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Advanced polymeric biomaterials

Hybrid polymeric biomaterials

Peptide/polymers hydrid biomaterials

About the project:

This project have two directions:

– provide bioactivity to inert polymers in order to improve their potential for use in biomedical applications. We work on films as well as on nanofibres targeting many applications

– the design of monomers containing peptide sequences and polymerize them to provide new class of peptide-based copolymers.

Contact:

Coline Pinese
Coline Pinese
Benjamin Nottelet
Benjamin Nottelet
Vincent Darcos
Vincent Darcos
Audrey Bethry
Audrey Bethry
Xavier Garric
Xavier Garric

Students:

Laura Arsenie
Laura Arsenie
Ayman El Jundi
Ayman El Jundi

Collaborations:

Pr Subra et Pr Amblard (IBMM-peptides, UMR 5247), Sing Yian Chew (NTU, Singapore)

Funding:

Bioactive peptides grafted silicone dressings: A simple and specific method

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Materials Today Chemistry 4, 73–83 (2017)

Pinese, C., Jebors, S., Stoebner, P. E., Humblot, V., Verdié, P., Causse, L., Garric, X., Taillades, H., Martinez, J., Mehdi, A. & Subra, G

 

ABSTRACT

The need for bioactive dressings increases with the population aging and the prevalence of chronic diseases. In contrast, there are very few dressings on the market which are designed to display a chosen bioactivity. In this context, we investigated the surface-functionalization of silicone wound dressing with bioactive peptides. One of the challenges was to avoid multistep grafting reactions involving catalysts, solvents or toxic reagents, which are not suitable for the fabrication of medical devices at an industrial scale. In the other hand, a covalent bonding was necessary to avoid the loss of the biological effect by progressive removal of the peptide in biological fluids generated by the wound. To solve these limitations, we developed a strategy allowing an easy and direct functionalization of silicone. This strategy relies on hybrid silylated bioactive peptides, which chemoselectively react with plasma-activated silicone surfaces. We synthesized three hybrid peptides with wound healing properties, which were grafted on commercially available silicone dressings Cerederm® and Mepitel®. Grafted dressings were evaluated in vitro and enabled a quicker scare recovery and extracellular matrix deposition with human dermal fibroblasts. These results were confirmed by in vivo studies showing an enhanced wound-healing of the pig skin. By this simple method, we transformed inert dressing into bioactive dressing which showed properties of wound healing.

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Turning peptides in comb silicone polymers

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J. Pept. Sci. 21, 243–247 (2015)

Jebors, S., Pinese, C., Nottelet, B., Parra, K., Amblard, M., Mehdi, A., Martinez, J. & Subra, G

 

ABSTRACT

We have recently reported on a new class of silicone-peptide biopolymers obtained by polymerization of di-functionalized chlorodimethylsilyl hybrid peptides. Herein we describe a related strategy based on dichloromethylsilane-derived peptides, which yields novel polymers with a polysiloxane backbone, comparable to a silicone bearing pendent peptide chains. Interestingly, polymerization is chemoselective towards amino acids side-chains, proceeds in a single step in very mild conditions (neutral pH, water, room temperature). As potential application, a cationic sequence was polymerized and used an antibacterial coating.

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A New Way to Silicone-Based Peptide Polymers.

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Angew. Chem.-Int. Edit. 54, 3778–3782 (2015).

Jebors, S., Ciccione, J., Al-Halifa, S., Nottelet, B., Enjalbal, C., M’Kadmi, C., Amblard, M., Mehdi, A., Martinez, J.

ABSTRACT

We describe a new class of silicone-peptides biopolymers obtained by a straightforward polymerization in water using tailored chlorodimethylsilyl peptides blocks as monomeric units. This general strategy is applicable to any type of peptide sequences, yielding linear or branched polymer chains composed of well defined peptide sequences.

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Synthesis of peptide-grafted comb polypeptides via polymerisation of NCA-peptides.

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Chem. Commun. 49, 409–411 (2013).

Enomoto, H., Nottelet, B., Al Halifa, S., Enjalbal, C., Dupre, M., Tailhades, J., Coudane, J., Subra, G., Martinez, J. & Amblard, M

ABSTRACT

The objective of this work was to develop and study new biodegradable thermoplastics with improved mechanical properties for potential use as temporary implantable biomaterials. Linear Poloxamer and star-shaped Poloxamine have been used as macroinitiators for the Ring-Opening Polymerization (ROP) of lactide to yield high molecular weight PLA-based thermoplastic block copolymers. The influence of the nature of the macroinitiator, PLA crystallinity and initial molecular weight on the copolymers properties was investigated by performing a 7-week degradation test in PBS. The evaluation of water uptakes and molecular weights during the degradation pointed out an early hydrolytic degradation of the 100 kg∙mol-1 copolymers compared to the 200 kg/mol ones (molecular weight decrease of ca. 40 % and 20 %, respectively). A dramatic loss of tensile mechanical properties was also observed for the 100 kg/mol copolymers whereas the 200 kg∙mol-1 copolymers showed stable or even slightly improved properties with Young’s moduli around 500 MPa and yield strains around 3 to 4%. Finally, the cytocompatibility of the more stable 200 kg∙mol-1 copolymers was confirmed by murine mesenchymal stem cells (MSCs) culture.

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Nanocomposites:

Nanocomposites for bone regeneration

About the project:

Contact:

Vincent Darcos
Vincent Darcos
Audrey Bethry
Audrey Bethry

Students:

Prescillia Lagarrigue
Prescillia Lagarrigue

Collaborations:

Prof. Combes (CIRIMAT, Toulouse), Prof. Oliva (University of Naples), Prof. Malinconico (IPCB, Naples)

Funding:

Carnot Balard Cirimat

New synthesis method of HA/P(D,L)LA composites: study of fibronectin adsorption and their effects in osteoblastic behavior for bone tissue engineering

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Journal of Materials Science: Materials in Medicine (2016), 27(9), 1-10

Yala,S., Boustta,M; Gallet, O; Hindie, M; Carreiras, F; Benachour, H; Sidane, D; Khireddine, H.

 

ABSTRACT

A novel synthetic method to synthesize hydroxyapatite​/poly (D,​L) lactic acid biocomposite is presented in this study by mixing only the precursors hydroxyapatite and (D,​L) LA monomer without adding neither solvent nor catalyst.  Three compns. were successfully synthesized with the wt. ratios of 1​/1, 1​/3, and 3​/5 (hydroxyapatite​/(D,​L) lactic acid)​, and the grafting efficiency of poly (D,​L) lactic acid on hydroxyapatite surface reaches up to 84 %.  SEM and Fourier transform IR spectroscopy showed that the hydroxyapatite particles were successfully incorporated into the poly (D,​L) lactic acid polymer and X ray diffraction anal. showed that hydroxyapatite preserved its crystallinity after poly (D,​L) lactic acid grafting.  Differential scanning calorimetry shows that Tg of hydroxyapatite​/poly (D,​L) lactic acid composite is less than Tg of pure poly (D,​L) lactic acid, which facilitates the shaping of the composite obtained.  The addn. of poly (D,​L) lactic acid improves the adsorption properties of hydroxyapatite for fibronectin extracellular matrix protein.  Furthermore, the presence of poly (D,​L) lactic acid on hydroxyapatite surface coated with fibronectin enhanced pre-​osteoblast STRO-​1 adhesion and cell spreading.  These results show the promising potential of hydroxyapatite​/poly (D,​L) lactic acid composite as a bone substitute material for orthopedic applications and bone tissue engineering.

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Functionalized PCL/HA nanocomposites as microporous membranes for bone regeneration

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Mat. Sci. Eng. C-Mater. Biol. Appl. 48, 457–468 (2015)

Basile, M. A., d’Ayala, G. G., Malinconico, M., Laurienzo, P., Coudane, J., Nottelet, B., Della Ragione, F. & Oliva, A.

ABSTRACT

In the present work, microporous membranes based on poly(ε-caprolactone) (PCL) and PCL functionalized with amine (PCL-DMAEA) or anhydride groups (PCL-MAGMA) were realized by solvent–non solvent phase inversion and proposed for use in Guided Tissue Regeneration (GTR). Nanowhiskers of hydroxyapatite (HA) were also incorporated in the polymer matrix to realize nanocomposite membranes. Scanning Electron Microscopy (SEM) showed improved interfacial adhesion with HA for functionalized polymers, and highlighted substantial differences in the porosity. A relationship between the developed porous structure of the membrane and the chemical nature of grafted groups was proposed. Compared to virgin PCL, hydrophilicity increases for functionalized PCL, while the addition of HA influences significantly the hydrophilic characteristics only in the case of virgin polymer. A significant increase of in vitro degradation rate was found for PCL-MAGMA based membranes, and at lower extent of PCL-DMAEA membranes. The novel materials were investigated regarding their potential as support for cell growth in bone repair using multipotent mesenchymal stromal cells (MSC) as a model. MSC plated onto the various membranes were analyzed in terms of adhesion, proliferation and osteogenic capacity that resulted to be related to chemical as well as porous structure. In particular, PCL-DMAEA and the relative nanocomposite membranes are the most promising in terms of cell-biomaterial interactions.

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Nanocomposites for theranostic and soft/hard tissue interfacing

About the project:

This project aims at combining nanostructured polymers with inorganic particles (eg. SPIONs, dopped hydroxyapatite nanoparticles etc.) in a controlled manner to provide well defined interfaces as well as imaging opportunities.

Contact:

Benjamin Nottelet
Benjamin Nottelet

Students:

Hussein Awada
Hussein Awada
Assala Al Samad

Collaborations:

Dr. Laurencin, Dr. Guari, Prof. Larionova (IMNO, ICGM UMR 5253), Dr. Lemaire (MINT, Inserm 1066 – CNRS 6021), Dr. Franconi (platform PRISM), Prof. Gilbert (Renssaeler Institute, Troy, USA)

Funding:

Labex Chemisyst, France Life Imafing

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

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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.

Degradable elastomers and biomaterials mechanical behaviours:

Resorbable elastomers for medical applications

About the project:

This project is dedicated to the design and synthesis of biomaterials that exhibit mechanical properties of interest for soft tissue engineering like elastomeric or shape-memory properties.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Xavier Garric
Xavier Garric
Jean Coudane
Jean Coudane
Stéphane Dejean
Stéphane Dejean

Students:

Louis Gangolphe
Louis Gangolphe
Adrien Leroy

Collaborations:

Prof. Bossard (LRP, UMR 5520), Dr. Chagnon & Prof. Favier (TIMC-IMAG, UMR 5525)

Funding:

PhD Program (Doctoral school, University of Montpellier)

Degradable multi(aryl-azide) star copolymer as universal photo-crosslinker for elastomeric scaffolds

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Mater. Today Chem. 12, 209-221, (2019)

Gangolphe L., Déjean S., Bethry A., Hunger S., Pinese C., Garric X., Bossard F., Nottelet B.

ABSTRACT

Degradable elastomers with elastic properties close to those of soft-tissues are necessary for tissue-engineering. Most degradable elastomers developed so far are based on functional low molecular weight pre-polymers that are combined with molecular crosslinkers to yield the elastomeric 3D networks. To overcome this limitation, we present in this work the concept of star-shaped macromolecular multi(aryl-azide) photo-crosslinker that has the ability to efficiently crosslink any polymer containing C-H bonds independently of its molecular weight and without the need for pre-functionalization. This concept of universal crosslinking agent is illustrated with a star-shaped block copolymer composed of an 8-arm poly(ethylene glycol) core and poly(lactide) side arms functionalized with aryl-azide moieties (PEG8arm-PLA-fN3). It was selected due to its macromolecular nature that allows for an easy processing of electrospun photo-crosslinked scaffolds while making it possible to adapt its chemical nature with the one of the polymer matrix. A parameter study is first carried out on PEG8arm-PLA-fN3 / PLA-Pluronic®-PLA films to evaluate the impact of the polymers molecular weight, PEG/PLA ratios, and UV irradiation conditions on the crosslinking efficiency. This study confirms that high crosslinking efficiencies can be obtained with PEG8arm-PLA-fN3 (60%) compared to commercially availabe bis(aryl-azide) photo-crosslinker (below 15%). Optimal conditions are then used to yield electrospun microfibers (1-2 µm) crosslinked with PEG8arm-PLA-fN3 resulting in biocompatible and highly elastomeric scaffolds (ε_y>100%) compared to uncrosslinked scaffolds(ε_y<10%). In addition, we show that the degradation rate can be controlled over time depending on the blend content of PEG8arm-PLA-fN3. Taken together, these results demonstrate the potential of macromolecular multi(aryl-azide) photo-crosslinkers to develop original degradable elastomeric scaffolds for soft-tissue reconstruction.

Redox Reducible and Hydrolytically Degradable PEG-PLA Elastomers as Biomaterial for Temporary Drug-Eluting Medical Devices.

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Macromolecular Bioscience 16, 1792–1802 (2016)

Rupnik, S., Buwalda, S., Dejean, S., Bethry, A., Garric, X., Coudane, J. & Nottelet, B

ABSTRACT

With the aim to develop biomaterials for temporary medical devices, a series of novel reducible and/or degradable elastomers has been prepared from PLA‐b‐PEG‐b‐PLA copolymers photo‐crosslinked with diallyl sulfide or pentaerythritol tetrakis(3‐mercaptopropionate). Thermal and mechanical properties, including elastic limit and Young modulus, are assessed. Degradation is then evaluated under standard hydrolytic conditions. Reducibility of a selected elastomer is then illustrated using 2‐mercaptoethanol or glutathione as reducing agents. The redox‐sensitivity of the selected elastomer and the possibility to modulate the degradability are shown. Considering drug‐eluting elastomeric devices applications, anti‐inflammatory drug ibuprofen loading is illustrated with the two simplest elastomer formulations. A rapid or slow linear release is observed as a function of the low or high molecular weight of the triblock pre‐polymers. Finally, the cytocompatibility of the degradable elastomers is assessed with regard to their potential to favor or inhibit L929 murine fibroblasts proliferation as a function of the hydrophilicity/hydrophobicity of the triblock copolymers.

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Biodegradable networks for soft tissue engineering by thiol–yne photo cross-linking of multifunctional polyesters.

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RSC Adv. 4, 32017–32023 (2014).

Leroy, A., Al Samad, A., Garric, X., Hunger, S., Noël, D., Coudane, J. & Nottelet, B.

ABSTRACT

Novel biodegradable networks have been prepared by combination of post-polymerization modification of poly(e-caprolactone) and thiol-yne photo cross-linking. In a first step, a novel multifunctional poly(e-caprolactone) bearing propargyl groups (PCL-yne, 8 mol% substitution degree) was obtained in a rapid one-pot reaction and at a multigram scale. In a second step, PCL-yne and mixtures of PCL and PCL-yne were cross-linked via photoradical thiol-yne reaction in the presence of pentaerythritol tetrakis(3-mercaptopropionate) and various photoinitiators. The thermal properties and stabilities of the obtained networks have been evaluated before assessment of their mechanical properties. Finally, biocompatibility studies are reported with evaluation of the proliferation of L929 fibroblasts on the materials.

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Evaluation of biomaterials mechanical behaviours

About the project:

This project is dedicated to the design and synthesis of biomaterials that exhibit mechanical properties of interest for soft tissue engineering

Contact:

Benjamin Nottelet
Benjamin Nottelet
Xavier Garric
Xavier Garric
Jean Coudane
Jean Coudane
Stéphane Dejean
Stéphane Dejean

Students:

Louis Gangolphe
Louis Gangolphe
Adrien Leroy

Collaborations:

Funding:

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

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Acta Biomaterialia. XX, XXX–XXX (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.

Biomechanical behaviour of human bile duct wall and impact of cadaveric preservation processes.

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J. Mech. Behav. Biomed. 98, 291–300 (2019)

Girard E., Chagnon G., Gremen E., Calvez M., Boutonnat J., Trilling B., Nottelet B.

 

ABSTRACT

Biliary diseases are the third most common cause of surgical digestive disease. There is a close relationship between the mechanical performance of the bile duct and its physiological function. Data of biomechanical properties of human main bile duct are scarce in literature. Furthermore, mechanical properties of soft tissues are affected by these preservation procedures. The aim of the present work was, on the one hand, to observe the microstructure of the human bile duct by means of histological analysis, on the other hand, to characterize the mechanical behavior and describe the impact of different preservation processes. A mechanical study in a controlled environment consisting of cyclic tests was made. The results of the mechanical tests are discussed and explained using the micro-structural observations. The results show an influence of the loading direction, which is representative of an anisotropic behavior. A strong hysteresis due to the viscoelastic properties of soft tissues was also observed. Embalming and freezing preservation methods had an impact on the biomechanical properties of human main bile duct, with fiber network deterioration. That may further provide a useful quantitative baseline for anatomical and surgical training using embalming and freezing.

Mechanical behaviour׳s evolution of a PLA- b -PEG- b -PLA triblock copolymer during hydrolytic degradation.

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Journal of the Mechanical Behavior of Biomedical Materials 60, 288–300 (2016)

Breche, Q., Chagnon, G., Machado, G., Girard, E., Nottelet, B., Garric, X. & Favier, D.

 

ABSTRACT

PLA-b-PEG-b-PLA is a biodegradable triblock copolymer that presents both the mechanical properties of PLA and the hydrophilicity of PEG. In this paper, physical and mechanical properties of PLA-b-PEG-b-PLA are studied during in vitro degradation. The degradation process leads to a mass loss, a decrease of number average molecular weight and an increase of dispersity index. Mechanical experiments are made in a specific experimental set-up designed to create an environment close to in vivo conditions. The viscoelastic behaviour of the material is studied during the degradation. Finally, the mechanical behaviour is modelled with a linear viscoelastic model. A degradation variable is defined and included in the model to describe the hydrolytic degradation. This variable is linked to physical parameters of the macromolecular polymer network. The model allows us to describe weak deformations but become less accurate for larger deformations. The abilities and limits of the model are discussed.

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A non-linear viscoelastic model to describe the mechanical behavior’s evolution of biodegradable polymers during hydrolytic degradation

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Polymer Degradation and Stability 131, 145–156 (2016)

Breche, Q., Chagnon, G., Machado, G., Nottelet, B., Garric, X., Girard, E. & Favier, D.

 

ABSTRACT

The biodegradable triblock copolymer PLA-b-PEG-b-PLA presents, in its initial state, a non-linear viscoelastic behavior. Its mechanical properties evolves during the in vitro degradation process. Tensile and relaxation tests are performed at 2%, 4% and 6% of load strain for different degradation steps. In order to describe the behavior of the polymer during degradation, an adaptive quasi-linear viscoelastic model is considered. In a first step, the model calibrated on the non-degraded state, perfectly fits the load and relaxation curves for every strain. Then, based on considerations about the preservation of the normalized relaxation curves over degradation time, the adaptive quasi-linear viscoelastic model is adapted to degradation. A degradation parameter that drives the mechanical degradation kinetics is deduced for every tested degradation states. A physically motivated model is finally used to describe the degradation parameter at every degradation step. The whole constitutive model is very accurate to fit the mechanical curves at every strain during degradation.

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Smart/active surfaces

Antibacterial and antifouling surfaces

About the project:

Contact:

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

Students:

Sytze Buwalda
Sytze Buwalda
Adrien Leroy

Collaborations:

Prof. Lavigne (CHU Nîmes), Prof. Cavallaro (University of Palermo), Dr. Antonio Stocco (L2C, UMR5221), Dr. Moriarty, Dr. Eglin, Dr. Guillaume (AO Research Institute, Switzerland)

Funding:

AO-CMF grant, Campus France, Post-doctoral program UM, MENRT grant (ED 459)

Regioselective Halogenation of Poly(lactide) by Free-Radical Process.

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Macromol. React. Eng. 8, 141–148 (2014).

Beuille, E., Darcos, V., Coudane, J., Lacroix-Desmazes, P. & Nottelet, B.

ABSTRACT

Modification of the biodegradable and renewable poly(lactide) (PLA) to provide functional aliphatic polyesters is highly desirable to meet applications requirements. In this context, the objective of this work was to evaluate the possibility to use free-radical substitution as a simple and non-degrading method to yield the desired functional PLA. Halogenation of PLA was carried out in solution and various conditions of reaction have been evaluated. Halogenated PLAs were characterized by 1H NMR spectroscopy and size exclusion chromatography (SEC) to evaluate the substitution ratios and to check the non-degrading character of the radical modification. Furthermore, reactions on model compounds as well as MALDI-TOF analyses have been performed to elucidate the involved mechanism. The combined results proved the free-radical halogenation of PLA in solution to be regioselective with only the w-halogenated PLA being obtained without main-chain substitution.

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Advanced macromolecular chemistry and architectures:

Functional aliphatic polyesters

About the project:

This project aims at exploring various chemical strategies towards (multi)functional polyesters and evaluate their potential in the frame of biomedical applications.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Vincent Darcos
Vincent Darcos
Sylvie Hunger
Sylvie Hunger

Students:

Collaborations:

Dr Lacroix-Desmazes (IAM, ICGM UMR 5253)

Funding:

Regioselective Halogenation of Poly(lactide) by Free-Radical Process.

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Macromol. React. Eng. 8, 141–148 (2014).

Beuille, E., Darcos, V., Coudane, J., Lacroix-Desmazes, P. & Nottelet, B.

ABSTRACT

Modification of the biodegradable and renewable poly(lactide) (PLA) to provide functional aliphatic polyesters is highly desirable to meet applications requirements. In this context, the objective of this work was to evaluate the possibility to use free-radical substitution as a simple and non-degrading method to yield the desired functional PLA. Halogenation of PLA was carried out in solution and various conditions of reaction have been evaluated. Halogenated PLAs were characterized by 1H NMR spectroscopy and size exclusion chromatography (SEC) to evaluate the substitution ratios and to check the non-degrading character of the radical modification. Furthermore, reactions on model compounds as well as MALDI-TOF analyses have been performed to elucidate the involved mechanism. The combined results proved the free-radical halogenation of PLA in solution to be regioselective with only the w-halogenated PLA being obtained without main-chain substitution.

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Advanced and well-defined macromolecular architectures

About the project:

Within this project we take advantage of the opportunities offered by advanced macromolecular chemistry to design various macromolecular topologies and evaluate their potential compared to classical linear (co)polymers.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Vincent Darcos
Vincent Darcos
Sylvie Hunger
Sylvie Hunger

Students:

Assala Al Samad
Assala Al Samad

Collaborations:

Dr. Etrych, Dr. Koziolova, Dr. Kostka (Institute of Macromolecular Chemistry, Czech Republic)

Funding:

Campus France

N-(2-Hydroxypropyl)methacrylamide-Based Linear, Diblock, and Starlike Polymer Drug Carriers: Advanced Process for Their Simple Production

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Biomacromolecules 19, 4003–4013 (2018)

Koziolova, E., Kostka, L., Kotrchova, L., Subr, V., Konefal, R., Nottelet, B. & Etrych, T.

 

ABSTRACT

We developed a new simplified method for the synthesis of well-defined linear, diblock, or starlike N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer drug carriers using controlled reversible addition–fragmentation chain transfer polymerization. The prepared monodispersed polymers are after the drug attachment intended for enhanced anticancer therapy. This new approach significantly reduces the number of required synthetic steps and minimizes the consumption of organic solvents during the synthesis. As a result, highly defined linear, diblock, and starlike copolymers designed for pH-triggered drug activation/release in tumor tissue were formed in sufficient amounts for further physicochemical and biological studies. Within the synthesis, we also developed a new procedure for the selective deprotection of tert-butoxycarbonyl hydrazide and amine groups on hydrophilic HPMA copolymers, including the one-pot removal of polymer end groups. We studied and described in detail the kinetics and efficacy of the deprotection reaction. We believe the simplified synthetic approach facilitates the preparation of polymer conjugates bound by the pH-sensitive hydrazone bond and their application in tumor treatment.

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PCL-PEG graft copolymers with tunable amphiphilicity as efficient drug delivery systems

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Mat. Chem. B 4, 6228–6239 (2016)

Al Samad, A., Bethry, A., Koziolova, E., Netopilik, M., Etrych, T., Bakkour, Y., Coudane, J., El Omar, F. & Nottelet, B.

 

ABSTRACT

The development of flexible drug delivery systems that can be tuned as a function of the drug to be delivered and of the target disease is crucial in modern medicine. For this aim, novel amphiphilic poly(ε-caprolactone)-g-poly(ethylene glycol) (PCL-g-PEG) copolymers with well-controlled design were synthesized by thiol–yne photochemistry. The grafting density and the copolymer amphiphilicity were easily controlled via the reaction parameters: concentration, reaction time, PEG length and the molar ratio between PCL and PEG or the photoinitiator in the reaction mixture. The self-assembling behavior of the copolymers was studied and a correlation between the composition of PCL-g-PEG and the nanoaggregate diameter sizes (28 to 73 nm) and critical aggregation concentrations (1.1 to 4.3 mg L−1) was found. The influence of copolymer amphiphilicity on the drug loading was evaluated with various drugs including anticancer drugs (paclitaxel, ABT-199), drugs to overcome multidrug resistance in cancer cells (curcumin, elacridar), an anti-inflammatory drug (dexamethasone) and an antibacterial drug (clofazimine). Finally, the influence of amphiphilicity on curcumin release and toxicity towards MCF-7 cancer cell lines was studied. The impact of the grafting density, PEG length and the overall EG/CL ratio is discussed in detail. Curcumin loaded PCL-g-PEG with lower EG/CL ratios and shorter PEG chains showed higher toxicity compared to their more hydrophilic counterparts.

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From nanospheres to micelles: simple control of PCL-g-PEG copolymers’ amphiphilicity through thiol-yne photografting

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Polym. Chem. 6, 5093–5102 (2015)

Al Samad, A., Bakkour, Y., Fanny, C., El Omar, F., Coudane, J. & Nottelet, B

 

ABSTRACT

A simple method for the synthesis of a family of poly(ɛ-caprolactone)-g-polyethylene glycol (PCL-g-PEG) copolymers of controlled amphiphilicity and their use to generate nanospheres or micelles are reported. PCL-g-PEG with various compositions are prepared from a single strategy relying on a combination of post-polymerization modification and subsequent thiol-yne photografting. Alkyne-functional PCL (PCL-yne) are first obtained by anionic activation and reaction with propargyl bromide to yield PCL-yne with 8% alkyne groups. PEG-thiol is then reacted on PCL-yne under UV activation to yield the targeted graft copolymer by thiol-yne photoaddition. The advantage of the approach is that control over the composition is easily achieved yielding to amphiphilic graft copolymers with ethylene glycol/ caprolactone (EG/CL) ratios ranging from 0.1 to 1.3. Starting from this single strategy, it was therefore possible to obtain nanospheres (DH~55 nm) or micelles (DH~30 nm) by copolymers self-assembly depending on the ratio EG/CL. The potential of the PCL-g-PEG micelles as drug carrier was finally evaluated with curcumin that was efficiently encapsulated, protected and released over 80 days. Interestingly it was found that drug encapsulation efficiency and drug loading were higher for PCL-g-PEG copolymers compared to block PCL-b-PEG.

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