Ultrasound Stimulation of Piezoelectric Nanocomposite Hydrogels Boosts Chondrogenic Differentiation in Vitro, in Both a Normal and Inflammatory Milieu.

The use of piezoelectric nanomaterials combined with ultrasound stimulation is emerging as a promising approach for wirelessly triggering the regeneration of different tissue types. However, it has never been explored for boosting chondrogenesis. Furthermore, the ultrasound stimulation parameters used are often not adequately controlled. In this study, we show that adipose-tissue-derived mesenchymal stromal cells embedded in a nanocomposite hydrogel containing piezoelectric barium titanate nanoparticles and graphene oxide nanoflakes and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every 2 days for 10 days) dramatically boost chondrogenic cell commitment in vitro. Moreover, fibrotic and catabolic factors are strongly down-modulated: proteomic analyses reveal that such stimulation influences biological processes involved in cytoskeleton and extracellular matrix organization, collagen fibril organization, and metabolic processes. The optimal stimulation regimen also has a considerable anti-inflammatory effect and keeps its ability to boost chondrogenesis in vitro, even in an inflammatory milieu. An analytical model to predict the voltage generated by piezoelectric nanoparticles invested by ultrasound waves is proposed, together with a computational tool that takes into consideration nanoparticle clustering within the cell vacuoles and predicts the electric field streamline distribution in the cell cytoplasm. The proposed nanocomposite hydrogel shows good injectability and adhesion to the cartilage tissue ex vivo, as well as excellent biocompatibility in vivo, according to ISO 10993. Future perspectives will involve preclinical testing of this paradigm for cartilage regeneration.

Case report: 3D intracranial vessel wall MRI in Susac syndrome: potential relevance for diagnosis and therapeutic management.

Background: Susac syndrome (SS) is a rare immune-mediated vasculitis affecting retina, inner ear and brain. Assessment of central nervous system (CNS) involvement is currently based on standard brain magnetic resonance imaging (MRI) sequences. Accuracy of three dimensional (3D)-vessel wall imaging (VWI) was compared to standard sequences and contrast-enhanced-3D T2-fluid attenuated inversion recovery (CE-FLAIR) to assess CNS disease activity in two cases of definite SS. Methods: Brain MRI scan and retinal fluorescein angiogram (RFA) were performed at disease onset and at 1, 3, and 6 months after induction therapy start. CE-FLAIR and VWI based on 3D black-blood proton density weighted (PDW) with and without gadolinium were added to standard sequences on a 3 Tesla MRI scanner. Results: Contrast enhanced-VWI (CE-VWI) detected an abnormal diffuse leptomeningeal enhancement (LME) in both cases at onset and during follow-up. Pathological enhancement on CE-VWI persisted at 6-month brain MRI, despite absence of new lesions and disappearance of LME on CE-FLAIR. Follow-up RFA revealed new arterial wall hyperfluorescence in both cases. Conclusions: VWI may represent a useful tool for diagnosing and monitoring CNS disease activity in SS patients, as confirmed by concordance with RFA, leading treatment's choice and timing. Moreover, CE-VWI seemed at least as sensitive as CE-FLAIR in detecting LME, possibly being superior to the latter in posterior fossa. LME remission might be not accurate in predicting suppression of CNS inflammation in SS.

Enhancing Intermediate Vision in Patients Affected by Epiretinal Membrane Treated by Phaco-Vitrectomy.

BACKGROUND: The aim of this research was to see if a refractive enhanced monofocal IOL (Eyhance IOL, IOL Abbott Medical Optics, Inc., Santa Ana, CA, USA) can provide better intermediate vision in patients undergoing phaco-vitrectomy due to cataract and epiretinal macular membrane (ERM). METHODS: A nonrandomized prospective observational comparative study enrolled patients affected by cataract and ERM undergoing phaco-vitrectomy. A follow up of 6 months was established. Corrected and uncorrected visual acuity of both monocular and binocular types were assessed regarding intermediate and far distances. The CATQUEST 9-SF questionnaire was administered preoperatively and at the last follow-up. RESULTS: Twenty-three eyes of twenty-three patients were enrolled, with 11 in the enhanced monofocal group. The uncorrected and corrected distance visual acuity after 6 months was not statistically different. Both monocular and binocular uncorrected intermediate visual acuity after 6 months were higher in the enhanced monofocal group (p < 0.001). The corrected intermediate visual acuity after 6 months was higher in the enhanced monofocal group (p = 0.01). The CATQUEST-9SF questionnaire showed significant differences in the variation between the preoperative condition and six-month postoperative results (p < 0.001). CONCLUSIONS: This refractive enhanced monofocal IOL can provide better intermediate vision compared to a standard monofocal IOL in patients undergoing phaco-vitrectomy due to cataracts and ERM. Further studies are necessary to confirm these results.

Soft Perfusable Device to Culture Skeletal Muscle 3D Constructs in Air.

Devices for in vitro culture of three-dimensional (3D) skeletal muscle tissues have multiple applications, including tissue engineering and muscle-powered biorobotics. In both cases, it is crucial to recreate a biomimetic environment by using tailored scaffolds at multiple length scales and to administer prodifferentiative biophysical stimuli (e.g., mechanical loading). On the contrary, there is an increasing need to develop flexible biohybrid robotic devices capable of maintaining their functionality beyond laboratory settings. In this study, we describe a stretchable and perfusable device to sustain cell culture and maintenance in a 3D scaffold. The device mimics the structure of a muscle connected to two tendons: Tendon-Muscle-Tendon (TMT). The TMT device is composed of a soft (E ∼ 6 kPa) porous (pore diameter: ∼650 µm) polyurethane scaffold, encased within a compliant silicone membrane to prevent medium evaporation. Two tendon-like hollow channels interface the scaffold with a fluidic circuit and a stretching device. We report an optimized protocol to sustain C2C12 adhesion by coating the scaffold with polydopamine and fibronectin. Then, we show the procedure for the soft scaffold inclusion in the TMT device, demonstrating the device's ability to bear multiple cycles of elongations, simulating a protocol for cell mechanical stimulation. By using computational fluid dynamic simulations, we show that a flow rate of 0.62 mL/min ensures a wall shear stress value safe for cells (<2 Pa) and 50% of scaffold coverage by an optimal fluid velocity. Finally, we demonstrate the effectiveness of the TMT device to sustain cell viability under perfusion for 24 h outside of the CO2 incubator. We believe that the proposed TMT device can be considered an interesting platform to combine several biophysical stimuli, aimed at boosting skeletal muscle tissue differentiation in vitro, opening chances for the development of muscle-powered biohybrid soft robots with long-term operability in real-world environments.

Non-anti TNFα biologic agents for noninfectious uveitis associated with systemic inflammatory diseases: a systematic review.

INTRODUCTION: Noninfectious uveitis related to systemic inflammatory diseases represents a leading cause of blindness. Anti-TNFα agents are the first-line biologic therapy after traditional immunosuppressants, for ocular and systemic involvement. However, some patients fails anti-TNFα agents, due to primary inefficacy, loss of efficacy or adverse events. AREAS COVERED: This systematic review summarizes evidence on the efficacy and safety of non-anti-TNFα biologics in adult patients with noninfectious uveitis associated with systemic inflammatory diseases. The systematic review of PubMed and Embase yielded 3663 records, from which 16 studies were included (13 non-controlled, 3 controlled trials). Most studies focused on Behçet's syndrome (BS) and juvenile idiopathic arthritis (JIA) and assessed the efficacy of tocilizumab (n = 11), rituximab (n = 3), secukinumab (n = 1), or anakinra/canakinumab (n = 1). A body of evidence supports the use of tocilizumab BS and JIA-associated uveitis, for improving visual acuity, reducing central macular thickness, inducing ocular remission, and sparing corticosteroids. Preliminary data suggest that rituximab may represent a valid alternative, particularly in JIA, while anakinra/canakinumab might play a role in BS-associated uveitis. The role of secukinumab appears limited. EXPERT OPINION: Current evidence encourages investigations on the efficacy and safety of non-anti-TNFα agents in noninfectious non-idiopathic uveitis.

A Novel Approach for Multiple Material Extrusion in Arthroscopic Knee Surgery.

Articular cartilage defects and degenerative diseases are pathological conditions that cause pain and the progressive loss of joint functionalities. The most severe cases are treated through partial or complete joint replacement with prostheses, even if the interest in cartilage regeneration and re-growth methods is steadily increasing. These methods consist of the targeted deposition of biomaterials. Only a few tools have been developed so far for performing these procedures in a minimally invasive way. This work presents an innovative device for the direct deposition of multiple biomaterials in an arthroscopic scenario. The tool is easily handleable and allows the extrusion of three different materials simultaneously. It is also equipped with a flexible tip to reach remote areas of the damaged cartilage. Three channels are arranged coaxially and a spring-based dip-coating approach allows the fabrication and assembly of a bendable polymeric tip. Experimental tests were performed to characterize the tip, showing the ability to bend it up to 90° (using a force of ~ 1.5 N) and to extrude three coaxial biomaterials at the same time with both tip straight and tip fully bent. Rheometric analysis and fluid-dynamic computational simulations were performed to analyze the fluids' behavior; the maximum shear stresses were observed in correspondence to the distal tip and the channel convergence chamber, but with values up to ~ 1.2 kPa, compatible with a safe extrusion of biomaterials, even laden with cells. The cells viability was assessed after the extrusion with Live/Dead assay, confirming the safety of the extrusion procedures. Finally, the tool was tested arthroscopically in a cadaveric knee, demonstrating its ability to deliver the biomaterial in different areas, even ones that are typically hard-to-reach with traditional tools.

Adaptive Optics Imaging to Analyze the Photoreceptor Layer Reconstitution in Acute Syphilitic Posterior Placoid Chorioretinopathy.

Acute posterior syphilitic placoid chorioretinopathy (ASPPC) is a rare ocular manifestation of syphilis characterized by outer retinal layers involvement and drop in visual acuity. The current work documents outer retinal layer involvement in this pathology and their reconstitution with treatment by means of adaptive optics (AO). Three eyes of two patients together with four controls eyes were included in the study. Patients underwent optical coherence tomography (OCT) and OCT angiography (OCTA) scan centered on fovea, where vessel density (VD) and vessel perfusion (VP) were calculated. AO images centered on fovea were acquired and cone density (CD) and cone spacing (CS) were measured and compared to control group. Multimodal imaging was performed at presentation, at 10 days, and at 2-month follow-up. All eyes improved in visual acuity, with reconstitution in outer retinal layers at 2-month follow-up. Overall choriocapillary layer VD and VP improved. AO imaging was able to identify outer retinal alterations at presentation and at follow-ups, with improvement in tissue architecture. CD and CS was respectively lower and greater than controls at all follow-ups and improved within patients at the 2-month follow-up. In conclusion, AO was able to document outer retinal alterations in ASPPC at presentation and improvement over the follow-up, representing a tool to study photoreceptor layer involvement in this pathology.

Modeling Self-Rollable Elastomeric Films for Building Bioinspired Hierarchical 3D Structures.

In this work, an innovative model is proposed as a design tool to predict both the inner and outer radii in rolled structures based on polydimethylsiloxane bilayers. The model represents an improvement of Timoshenko's formula taking into account the friction arising from contacts between layers arising from rolling by more than one turn, hence broadening its application field towards materials based on elastomeric bilayers capable of large deformations. The fabricated structures were also provided with surface topographical features that would make them potentially usable in different application scenarios, including cell/tissue engineering ones. The bilayer design parameters were varied, such as the initial strain (from 20 to 60%) and the bilayer thickness (from 373 to 93 µm). The model matched experimental data on the inner and outer radii nicely, especially when a high friction condition was implemented in the model, particularly reducing the error below 2% for the outer diameter while varying the strain. The model outperformed the current literature, where self-penetration is not excluded, and a single value of the radius of spontaneous rolling is used to describe multiple rolls. A complex 3D bioinspired hierarchical elastomeric microstructure made of seven spirals arranged like a hexagon inscribed in a circumference, similar to typical biological architectures (e.g., myofibrils within a sarcolemma), was also developed. In this case also, the model effectively predicted the spirals' features (error smaller than 18%), opening interesting application scenarios in the modeling and fabrication of bioinspired materials.

Piezoelectric nanocomposite bioink and ultrasound stimulation modulate early skeletal myogenesis.

Despite the significant progress in bioprinting for skeletal muscle tissue engineering, new stimuli-responsive bioinks to boost the myogenesis process are highly desirable. In this work, we developed a printable alginate/Pluronic-based bioink including piezoelectric barium titanate nanoparticles (nominal diameter: ∼60 nm) for the 3D bioprinting of muscle cell-laden hydrogels. The aim was to investigate the effects of the combination of piezoelectric nanoparticles with ultrasound stimulation on early myogenic differentiation of the printed structures. After the characterization of nanoparticles and bioinks, viability tests were carried out to investigate three nanoparticle concentrations (100, 250, and 500 µg mL-1) within the printed structures. An excellent cytocompatibility was confirmed for nanoparticle concentrations up to 250 µg mL-1. TEM imaging demonstrated the internalization of BTNPs in intracellular vesicles. The combination of piezoelectric nanoparticles and ultrasound stimulation upregulated the expression of MYOD1, MYOG, and MYH2 and enhanced cell aggregation, which is a crucial step for myoblast fusion, and the presence of MYOG in the nuclei. These results suggest that the direct piezoelectric effect induced by ultrasound on the internalized piezoelectric nanoparticles boosts myogenesis in its early phases.

Primers for the Adhesion of Gellan Gum-Based Hydrogels to the Cartilage: A Comparative Study.

A stable adhesion to the cartilage is a crucial requisite for hydrogels used for cartilage regeneration. Indeed, a weak interface between the tissue and the implanted material may produce a premature detachment and thus the failure of the regeneration processes. Fibrin glue, cellulose nanofibers and catecholamines have been proposed in the state-of-the-art as primers to improve the adhesion. However, no studies focused on a systematic comparison of their performance. This work aims to evaluate the adhesion strength between ex vivo cartilage specimens and polysaccharide hydrogels (gellan gum and methacrylated gellan gum), by applying the mentioned primers as intermediate layer. Results show that the fibrin glue and the cellulose nanofibers improve the adhesion strength, while catecholamines do not guarantee reaching a clinically acceptable value. Stem cells embedded in gellan gum hydrogels reduce the adhesion strength when fibrin glue is used as a primer, being anyhow still sufficient for in vivo applications.

RGD-Functionalized Hydrogel Supports the Chondrogenic Commitment of Adipose Mesenchymal Stromal Cells.

Articular cartilage is known to have limited intrinsic self-healing capacity when a defect or a degeneration process occurs. Hydrogels represent promising biomaterials for cell encapsulation and injection in cartilage defects by creating an environment that mimics the cartilage extracellular matrix. The aim of this study is the analysis of two different concentrations (1:1 and 1:2) of VitroGel® (VG) hydrogels without (VG-3D) and with arginine-glycine-aspartic acid (RGD) motifs, (VG-RGD), verifying their ability to support chondrogenic differentiation of encapsulated human adipose mesenchymal stromal cells (hASCs). We analyzed the hydrogel properties in terms of rheometric measurements, cell viability, cytotoxicity, and the expression of chondrogenic markers using gene expression, histology, and immunohistochemical tests. We highlighted a shear-thinning behavior of both hydrogels, which showed good injectability. We demonstrated a good morphology and high viability of hASCs in both hydrogels. VG-RGD 1:2 hydrogels were the most effective, both at the gene and protein levels, to support the expression of the typical chondrogenic markers, including collagen type 2, SOX9, aggrecan, glycosaminoglycan, and cartilage oligomeric matrix protein and to decrease the proliferation marker MKI67 and the fibrotic marker collagen type 1. This study demonstrated that both hydrogels, at different concentrations, and the presence of RGD motifs, significantly contributed to the chondrogenic commitment of the laden hASCs.

Monolithic Three-Dimensional Functionally Graded Hydrogels for Bioinspired Soft Robots Fabrication.

Bioinspired soft robotics aims at reproducing the complex hierarchy and architecture of biological tissues within artificial systems to achieve the typical motility and adaptability of living organisms. The development of suitable fabrication approaches to produce monolithic bodies provided with embedded variable morphological and mechanical properties, typically encountered in nature, is still a technological challenge. Here we report on a novel manufacturing approach to produce three-dimensional functionally graded hydrogels (3D-FGHs) provided with a controlled porosity gradient conferring them variable stiffness. 3D-FGHs are fabricated by means of a custom-designed liquid foam templating (LFT) technique, which relies on the inclusion of air bubbles generated by a blowing agent into the monomer-based template solution during ultraviolet-induced photopolymerization. The 3D-FGHs' apparent Young's modulus ranges from 0.37 MPa (bulky hydrogel region) to 0.09 MPa (highest porosity region). A fish-shaped soft swimmer is fabricated to demonstrate the feasibility of the LFT technique to produce bioinspired robots. Mobility tests show a significant improvement in terms of swimming speed when the robot is provided with a graded body. The proposed manufacturing approach constitutes an enabling solution for the development of macroscopic functionally graded hydrogel-based structures usable in biomimetic underwater soft robotics applications.

Non-infectious uveitis burden on quality of life and work impairment assessed through different psychometric questionnaires.

BACKGROUND: The purpose of this study was to evaluate the association between a novel psychometric 12-item questionnaire (U-qest) and other validated questionnaires to assess quality of life and work impairment in patients with non-infectious uveitis. METHODS: Data were collected at baseline and 3 months postbaseline using U-qest and two other validated questionnaires: The National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25) and the 12-Item Short-Form Health Survey (SF-12). RESULTS: A total of 136 patients (52.2% female) aged 47.9 ± 14.8 years (mean ± SD) were enrolled in 14 uveitis referral centres. U-qest correlated moderately with VFQ-25 and SF-12 at baseline and at 3 months. Both U-qest and VFQ-25 scores improved as disease improved; however, U-qest also detected improvement in patients for whom VFQ-25 scores did not improve. Disease activity was shown to significantly affect activity impairment. Patients and physicians expressed positive perceptions regarding the use and benefit of this instrument. U-qest showed very good reliability in terms of internal consistency (Cronbach's alpha = 0.91). CONCLUSIONS: U-qest can be considered a useful tool to assess the burden of uveitis on quality of life.

Vitreoschisis and retinal detachment: New insight in proliferative vitreoretinopathy.

PURPOSE: To assess the occurrence of peripheral vitreoschisis-induced vitreous cortex remnants (p-VCRs) in primary rhegmatogenous retinal detachment (RD) and investigate whether the presence of p-VCRs results in a greater risk of RD recurrence, secondary to Proliferative Vitreoretinopathy (PVR) development after pars plana vitrectomy (PPV). METHODS: Patients who underwent PPV for primary rhegmatogenous RD between January 2016 and December 2018 were included. The presence of residual p-VCRs was confirmed intraoperatively using triamcinolone acetonide (TA). Patients with p-VCRs were divided into two groups: Group A comprised of patients who underwent PPV without p-VCR removal, while Group B included patients who underwent PPV with p-VCR removal. RESULTS: Four hundred-thirteen eyes with evidence of p-VCR were analyzed. Two-hundred-twenty-three eyes underwent PPV without VCR removal (Group A), while 190 eyes underwent PPV with p-VCR removal (Group B). Primary anatomical success was 91.5% in the Group A and 95.4% in the group B. Retinal re-detachment due to PVR occurred in 17 (7.6%) eyes in Group A and in four (2.1%) eyes in Group B within the first 3 months (p = 0.01). Among group A, in 11 eyes, there was a diffuse posterior PVR grade C, while six eyes were focal PVR grade C. In Group B, we observed four retinal re-detachment due to focal PVR grade C. CONCLUSION: The presence of p-VCRs seems to be associated with a higher incidence of PVR development and might also result in more complex RD recurrence, this suggests the need for more aggressive VCRs removal during the first surgery.

Bilateral choroidal metastasis from adenoid cystic carcinoma of the submandibular salivary gland.

PURPOSE: A case of bilateral choroidal metastasis from an adenoid cystic carcinoma of the submandibular gland is described. CASE DESCRIPTION: A 45-years-old woman with a history of metastatic adenoid cystic carcinoma presented with visual impairment in both eyes. Fundus images showed bilateral creamy-white choroidal masses. Optical coherence tomography revealed subretinal fluid with high reflective speckles and a "lumpy bumpy" anterior contour of the lesions. Fluorescein angiography showed a hypofluorescent pattern of the lesions in early arterial phases, and progressive late hyperfluorescence. A diagnosis of bilateral choroidal metastasis from adenoid cystic carcinoma was made. The patient was advised to underwent palliative chemotherapy, but she expired a few weeks after the diagnosis. CONCLUSION: Salivary gland carcinoma rarely metastasizes to the choroid, with few cases described in literature. In patients with a history of salivary glands tumor the possibility of choroidal metastatization should always be considered.

The role of anterior segment optical coherence tomography in uveitis-glaucoma-hyphema syndrome.

PURPOSE: To describe features of uveitis-glaucoma-hyphema (UGH) syndrome, using Anterior Segment-Optical Coherence Tomography (AS-OCT) and Ultrasound Biomicroscopy (UBM) and to evaluate the diagnostic role of AS-OCT as an imaging technique alternative to UBM. DESIGN: Retrospective case series. METHODS: Four eyes of 4 patients with UGH syndrome were analyzed. All patients reported previous uncomplicated cataract surgery with in-the-bag implantation of single-piece-intraocular lens (IOL). They underwent at presentation complete ophthalmological examination and imaging with slit-lamp anterior segment photographs, UBM and AS-OCT. RESULTS: Although AS-OCT did not allow to visualize the structures behind the iris, it displayed a contact between IOL (plate and/or haptics) and iris and IOL tilting in 3 out of 4 eyes. AS-OCT directly detected the cause of UGH syndrome in one eye, 2 eyes required some expedients to display the iris chafing, like scans in mydriasis and/or patient's gaze direction change. AS-OCT did not allow to appreciate the IOL-iris contact (showed by UBM technique) only in one eye, probably due to the change of patient position from supine to sitting, and consequent anteriorization of iris diaphragm. Furthermore AS-OCT showed fine details, as capsular bag collapse and indirect signs of haptic malposition in 3 out of 4 eyes. CONCLUSION: AS-OCT is a non-invasive technique that allows to determine IOL position and IOL-uveal contact in selected cases of UGH syndrome. Considering AS-OCT and UBM advantages and limitations, AS-OCT should be used as first imaging modality when clinical diagnosis is uncertain. When UGH diagnosis cannot be verified using AS-OCT, UBM should be performed.

Effects of the 3D Geometry Reconstruction on the Estimation of 3D Porous Scaffold Permeability.

3D scaffolds for tissue engineering typically need to adopt a dynamic culture to foster cell distribution and survival throughout the scaffold. It is, therefore, crucial to know fluids' behavior inside the scaffold architecture, especially for complex porous ones. Here we report a comparison between simulated and measured permeability of a porous 3D scaffold, focusing on different modeling parameters. The scaffold features were extracted by microcomputed tomography (µCT) and representative volume elements were used for the computational fluid-dynamic analyses. The objective was to investigate the sensitivity of the model to the degree of detail of the µCT image and the elements of the mesh. These findings highlight the pros and cons of the modeling strategy adopted and the importance of such parameters in analyzing fluid behavior in 3D scaffolds.

Graphene Oxide and Reduced Graphene Oxide Nanoflakes Coated with Glycol Chitosan, Propylene Glycol Alginate, and Polydopamine: Characterization and Cytotoxicity in Human Chondrocytes.

Recently, graphene and its derivatives have been extensively investigated for their interesting properties in many biomedical fields, including tissue engineering and regenerative medicine. Nonetheless, graphene oxide (GO) and reduced GO (rGO) are still under investigation for improving their dispersibility in aqueous solutions and their safety in different cell types. This work explores the interaction of GO and rGO with different polymeric dispersants, such as glycol chitosan (GC), propylene glycol alginate (PGA), and polydopamine (PDA), and their effects on human chondrocytes. GO was synthesized using Hummer's method, followed by a sonication-assisted liquid-phase exfoliation (LPE) process, drying, and thermal reduction to obtain rGO. The flakes of GO and rGO exhibited an average lateral size of 8.8 ± 4.6 and 18.3 ± 8.5 µm, respectively. Their dispersibility and colloidal stability were investigated in the presence of the polymeric surfactants, resulting in an improvement in the suspension stability in terms of average size and polydispersity index over 1 h, in particular for PDA. Furthermore, cytotoxic effects induced by coated and uncoated GO and rGO on human chondrocytes at different concentrations (12.5, 25, 50 and 100 µg/mL) were assessed through LDH assay. Results showed a concentration-dependent response, and the presence of PGA contributed to statistically decreasing the difference in the LDH activity with respect to the control. These results open the way to a potentially safer use of these nanomaterials in the fields of cartilage tissue engineering and regenerative medicine.

Piezoelectric Nanomaterials Activated by Ultrasound: The Pathway from Discovery to Future Clinical Adoption.

Electrical stimulation has shown great promise in biomedical applications, such as regenerative medicine, neuromodulation, and cancer treatment. Yet, the use of electrical end effectors such as electrodes requires connectors and batteries, which dramatically hamper the translation of electrical stimulation technologies in several scenarios. Piezoelectric nanomaterials can overcome the limitations of current electrical stimulation procedures as they can be wirelessly activated by external energy sources such as ultrasound. Wireless electrical stimulation mediated by piezoelectric nanoarchitectures constitutes an innovative paradigm enabling the induction of electrical cues within the body in a localized, wireless, and minimally invasive fashion. In this review, we highlight the fundamental mechanisms of acoustically mediated piezoelectric stimulation and its applications in the biomedical area. Yet, the adoption of this technology in a clinical practice is in its infancy, as several open issues, such as piezoelectric properties measurement, control of the ultrasound dose in vitro, modeling and measurement of the piezo effects, knowledge on the triggered bioeffects, therapy targeting, biocompatibility studies, and control of the ultrasound dose delivered in vivo, must be addressed. This article explores the current open challenges in piezoelectric stimulation and proposes strategies that may guide future research efforts in this field toward the translation of this technology to the clinical scene.