Living Microneedle Patch with Adipose-Derived Stem Cells Embedding for Diabetic Ulcer Healing

Stem cells have demonstrated values in diabetic ulcer (DU) treatments. Challenges in this area are focused on enhancing the localized curative effects of stem cells and improving diabetic wound healing efficiently. Herein, a novel living microneedle (MN) patch is presented as a localized delivery system of bioactive platelet derived growth factor D (PDGF-D) and human adipose-derived stem cells (ADSCs) for DU wound treatment. Compared with traditional complicated stem cell carriers, the MN patch can keep stem cell viability for ADSCs encapsulation and delivery, and possesses good mechanical strengths to penetrate the local skin wounds noninvasively. It is demonstrated that the delivery ADSCs are with the abilities of angiogenesis promotion during the DU wound healing; while the additive PDGF-D can contribute significantly to the proliferation of ADSCs, strengthening the cell function of ADSCs and further facilitating the healing processes. Thus, living MN patches accelerate vascularization, tissue regeneration, and collagen deposition in a wounded diabetic mouse model, suggesting their potential application to DU wound healing and other therapeutic applications.     

Stimuli‐Responsive Scaffold for Breast Cancer Treatment Combining Accurate Photothermal Therapy and Adipose Tissue Regeneration

Development of new therapeutic scaffolds to selectively destruct tumors under gentle conditions meanwhile promoting adipose tissue formation would be a promising strategy for clinical treatment of breast cancer. Herein, a stimuli‐responsive scaffold composed of polyacrylic acid‐g‐polylactic acid (PAA‐g‐PLLA) modified graphene oxide (GO) with a cleavable bond in between (GO‐PAA‐g‐PLLA), gambogic acid (GA), and polycaprolactone (PCL) is fabricated and then preseeded on adipose‐derived stem cells (ADSCs) for breast cancer treatment. This GO–GA‐polymer scaffold is able to simultaneously perform pH‐triggered low temperature (45 °C) photothermal therapy to selectively induce the apoptosis of tumor cells and significantly improve ADSCs growth without any photothermal damage. The low‐temperature photothermal therapy of the scaffolds can induce more than 95% of cell death for human breast cancer (MCF‐7) in vitro, which further completely inhibits tumor growth and finally eliminates tumor tissue in mice. Meanwhile, the prepared GO–GA‐polymer scaffold possesses the improved capability to stimulate the differentiation of ADSCs into adipocytes by upregulating adipo‐related gene expression, and significantly promotes new adipose tissue formation whether with or without NIR irradiation. These results successfully demonstrate that the prepared GO–GA‐polymer scaffolds with bifunctional properties will be a promising candidate for clinical cases involving both tumor treatment and tissue engineering.     

Biomimetic Composite Scaffolds to Manipulate Stem Cells for Aiding Rheumatoid Arthritis Management

Stem cell transplantation is a promising alternative therapy for rheumatoid arthritis (RA) patients, with the potential to suppress autoimmune in?ammation and prevent joint damage. However, widespread application of RA therapy based on stem cell transplantation is limited due to poor migration, local retention, and uncontrolled differentiation of stem cells. Here, inspired by the dynamic construction of bone matrix, a structurally and functionally optimized scaffold for loading bone marrow stem cells (BMSCs) is designed to aid RA management. The composite scaffolds consist of stiff 3D printing porous metal scaffolds (3DPMS) and soft multifunctional polysaccharide hydrogels, wherein 3DPMS meet the requirements for large‐scale bone defects caused by RA. Attractively, the fabricated hydrogels on the composite scaffold are self‐healable, injectable, biocompatible, and biodegradable, which endow the resultant scaffold many aspects mimicking the extracellular matrix (ECM). After encapsulation of BMSCs, hydrogels are administered into the inner pores of 3DPMS, abbreviated as BMSCs@3DPMS/hydrogels. In this study, BMSCs@3DPMS/hydrogels have a good effect on improving RA, such as remodeling of knee joint articular cartilage, inhibition of in?ammatory cytokines, and promotion of subchondral bone regeneration. Besides RA, the innovative scaffolds may also serve as an ideal biomaterial for other bone regenerative therapies in various orthopedic diseases.     

Nanostructured Biomaterials for Regeneration

Biomaterials play a pivotal role in regenerative medicine, which aims to regenerate and replace lost/dysfunctional tissues or organs. Biomaterials (scaffolds) serve as temporary 3D substrates to guide neo tissue formation and organization. It is often beneficial for a scaffolding material to mimic the characteristics of extracellular matrix (ECM) at the nanometer scale and to induce certain natural developmental or/and wound healing processes for tissue regeneration applications. This article reviews the fabrication and modification technologies for nanofibrous, nanocomposite, and nanostructured drug‐delivering scaffolds. ECM‐mimicking nanostructured biomaterials have been shown to actively regulate cellular responses including attachment, proliferation, differentiation, and matrix deposition. Nanoscaled drug delivery systems can be successfully incorporated into a porous 3D scaffold to enhance the tissue regeneration capacity. In conclusion, nanostructured biomateials are a very exciting and rapidly expanding research area, and are providing new enabling technologies for regenerative medicine.     

A Bi‐Lineage Conducive Scaffold for Osteochondral Defect Regeneration

Because cartilage and bone tissues have different lineage‐specific biological properties, it is challenging to fabricate a single type of scaffold that can biologically fulfill the requirements for regeneration of these two lineages simultaneously within osteochondral defects. To overcome this challenge, a lithium‐containing mesoporous bioglass (Li‐MBG) scaffold is developed. The efficacy and mechanism of Li‐MBG for regeneration of osteochondral defects are systematically investigated. Histological and micro‐CT results show that Li‐MBG scaffolds significantly enhance the regeneration of subchondral bone and hyaline cartilage‐like tissues as compared to pure MBG scaffolds, upon implantation in rabbit osteochondral defects for 8 and 16 weeks. Further investigation demonstrates that the released Li+ ions from the Li‐MBG scaffolds may play a key role in stimulating the regeneration of osteochondral defects. The corresponding mechanistic pathways involve Li+ ions enhancing the proliferation and osteogenic differentiation of bone mesenchymal stem cells (BMSCs) through activation of the Wnt signalling pathway, as well as Li+ ions protecting chondrocytes and cartilage tissues from the inflammatory osteoarthritis (OA) environment through activation of autophagy. These findings suggest that the incorporation of Li+ ions into bioactive MBG scaffolds is a viable strategy for fabricating bi‐lineage conducive scaffolds that enhance regeneration of osteochondral defects.     

Peripheral Nerve Regeneration with 3D Printed Bionic Scaffolds Loading Neural Crest Stem Cell Derived Schwann Cell Progenitors

Peripheral nerve injuries are one of the most common types of traumatic damage to the nervous system. Treatment of peripheral nerve injuries aims to promote axon regrowth by imitating and improving the microenvironment for sciatic nerve regeneration. In this study, regeneration efficiency and behavior of peripheral nerves are compared under three treatment strategies: 1) transplantation of Schwann cell progenitors induced from purified neural crest stem cells; 2) implantation of a multiscale scaffold based on high-resolution 3D printing; and 3) implantation of this bionic scaffold loading Schwann cell progenitors. The results of structural, electrophysiological, and behavioral tests demonstrate that the three treatment strategies result in different degrees of regeneration. The purified neural crest stem cells differentiate into functional Schwann cells and promote axon regeneration. The multifunctional 3D printed scaffold promotes oriented growth and myelination, and the myelinated nerve regrows with increased density and without visible scaffolds after six months. For the regeneration, scaffold treatment produces better performance than cell graft alone. Finally, it is shown that implantation of multiscale scaffolds preloaded with neural crest stem cell derived Schwann cell progenitors is the best strategy to promote peripheral nerve regeneration with improved anatomy and function among the three different strategies.     

Stem Cell-Recruiting Injectable Microgels for Repairing Osteoarthritis

The differentiation potentials and viability of stem cells are often impaired during cell isolation and delivery. Inspired by the phenomenon where islands can recruit seabirds for nesting, “cell island” microgels (MGs), that is, growth factor-loaded methacrylated hyaluronic acid and heparin blend MGs, which can recruit endogenous stem cells and promote chondrogenic differentiation, are constructed using microfluidic technology and photopolymerization processes, followed by non-covalently binding platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta3 (TGF-β3). The loading efficiency of PDGF-BB and TGF-β3 are 96% and 91%, respectively. In vitro and in vivo experiments find that the “cell island” MGs can enhance the migratory capacity of cells and recruit them from their niche via releasing PDGF-BB. Meanwhile, by using hyaluronic acid, the “cell island” MGs provide a suitable microenvironment for cell attachment and spreading. Furthermore, the “cell island” MGs induce chondrogenic differentiation of the recruited cells via releasing TGF-β3 and present a promising therapeutic effect for osteoarthritis. In sum, this developed “cell island” MG might serve as a temporary “nest site” to allow the migration, adhesion, and differentiation of endogenous stem cells, which can be a promising candidate rather than the conventional cell-seeded scaffolds for promoting tissue regeneration.     

Nanofibrous Patches for Spinal Cord Regeneration

The difficulty in spinal cord regeneration is related to the inhibitory factors for axon growth and the lack of appropriate axon guidance in the lesion region. Here scaffolds are developed with aligned nanofibers for nerve guidance and drug delivery in the spinal cord. Blended polymers including poly(L ‐lactic acid) (PLLA) and poly(lactide‐co‐glycolide) (PLGA) are used to electrospin nanofibrous scaffolds with a two‐layer structure: aligned nanofibers in the inner layer and random nanofibers in the outer layer. Rolipram, a small molecule that can enhance cAMP (cyclic adenosine monophosphate) activity in neurons and suppress inflammatory responses, is immobilized onto nanofibers. To test the therapeutic effects of nanofibrous scaffolds, the nanofibrous scaffolds loaded with rolipram are used to bridge the hemisection lesion in 8‐week old athymic rats. The scaffolds with rolipram increase axon growth through the scaffolds and in the lesion, promote angiogenesis through the scaffold, and decrease the population of astrocytes and chondroitin sulfate proteoglycans in the lesion. Locomotor scale rating analysis shows that the scaffolds with rolipram significantly improved hindlimb function after 3 weeks. This study demonstrates that nanofibrous scaffolds offer a valuable platform for drug delivery for spinal cord regeneration.     

Microfluidic 3D Printing Responsive Scaffolds with Biomimetic Enrichment Channels for Bone Regeneration

Tissue-engineered scaffolds have been extensively explored for treating bone defects; however, slow and insufficient vascularization throughout the scaffolds remains a key challenge for further application. Herein, a versatile microfluidic 3D printing strategy to fabricate black phosphorus (BP) incorporated fibrous scaffolds with photothermal responsive channels for improving vascularization and bone regeneration is proposed. The thermal channeled scaffolds display reversible shrinkage and swelling behavior controlled by near-infrared irradiation, which facilitates the penetration of suspended cells into the scaffold channels and promotes the prevascularization. Furthermore, the embedded BP nanosheets exhibit intrinsic properties for in situ biomineralization and improve in vitro cell proliferation and osteogenic differentiation. Following transplantation in vivo, these channels also promote host vessel infiltration deep into the scaffolds and effectively accelerate the healing process of bone defects. Thus, it is believed that these near-infrared responsive channeled scaffolds are promising candidates for tissue/vascular ingrowth in diverse tissue engineering applications.     

Silk Biomaterials with Vascularization Capacity

Functional vascularization is critical for the clinical regeneration of complex tissues such as kidney, liver, or bone. The immobilization or delivery of growth factors has been explored to improve vascularization capacity of tissue‐engineered constructs; however, the use of growth factors has inherent problems such as the loss of signaling capability and the risk of complications including immunological responses and cancer. Here, a new method of preparing water‐insoluble silk protein scaffolds with vascularization capacity using an all‐aqueous process is reported. Acid is added temporally to tune the self‐assembly of silk in the lyophilization process, resulting in water‐insoluble scaffold formation directly. These biomaterials are mainly noncrystalline, offering improved cell proliferation than previously reported silk materials. These systems also have an appropriate softer mechanical property that could provide physical cues to promote cell differentiation into endothelial cells, and enhance neovascularization and tissue ingrowth in vivo without the addition of growth factors. Therefore, silk‐based degradable scaffolds represent an exciting biomaterial option, with vascularization capacity for soft tissue engineering and regenerative medicine.     

Biomimetic Elastomeric Bioactive Siloxane‐Based Hybrid Nanofibrous Scaffolds with miRNA Activation: A Joint Physico‐Chemical‐Biological Strategy for Promoting Bone Regeneration

Rapid and efficient disease‐induced or critical‐size bone regeneration remains a challenge in tissue engineering due to the lack of highly bioactive biomaterial scaffolds. Physical structures such as nanostructures, chemical components such as silicon elements, and biological factors such as genes have shown positive effects on bone regeneration. Herein, a bioactive photoluminescent elastomeric silicate‐based nanofibrous scaffold with sustained miRNA release is reported for promoting bone regeneration based on a joint physico‐chemical‐biological strategy. Bioactive nanofibrous scaffolds are fabricated by cospinning poly (ε‐caprolactone) (PCL), elastomeric poly (citrates‐siloxane) (PCS), and bioactive osteogenic miRNA nanocomplexes (denoted PPM nanofibrous scaffolds). The PPM scaffolds possess uniform nanostructures, significantly enhanced tensile stress (≈15 MPa) and modulus (≈32 MPa), improved hydrophilicity (30–60°), controlled biodegradation, and strong blue fluorescence. Bioactive miRNA complexes are efficiently loaded into the nanofibrous matrix and exhibit long‐term release for up to 70 h. The PPM scaffolds significantly promote the adhesion, proliferation, and osteoblast differentiation of bone marrow stem cells in vitro and enhanced rat cranial defect restoration (12 weeks) in vivo. This work reports an attractive joint physico‐chemical‐biological strategy for the design of novel cell/protein‐free bioactive scaffolds for synergistic tissue regeneration.     

Electric Field Assisted Microfluidic Platform for Generation of Tailorable Porous Microbeads as Cell Carriers for Tissue Engineering

Injection of cell‐laden scaffolds in the form of mesoscopic particles directly to the site of treatment is one of the most promising approaches to tissue regeneration. Here, a novel and highly efficient method is presented for preparation of porous microbeads of tailorable dimensions (in the range ≈300–1500 mm) and with a uniform and fully interconnected internal porous texture. The method starts with generation of a monodisperse oil‐in‐water emulsion inside a flow‐focusing microfluidic device. This emulsion is later broken‐up, with the use of electric field, into mesoscopic double droplets, that in turn serve as a template for the porous microbeads. By tuning the amplitude and frequency of the electric pulses, the template droplets and the resulting porous bead scaffolds are precisely produced. Furthermore, a model of pulsed electrodripping is proposed that predicts the size of the template droplets as a function of the applied voltage. To prove the potential of the porous microbeads as cell carries, they are tested with human mesenchymal stem cells and hepatic cells, with their viability and degree of microbead colonization being monitored. Finally, the presented porous microbeads are benchmarked against conventional microparticles with nonhomogenous internal texture, revealing their superior performance.     

3D Superelastic Scaffolds Constructed from Flexible Inorganic Nanofibers with Self‐Fitting Capability and Tailorable Gradient for Bone Regeneration

Repair of bone defects with irregular shapes or at soft tissue insertion sites faces a huge challenge. Scaffolds capable of adapting to bone cavities, generating stiffness gradients, and inducing osteogenesis are necessary. Herein, a superelastic 3D ceramic fibrous scaffold is developed by assembly of intrinsically rigid, structurally flexible electrospun SiO₂ nanofibers with chitosan as bonding sites (SiO₂ NF‐CS) via a lyophilization technique. SiO₂ NF‐CS scaffolds exhibit excellent elasticity (full recovery from 80% compression), fast recovery rate (>500 mm min^?1), and good fatigue resistance (>10 000 cycles of compression) in an aqueous medium. SiO₂ NF‐CS scaffolds induce human mesenchymal stem cell (hMSC) elongation and differentiation into osteoblasts. In vivo self‐fitting capability is demonstrated by implanting compressed SiO₂ NF‐CS scaffolds into different shaped mandibular defects in rabbits, with a spontaneous recovery and full filling of defects. Rat calvarial defect repair validates enhanced bone formation and vascularization by cell (hMSC) histomorphology analysis. Further, subchondral bone scaffolds with gradations in SiO₂ nanofibers are developed, leading to a stiffness gradient and spatially chondrogenic and osteogenic differentiation of hMSCs. This work presents a type of 3D ceramic fibrous scaffold, which can closely match bone defects with irregular shapes or at different implant sites, and is promising for clinical translation.     

Inverted‐Colloidal‐Crystal Hydrogel Matrices as Three‐Dimensional Cell Scaffolds

Successful engineering of functional tissues requires the development of three‐dimensional (3D) scaffolds that can provide an optimum microenvironment for tissue growth and regeneration. A new class of 3D scaffolds with a high degree of organization and unique topography is fabricated from polyacrylamide hydrogel. The hydrogel matrix is molded by inverted colloidal crystals made from 104 μm poly(methyl methacrylate) spheres. The topography of the scaffold can be described as hexagonally packed 97 μm spherical cavities interconnected by a network of channels. The scale of the long‐range ordering of the cavities exceeds several millimeters. In contrast to analogous material in the bulk, hydrogel shaped as an inverted opal exhibits much higher swelling ratios; its swelling kinetics is an order of magnitude faster as well. The engineered scaffold possesses desirable mechanical and optical properties that can facilitate tissue regeneration while allowing for continuous high‐resolution optical monitoring of cell proliferation and cell–cell interaction within the scaffold. The scaffold biocompatibility as well as cellular growth and infiltration within the scaffold were observed for two distinct human cell lines which were seeded on the scaffold and were tracked microscopically up to a depth of 250 μm within the scaffold for a duration of up to five weeks. Ease of production, a unique 3D structure, biocompatibility, and optical transparency make this new type of hydrogel scaffold suitable for most challenging tasks in tissue engineering.     

3D Printing of Bilineage Constructive Biomaterials for Bone and Cartilage Regeneration

Owing to the different biological properties of articular cartilage and subchondral bone, it remains significant challenge to construct a bi‐lineage constructive scaffold. In this study, manganese (Mn)‐doped β‐TCP (Mn‐TCP) scaffolds with varied Mn contents are prepared by a 3D‐printing technology. The effects of Mn on the physicochemical properties, bioactivity, and corresponding mechanism for stimulating osteochondral regeneration are systematically investigated. The incorporation of Mn into β‐TCP lowers the lattices parameters and crystallization temperatures, but improves the scaffold density and compressive strength. The ionic products from Mn‐TCP significantly improve the proliferation of both rabbit chondrocytes and mesenchymal stem cells (rBMSCs), as well as promote the differentiation of chondrocytes and rBMSCs. The in vivo study shows that Mn‐TCP scaffolds distinctly improve the regeneration of subchondral bone and cartilage tissues as compared to TCP scaffolds, upon transplantation in rabbit osteochondral defects for 8 and 12 weeks. The mechanism is closely related to the Mn²⁺ ions significantly stimulated the proliferation and differentiation of chondrocytes through activating HIF pathway and protected chondrocytes from the inflammatory osteoarthritis environment by activating autophagy. These findings suggest that 3D‐printing of Mn‐containing scaffolds with improved physicochemical properties and bilineage bioactivities represents an intelligent strategy for regenerating osteochondral defects.     

Carbon Nanotube Coatings on Bioglass‐Based Tissue Engineering Scaffolds

The coating of highly porous Bioglass^® based 3D scaffolds with multi‐walled carbon nanotubes (CNT) was investigated. Foam like Bioglass^® scaffolds were fabricated by the replica technique and electrophoretic deposition was used to deposit homogeneous layers of CNT throughout the scaffold pore structure. The optimal experimental conditions were determined to be: applied voltage 15 V and deposition time 20 minutes, utilizing a concentrated aqueous suspension of CNT with addition of a surfactant and iodine. The scaffold pore structure remained invariant after the CNT coating, as assessed by SEM. The incorporation of CNTs induced a nanostructured internal surface of the pores which is thought to be beneficial for osteoblast cell attachment and proliferation. Bioactivity of the scaffolds was assessed by immersion studies in simulated body fluid (SBF) for periods of up to 2 weeks and the subsequent determination of hydroxyapatite (HA) formation. The presence of CNTs can enhance the bioactive behaviour of the scaffolds since CNTs can serve as template for the ordered formation of a nanostructured HA layers, which does not occur on uncoated Bioglass^® surfaces.     

Using Plasma Deposits to Promote Cell Population of the Porous Interior of Three‐Dimensional Poly(D,L‐Lactic Acid) Tissue‐Engineering Scaffolds

Cell adhesion and proliferation on poly(D,L ‐lactic acid) (P_DLLA) tissue‐engineering scaffolds is low. This is generally regarded to be due to the surface chemistry of the P_DLLA polymer, although topographic features often worsen the situation. This study reports for the first time successful deposition of a plasma polymer throughout the porous network of a three‐dimensional scaffold. This allylamine plasma deposit was used to improve cell adhesion on the P_DLLA surface. X‐ray photoelectron spectroscopy (XPS) analysis of sectioned scaffolds was used to demonstrate the penetration of nitrogen species to the inner surfaces and to compare the virgin P_DLLA scaffold and the plasma polymer coated P_DLLA scaffold with plasma‐grafted allylamine. The nitrogen concentration at the exterior and interior scaffold surfaces was greater for the plasma deposits than for the grafted surfaces, and the chemical state of the incorporated surface nitrogen using the two methods was found to be different. Evaluation in vitro was carried out by studying 3T3 fibroblast attachment, morphology, and metabolic activity on the scaffolds. Cell activity and attachment was found to be greater for the plasma deposits than the plasma‐grafted P_DLLA scaffolds, and both were greater than for the virgin P_DLLA scaffolds. It is concluded that plasma deposition is a viable method of increasing cell attachment throughout porous P_DLLA scaffolds without changing the bulk characteristics of the polymer.     

Mesenchymal Stem Cell-Laden Composite β Cell Porous Microgel for Diabetes Treatment

Type 1 diabetes mellitus is a chronic metabolic condition characterized by the autoimmune damage of pancreatic β cells. As an alternative to continuous exogenous insulin administration of insulin, β cell transplantation is shown to provide an alternative approach for controlling hyperglycemia in diabetes. However, β cell transplantation faces significant challenges of low β cell proliferation and immunologic insults. Thus, novel approaches capable of promoting the islet microenvironment for sustainability is highly desired. This study develops mesenchymal stem cell (MSC)-laden composite β cell porous microgels (MGs) to address sustainability for the treatment of diabetes. The MGs are prepared via microfluidic droplet templates encapsulating both MSCs and β cells with porogen for creating a porous structure. In addition to offering a suitable microenvironment for nutrient delivery, the porous structure promoted β cell growth and insulin secretion. The outstanding anti-apoptotic and immunomodulatory roles of MSCs further provide a favorable environment for β cell survival and function. On this basis, the therapeutic performance of the MGs in reducing hyperglycemia and achieving sustained glycemic control in diabetic mice is demonstrated. Collectively, these results show that the novel MGs have great potential for the treatment of diabetes providing a promising platform for clinical β cell transplantation.     

Magnesium Gradient-Based Hierarchical Scaffold for Dual-Lineage Regeneration of Osteochondral Defect

Osteochondral regeneration remains a great challenge due to the limited self-healing ability and the complexity of its hierarchical structure and composition. Mg²⁺ and hypoxia are two effective modulators in boosting chondrogenesis. To this end, a double-layered scaffold (D) consisting of a hydrogel layer on a porous cryogel is fabricated to mimic the hierarchical structure of osteochondral tissue. An Mg²⁺ gradient is incorporated into the double-layered scaffold with hypoxia-mimicking deferoxamine (DFO) embedded in the hydrogel (D-Mg-DFO), which remarkably augments the dual-lineage regeneration of both cartilage and subchondral bone. The higher Mg²⁺ supplementation from the upper hydrogel, associated with its hypoxia-mimicking situation and small pore size, exhibits promotive effects on chondrogenic differentiation. The lower Mg²⁺ supplementation from the bottom cryogel, associated with its interconnected macroporous structure, achieves multiple contributions in stem cell migration from bone marrow cavity, matrix mineralization, and osteogenesis. Furthermore, rabbits’ trochlea osteochondral defects are established to evaluate the regenerative outcome. Compared to control scaffolds containing only Mg²⁺ or DFO, the D-Mg-DFO scaffold presents the best regenerative effect under the synergistic contribution of multiple factors. Overall, this work provides a new design of scaffold toward an effective repair of cartilage defect.     

Graphene-Based Nanomaterials for Neuroengineering: Recent Advances and Future Prospective

Graphene unique physicochemical properties made it prominent among other allotropic forms of carbon, in many areas of research and technological applications. Interestingly, in recent years, many studies exploited the use of graphene family nanomaterials (GNMs) for biomedical applications such as drug delivery, diagnostics, bioimaging, and tissue engineering research. GNMs are successfully used for the design of scaffolds for controlled induction of cell differentiation and tissue regeneration. Critically, it is important to identify the more appropriate nano/bio material interface sustaining cells differentiation and tissue regeneration enhancement. Specifically, this review is focussed on graphene-based scaffolds that endow physiochemical and biological properties suitable for a specific tissue, the nervous system, that links tightly morphological and electrical properties. Different strategies are reviewed to exploit GNMs for neuronal engineering and regeneration, material toxicity, and biocompatibility. Specifically, the potentiality for neuronal stem cells differentiation and subsequent neuronal network growth as well as the impact of electrical stimulation through GNM on cells is presented. The use of field effect transistor (FET) based on graphene for neuronal regeneration is described. This review concludes the important aspects to be controlled to make graphene a promising candidate for further advanced application in neuronal tissue engineering and biomedical use.