A sensory-motor hand prosthesis with integrated thermal feedback.

BACKGROUND: Recently, we reported the presence of phantom thermal sensations in amputees: thermal stimulation of specific spots on the residual arm elicited thermal sensations in their missing hands. Here, we exploit phantom thermal sensations via a standalone system integrated into a robotic prosthetic hand to provide real-time and natural temperature feedback. METHODS: The subject (a male adult with unilateral transradial amputation) used the sensorized prosthesis to manipulate objects and distinguish their thermal properties. We tested his ability to discriminate between (1) hot, cold, and ambient temperature objects, (2) different materials (copper, glass, and plastic), and (3) artificial versus human hands. We also introduced the thermal box and block test (thermal BBT), a test to evaluate real-time temperature discrimination during standardized pick-and-place tasks. FINDINGS: The subject performed all three discrimination tasks above chance level with similar accuracies as with his intact hand. Additionally, in all 15 sessions of the thermal BBT, he correctly placed more than half of the samples. Finally, the phantom thermal sensation was stable during the 13 recording sessions spread over 400 days. CONCLUSION: Our study paves the way for more natural hand prostheses that restore the full palette of sensations. FUNDING: This work was funded by the Bertarelli Foundation (including the Catalyst program); the Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) Robotics; the European Union's Horizon 2020 research and innovation program; the Horizon Europe Research & Innovation Program; the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP); and the Tuscany Health Ecosystem.

Revealing the complexity of ultra-soft hydrogel re-swelling inside the brain.

The brain is an ultra-soft viscoelastic matrix. Sub-kPa hydrogels match the brain's mechanical properties but are challenging to manipulate in an implantable format. We propose a simple fabrication and processing sequence, consisting of de-hydration, patterning, implantation, and re-hydration steps, to deliver brain-like hydrogel implants into the nervous tissue. We monitored in real-time the ultra-soft hydrogel re-swelling kinetics in vivo using microcomputed tomography, achieved by embedding gold nanoparticles inside the hydrogel for contrast enhancement. We found that re-swelling in vivo strongly depends on the implant geometry and water availability at the hydrogel-tissue interface. Buckling of the implant inside the brain occurs when the soft implant is tethered to the cranium. Finite-element and analytical models reveal how the shank geometry, modulus and anchoring govern in vivo buckling. Taken together, these considerations on re-swelling kinetics of hydrogel constructs, implant geometry and soft implant-tissue mechanical interplay can guide the engineering of biomimetic brain implants.

Restoration of natural thermal sensation in upper-limb amputees.

The use of hands for gathering rich sensory information is essential for proper interaction with the environment; therefore, the restoration of sensation is critical for reestablishing the sense of embodiment in hand amputees. Here, we show that a noninvasive wearable device can be used to provide thermal sensations on amputees' phantom hands. The device delivers thermal stimuli to specific regions of skin on their residual limb. These sensations were phenomenologically similar to those on the intact limbs and were stable over time. Using the device, the subjects could successfully exploit the thermal phantom hand maps to detect and discriminate different thermal stimuli. The use of a wearable device that provides thermal sensation can increase the sense of embodiment and improve life quality in hand amputees.

A finite element model of the mechanical interactions between peripheral nerves and intrafascicular implants.

Objective.Intrafascicular peripheral nerve implants are key components in the development of bidirectional neuroprostheses such as touch-enabled bionic limbs for amputees. However, the durability of such interfaces is hindered by the immune response following the implantation. Among the causes linked to such reaction, the mechanical mismatch between host nerve and implant is thought to play a decisive role, especially in chronic settings.Approach.Here we focus on modeling mechanical stresses induced on the peripheral nerve by the implant's micromotion using finite element analysis. Through multiple parametric sweeps, we analyze the role of the implant's material, geometry (aspect-ratio and shape), and surface coating, deriving a set of parameters for the design of better-integrated implants.Main results.Our results indicate that peripheral nerve implants should be designed and manufactured with smooth edges, using materials at most three orders of magnitude stiffer than the nerve, and with innovative geometries to redistribute micromotion-associated loads to less delicate parts of the nerve such as the epineurium.Significance.Overall, our model is a useful tool for the peripheral nerve implant designer that is mindful of the importance of implant mechanics for long term applications.

Compliant peripheral nerve interfaces.

Peripheral nerve interfaces (PNIs) record and/or modulate neural activity of nerves, which are responsible for conducting sensory-motor information to and from the central nervous system, and for regulating the activity of inner organs. PNIs are used both in neuroscience research and in therapeutical applications such as precise closed-loop control of neuroprosthetic limbs, treatment of neuropathic pain and restoration of vital functions (e.g. breathing and bladder management). Implantable interfaces represent an attractive solution to directly access peripheral nerves and provide enhanced selectivity both in recording and in stimulation, compared to their non-invasive counterparts. Nevertheless, the long-term functionality of implantable PNIs is limited by tissue damage, which occurs at the implant-tissue interface, and is thus highly dependent on material properties, biocompatibility and implant design. Current research focuses on the development of mechanically compliant PNIs, which adapt to the anatomy and dynamic movements of nerves in the body thereby limiting foreign body response. In this paper, we review recent progress in the development of flexible and implantable PNIs, highlighting promising solutions related to materials selection and their associated fabrication methods, and integrated functions. We report on the variety of available interface designs (intraneural, extraneural and regenerative) and different modulation techniques (electrical, optical, chemical) emphasizing the main challenges associated with integrating such systems on compliant substrates.

Epineural optogenetic activation of nociceptors initiates and amplifies inflammation.

Activation of nociceptor sensory neurons by noxious stimuli both triggers pain and increases capillary permeability and blood flow to produce neurogenic inflammation1,2, but whether nociceptors also interact with the immune system remains poorly understood. Here we report a neurotechnology for selective epineural optogenetic neuromodulation of nociceptors and demonstrate that nociceptor activation drives both protective pain behavior and inflammation. The wireless optoelectronic system consists of sub-millimeter-scale light-emitting diodes embedded in a soft, circumneural sciatic nerve implant, powered and driven by a miniaturized head-mounted control unit. Photostimulation of axons in freely moving mice that express channelrhodopsin only in nociceptors resulted in behaviors characteristic of pain, reflecting orthodromic input to the spinal cord. It also led to immune reactions in the skin in the absence of inflammation and potentiation of established inflammation, a consequence of the antidromic activation of nociceptor peripheral terminals. These results reveal a link between nociceptors and immune cells, which might have implications for the treatment of inflammation.

Modular microporous hydrogels formed from microgel beads with orthogonal thermo-chemical responsivity: Microfluidic fabrication and characterization.

Despite the significant advances in designing injectable bulk hydrogels, the inability to control the pore interconnectivity and decoupling it from the matrix stiffness has tremendously limited the applicability of stiff, flowable hydrogels for 3D cellular engineering, e.g., in hard tissue engineering. To overcome this persistent challenge, here, we introduce a universal method to convert thermosensitive macromolecules with chemically-crosslinkable moieties into annealable building blocks, forming 3D microporous beaded scaffolds in a bottom-up approach. In particular, we show gelatin methacryloyl (GelMA), a widely used biomaterial in tissue engineering, may be converted into physically-crosslinked microbeads using a facile microfluidic approach, followed by flow of the microbead suspension and chemical crosslinking in situ to fabricate microporous beaded GelMA (B-GelMA) scaffolds with interconnected pores, promoting cell functionality and rapid (within minutes) 3D seeding in stiff scaffolds, which are otherwise impossible in the bulk gel counterparts. This novel approach may set the stage for the next generation modular hydrogels with orthogonal porosity and stiffness made up of a broad range of natural and synthetic biomaterials. •This method combines well-known flow focusing microfluidic devices with facile post-processing steps to fabricate microporous scaffolds.•Temperature-driven physical crosslinking of the microbeads enables the facile purification of gel building blocks without further chemical reactions.•This method provides a simple approach to fabricate microporous scaffolds, which overcomes some of the challenges of newly emerging beaded scaffolds, including oxygen-mediated impaired crosslinking.

Microfluidic-enabled bottom-up hydrogels from annealable naturally-derived protein microbeads.

Naturally-derived proteins, such as collagen, elastin, fibroin, and gelatin (denatured collagen) hold a remarkable promise for tissue engineering and regenerative medicine. Gelatin methacryloyl (GelMA), synthesized from the methacryloyl modification of gelatin, mimicking the structure of extracellular matrix, has widely been used as a universal multi-responsive scaffold for a broad spectrum of applications, spanning from cell therapy to bioprinting and organoid development. Despite the widespread applications of GelMA, coupled stiffness and porosity has inhibited its applications in 3D cellular engineering wherein a stiff scaffold with large pores is demanded (e.g., at concentrations >10 wt%). Taking advantage of the orthogonal thermo-chemical responsivity of GelMA, we have developed microfluidic-assisted annealable GelMA beads, that are first stabilized by temperature-mediated physical crosslinking, flowed to form a scaffold structure, and then chemically annealed using light to fabricate novel bead-based 3D GelMA scaffolds with high mechanical resilience. We show how beaded GelMA (B-GelMA) provides a self-standing microporous environment with an orthogonal void fraction and stiffness, promoting cell adhesion, proliferation, and rapid 3D seeding at a high polymer concentration (∼20 wt%) that would otherwise be impossible for bulk GelMA. B-GelMA, decorated with methacryloyl and arginylglycylaspartic acid (RGD) peptide motifs, does not require additional functionalization for annealing and cell adhesion, providing a versatile biorthogonal platform with orthogonal stiffness and porosity for a myriad of biomedical applications. This technology provides a universal method to convert polymeric materials with orthogonal physico-chemical responsivity to modular platforms, opening a new horizon for converting bulk hydrogels to beaded hydrogels (B-hydrogels) with decoupled porosity and stiffness.