Robotics has been proposed as a promising solution for treating individuals with motor, sensory, and/or cognitive disabilities. Despite the great technological effort put into this field, the translation of robots from the laboratory to the clinical environment is not a seamless and smooth process, and their real-world adoption remains limited. Several barriers to the introduction of robotics in clinical practice have been identified, including a lack of sufficient scientific evidence about its actual cost/effectiveness, resistance to adopting these technologies, and economic, ethical, and regulatory restraints. Fit for Medical Robotics (Fit4MedRob) is an ambitious Initiative designed to bridge the gap between technological innovation and clinical application. One of the main goals of the Initiative is to conduct large-scale pragmatic trials to evaluate the effectiveness and the sustainability of commercially available robotic solutions. To guide the design of these trials, different online surveys have been implemented and delivered to identify the needs of healthcare practitioners and patients at different phases of the disease (acute to chronic) and therapeutic settings (hospital to home care). The results of the Initiative will suggest new organizational models to effectively introduce robotics-assisted rehabilitation into clinical practice. The paper will report on the opportunities of robotics for rehabilitation, the barriers to their clinical implementation, and the proposal of Fit4MedRob to overcome such limitations and facilitate the effective clinical implementation of robotic solutions.

One of the significant barriers to the adoption of rehabilitation robotics into clinical care over the last 30 years has been the high investment costs of the technology. There have been limited efforts to understand the healthcare economics of implementing rehabilitation robotics compared to usual care. From the few studies that have investigated the cost, the findings have had limited generalizability to other clinical settings or contexts due to diverse healthcare models and the complexity of implementation factors. This study compares three organizational models in rehabilitation centers across the USA, UK, and Italy. We developed a common formula to compute cost differences between robotics and usual care for the upper limb and conducted a deterministic sensitivity analysis to identify key cost-influencing parameters. Results indicate that models where a single therapist supervises multiple patients can lead to significant economic savings: the Veteran Affairs in the US could achieve 18% savings with full utilization of robotic treatment slots (4300 h/year) and Italy’s Fondazione don Gnocchi rehabilitation model could realize 30% savings (6187 h/year). Conversely, the organizational model adopted by the RATULS study in UK generates 105% additional costs with 1820 h/year of robotics usage, mainly due to the 1:1 therapist-patient ratio adopted.

IntroductionMost patients suffering from neurological disorders endure varying degrees of upper limb dysfunction, limiting their everyday activities, with only a limited number regaining full arm use. Robotic and technological rehabilitation has been demonstrated to be a feasible solution to guarantee an effective rehabilitation to recover upper limb performance or to prevent complications of upper limb immobility. However, there is currently a lack of studies which analyze the sustainability of robotic and technological rehabilitation by comparing its costs to conventional rehabilitation pathways.MethodsSince technology-based and conventional rehabilitation of the upper limb have been demonstrated to have comparable efficacy when the rehabilitation dose is matched, our study concentrates on a cost minimization analysis. The aim of the study is to compare the costs of a “mixed” rehabilitation cycle, which combines conventional and technology-based treatments (the latter delivered with a single therapist supervising several patients), with a cycle of purely conventional treatments. This has been done by developing a cost model and retrospectively analyzing the costs sustained by an Italian hospital which has adopted such a mixed model. A sensitivity analysis has been done to identify the parameters of the model that have the greatest influence on cost difference and to evaluate their optimal values in terms of efficiency of mixed rehabilitation. Finally, probabilistic simulations have been applied to consider the variability of model parameters around such optimized values and evaluate the probability of achieving a given level of savings.ResultsWe found a cost difference of 49.60 € per cycle in favor of mixed rehabilitation. The sensitivity analysis demonstrated that, in the situation of the hospital under investigation, the parameter having the largest influence on the cost difference is the number of robotic treatments in a mixed rehab cycle. Probabilistic simulations indicate a probability higher than 98% of an optimized mixed rehabilitation cycle being less expensive than a pure conventional one.ConclusionThrough a retrospective cost analysis, we found that the technology-based mixed rehabilitation approach, within a specific organizational model allowing a single physiotherapist to supervise up to four patients concurrently, allowed cost savings compared to the conventional rehabilitation model.

The growing number of children using mobile devices and Internet services, given the complexity and risks of the online world, is raising great concerns in parents, caregivers and teachers. Hence, many efforts have been developed to promote a safe, confident and aware use of these devices and services. Among these efforts, in 2017 Google introduced the "Be Internet Awesome" program, and the related serious game Interland. In this paper, we present Interland For All (I4A), anAR evolution of Interland, developed by Fondazione Don Carlo Gnocchi and Fondazione Mondo Digitale ETS, aiming to extend Interland's accessibility to children with some degree of impairment (such as hearing, visual or cognitive). I4A comprises both physical and virtual components running on a smartphone, including some aids specifically targeted to frail children, who could be more exposed to the online risks. The software has been tested by a lower secondary school class and their parents during the RomeCup 2023 event, receiving overall positive feedback but also highlighting some technical shortcomings. The prototype nature of this project requires further studies to investigate in a more structured way its effectiveness, its limitations and possible evolutions. In particular, the mixed use of physical and virtual components deserves to be further fostered, given its potential both in the educational field and in rehabilitation.

Background The majority of stroke survivors experiences significant hand impairments, as weakness and spasticity, with a severe impact on the activity of daily living. To objectively evaluate hand deficits, quantitative measures are needed. The aim of this study is to assess the reliability, the validity and the discriminant ability of the instrumental measures provided by a robotic device for hand rehabilitation, in a sample of patients with subacute stroke. Material and methods In this study, 120 patients with stroke and 40 controls were enrolled. Clinical evaluation included finger flexion and extension strength (using the Medical Research Council, MRC), finger spasticity (using the Modified Ashworth Scale, MAS) and motor control and dexterity during ADL performance (by means of the Frenchay Arm Test, FAT). Robotic evaluations included finger flexion and extension strength, muscle tone at rest, and instrumented MAS and Modified Tardieu Scale. Subjects were evaluated twice, one day apart, to assess the test-retest reliability of the robotic measures, using the Intraclass Correlation Coefficient (ICC). To estimate the response stability, the standard errors of measurement and the minimum detectable change (MDC) were also calculated. Validity was assessed by analyzing the correlations between the robotic metrics and the clinical scales, using the Spearman’s Correlation Coefficient (r). Finally, we investigated the ability of the robotic measures to distinguish between patients with stroke and healthy subjects, by means of Mann-Whitney U tests. Results All the investigated measures were able to discriminate patients with stroke from healthy subjects ( p < 0.001). Test-retest reliability was found to be excellent for finger strength (in both flexion and extension) and muscle tone, with ICCs higher than 0.9. MDCs were equal to 10.6 N for finger flexion, 3.4 N for finger extension, and 14.3 N for muscle tone. Conversely, test-retest reliability of the spasticity measures was poor. Finally, finger strength (in both flexion and extension) was correlated with the clinical scales (r of about 0.7 with MRC, and about 0.5 with FAT). Discussion Finger strength (in both flexion and extension) and muscle tone, as provided by a robotic device for hand rehabilitation, are reliable and sensitive measures. Moreover, finger strength is strongly correlated with clinical scales. Changes higher than the obtained MDC in these robotic measures could be considered as clinically relevant and used to assess the effect of a rehabilitation treatment in patients with subacute stroke.

Background and Purpose: After stroke, only 12% of survivors obtain complete upper limb (UL) functional recovery, while in 30% to 60% UL deficits persist. Despite the complexity of the UL, prior robot-mediated therapy research has used only one robot in comparisons to conventional therapy. We evaluated the efficacy of robotic UL treatment using a set of 4 devices, compared with conventional therapy. Methods: In a multicenter, randomized controlled trial, 247 subjects with subacute stroke were assigned either to robotic (using a set of 4 devices) or to conventional treatment, each consisting of 30 sessions. Subjects were evaluated before and after treatment, with follow-up assessment after 3 months. The primary outcome measure was change from baseline in the Fugl-Meyer Assessment (FMA) score. Secondary outcome measures were selected to assess motor function, activities, and participation. Results: One hundred ninety subjects completed the posttreatment assessment, with a subset (n = 122) returning for follow-up evaluation. Mean FMA score improvement in the robotic group was 8.50 (confidence interval: 6.82 to 10.17), versus 8.57 (confidence interval: 6.97 to 10.18) in the conventional group, with no significant between-groups difference (adjusted mean difference −0.08, P = 0.948). Both groups also had similar change in secondary measures, except for the Motricity Index, with better results for the robotic group (adjusted mean difference 4.42, P = 0.037). At follow-up, subjects continued to improve with no between-groups differences. Discussion and Conclusions: Robotic treatment using a set of 4 devices significantly improved UL motor function, activities, and participation in subjects with subacute stroke to the same extent as a similar amount of conventional therapy. Video Abstract is available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A291).

Robot-mediated therapy is a viable approach for upper limb rehabilitation. The upper limb is a highly complex segment and the identification of the appropriate devices capable of rehabilitating it globally (from the shoulder to the hand) in clinical practice is crucial. In this work, we aimed: (i) to describe an approach used in identifying a set of technological and robotic devices to globally treat the upper limb, and (ii) to evaluate the feasibility of the identified set in clinical practice. Using an ad-hoc form, a multidisciplinary team identified a set of four robotic and sensor-based devices to treat globally the upper limb. Then, 30 stroke patients were enrolled and assigned to two groups: the robotic group (RG), where patients were treated with the robotic set, or the conventional group (CG). All patients were evaluated before and after the treatment. In the RG the patients used all the devices (one in each rehabilitation session); the treatment was well accepted, without drop-outs or adverse events. Using a multidisciplinary approach, we identified a set of technological and robotic devices to treat the upper limb globally, and then we experimented to ascertain its feasibility, in a pilot study. Robotics offers a considerable number of devices for rehabilitation that should be selected according to rehabilitation aims and feasibility in clinical practice.

Long-term motor deficits affect approximately two thirds of stroke survivors, reducing their quality of life. An effective rehabilitation therapy requires intense and repetitive training, which is resource demanding. Virtual Agents (VAs) and Socially Assistive Robots (SARs) offer high intensity, repetitive and reproducible therapy and are thus both promising as rehabilitation tools. In this paper, we compare a SAR and a VA during a rehabilitation task in terms of users’ engagement and movement performance, while leveraging neuroscientific methods to investigate potential differences at the neural level. Results show that our participants’ performance on the exercise was higher with a SAR than with a VA, which was especially clear under conditions of decreased perceptual information. Our participants reported higher levels of engagement with the SAR. Taken together, we provide evidence that SARs are a favorable alternative to VAs as rehabilitation tools.

Here we describe a simple approach for the simultaneous detection of multiple microRNAs (miRNAs) using a single nanostructured reagent as surface plasmon resonance imaging (SPRi) enhancer and without using enzymatic reactions, sequence specific enhancers or multiple enhancing steps as normally reported in similar studies. The strategy involves the preparation and optimisation of neutravidin-coated gold nanospheres (nGNSs) functionalised with a previously biotinylated antibody (Ab) against DNA/RNA hybrids. The Ab guarantees the recognition of any miRNA sequence adsorbed on a surface properly functionalised with different DNA probes; at the same time, gold nanoparticles permit to detect this interaction, thus producing enough SPRi signal even at a low ligand concentration. After a careful optimisation of the nanoenhancer and after its characterisation, the final assay allowed the simultaneous detection of four miRNAs with a limit of detection (LOD) of up to 0.5 pM (equal to 275 attomoles in 500 μL) by performing a single enhancing injection. The proposed strategy shows good signal specificity and permits to discriminate wild-type, single- and triple-mutated sequences much better than non-enhanced SPRi. Finally, the method works properly in complex samples (total RNA extracted from blood) as demonstrated by the detection of four miRNAs potentially related to multiple sclerosis used as case study. This proof-of-concept study confirms that the approach provides the possibility to detect a theoretically unlimited number of miRNAs using a simple protocol and an easily prepared enhancing reagent, and may further facilitate the development of affordable multiplexing miRNA screening for clinical purposes.

The use of exosomes for diagnostic and disease monitoring purposes is becoming particularly appealing in biomedical research because of the possibility to study directly in biological fluids some of the features related to the organs from which exosomes originate. A paradigmatic example are brain-derived exosomes that can be found in plasma and used as a direct read-out of the status of the central nervous system (CNS). Inspired by recent remarkable development of plasmonic biosensors, we have designed a surface plasmon resonance imaging (SPRi) assay that, taking advantage of the fact that exosome size perfectly fits within the surface plasmon wave depth, allows the detection of multiple exosome subpopulations of neural origin directly in blood. By use of an array of antibodies, exosomes derived from neurons and oligodendrocytes were isolated and detected with good sensitivity. Subsequently, by injecting a second antibody on the immobilized vesicles, we were able to quantify the amount of CD81 and GM1, membrane components of exosomes, on each subpopulation. In this way, we have been able to demonstrate that they are not homogeneously expressed but exhibit a variable abundance according to the exosome cellular origin. These results confirm the extreme variability of exosome composition and demonstrate how SPRi can provide an effective tool for their characterization. Besides, our work paves the road toward more precise clinical studies on the use of exosomes as potential biomarkers of neurodegenerative diseases.

Virtual reality for the treatment of motor impairment is a burgeoning application of digital technology in neurorehabilitation. Virtual reality systems pose an opportunity for health care providers to augment the dose of task-oriented exercises delivered both in the clinic, and via telerehabilitation models in the home. The technology is almost exclusively applied as an adjunct to traditional approaches and is typically characterized by the use of gamified exergames which feature task-oriented physiotherapy exercises. At present, evidence for the efficacy of this technology is sparse, with some reviews suggesting it is the same or no better than conventional approaches. The purpose of this article is to provide real-world insights on the adoption of a virtual reality by 3 European clinics in 3 different service delivery models. These include an inpatient setting for Parkinson disease, a kiosk model for pediatric neurorehabilitation, and a home-based telerehabilitation model for neurologic patients. Motivations, settings, requirements for the pathology, outcomes, and challenges encountered during this process are reported with the objective of priming clinicians on what to expect when implementing virtual reality in neurorehabilitation.

Multiple ligand presentation is a powerful strategy to enhance the affinity of a probe for its corresponding target. A promising application of this concept lies in the analytical field, where surface immobilized probes interact with their corresponding targets in the context of complex biological samples. Here we investigate the effect of multiple epitope presentation (MEP) in the challenging context of IgE-detection in serum samples using peptide microarrays, and evaluate the influence of probes surface density on the assay results. Using the milk allergen alpha-lactalbumin as a model, we have synthesized three immunoreactive epitope sequences in a linear, branched and tandem form and exploited a chemoselective click strategy (CuAAC) for their immobilization on the surface of two biosensors, a microarray and an SPR chip both modified with the same clickable polymeric coating. We first demonstrated that a fine tuning of the surface peptide density plays a crucial role to fully exploit the potential of oriented and multiple peptide display. We then compared the three multiple epitope presentations in a microarray assay using sera samples from milk allergic patients, confirming that a multiple presentation, in particular that of the tandem construct, allows for a more efficient characterization of IgE-binding fingerprints at a statistically significant level. To gain insights on the binding parameters that characterize antibody/epitopes affinity, we selected the most reactive epitope of the series (LAC1) and performed a Surface Plasmon Resonance Imaging (SPRi) analysis comparing different epitope architectures (linear versus branched versus tandem). We demonstrated that the tandem peptide provides an approximately twofold increased binding capacity with respect to the linear and branched peptides, that could be attributed to a lower rate of dissociation (Kd).

Extracellular vesicles (EVs) from mesenchymal stromal cells (MSC) are emerging as valuable therapeutic agents for tissue regeneration and immunomodulation, but their clinical applications have so far been limited by the technical restraints of current isolation and characterisation procedures. This study shows for the first time the successful application of Raman spectroscopy as label-free, sensitive and reproducible means of carrying out the routine bulk characterisation of MSC-derived vesicles before their use in vitro or in vivo, thus promoting the translation of EV research to clinical practice. The Raman spectra of the EVs of bone marrow and adipose tissue-derived MSCs were compared with human dermal fibroblast EVs in order to demonstrate the ability of the method to distinguish the vesicles of the three cytotypes automatically with an accuracy of 93.7%. Our data attribute a Raman fingerprint to EVs from undifferentiated and differentiated cells of diverse tissue origin, and provide insights into the biochemical characteristics of EVs from different sources and into the differential contribution of sphingomyelin, gangliosides and phosphatidilcholine to the Raman spectra themselves.

Gold nanorods are an important kind of nanoparticles characterized by peculiar plasmonic properties. Despite their widespread use in nanotechnology, the synthetic methods for the preparation of gold nanorods are still not fully optimized. In this paper we describe a new, highly efficient, two-step protocol based on the use of hydroquinone as a mild reducing agent. Our approach allows the preparation of nanorods with a good control of size and aspect ratio (AR) simply by varying the amount of hexadecyl trimethylammonium bromide (CTAB) and silver ions (Ag+) present in the "growth solution". By using this method, it is possible to markedly reduce the amount of CTAB, an expensive and cytotoxic reagent, necessary to obtain the elongated shape. Gold nanorods with an aspect ratio of about 3 can be obtained in the presence of just 50 mM of CTAB (versus 100 mM used in the standard protocol based on the use of ascorbic acid), while shorter gold nanorods are obtained using a concentration as low as 10 mM.

In order to minimize the impact of systemic toxicity of drugs in the treatment of local acute and chronic inflammatory reactions, the achievement of reliable and efficient delivery of therapeutics in/through the skin is highly recommended. While the use of nanoparticles is now an established practice for drug intravenous targeted delivery, their transdermal penetration is still poorly understood and this important administration route remains almost unexplored. In the present study, we have synthesized magnetic (iron oxide) nanoparticles (MNP) coated with an amphiphilic polymer, developed a water-in-oil emulsion formulation for their topical administration and compared the skin penetration routes with the same nanoparticles deposited as a colloidal suspension. Transmission and scanning electron microscopies provided ultrastructural evidence that the amphiphilic nanoparticles (PMNP) cream formulation allowed the efficient penetration through all the skin layers with a controllable kinetics compared to suspension formulation. In addition to the preferential follicular pathway, also the intracellular and intercellular routes were involved. PMNP that crossed all skin layers were quantified by inductively coupled plasma mass spectrometry. The obtained data suggests that combining PMNP amphiphilic character with cream formulation improves the intradermal penetration of nanoparticles. While PMNP administration in living mice via aqueous suspension resulted in preferential nanoparticle capture by phagocytes and migration to draining lymph nodes, cream formulation favored uptake by all the analyzed dermis cell types, including hematopoietic and non-hematopoietic. Unlike aqueous suspension, cream formulation also favored the maintenance of nanoparticles in the dermal architecture avoiding their dispersion and migration to draining lymph nodes via afferent lymphatics.

The detection of biomarkers by means of Surface Enhanced Raman Spectroscopy (SERS) is foreseen to became a very important tool in the clinical practice because of its excellent sensitivity and potential for the simultaneous detection of multiple biomarkers. In the present paper we describe how it was possible to build a sensor for the detection of genetic biomarkers involved in acute myeloid leukemia. The assay is based on the use of a specifically designed SERS substrate made of a 2D crystal structure of polymeric pillars embedded in a gold layer. This substrate is characterized by good enhancing properties coupled with an excellent homogeneity. The SERS substrate was conjugated with DNA probes complementary to a target sequence and used in a sandwich assay with gold nanoparticles labeled with a second DNA probe and a Raman reporter. The so developed assay allowed the detection of a leukemia biomarker (WT1 gene) and an housekeeping gene with low picomolar sensitivity. At last, we optimized the assay in order to tackle one of the main limitations of SERS based assay: the loss of signal that is observed when the Raman spectra are collected in liquid. Combining a preferential functionalization on the polymeric pillars with a different height of the polymer pillars from the gold layer the assay demonstrated its effectiveness even when measured in buffer.

In this article, we describe how it is possible to tune the size and the aspect ratio of gold nanorods obtained using a highly efficient protocol based on the use of hydroquinone as a reducing agent by varying the amounts of CTAB and silver ions present in the “seed-growth” solution. Our approach not only allows us to prepare nanorods with a four times increased Au3+ reduction yield, when compared with the commonly used protocol based on ascorbic acid, but also allows a remarkable reduction of 50–60 % of the amount of CTAB needed. In fact, according to our findings, the concentration of CTAB present in the seed-growth solution do not linearly influence the final aspect ratio of the obtained nanorods, and an optimal concentration range between 30 and 50 mM has been identified as the one that is able to generate particles with more elongated shapes. On the optimized protocol, the effect of the concentration of Ag+ ions in the seed-growth solution and the stability of the obtained particles has also been investigated.

We present a new 3D surface-enhanced Raman spectroscopy substrate made of branched gold nanoparticles supported on ZnO tetrapods that was proved to be effective in different biomedical application such as drug detection and cancer cells analysis.