Peripheral neuropathies due to traumatic injuries are a common cause of considerable disability worldwide.Peripheral nerve regeneration seldom leads to total functional recovery,and therefore the identification of novel techniques and devices to promote nerve regeneration represents a challenge in neuroscience.Autologous nerve grafting is considered the gold standard for bridging nerve lesion,but in most of the cases the use of artificial tubular guides is needed.Thus,regenerative medicine requires reliable nerve conduits and good source of cells to refine this process.In the last decades,the use of artificial synthetic or natural guides (such as methacrylate,agarose,hyaluronic acid,or chitosan-based) was widely evaluated,however,clinicians are still waiting for an alternative scaffold possessing the best properties and which is able to support complete nerve regeneration and functional recovery.Polyamidoamines (PAAs) are a well-known family of synthetic biocompatible and biodegradable polymers,which can be prepared as soft hydrogels characterized by low interfacial tension and tunable elasticity.We evaluated,for the first time,the in vivo performance of an amphoteric agmatine-derived PAA hydrogel,obtained by radical polymerization of a soluble functional oligomeric precursor and shaped as conduit,for nerve regeneration in a rat sciatic nerve cut model.The animals were analyzed at 30,90 and 180 days post-surgery.Agmatine-PAA hydrogel conduit proved able to support nerve regeneration.Good surgical outcomes were achieved with no signs of inflammation or neuroma.Moreover,the gait and the thermal sensitivity analyses demonstrated movement improvement and sensitive recovery,indicating that nerve regeneration was morphologically sound and the quality of functional recovery satisfactory.Importantly,the conduits were processed for light microscopy and morphometric analysis.The measurements of axon size,myelin thickness and fiber density showed complete nerve regeneration,totally covering the gap in the central part of the conduit.Therefore,the agmantine-derived PAA conduits represent a novel and promising material for peripheral nerve regeneration.In order to improve their biomechanical properties,more recently,we studied in vitro the 1,4-bis(acryloyl)piperazine-derived PAA hydrogels,which exhibited a combination of mechanical strength,biocompatibility,biodegradability,ability to induce cell adhesion and to maintain viability of Schwann cells (SCs) and sensory neurons of dorsal root ganglia.On this basis,the piperazine-derived PAA hydrogels ascribed as potential scaffolds for in vivo peripheral nerve regeneration,and in vivo experiments are in progress.Recently,there has been also considerable interest in utilizing stem cells for regenerative medicine,due to their proved capability to support nerve regeneration.Indeed,the mesenchymal stem cells from adipose tissue (ASC) are able to differentiate into SCs-like phenotype (dASC),mimicking the cells naturally forming and supporting the peripheral nerves.The autologous ASC are easily obtainable and rapidly expandable in culture.In vitro and in vivo analyses on different scaffolds demonstrated their potential for nerve regeneration.Additionally,y-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the adult brain.The GABA-ergic ligands revealed as promising tools to promote nerve regeneration.Indeed,the metabotropic GABA-B receptors are functionally expressed in SC,where they are regulate SC physiology and the development of the peripheral nervous system.We also characterized the GABA-B receptors in dASC,assessing the effect of a specific GABA-B agonist (baclofen) on stem cell proliferation and neurotrophic potential.Adipose stem cells were found to express all the subunits that form a functional GABA-B receptor (i.e.GABA-B1a,GABA-B1b and GABA-B2).Interestingly,baclofen-stimulation decreased the dASC proliferation,modulating the expression levels and release of brain derived neurotrophic factor and nerve growth factor from dASC.Therefore,GABA-B functional receptor may be an exploitable pharmacological target to modulate ASC physiology and to improve peripheral nerve regeneration.In conclusion,our findings demonstrate that PAA hydrogel conduits are a novel,implantable material providing a good support for peripheral nerve regeneration.The potentiality for the best PAAs hydrogel conduits,functionalized with ASC and GABAergic ligands is a matter of further analysis,which are still in progress.Their practical translation to clinical medicine will represent the future biomaterial- and cell-based therapies for the regeneration of the peripheral nervous system.