Tissue engineering and medical devices
Biomaterials for tissue engineering
Hyperelastic and absorbable architected biomaterials dedicated to soft tissue reconstruction.
About the project:
This objective of this project is to combine selected degradable polymers and the electrospinning process to produce architected scaffolds to be used in soft tissue engineering. The prediction of the degradation rates, of the evolution of the scaffolds mechanical properties, and of the cells/scaffolds construct behaviour are also forseen.
Contact:
Students:
Collaborations:
Funding:
Laboratoire URGO
Medical devices:
Anti-adhesion degradable medical device
About the project:
We are working mainly on two axes:
Anti-adhesion, self expanding, degradable medical device for the prevention of intra-uterine adhesions.
Anti-adhesion and degradable medical device for the prevention of post-operative adhesions in orthopedic surgery
Contact:
Vincent Letouzey
Students:
Salomé Leprince
Stéphanie Huberlant
Lucie Allegre
Collaborations:
Service de Gynécologie Obstétrique (CHU Nîmes)
Pr Michel Chammas (Orthopaedic Surgery Service, CHU Montpellier)
Womed
Funding:
SATT AxLR, Région Occitanie, CHU Nîmes, Université de Montpellier
Algerian Government Excellence grant
A new bioabsorbable polymer film to prevent peritoneal adhesions validated in a post-surgical animal model
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Allegre, L., Le Teuff, I., Leprince, S., Warembourg, S., Taillades, H., Garric, X., Letouzey, V. & Huberlant, S.
ABSTRACT
Background – Peritoneal adhesions are a serious surgical postoperative complication. The aim of this study is to investigate, in a rat model, the anti-adhesive effects of a bioabsorbable film of polymer combining polyethylene glycol and polylactic acid that can be easily applied during surgery.
Materials and Methods – Sixty three animals were randomized into five groups according to the anti- adhesion treatment: Hyalobarrier®, Seprafilm®, Polymer A (PA), Polymer B (PB), and control. The rats were euthanized on days 5 and 12 to evaluate the extent, severity and degree of adhesions and histopathological changes. Three animals were euthanized at day 2 in PA, PB and control groups to observe the in vivo elimination.
Results – Macroscopic adhesion formation was significantly lower in the PA group than in the control group at day 5 (median adhesion score 0±0 vs 9.6 ±0.5 p=0.002) and at day 12 (0±0 vs 7.3±4 p=0.02). Furthermore, median adhesion score at day 5 was significantly lower in the PA group than in the Seprafilm® group (0±0 vs 4.2± 3.9 p = 0.03). Residence time of PA seems longer than PB.
Conclusion – The PA bioabsorbable film seems efficient in preventing the formation of peritoneal adhesions
Advanced wound dressings
About the project:
This project gathers different approaches towards original and/or advanced wound dressings. It is based on the combination of 1) degradable polymers exhibiting controlled degradation rates and mechanical properties, 2) chemical modifications and 3) 3D printing techniques or electrospinning to design innovative wound dressings.
Contact:
Students:
Collaborations:
Laboratoire URGO
Pr. Tatiana Budtova and Dr. Sytze Buwalda (CEMEF, Mines Paristech)
Funding:
CNRS interdisciplinary PhD program
Preliminary in vivo study of biodegradable PLA-PEU-PLA anti-adhesion membranes in a rat Achilles tendon model of peritendinous adhesions
BIOMATERIALS SCIENCE 2022,10, 1776-1786
Hadda, Zebiri, Van Den Berghe Helene, Paunet Tom, Wolf-Mandroux Aurelie, Bethry Audrey, Taillades Hubert, Yohan Jean Noel, Yohan Jean Noël, Nelly Pirot, Botteron Catherine, Chammas Michel, Chammas Pierre-Emmanuel and Garric Xavier
ABSTRACT
Peritendinous adhesions are complications known to occur up to 6 weeks after surgery and cause chronic pain and disability. Anti-adhesion barriers are currently the best option for prevention. In a previous study, we designed two biodegradable membranes, D-PACO1 and D-PACO2, based on new triblock copolymers and conducted in vitro evaluations. The membranes maintained filmogenic integrity, had degradation rates that promoted anti-adhesion and were biocompatible, suggesting their safe and effective use as anti-adhesion devices. To test this hypothesis, we conducted a preliminary in vivo study in a rat model of peritendinous adhesions and evaluated the membranes’ degradation rates, tendon healing and anti-adhesion effect compared to non-surgical and surgical control groups 2 and 10 weeks after surgery. Macroscopic evaluation showed membranes were effective in reducing the extent and severity of adhesions. Membranes acted as physical barriers at 2 weeks and underwent a complete or significant biodegradation at 10 weeks. D-PACO2 had a longer degradation rate compared to D-PACO1, was more effective in reducing adhesions and is expected to be more effective in promoting tendon healing. The tendency of D-PACO1 to promote tendon healing while D-PACO2 did not interfere with healing highlights the need to redesign the porosity of the D-PACO membranes for optimal nutrient diffusion, while maintaining their anti-adhesion effect and clinical usability. Preliminary findings revealed that adhesions form beyond the 6 weeks cited in the literature. In this study, adhesion formation continued for up to 10 weeks, underlining the need to increase the experimental period and sample size of future experiments evaluating anti-adhesion membranes.
Protein-Polymer Bioconjugates Prepared by Post-Polymerization Modification of Alternating Copolymers
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2022
Saxer, S.; Erdogan, O.; Paniagua, C.; Chavanieu, A.; Garric, X.; Darcos, V.
ABSTRACT
Protein-polymer bioconjugates have shown great promise in biomedical and life science applications including drug delivery and diagnosis. The current bioconjugation strategies suffer from lack of efficiency and versatility. In this article, poly(styrene-alt-maleic anhydride) copolymers were first prepared by RAFT polymerization and characterized by different analytical techniques. Then, the poly(styrene-alt-maleic anhydride) precursors were functionalized with primary amine such as azidopropylamine and amino poly(ethylene glycol). The reaction of amino compounds with maleic anhydride was found to be a highly efficient, a versatile, and a facile chemical ligation reaction for the synthesis of macromolecules with quantitative yield under mild conditions. The main benefit is the incorporation of a wide range of functionality by easily changing the primary amine compound. For the amphiphilic graft copolymers based on poly(ethylene glycol), aggregation behavior in water was investigated. In a second part, azido-functionalized polystyrene copolymers were used to prepare a new protein-polymer bioconjugate by copper-free click chemistry reaction.
Syntheses of biodegradable graft copolymers from sodium caseinate and poly 3 -caprolactone or poly lactic acid. Applications to the compatibilization of sodium caseinate/polyester blends
Materials Today Chemistry 27 (2023) 101345
L.Viora, T. Tichané, A. Taguet, X. Garric, J. Coudane, H. Van Den Berghe
ABSTRACT
Casein (and its sodium salt, sodium caseinate, SC) is an inexpensive natural milk protein that is used as a biodegradable biomaterial, especially to produce packaging films. However, to enhance some of its properties, it needs to be blended with other polymers, which should preferably be biodegradable such as poly lactic acid (PLA) and poly ε-caprolactone (PCL). New SC-g-PLA and SC-g-PCL graft copolymers have been prepared and unambiguously characterized, in particular by 1H and DOSY NMR. The grafting degrees are high (between 24 and 35% by weight) and result in variations of properties, such as hydrophobicity and thermal properties. The microstructures of SC/PLA and SC/PCL blends were studied and compared, with and without the addition of the SC-g-PLA and SC-g-PCL copolymers to test the compatibilization capacity of these new biodegradable copolymers.
Chemical modification of edible sodium caseinate: A new grafting method of oleic acid. Characterization and thermal properties of the conjugate
Food Chemistry Volume 408, 15 May 2023, 135140
Teddy Tichané, Laurianne Viora, Xavier Garric, Emmanuel Klem-Robin, Jean Coudane, Hélène Van Den Berghe
ABSTRACT
Sodium caseinate is a well-known amphiphilic protein derived from natural products currently used for the preparation of edible films. To improve some properties, especially to decrease the hydrophilicity and water solubility of the caseinate, the covalent grafting of a hydrophobic edible fatty acid, namely oleic acid, onto caseinate, appears to be a solution. We describe a new synthesis method for the chemical modification of sodium caseinate involving the synthesis of an acid chloride derivative from oleic acid and a phase transfer catalysis reaction in a biphasic medium. Under these conditions, free amine and alcohol groups of the caseinate are likely to be grafted with a fairly high (>50 %) substitution degree. The caseinate derivative is finely characterized, in particular by DOSY NMR, to assess the formation of a casein/oleic acid grafted compound as well as the absence of residual oleic acid.
Dual-crosslinked degradable elastomeric networks with self-healing properties: bringing multi(catechol) star block copolymers into play
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ACS Appl. Mater. Interfaces 15, 2077-2091 (2023)
Mathilde Grosjean, Louis Gangolphe, Stéphane Dejean, Sylvie Hunger, Audrey Bethry, Frédéric Bossard, Xavier Garric, Benjamin Nottelet
ABSTRACT
In the biomedical field, degradable chemically crosslinked elastomers are interesting materials for tissue engineering applications since they present rubber-like mechanical properties matching with those of soft tissues and are able to preserve their 3D structure over degradation. Their use in biomedical applications requires surgical handling and implantation that can be source of accidental damages responsible for 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 from two methods. The first approach is based on the mix of hydrophobic PEG-PLA star-shaped copolymers functionalized either with 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/re-association 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 crosslinks. The performances of networks from mix copolymers vs. bifunctional copolymers are compared and demonstrate the superiority of the later. The biocompatibility of the materials is also demonstrated and confirm the potential of these degradable 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
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Biomacromolecules XX, XX (2022)
Mathilde Grosjean, Edouard Girard, Audrey Bethry, Grégory Chagnon, Xavier Garric, Benjamin Nottelet
ABSTRACT
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.
Poly(ε-caprolactone)-Based Graft Copolymers: Synthesis Methods and Applications in the Biomedical Field: A Review
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Jean Coudane, Benjamin Nottelet, Julia Mouton, Xavier Garric, Hélène Van Den Berghe
ABSTRACT
Synthetic biopolymers are attractive alternatives to biobased polymers, especially because they rarely induce an immune response in a living organism. Poly ε-caprolactone (PCL) is a well-known synthetic aliphatic polyester universally used for many applications, including biomedical and environmental ones. Unlike poly lactic acid (PLA), PCL has no chiral atoms, and it is impossible to play with the stereochemistry to modify its properties. To expand the range of applications for PCL, researchers have investigated the possibility of grafting polymer chains onto the PCL backbone. As the PCL backbone is not functionalized, it must be first functionalized in order to be able to graft reactive groups onto the PCL chain. These reactive groups will then allow the grafting of new reagents and especially new polymer chains. Grafting of polymer chains is mainly carried out by “grafting from” or “grafting onto” methods. In this review we describe the main structures of the graft copolymers produced, their different synthesis methods, and their main characteristics and applications, mainly in the biomedical field.
Bioresorbable bilayered elastomers/hydrogels constructs with gradual interfaces for the fast actuation of self-rolling tubes
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ACS Appl. Mater. Interfaces 14, 43719–43731 (2022)
Mathilde Grosjean, Sidzigui Ouedraogo, Stéphane Déjean, Xavier Garric, Valeriy Luchnikov, Arnaud Ponche, Noëlle Mathieu, Karine Anselme, Benjamin Nottelet
ABSTRACT
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 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 seconds 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.
Polyester-polydopamine copolymers for intravitreal drug delivery: role of polydopamine drug-binding properties on extending drug release
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Biomacromolecules 23, 4388-4400, (2022)
Floriane Bahuon, Vincent Darcos, Sulabh Patel, Zana Marin, Jean Coudane, Grégoire Schwach, and Benjamin Nottelet
ABSTRACT
This work reports on a novel polyester copolymer containing poly(dopamine), a synthetic analogue of natural melanin, evaluated in sustained-release drug delivery system for ocular intravitreal administration of drugs. More specifically, a graft copolymer of poly(ε-caprolactone)-graft-poly(dopamine) (PCL-g-PDA) has been synthesized, and was shown to further extend the drug release benefits of state-of-the-art biodegradable intravitreal implants made of poly(lactide) and poly(lactide-co-glycolide). The innovative biomaterial combines the documented drug-binding properties of melanin naturally present in the eye, with the established ocular tolerability and biodegradation of polyester implants. The PCL-g-PDA copolymer was obtained by a two-step modification of PCL with a final PDA content around 2-3 wt.%, and was fully characterised by SEC, NMR, and DOSY NMR. The thermoplastic nature of PCL-g-PDA allowed its simple processing by hot-melt compression moulding to prepare small implants. The properties of unmodified PCL and PCL-g-PDA implants were studied and compared in terms of thermal properties (DSC), thermal stability (TGA), degradability and in vitro cytotoxicity. PCL and PCL-g-PDA implants exhibited similar degradation properties in vitro and were both stable under physiological conditions over 110 days. Likewise, both materials were non-cytotoxic towards L929 and ARPE-19 cells. The drug-loading and in vitro release properties of the new materials were investigated with dexamethasone (DEX) and ciprofloxacin hydrochloride (CIP) as representative drugs featuring low and high melanin binding affinities, respectively. In comparison to unmodified PCL, PCL-g-PDA implants showed significant extension of drug release most likely because of specific drug-catechol interaction with the PDA moieties of the copolymer. The present study confirms the advantages of designing PDA-containing polyesters as a class of biodegradable and biocompatible thermoplastics that can modulate and remarkably extend drug release kinetics thanks to their unique drug binding properties, especially, but not limited to, for ocular applications.
Implantable medical devices for soft tissues
About the project:
We design polymers to improve or create new implants in the field of soft tissue regeneration (ligament prosthesis, hernia…)
Contact:
Students:
Collaborations:
Société Biom’up (CHU Montpellier), Dr Danièle Noël (IRMB, U1183, Montpellier)
Funding:
Industrial grant CIFRE Biom’up, MENRT grant (ED CBS2)
Dual-crosslinked degradable elastomeric networks with self-healing properties: bringing multi(catechol) star block copolymers into play
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ACS Appl. Mater. Interfaces 15, 2077-2091 (2023)
Mathilde Grosjean, Louis Gangolphe, Stéphane Dejean, Sylvie Hunger, Audrey Bethry, Frédéric Bossard, Xavier Garric, Benjamin Nottelet
ABSTRACT
In the biomedical field, degradable chemically crosslinked elastomers are interesting materials for tissue engineering applications since they present rubber-like mechanical properties matching with those of soft tissues and are able to preserve their 3D structure over degradation. Their use in biomedical applications requires surgical handling and implantation that can be source of accidental damages responsible for 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 from two methods. The first approach is based on the mix of hydrophobic PEG-PLA star-shaped copolymers functionalized either with 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/re-association 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 crosslinks. The performances of networks from mix copolymers vs. bifunctional copolymers are compared and demonstrate the superiority of the later. The biocompatibility of the materials is also demonstrated and confirm the potential of these degradable 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
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Biomacromolecules XX, XX (2022)
Mathilde Grosjean, Edouard Girard, Audrey Bethry, Grégory Chagnon, Xavier Garric, Benjamin Nottelet
ABSTRACT
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 elastomers/hydrogels constructs with gradual interfaces for the fast actuation of self-rolling tubes
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ACS Appl. Mater. Interfaces 14, 43719–43731 (2022)
Mathilde Grosjean, Sidzigui Ouedraogo, Stéphane Déjean, Xavier Garric, Valeriy Luchnikov, Arnaud Ponche, Noëlle Mathieu, Karine Anselme, Benjamin Nottelet
ABSTRACT
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 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 seconds 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.
Evaluation of a biodegradable PLA–PEG–PLA internal biliary stent for liver transplantation: in vitro degradation and mechanical properties
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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
Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP‐Dependent Regulation
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William Ong, Nicolas Marinval, Junquan Lin, Mui Hoon Nai, Yee-Song Chong, Coline Pinese, Sreedharan Sajikumar, Chwee Teck Lim, Charles Ffrench-Constant, Marie E. Bechler, and Sing Yian Chew
ABSTRACT
A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes-associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.
In Vivo Tissue-Engineered Vascular Grafts
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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.
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 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.
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.
In vivo evaluation of hybrid patches composed of PLA based copolymers and collagen/chondroitin sulfate for ligament tissue regeneration: Hybrid Patches for Ligament Reconstruction
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J. Biomed. Mater. Res. B 105, 1778–1788 (2017)
Pinese, C., Gagnieu, C., Nottelet, B., Rondot-Couzin, C., Hunger, S., Coudane, J. & Garric, X.
ABSTRACT
Biomaterials for soft tissues regeneration should exhibit sufficient mechanical strength, demonstrating a mechanical behavior similar to natural tissues and should also promote tissues ingrowth. This study was aimed at developing new hybrid patches for ligament tissue regeneration by synergistic incorporation of a knitted structure of degradable polymer fibers to provide mechanical strength and of a biomimetic matrix to help injured tissues regeneration. PLA‐ Pluronic® (PLA‐P) and PLA‐Tetronic® (PLA‐T) new copolymers were shaped as knitted patches and were associated with collagen I (Coll) and collagen I/chondroitine‐sulfate (Coll CS) 3‐dimensional matrices. In vitro study using ligamentocytes showed the beneficial effects of CS on ligamentocytes proliferation. Hybrid patches were then subcutaneously implanted in rats for 4 and 12 weeks. Despite degradation, patches retained strength to answer the mechanical physiological needs. Tissue integration capacity was assessed with histological studies. We showed that copolymers, associated with collagen and chondroitin sulfate sponge, exhibited very good tissue integration and allowed neotissue synthesis after 12 weeks in vivo. To conclude, PLA‐P/CollCS and PLA‐T/CollCS hybrid patches in terms of structure and composition give good hopes for tendon and ligament regeneration.
Rolled knitted scaffolds based on PLA-pluronic copolymers for anterior cruciate ligament reinforcement: A step by step conception
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J. Biomed. Mater. Res. B 105, 735–743 (2017)
Pinese, C., Gagnieu, C., Nottelet, B., Rondot-Couzin, C., Hunger, S., Coudane, J. & Garric, X.
ABSTRACT
The aim of this study was to prepare a new knitted scaffold from PLA‐Pluronic block copolymers for anterior cruciate ligament reconstruction. The impact of sterilization methods (beta‐ray and gamma‐ray sterilization) on copolymers was first evaluated in order to take into account the possible damages due to the sterilization process. Beta‐ray radiation did not significantly change mechanical properties in contrast to gamma‐ray sterilization. It was shown that ACL cells proliferate onto these copolymers, demonstrating their cytocompatibility. Thirdly, in order to study the influence of shaping on mechanical properties, several shapes were created with copolymers yarns: braids, ropes and linear or rolled knitted scaffolds. The rolled knitted scaffold presented interesting mechanical characteristics, similar to native anterior cruciate ligament (ACL) with a 67 MPa Young’s Modulus and a stress at failure of 22.5 MPa. These findings suggest that this three dimensional rolled knitted scaffold meet the mechanical properties of ligament tissues and could be suitable as a scaffold for ligament reconstruction.
Biomedical innovation
Hydrogels from biocompatible polymers for actinide decontamination
About the project:
Hydrogels from biocompatible polymers for actinide decontamination (DECAP). The DECAP project is focused on the development of innovative hydrogels prepared from polymeric materials for external actinide decontamination. The objective is to prepare new chelating macromolecules able to complex radionuclides with the controlled synthesis of complexing copolymers.
Contact:
Students:
Collaborations:
Florence Agnely (Institut Galien Paris-Sud), Nicolas Dacheux (Institut de Chimie Séparative de Marcoule), Sophie Monge (Institut Charles Gerhardt de Montpellier)
Funding:
ANR ASTRID
Implantable medical device for the capture and destruction of cancer cells in vivo.
About the project:
Contact:
Students:
Collaborations:
Dr Jean-Marie Ramirez (IBMM, Montpellier) ; Dr Benoit Charlot (IES, Montpellier)
Funding:
Region Occitanie, SATT AxLR CAPDCM
3D printing and shaping processes for improved medical devices
About the project:
Contact:
Students:
Collaborations:
Funding:
PLA scaffolds production from Thermally Induced Phase Separation: Effect of process parameters and development of an environmentally improved route assisted by supercritical carbon dioxide
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Supercrit. Fluids 136, 123–135 (2018)
Gay, S., Lefebvre, G., Bonnin, M., Nottelet, B., Boury, F., Gibaud, A. & Calvignac, B.
ABSTRACT
In this work, a relatively large scale of PLA scaffolds was produced using thermally induced phase separation (TIPS) combined with a supercritical carbon dioxide (SC-CO2) drying step as a green alternative. For the TIPS step, the phase separation of PLA and 1,4-dioxane solvent was controlled by adjusting the process conditions such as the polymer concentration and molecular weight, the 1,4-dioxane solvent power and the cooling conditions. The scaffolds morphology was analyzed by scanning electron microscopy. Their structural and mechanical properties were correlated together with the possibility to tune them by controlling the process conditions. An environmental analysis using the Life Cycle Assessment (LCA) methodology confirmed a reduction of at least 50% of the environmental impact of the whole process using the SC-CO2 drying compared to the traditional freeze-drying technology. This work is the first known attempt to conduct the LCA methodology on TIPS process for the PLA scaffolds production.