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Benjamin Nottelet

Benjamin Nottelet

Professor, Faculty of pharmacy, University of Montpellier

Benjamin initially graduated as a chemical engineer from the Ecole Nationale Supérieure de Chimie of Montpellier (ENSCM), France before completing an industrial PhD on degradable polymers from the University of Montpellier (UM) in 2005 in contract with RHODIA in the group of Prof. Vert. He then worked in the Macromolecular Engineering and Architectures group of ENSCM in the group of Prof. Boutevin before joining the Department of Pharmaceutics and Biopharmaceutics of Prof. Gurny at the University of Geneva (UNIGE) to develop scaffolds for tissue engineering and drug delivery systems. In 2008, he became Associate Professor in the Faculty of Pharmacy at UM and joined the Department of Artificial Biopolymers of IBMM of Prof. Coudane, where he was appointed Full Professor in 2018.  His research activities focus on the synthesis and modification of degradable polymers for advanced biomedical applications and include hybrid biomaterials, bioactive surfaces, and multifunctional polymers.

Part of his recent work focuses on the synthesis and design of (1) innovative multifunctional degradable polymers for use in the field of drug delivery with smart and stimuli-responsive systems or (2) macromolecular contrast agents in the field of diagnostic allowing for MRI or X-ray imaging in of medical devices, or of theranostic approaches.

Another part of his research focuses on (3) hybrid biomaterials including peptide-based polymers or nanocomposites,  and degradable elastomers for tissue engineering applications, as well as the development of  (4) surface modification strategies to yield active surfaces in the frame of antibacterial and of imaging applications.

Benjamin is member of the editorial board of Multifunctional Materials and is co-author of over 70 papers and 3 patents.

Contact:

Benjamin.nottelet(a)umontpellier.fr
+33(0)4-11-75-96-97
Orcid n°: 0000-0002-8577-9273

5  recent papers :

A. El Jundi, M. Morille, N. Bettache, A. Bethry, J. Berthelot, J. Salvador, S. Hunger, Y. Bakkour, E. Belamie, B. Nottelet. Degradable double hydrophilic block copolymers and tripartite polyionic complex micelles thereof for small interfering ribonucleic acids (siRNA) delivery J. Colloid. Interface Sci. 2020,580, 449.

Girard E., Chagnon G., Broisat A., Dejean S., Soubies A., Gil H., Sharkawi T., Boucher F. Roth G.S., Trilling B., Nottelet B.From in vitro evaluation to human post-mortem pre-validation of a radiopaque and resorbable internal biliary stent for liver transplantation applications. Acta Biomater. 2020, 106, 66.

Hussein Awada, Assala Al Samad, Danielle Laurencin,* Ryan Gilbert, Xavier Dumail, Ayman El Jundi, Audrey Bethry, Rebecca Pomrenke, Christopher Johnson, Laurent Lemaire, Florence Franconi, Gautier Félix, Joulia Larionova, Yannick Guari, Benjamin Nottelet*, Controlled Anchoring of Iron Oxide Nanoparticles on Polymeric Nanofibers: Easy Access to Core@Shell Organic−Inorganic Nanocomposites for Magneto-Scaffolds ACS Appl. Mater. Interfaces 2019, 11, 9519.

Anita Schulz, Laurent Lemaire, Audrey Bethry, Lucie Allègre, Maïda Cardoso, Florence Bernex, Florence Franconi, Christophe Goze-Bac, Hubert Taillades, Xavier Garric, Benjamin Nottelet. UV-triggered photoinsertion of contrast agent onto polymer surface for in vivo MRI-visible medical devices. Multifunctional Materials 2019, 2, 0240012019.

Louis Gangolphe, Stéphane Déjean, Audrey Bethry, Sylvie Hunger, Coline Pinese, Xavier Garric, Frédéric Bossard, Benjamin Nottelet. Degradable multi(aryl-azide) star copolymer as universal photo-crosslinker for elastomeric scaffolds Mat. Today Chem. 2019, 12, 209.

Long-term in vivo performances of polylactide / iron oxide nanoparticles core-shell fibrous nanocomposites as MRI-visible magneto-scaffolds

Biomat. Sci. XX, XXX–XXX (2021)

 Awada H., Seene S., Laurencin D., Lemaire L., Franconi F., Bernex F., Bethry A., Garric X., Guari Y., Nottelet B.

ABSTRACT

There is a growing interest in magnetic nanocomposites in biomaterials science. In particular, nanocomposites that combine poly(lactide) (PLA) nanofibers and super paramagnetic iron oxide nanoparticles (SPIONs), which can be obtained by either electrospinning of a SPIONs suspension in PLA or by precipitating SPIONs at the surface of PLA, are well documented in the literature. However, these two classical processes yield nanocomposites with altered materials properties, and their long-term in vivo fate and performances have in most cases only been evaluated over short periods of time. Recently, we reported a new strategy to prepare well-defined PLA@SPIONs nanofibers with a quasi-monolayer of SPIONs anchored at the surface of PLA electrospun fibers. Herein, we report on a 6-month in vivo rat implantation study with the aim of evaluating the long-term magnetic resonance imaging (MRI) properties of this new class of magnetic nanocomposites, as well as their tissue integration and degradation. Using clinically relevant T2-weighted MRI conditions, we show that the PLA@SPIONs nanocomposites are clearly visible up to 6 months. We also evaluate here by histological analyses the slow degradation of the PLA@SPIONs, as well as their biocompatibility. Overall, these results make these nanocomposites attractive for the development of magnetic biomaterials for biomedical applications.

Assessing the combination of magnetic field stimulation, iron oxide nanoparticles, and aligned electrospun fibers for promoting neurite outgrowth from dorsal root ganglia in vitro

Acta Biomaterialia 131, 302–313 (2021)

Funnell J.L., Ziemba A.M., Nowak J.F., Awada H., Prokopiou N., Samuel J., Guari Y., Nottelet B., Gilbert R.J.

ABSTRACT

Magnetic fiber composites combining superparamagnetic iron oxide nanoparticles (SPIONs) and electrospun fibers have shown promise in tissue engineering fields. Controlled grafting of SPIONs to the fibers post-electrospinning generates biocompatible magnetic composites without altering desired fiber morphology. Here, for the first time, we assess the potential of SPION-grafted scaffolds combined with magnetic fields to promote neurite outgrowth by providing contact guidance from the aligned fibers and mechanical stimulation from the SPIONs in the magnetic field. Neurite outgrowth from primary rat dorsal root ganglia (DRG) was assessed from explants cultured on aligned control and SPION-grafted electrospun fibers as well as on non-grafted fibers with SPIONs dispersed in the culture media. To determine the optimal magnetic field stimulation to promote neurite outgrowth, we generated a static, alternating, and linearly moving magnet and simulated the magnetic flux density at different areas of the scaffold over time. The alternating magnetic field increased neurite length by 40% on control fibers compared to a static magnetic field. Additionally, stimulation with an alternating magnetic field resulted in a 30% increase in neurite length and 62% increase in neurite area on SPION-grafted fibers compared to DRG cultured on PLLA fibers with untethered SPIONs added to the culture media. These findings demonstrate that SPION-grafted fiber composites in combination with magnetic fields are more beneficial for stimulating neurite outgrowth on electrospun fibers than dispersed SPIONs.

Poly(Aspartic Acid) Functionalized Poly(e-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers

Pharmaceutics 12, 885 (2020)

Rotman S.G., Moriarty T.F., Nottelet B., Grijpma D.W., Eglin D., Guillaume O.

ABSTRACT

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and currently available local antibiotic treatments. Targeting bacteria within the bone requires highly efficient delivery of antimicrobials to the infected bone tissue. In this work, a biodegradable microsphere carrier loaded with antibiotics and with specific affinity to bone mineral was developed. Two widely used antibiotics, i.e. Gentamicin-AOT (GM-AOT) and Ciprofloxacin (CF) were embedded in poly(ϵ-caprolactone) (PCL) microspheres fabricated by oil-in-water emulsion techniques with carboxylated poly(vinyl alcohol) (cPVA) as surfactant. The carboxylic acid groups present at the PCL/cPVA microsphere surface were functionalized with aspartic acid oligomers (ASP) granting bone targeting properties. We report on cPVA synthesis, microsphere formulation and antibiotic loading of PCL/cPVA-ASP microspheres. Antibiotic loaded PCL/cPVA-ASP microspheres show sustained release of its antibiotic load and can inhibit bacterial growth in vitro for up to 6 days. PCL/cPVA-ASP microspheres show enhanced affinity to mineralized substrates compared to non-functionalized PCL/cPVA microspheres. These findings support further development of these bone targeting antibiotic carriers for potential treatment of persistent bone infections.

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Evaluation of a biodegradable PLA–PEG–PLA internal biliary stent for liver transplantation: in vitro degradation and mechanical properties

J. Biomed. Mater. Res. 1-10, (2020)

Girard E., Chagnon G., Moreau-Gaudry A., Letoublon C., Favier D., Dejean S., Trilling B., Nottelet B.

 

ABSTRACT

Internal biliary stenting during biliary reconstruction in liver transplantation decrease anastomotic biliary complications. Implantation of a resorbable internal biliary stent (RIBS) is interesting since it would avoid an ablation gesture. The objective of present work was to evaluate adequacy of selected PLA-b-PEG-b-PLA copolymers for RIBS aimed to secure biliary anastomose during healing and prevent complications, such as bile leak and stricture. The kinetics of degradation and mechanical properties of a RIBS prototype were evaluated with respect to the main bile duct stenting requirements in liver transplantation. For this purpose, RIBS degradation under biliary mimicking solution versus standard phosphate buffer control solution was discussed. Morphological changes, mass loss, water uptake, molecular weight, permeability, pH variations, and mechanical properties were examined over time. The permeability and mechanical properties were evaluated under simulated biliary conditions to explore the usefulness of a PLA-b-PEG-b-PLA RIBS to secure biliary anastomosis. Results showed no pH influence on the kinetics of degradation, with degradable RIBS remaining impermeable for at least 8 weeks, and keeping its mechanical properties for 10 weeks. Complete degradation is reached at 6 months. PLA-b-PEG-b-PLA RIBS have the required in vitro degradation characteristics to secure biliary anastomosis in liver transplantation and envision in vivo applications

Double hydrophilic block copolymers self-assemblies in biomedical applications

Adv. Colloid Interface Sci 283, 102213, (2020)

A. El Jundi, S. Buwalda, Y. Bakkour, X. Garric, B. Nottelet

 

ABSTRACT

Double-hydrophilic block copolymers (DHBCs), consisting of at least two different water-soluble blocks, are an alternative to the classical amphiphilic block copolymers and have gained increasing attention in the field of biomedical applications. Although the chemical nature of the two blocks can be diverse, most classical DHBCs consist of a bioeliminable non-ionic block to promote solubilization in water, like poly(ethylene glycol), and a second block that is more generally a pH-responsive block capable of interacting with another ionic polymer or substrate. This second block is generally non-degradable and the presence of side chain functional groups raises the question of its fate and toxicity, which is a limitation in the frame of biomedical applications. In this review, following a first part dedicated to recent examples of non-degradable DHBCs, we focus on the DHBCs that combine a biocompatible and bioeliminable non-ionic block with a degradable functional block including polysaccharides, polypeptides, polyesters and other miscellaneous polymers. Their use to design efficient drug delivery systems for various biomedical applications through stimuli-dependent self-assembly is discussed along with the current challenges and future perspectives for this class of copolymers.

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Degradable double hydrophilic block copolymers and tripartite polyionic complex micelles thereof for small interfering ribonucleic acids (siRNA) delivery

J. Colloid Interface 580, 449, (2020)

A. El Jundi, M. Morille, N. Bettache, A. Bethry, J. Berthelot, J. Salvador, S. Hunger, Y. Bakkour, E. Belamie, B. Nottelet

 

ABSTRACT

Polymer vectors for gene therapy have been largely investigated as an alternative to viral vectors. In particular, double hydrophilic block copolymers (DHBCs) have shown potential in this domain, but to date studies mainly focus on non-degradable copolymers, which may be a restriction for further development. To overcome this limitation, we synthesized a DHBC (PEG43-b-PCL12(COOH)6.5) composed of a poly(ethylene glycol) (PEG) non-ionic and bioeliminable block and a degradable carboxylic acid-functionalized poly(e-caprolactone) (PCL) block. The potential of this DHBC as an original vector for small interfering ribonucleic acids (siRNA) to formulate tripartite polyionic complex (PIC) micelles with poly(lysine) (PLL) was evaluated. We first studied the impact of the charge ratio (R) on the size and the zeta potential of the resulting micelles. With a charge ratio R=1, one formulation with optimized physico-chemical properties showed the ability to complex 75 % of siRNA. We showed a stability of the micelles at pH 7.4 and a disruption at pH 5, which allowed a pH-triggered siRNA release and proved the pH-stimuli responsive character of the tripartite micelles. In addition, the tripartite PIC micelles were shown to be non-cytotoxic below 40 µg/mL. The potential of these siRNA vectors was further evaluated in vitro: it was found that the tripartite PIC micelles allowed siRNA internalization to be 3 times higher than PLL polyplexes in murine mesenchymal stem cells, and were able to transfect human breast cancer cells. Overall, this set of data pre-validates the use of degradable DHBC as non-viral vectors for the encapsulation and the controlled release of siRNA, which may therefore constitute a sound alternative to non-degradable and/or cytotoxic polycationic vectors.

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Graft Copolymers with Tunable Amphiphilicity tailored for Efficient Dual Drug Delivery via Encapsulation and pH-sensitive Drug Conjugation

Polymer Chemistry 11, 4438–4453 (2020)

Bláhová M., Randárová E., Konefał R., Nottelet B., Etrych T.

ABSTRACT

Polymer-based drug delivery systems may significantly improve cancer therapy. We developed amphiphilic poly(e-caprolactone)-graft-(poly-N-(2-hydroxypropyl) methacrylamide) copolymers (PCL-graft-pHPMA) with tunable amphiphilicity intended for efficient dual delivery via simultaneous encapsulation of hydrophobic drug, Bcl-2 inhibitor ABT-199, and pH-sensitive conjugation of other  chemotherapeutics, doxorubicin, to desired sites, e.g. tumors. Using controlled RAFT polymerization and click chemistry well-defined PCL-graft-pHPMA of diverse Mw and physical properties were prepared. By simple dissolution they self-assembled into highly stable micelles with Dh ≈ 25 nm and low critical micelle concentration (around 5 μg mL-1). The total drug payload reached 17 wt % while maintaining system solubility. The micelles exhibited long-term stability in buffers, while they were cleaved in the presence of lipase, thus proving degradation and drug release after uptake to lysosomes of cancer cells with minimal drug leakage during blood circulation. PCL-graft-pHPMA micelles may serve as a long-circulating drug depo for effective dual therapy of diverse malignancies.

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In Vivo Tissue-Engineered Vascular Grafts

Tissue-Engineered Vascular Grafts, Reference Series in
Biomedical Engineering

Walpoth B.H., de Valence S., Tille J-C., Mugnai D., Sologashvili T., Mrówczyński W.,
Cikirikcioglu M., Pektok E., Osorio S., Innocente F., Bochaton-Piallat M-L., Nottelet B., Kalangos A., Gurny R.

ABSTRACT

Vascular grafts are needed for coronary and peripheral vascular bypass surgeries as well as for access surgeries for hemodialysis and reconstruction of congenital heart defects. Despite good results in the large caliber, small caliber (<6 mm) show unsatisfactory clinical results. Tissue-engineered vascular grafts (TEVG) have been made using several approaches ranging from acellular synthetic or biologic polymer scaffolds to decellularized natural matrices, self-assembled cell-based bioreactor matured, or 3D cell-printed constructs. This chapter will focus mainly on in vivo tissue engineering which was used as first-in-man. This is based on an acellular, synthetic, degradable, polymer scaffold which is repopulated by the host cells after implantation to create a “neo-artery.” Advantages are shelf-readiness; simple, costeffective manufacturing; and avoidance of bioreactor cell maturation. Short-, mid-, and long-term experimental and clinical results show good cellular remodeling with extracellular matrix formation and endothelialization as well as patency and function. Thus, the approach of using an acellular, synthetic, biodegradable scaffold is an optimal clinical option for TEVG.

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Synergistic Anti-fouling and Bactericidal Poly(ether ether ketone) Surfaces via a One-step Photomodification

Mater Sci Eng C. 111,110811 (2020)

Buwalda S., Rotman S., Eglin D., Moriarty F., Bethry A., Garric X., Guillaume O., Nottelet B.

ABSTRACT

Implants of poly(ether ether ketone) (PEEK) are gaining importance in surgical bone reconstruction of the skull. As with any implant material, PEEK is susceptible to bacterial contamination and occasionally PEEK implants were removed from patients because of infection. To address this problem, a combination of anti-fouling and bactericidal polymers are grafted onto PEEK. The originality is that anti-fouling (modified poly(ethylene glycol)) and bactericidal (quaternized poly(dimethylaminoethyl acrylate)) moieties are simultaneously and covalently grafted onto PEEK via UV photoinsertion. The functionalized PEEK surfaces are evaluated by water contact angle measurements, FTIR, XPS and AFM. Grafting of anti-fouling and bactericidal polymers significantly reduces Staphylococcus aureus adhesion on PEEK surfaces without exhibiting cytotoxicity in vitro. This study demonstrates that grafting combinations of anti-fouling and bactericidal polymers synergistically prevents bacterial adhesion on PEEK implants. This approach shows clinical relevance as grafting is rapid, does not modify PEEK properties and can be conducted on pre-formed implants.

Role of Polymer Micelles in the Delivery of Photodynamic Therapy Agent to Liposomes and Cells

Cancers. 12, 384 (2020)

Gibot L., Demazeau M., Pimienta V., Mingotaud A-F., Vicendo P., Collin F., Martins-Froment N., Dejean S., Nottelet B., Roux C.,Lonetti B.

 

ABSTRACT

The use of nanocarriers for hydrophobic photosensitizers in the context of photodynamic therapy (PDT) to improve pharmacokinetics and biodistribution is well established. However, the mechanisms at play in the internalization of nanocarriers are not well elucidated despite being crucial to inspiring nanocarrier design. Here we focus on the mechanisms involved in copolymer PEO-PCL and PEO-PS micelles – membrane interactions through complementary physico-chemical studies on biomimetic membranes and biological experiments on 2D and 3D cell cultures. Förster Resonance Energy Transfer measurements on fluorescently labelled lipid vesicles and flow cytometry on two cancerous cell lines allowed evaluation of the uptake of a photosensitizer, Pheophorbide a (Pheo), and copolymer chains towards model membranes and cells respectively. The effects of calibrated light illumination for PDT treatment on lipid vesicle membranes, i.e. leakage and formation of oxidized lipids, and cell viability, were assessed. No significant differences were observed between the ability of PEO-PCL and PEO-PS micelles to deliver Pheo to model membranes, but Pheo was found in higher concentrations in cells in the case of PEO-PCL. These higher Pheo concentrations did not correspond to better performances in PDT treatment. We thus highlighted subtle differences in PEO-PCL and PEO-PS micelles for the delivery of Pheo.