Self-powered PVDF/PCL Composite Scaffolds For Peripheral Nerve Regeneration Over Long-range Nerve Defects

Peripheral nerve injury(PNI)is a worldwide clinical problem which annually affects more than one million people.Nerve defect is one of the most serious cases of PNI as it leads to loss of motor function and sensory perception,which directly impairs the quality and longevity of human life.Even the so-called “gold standard”,autograft transplantation,is hampered by serious issues such as limited supplies,lesions at donor site,multiple surgeries and disproportion in size and structure.Nerve guidance conduits(NGCs),which usually come at minimal cost,has been a clinically approved alternative treatment to autograft.Various strategies have been developed in order to create a more conductive microenvironment in NGCs,including the use of biological factors,nanomaterials,cell therapies as well as electrical stimulation(ES).Among all these strategies,electrical conductivity is extremely vital since it can guide the regenerating axons across the gap to connect with the distal stump by biological signal transduction.Recently,piezoelectric materials attract more and more attention due to the possibility of converting ambient mechanical energy into electric signals without an external source or implantation of electrodes.Among piezoelectric polymers,polyvinylidene fluoride(PVDF)is the most popular one for biomedical applications due to its optimal piezoelectric properties and biocompatibility.However,its bad biodegradation often means a second surgical procedure is indispensable.Second,the biocompatibility needs to be improved compared with traditional biological materials.Therefore,a biodegradable material polycaprolactone(PCL)was used to blend with PVDF to improve the properties of individual polymers.On the one hand,the blend of PCL with PVDF could simultaneously improve mechanical properties,biocompatibility,as well as biodegradation.On the other hand,the composite scaffolds still maintain satisfactory piezoelectric properties to generate sufficient ES signals for nerve repair.In this study,a 3D structured PVDF/PCL composite nerve tissue engineering scaffold was fabricated by a simple cast/annealing-solvent displacement method.The morphological features of scaffolds were analyzed and the sample exhibits high porosity.The composite scaffolds exhibit ideal flexibility and rigidity due to the blend of PCL.FTIR and XRD analyses indicated the increased transformation of piezoelectric β-phase during preparation.Meanwhile,marked piezoresponse was observed in PVDF/PCL composites and the piezoelectric effect was independence of the morphology.All scaffolds were largely non-toxic to RSCs,showing satisfactory in vitro biocompatibility.Meanwhile,RSCs incubated with PVDF/PCL scaffolds exhibit higher cell viability and more neurite extension compared to PCL.For in vivo studies,the 20% PVDF/PCL NGCs were used to bridge a 15-mm rat sciatic nerve defect.An encouraging level of nerve regeneration for piezoelectric scaffolds have achieved that they have comparable results to “gold standard” in terms of electrophysiological,morphological and functional restoration at 4 months after implantation.By calculating the percentage mass loss of the conduits after implantation,we noticed that up to 9.1% PVDF/PCL scaffolds were degraded,while PCL scaffolds only lost an average of 6.6%.Collectively,this study not only confirms that PVDF-based biomaterials have great potential for long-range nerve defects,but also provides promising evidence for further studies in piezoelectric tissue engineering scaffolds.