm. Biopharm. 97, 350–370 (2015)

Nottelet, B., Darcos, V. & Coudane, J

 

ABSTRACT

Medical imaging is a cornerstone of modern medicine. In that context the development of innovative imaging systems combining biomaterials and contrast agents (CAs)/imaging probes (IPs) for improved diagnostic and theranostic applications focuses intense research efforts. In particular, the classical aliphatic (co)polyesters poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) and poly(e-caprolactone) (PCL), attract much attention due to their long track record in the medical field. This review aims therefore at providing a state-of-the-art of polyester-based imaging systems. In a first section a rapid description of the various imaging modalities, including magnetic resonance imaging (MRI), optical imaging, computed tomography (CT), ultrasound (US) and radionuclide imaging (SPECT, PET) will be given.  Then, the two main strategies used to combine the CAs/IPs and the polyesters will be discussed. In more details we will first present the strategies relying on CAs/IPs encapsulation in nanoparticles, micelles, dendrimers or capsules. We will then present chemical modifications of polyesters backbones and/or polyester surfaces to yield macromolecular imaging agents. Finally, opportunities offered by these innovative systems will be illustrated with some recent examples in the fields of cell labeling, diagnostic or theranostic applications and medical devices.

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Polymers for in vitro diagnostics

Project Biosensors

About the project:

Implantable biosensors for cancer biomarkers detection. The project is focused on the development of implantable biosensors based on polymer-peptide conjugate for cancer biomarkers detection.

Biosensor

Contact:

Vincent Darcos
Vincent Darcos

Students:

Collaborations:

Dr May Morris (Institut des Biomolécules Max Mousseron), Pr. Pascal Pujol (CHU Montpellier)

Funding:

Key Initiative MUSE « Biomarkers & Therapy », Université de Montpellier

Offre de position post-doctorale « Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Offre de position post-doctorale

« Projet DECAP, Hydrogels pour la décontamination corporelle d’actinides à base de polymères biocompatibles »

Montpellier France

Laboratoire d’accueil : Département « Biopolymères Artificiels », Institut des Biomolécules Max Mousseron (UMR 5247), Université de Montpellier, France

Durée du projet : 8 mois

Date de début du contrat souhaité : février/mars 2021

Financement : ANR

 

Projet :

Le projet DECAP concerne le développement d’hydrogels à base de polymères originaux en vue de la décontamination corporelle externe d’actinides. L’objectif est de synthétiser et de formuler sous forme d’hydrogel de nouveaux polymères chélatants de radionucléides. La mise au point de ces systèmes à base de polymères sera réalisée selon un cahier des charges précis. Ce projet pluridisciplinaire va de la synthèse et la polymérisation de monomères fonctionnels à l’étude biologique des formulations, en passant par les études des propriétés de complexation. Dans ce cadre, un consortium pluridisciplinaire a été élaboré associant l’Institut des Biomolécules Max Mousseron (IBMM) et l’Institut Charles Gerhardt (ICG) de Montpellier, l’Institut de Chimie Séparative de Marcoule (ICSM) et Institut Galien Paris-Sud (IGPS). Le candidat devra faire le lien entre les différentes équipes impliquées.

Des détails supplémentaires seront donnés aux candidats intéressés par ce projet.

 

Profil du candidat recherché :

Le(la) candidat(e) devra être titulaire d’un doctorat en chimie organique ou en chimie des polymères. Il(elle) devra posséder de solides compétences en chimie organique et/ou macromoléculaire. Une expérience dans le domaine des procédés de séparation et/ou sorption serait un plus. Il(elle) devra avoir le goût pour aborder un sujet de recherche expérimental et pluridisciplinaire. Il(elle) devra avoir d’excellentes capacités pour le travail en équipe et être à l’aise dans la communication. Il(elle) devra faire preuve d’autonomie dans son organisation et d’esprit d’initiative.

Modalités de candidature :

Merci de postuler obligatoirement sur le site emploi.cnrs.fr (Référence UMR5247-MORJOL-007) et d’envoyer votre CV et votre lettre de motivation par courrier électronique à Vincent DARCOS et à Sophie MONGE-DARCOS au plus tard le 18 janvier 2021 minuit.

Emails : vincent.darcos@umontpellier.fr et sophie.monge-darcos@umontpellier.fr

Modulation of protein release from penta-block copolymer microspheres European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020)

European Journal of Pharmaceutics and Biopharmaceutics 152, 175–182 (2020).

Minh-Quan Le, Jean-Christophe Gimel, Xavier Garric, Thao-Quyen Nguyen-Pham, Cédric Paniagua, Jérémie Riou, Marie-Claire Venier-Julienne,

 

ABSTRACT

Releasing a protein according to a zero-order profile without protein denaturation during the polymeric microparticle degradation process is very challenging. The aim of the current study was to develop protein-loaded microspheres with new PLGA based penta-block copolymers for a linear sustained protein release. Lysozyme was chosen as model protein and 40 µm microspheres were prepared using the solid-in-oil-in-water solvent extraction/evaporation process. Two types of PLGA-P188-PLGA penta-block copolymers were synthetized with two PLGA-segments molecular weight (20 kDa or 40 kDa). The resulting microspheres (50P20-MS and 50P40-MS) had the same size, an encapsulation efficiency around 50–60% but different porosities. Their protein release profiles were complementary: linear but non complete for 50P40-MS, non linear but complete for 50P20-MS. Two strategies, polymer blending and microsphere mixing, were considered to match the release to the desired profile. The (1:1) microsphere mixture was successful. It induced a bi-phasic release with a moderate initial burst (around 13%) followed by a nearly complete linear release for 8 weeks. This study highlighted the potential of this penta-block polymer where the PEO block mass ratio influence clearly the Tg and consequently the microsphere structure and the release behavior at 37 °C. The (1:1) mixture was a starting point but could be finely tuned to control the protein release.

In Vivo Evaluation of the Efficacy and Safety of a Novel Degradable Polymeric Film for the Prevention of Intrauterine Adhesions.

Journal of Minimally Invasive Gynecology (2020)

Stéphanie Huberlant, Salomé Leprince, Lucie Allegre, Sophie Warembourg, Isabelle Leteuff, Hubert Taillades, Xavier Garric., Renaud de Tayrac, Vincent Letouzey.

ABSTRACT

To study the safety of a degradable polymeric film (DPF) and its efficacy on reducing the risk of intrauterine-adhesion (IUA) formation in a rat model.A series of case-control studies relying on random allocation, where feasible.The animal models comprised female and male Oncins France Strain A and female Wistar rats.The Oncins France Strain A rats were used for in vivo evaluation of the impact of the DPF on endometrial thickness and its effect on fertility. For in vivo evaluation of the biologic response, 40 Wistar rats were randomly allocated to intervention and control groups, with matched sampling time after surgery. Finally, for the in vivo evaluation of the DPF’s efficacy on IUA prevention, a total of 24 Wistar rats were divided into 3 groups: 1 treated with the DPF, 1 treated with hyaluronic acid gel, and a sham group. The DPF did not have a significant impact on endometrial thickness, and there were no significant differences in the number of conceived or prematurely terminated pregnancies, confirming its noninferiority to no treatment. The DPF did not induce irritation at 5 days and 28 days. Finally, the DPF significantly reduced the likelihood of complete IUA formation compared with hyaluronic acid gel– and sham-implanted animals, where only 27% of the animals had their uterine cavity obliterated compared with 80% and 100%, respectively.The DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Hyaluronic Acid-Poly(N-acryloyl glycinamide) Copolymers as Sources of Degradable Thermoresponsive Hydrogels for Therapy

Gels 2020, 6(4), 42

Mahfoud Boustta and Michel Vert

 

ABSTRACT

One-pot free-radical polymerization of N-acryloyl glycinamide in the presence of hyaluronic acid as transfer-termination agent led to new copolymers in high yields without any chemical activation of hyaluronic acid before. All the copolymers formed thermoresponsive hydrogels of the Upper Critical Solution Temperature-type in aqueous media. Gel properties and the temperature of the reversible gel ↔ sol transition depended on feed composition and copolymer concentration. Comparison with mixtures of hyaluronic acid-poly(N-acryloyl glycinamide) failed in showing the expected formation of graft copolymers conclusively because poly(N-acryloyl glycinamide) homopolymers are also thermoresponsive. Grafting and formation of comb-like copolymers were proved after degradation of inter-graft hyaluronic acid segments by hyaluronidase. Enzymatic degradation yielded poly(N-acryloyl glycinamide) with sugar residues end groups as shown by NMR. In agreement with the radical transfer mechanism, the molar mass of these released poly(N-acryloyl glycinamide) grafts depended on the feed composition. The higher the proportion of hyaluronic acid in the feed, the lower the molar mass of poly(N-acryloyl glycinamide) grafts was. Whether molar mass can be made low enough to allow kidney filtration remains to be proved in vivo. Last but not least, Prednisolone was used as model drug to show the ability of the new enzymatically degradable hydrogels to sustain progressive delivery for rather long periods of time in vitro.DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

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