Leonardo Ricotti

Implantable devices for controlled drug release are extremely promising for the treatment of chronic diseases, such as type 1 diabetes, chronic pain, and others. However, these systems still require periodic invasive refills, which can result in clinical complications and patient discomfort. Previous works introduced the opportunity for a non-invasive refilling of these devices through ingestible capsules. However, concerns remain regarding repeated tissue perforation of the intestinal wall and the corresponding risk of fistula formation. This study presents a novel trans-intestinal port system enabling non-invasive refilling of implanted devices designed to create a stable and controlled interface between the device and the intestinal lumen. The system aims to avoid tissue damage due to repeated needle insertions, ensure proper alignment between the device and capsule, and prevent leakage of digestive fluids into the peritoneal cavity. The design and fabrication of this trans-intestinal port are presented, together with the results of bench tests and a preliminary short-term in vivo test. These findings highlight the potential of the proposed trans-intestinal port as an innovative solution to enable a non-invasive periodic refilling of implantable drug delivery systems, paving the way to a full validation of this technology in the future, which will require long-term in vivo experiments.

Mesenchymal stem cells (MSCs) hold significant promise for tissue engineering and regenerative medicine thanks to their combination of accessibility and multilineage differentiation potential. Among the several factors that influence MSC function, mechanical properties are increasingly recognized as key regulators of cell fate decisions. Despite their importance, the variability of these properties across biologically relevant conditions remains poorly characterized. In this study, we used atomic force microscopy nanoindentation to quantify two mechanical parameters in human adipose tissue-derived MSCs: the Young's modulus (E) and, for the first time in this cell type, the poroelastic diffusion constant (Dp). Measurements were performed on 120 cells derived from six human subjects (three female and three male), at two passages (P4 and P7), and in two subcellular compartments (above the nucleus and above the cytoplasm). Results revealed statistically significant mechanical heterogeneity across subjects, higher values with increasing passages for both E and Dp, and a sex-based difference in E, with female-derived cells being stiffer, but no differences in Dp. These findings preliminarily reveal and quantify mechanical heterogeneity in MSCs, and underscore the need for considering biological variables when designing MSC-based therapies for regenerative medicine and tissue engineering. Our dataset, based on a relatively small sample size, is not intended to capture the full variability of these factors. Instead, it provides preliminary data collected under consistent conditions, intended to inform the estimation of optimal sample sizes for future large-scale studies investigating mechanical heterogeneity.

Neuroinflammation contributes to the progression of many neurological diseases. Here, we explore whether ultrasound can reduce microglia-mediated inflammation in vitro and in vivo. We tested a broad range of ultrasound parameters in a BV2 microglial cell line, treated with lipopolysaccharide (LPS) to induce an inflammatory response. We found that specific combinations of centre frequency, acoustic pressure and treatment duration can significantly lower the levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. These effects lasted up to 72 h and were associated with the downregulation of the nuclear factor κB (NF-κB), suggesting a mechanistic link between ultrasound and inflammation. Further investigation in vivo, in LPS-treated mice, revealed a reduction in TNF-α expression in the hippocampus following ultrasound. Overall, our findings showcase the potential of ultrasound as a non-invasive therapeutic strategy to reduce neuroinflammation and restore brain homeostasis.

The field of soft robotics has shown unprecedented growth in research efforts, scientific achievements, and technological advancements. Bioinspiration and biomimetics have played an instrumental role in the birth and growth of soft robotics. What is next for this field? To promote soft robotics research to the next level and have a broader impact in robotics and engineering fields, in this roadmap, we argue that two research directions should be strengthened (i) more structured, formal methods and tools for designing and developing soft robots and bioinspired robots (ii) more concrete applications of bioinspired soft robots in diverse sectors of human activities. This article provides a roadmap for the design of bioinspired soft robots, the integration of soft robot systems, and their applications in industry and services. Scientists and experts describe the state-of-the art and the perspectives of bioinspired, model-informed design of soft robots, outlining the challenges in developing complex soft robotic systems, and applications of soft robots in diverse fields.

The foreign body reaction often hinders the success of implantable devices, leading to fibrotic encapsulation. Controlling the post-implantation inflammatory phase is key to mitigating the foreign body reaction and promoting device integration. This paper compares three coating strategies for including anti-inflammatory agents onto polyether-ether-ketone (PEEK) surfaces, applying two different zwitterions, namely the 2-methacryloyloxyethyl phosphorylcholine (MPC) and [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA). Two different PEEK surface types were also compared, namely “rough surface” and “smooth surface” (average roughness: 7 μm ± 4 μm and 1.4 μm ± 0.3 μm, respectively). Focused ion beam-scanning electron microscopy (FIB-SEM) confirmed qualitatively the presence of a thin coating layer with an estimated thickness of 100 nm. X-ray photoelectron spectroscopy and water contact angle measurements showed that both MPC and SBMA coatings were highly stable on the PEEK substrates for up to 8 weeks in simulated physiological conditions, when anchored to the PEEK surfaces by exploiting zwitterionic copolymers with N-[3-(dimethylamino)propyl]acrylamide and using a polydopamine adhesive layer. These coatings were also tested in vitro, evaluating their effects on cell adhesion, and the production of inflammatory markers such as interleukin-1β, interleukin-6, tumor necrosis factor-α and nitric oxide from M1 macrophages. The MPC-based coating on smooth PEEK surfaces showed the most remarkable effects, significantly supporting macrophage viability, reducing the release of pro-inflammatory cytokines, and inhibiting nitric oxide release, suggesting a superior capability to modulate inflammation. These findings pave the way for functional coatings to be used in vivo, with the aim of improving PEEK implants’ safety, integration, and longevity.

Peripheral nerve injuries often result in nerve damage that significantly compromises functional recovery. Current treatments have substantial limitations. Engineered nerve guidance conduits emerge as a promising alternative, but their efficacy is limited when bridging large gap injuries. Schwann cells, which are essential for nerve regeneration, require a supportive microenvironment to maintain their regenerative function. Recent advances in tissue engineering focus on combining functional biomaterials and external stimuli, such as electrical stimulation, to achieve nerve guidance conduits that enhance regeneration. This study presents a piezoelectric chitosan scaffold loaded with barium titanate nanoparticles, designed for wireless electrical stimulation of Schwann cells through low-intensity pulsed ultrasound. The scaffold is engineered with an anisotropic pore microstructure to provide biomimicry. Morphological and mechanical characterization confirms that the scaffold exhibits structural properties similar to those of native neural tissue. Using a highly controlled in vitro ultrasound system, we optimize stimulation parameters to maximize cell migration and evaluate neurotrophic factor production. Gene expression analyses reveal the upregulation of cell motility and regeneration pathways. These findings demonstrate that ultrasound-activated chitosan scaffolds hold significant potential as a noninvasive tool for improving nerve regeneration, offering a comprehensive in vitro analysis to facilitate future preclinical and clinical translation.

Skeletal muscle tissue represents an attractive powering component for biohybrid robots, as traditional actuators used in the soft robotic context often rely on complex mechanisms and lack scalability at small dimensions. This article proposes a monolithic biohybrid flexure mechanism actuated by a bioengineered skeletal muscle tissue. The design leverages the contractile properties of a bioengineered skeletal muscle to produce a bending motion in a monolithic, tubular mechanism made of a soft and biocompatible silicone blend. This structure integrates two cylindrical pillars that facilitate force transmission from the bioengineered muscle tissue. Performance assessments reveal excellent contractile and stable behavior upon electrical stimulation, compared to current biohybrid actuation systems, with enhanced performance as the mechanism's internal and external diameters decrease. Finite‐element simulations further reveal distinct force–displacement responses in mechanisms with different flexural rigidity. This innovative, scalable, and easy‐to‐fabricate design represents a significant step forward in the development of novel biohybrid machines.

Biohybrid actuators exploit the contraction of biological components (muscle cells) to produce a force. In particular, bottom-up approaches use tissue engineering techniques, by coupling cells with a proper scaffold to obtain constructs undergoing contraction and guaranteeing actuation in biohybrid devices. However, the fabrication of actuators able to recapitulate the organization and maturity of native muscle is not trivial. In this field, quasi-two-dimensional (2D) substrates are raising interest due to their high surface/thickness ratio and the possibility of functionalizing their surface. In this work, we fabricated micropatterned thin films made of poly(styrene-butadiene-styrene) (SBS) doped with barium titanate nanoparticles (BTNPs) for fostering myogenic differentiation. We investigated material concentrations and fabrication process parameters to obtain thin microgrooved films with an average thickness below 1 μm, thus featured by a relatively low flexural rigidity and with an anisotropic topography to guide cell alignment and myotube formation. The embodiment of BTNPs did not significantly affect the film's mechanical properties. Interestingly, the presence of BTNPs enhanced the expression of myogenic differentiation markers (i.e., MYH1, MYH4, MYH8, and ACTA1). The results show the promising potential of SBS thin films doped with BTNPs, opening avenues in the fields of biohybrid actuation and skeletal muscle tissue engineering.