Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-dependent Regulation

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

Scaffold-mediated sequential drug/gene delivery to promote nerve regeneration and remyelination following traumatic nerve injuries

Neural tissue regeneration following traumatic injuries is often subpar. As a result, the field of neural tissue engineering has evolved to find therapeutic interventions and has seen promising outcomes. However, robust nerve and myelin regeneration remain elusive. One possible reason may be the fact that tissue regeneration often follows a complex sequence of events in a temporally-controlled manner. Although several other fields of tissue engineering have begun to recognise the importance of delivering two or more biomolecules sequentially for more complete tissue regeneration, such serial delivery of biomolecules in neural tissue engineering remains limited. This review aims to highlight the need for sequential delivery to enhance nerve regeneration and remyelination after traumatic injuries in the central nervous system, using spinal cord injuries as an example. In addition, possible methods to attain temporally-controlled drug/gene delivery are also discussed for effective neural tissue regeneration.NRF (Natl Research Foundation, S’pore)NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Accepted versio

Design of Hybrid Polymer Nanofiber/Collagen Patches Releasing IGF and HGF to Promote Cardiac Regeneration

Cardiovascular diseases are the leading cause of death globally. Myocardial infarction in particular leads to a high rate of mortality, and in the case of survival, to a loss of myocardial functionality due to post-infarction necrosis. This functionality can be restored by cell therapy or biomaterial implantation, and the need for a rapid regeneration has led to the development of bioactive patches, in particular through the incorporation of growth factors (GF). In this work, we designed hybrid patches composed of polymer nanofibers loaded with HGF and IGF and associated with a collagen membrane. Among the different copolymers studied, the polymers and their porogens PLA-Pluronic-PLA + PEG and PCL + Pluronic were selected to encapsulate HGF and IGF. While 89 and 92% of IGF were released in 2 days, HGF was released up to 58% and 50% in 35 days from PLA-Pluronic-PLA + PEG and PCL + Pluronic nanofibers, respectively. We also compared two ways of association for the loaded nanofibers and the collagen membrane, namely a direct deposition of the nanofibers on a moisturized collagen membrane (wet association), or entrapment between collagen layers (sandwich association). The interfacial cohesion and the degradation properties of the patches were evaluated. We also show that the sandwich association decreases the burst release of HGF while increasing the release efficiency. Finally, we show that the patches are cytocompatible and that the presence of collagen and IGF promotes the proliferation of C2C12 myoblast cells for 11 days. Taken together, these results show that these hybrid patches are of interest for cardiac muscle regeneration

Polymères synthétiques dégradables pour la conception de dispositifs médicaux implantables

Le secteur des dispositifs médicaux implantables est un secteur des produits de santé en pleine expansion et particulièrement dynamique dans le domaine de la recherche. En effet, pour améliorer la prise en charge des patients et s’adapter au mieux aux exigences cliniques, les chercheurs du domaine conçoivent de nouveaux types de dispositifs médicaux. Pour cela, ils utilisent différentes familles de biomatériaux présentant des caractéristiques chimiques et physiques très variées de façon à proposer aux cliniciens des produits de santé parfaitement adaptés aux applications biomédicales. Dans cet article, nous montrons, grâce à un exemple, comment à partir d’une famille de biomatériaux (les polymères dégradables), il est possible de concevoir un dispositif médical implantable pour la prise en charge thérapeutique de la rupture du ligament croisé antérieur. Les principales étapes conduisant à la conception d’un renfort ligamentaire total sont détaillées dans cette étude. Elles vont de la synthèse et la caractérisation de polymères dégradables jusqu’à la mise en forme en tricot, en passant par l’étude de l’influence de la stérilisation sur les propriétés mécaniques et la vérification de la cytocompatibilité

Rolled knitted scaffolds based on PLA-pluronic copolymers for anterior cruciate ligament reinforcement: A step by step conception

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Investigation on the properties of linear PLA-poloxamer and star PLA-poloxamine copolymers for temporary biomedical applications.

International audienceThe objective of this work was to develop and study newbiodegradable thermoplastics with improvedmechanical 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−1 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−1 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

In vivo evaluation of hybrid patches composed of PLA based copolymers and collagen/chondroitin sulfate for ligament tissue regeneration

International audienc

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

International audienc

Sustained delivery of siRNA/mesoporous silica nanoparticle complexes from nanofiber scaffolds for long-term gene silencing

A low toxicity and efficient delivery system is needed to deliver small interfering RNAs (siRNA) in vitro and in vivo. The use of mesoporous silica nanoparticles (MSN) is becoming increasingly common due to its biocompatibility, tunable pore size and customizable properties. However, bolus delivery of siRNA/MSN complexes remains suboptimal, especially when a sustained and long-term administration is required. Here, we utilized electrospun scaffolds for sustained delivery of siRNA/MSN-PEI through surface adsorption and nanofiber encapsulation. As a proof-of-concept, we targeted collagen type I expression to modulate fibrous capsule formation. Surface adsorption of siRNA/MSN-PEI provided sustained availability of siRNA for at least 30 days in vitro. As compared to conventional bolus delivery, such scaffold-mediated transfection provided more effective gene silencing (p < 0.05). On the contrary, a longer sustained release was attained (at least 5 months) when siRNA/MSN-PEI complexes were encapsulated within the electrospun fibers. In vivo subcutaneous implantation and biodistribution analysis of these scaffolds revealed that siRNA remained localized up to ~290 m from the implants. Finally, a fibrous capsule reduction of ~45.8 % was observed after 4 weeks in vivo as compared to negative scrambled siRNA treatment. Taken together, these results demonstrate the efficacy of scaffold-mediated sustained delivery of siRNA/MSN-PEI for long-term non-viral gene silencing applications.ASTAR (Agency for Sci., Tech. and Research, S’pore)MOE (Min. of Education, S’pore)NMRC (Natl Medical Research Council, S’pore)Accepted versio