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Abstract Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.

Therapeutic ultrasound for brain stimulation has increased in the last years. This energy has shown promising results for treating Alzheimer’s disease, Parkinson’s disease and traumatic brain injury, among other conditions. However, the application of ultrasound in the brain should trespass a natural but highly attenuating and distorting barrier, the cranium. Implantable ceramic materials can be used to replace part of the cranium as an alternate method to enhance ultrasound transmission. In this work, it is presented the acoustic characterization of alumina ceramic disks that can be employed as cranial implants for acoustic windows-to-the-brain. Alumina samples were prepared using current-activated pressure-assisted densification and were acoustically characterized. Acoustic impedance and attenuation of the samples were determined for different porosities. Additionally, measured and modeled acoustic fields are presented and analyzed in terms of the total ultrasound transmitted through the ceramics. Results indicate a resonant behavior in the alumina disks when the thickness corresponds to a half-wavelength of ultrasound; this resonance permits a total of 95.4% of ultrasound transmission; for thicknesses out of the resonant zone, transmission is 53.0%. Alumina proves to be an excellent medium for ultrasound transmission that, in conjunction with its mechanical and optical properties, can be useful for cranium replacement in mixed opto-acoustic applications.

Brain neurodegenerative diseases are central nervous system (CNS) affections typically common in older adults. A new therapeutic approach for them consists of providing specific drugs to the CNS through blood circulation; however, the Blood–Brain Barrier (BBB) prevents almost 100% of neurotherapeutics from reaching the brain. There are indications that Focused Ultrasound (FUS), temporarily placed in the BBB, can achieve a controlled increase in temperature at its focus, allowing temporary, localized, and reversible opening of this barrier, which facilitates the temporary delivery of specific drugs. This work presents a FUS-based protocol for the local, temporary, and reversible opening of the BBB in Wistar rats. The proposed protocol specifies certain power, treatment times, and duty cycle to controllably increase the temperature at the region of interest, i.e., the substantia nigra. Numerical simulations using commercial software based on the finite element method were carried out to determine the optimal size of the craniotomies for nearly full-acoustic transmission. Experiments in rats were performed with the parameters used during computational simulations to determine the adequate opening of the BBB. For this, craniotomies of different sizes were made at coordinates of the substantia nigra, and FUS was applied from the exterior. The opening of the BBB was evaluated using Evans Blue (EB) as an indicator of the crossing of the dye from the blood vessels to brain tissue. Numerical simulations demonstrated a major distance reached by the ultrasound focus with a bigger diameter. Experimental results show the local, temporary, and reversible opening of the BBB through a 10 mm diameter craniotomy, which effectively allowed placing the ultrasound focus over the substantia nigra, unlike a 6 mm diameter craniotomy in which there is a deviation of the focus through that window. Moreover, from these results, it was also determined that the disruption of the BBB was reversible, with an opening duration of 6 h after FUS application. The experimental work developed in this study resulted in a minimally invasive method for the temporary opening of the BBB.

Non-invasive Functional Electrical Stimulation (FES) is a technique applied for motor rehabilitation of patients with central nervous system injury. This technique requires programmable multichannel systems to configure the stimulation parameters (amplitude, frequency, and pulse width). Most FES systems are based on microcontrollers with fixed architecture; this limits the control of the parameters and the scaling to multiple channels. Although field programmable gate arrays (FPGA) have been used in FES systems as alternative to microcontrollers, most of them focus on signal acquisition, processing, or communication functions, or are for invasive stimulation. A few FES systems report using FPGAs for parameter configuration and pulse generation in non-invasive FES. However, generally they limit the value of the frequency or amplitude parameters to enable multichannel operation. This restricts free selection of parameters and implementation of modulation patterns, previously reported to delay FES-induced muscle fatigue. To overcome those limitations, this paper presents a proof-of-concept (technology readiness level three-TRL 3) regarding the technical feasibility and potential use of an FPGA-based pulse generator for non-invasive FES applications (PG-nFES). The main aims were: (1) the development of a flexible pulse generator for FES applications and (2) to perform a proof-of-concept of the system, comprising: electrical characterization of the stimulation parameters, and verification of its potential for upper limb FES applications. Biphasic stimulation pulses with high linearity (r2 > 0.9998) and repeatability (>0.81) were achieved by combining the PG-nFES with a current-controlled output stage. Average percentage error in the characterizations was under 3% for amplitude (1–48 mA) and pulse width (20–400 μs), and 0% for frequency (10–150 Hz). A six-channel version of the PG-nFES was implemented to demonstrate the scalability feature. The independence of parameters was tested with three patterns of co-modulation of two parameters. Moreover, two complete FES channels were implemented and the claimed features of the PG-nFES were verified by performing upper limb functional movements involving the hand and the arm. Finally, the system enabled implementation of a stimulation pattern with co-modulation of frequency and pulse width, applied successfully for efficient elbow during repetitions of a functional movement.

Diabetic foot is one of the most serious complications in patients with diabetes mellitus. It is distinguished by the development of ulcerations on the sole of the foot. Before the appearance of these, patients with diabetes suffer changes in the tissues of the foot and nearby tissues. This work proposes systems that measure and identify the changes in the physical characteristics of the foot tissues in two study groups, diabetic patients and healthy subjects, with the purpose of proposing tools to physicians to follow up each patient and identify with certainty the evolution in symptoms. The results of the temperature systems show that there is an average temperature difference of ~2 °C between diabetic patients and healthy subjects. Using an electrical impedance system, a frequency window was found between 5 kHz and 22 kHz, where the impedance is significantly different (p > 0.001) between diabetic and healthy patients. The system oriented to macules on the skin is able to identify the type of macules developed by the diabetic patient. In temperature measurement with images from a smartphone, plantar temperature monitoring was achieved in at-risk areas in uncontrolled environments. The results presented in this work were obtained in a time period from 2014 to 2022. Considering the standardization of this equipment when making a diagnosis regarding the study of tissues in the diabetic foot, it will be possible to detect it early. Through differences between the measurements, we have an indicator of the patient’s evolution, and we must highlight that these systems are easy to install, easy to interpret and low cost. Currently, there are no systems with these characteristics, which is why the early detection of diabetic foot is being widely studied.

Microwave ablation is commonly used in soft tissue tumors, but its application in bone tumors has been barely analyzed. Antennas to treat bone tissue (~3 cm2), has been lately designed. Bone tumors at pathological stage T1 can reach 8 cm wide. An antenna cannot cover it; therefore, our goal is to evaluate the thermal performance of multi-antenna arrays. Linear, triangular, and square configurations of double slot (DS) and monopole (MTM) antennas were evaluated. A parametric study (finite element method), with variations in distance between antennas (ad) and bone thickness (bt) was implemented. Array feasibility was evaluated by SWR, ablated tissue volume, etc. The linear configuration with DS and MTM antennas showed SWR ≤ 1.6 for ad = 1 mm–15 mm and bt = 20 mm–40 mm, and ad = 10 mm–15 mm and bt = 25 mm–40 mm, respectively; the triangular showed SWR ≤ 1.5 for ad = 5 mm–15 mm and bt = 20 mm–40 mm and ad = 10 mm–15 mm and bt = 25 mm–40 mm. The square configuration (DS) generated SWR ≤ 1.5 for ad = 5 mm–20 mm and bt = 20 mm–40 mm, and the MTM, SWR ≤ 1.5 with ad = 10 mm and bt = 25 mm–40 mm. Ablated tissue was 4.65 cm3–10.46 cm3 after 5 min. According to treatment time and array configuration, maximum temperature and ablated tissue is modified. Bone tumors >3 cm3 can be treated by these antenna-arrays.