Biocompatibility of medical implants poses a significant challenge in medical technology. Neural implants, integral to curative therapies, initially exhibit efficacy but can lead to unforeseen long-term side effects. The material composition and dimensions of implants are critical factors influencing their biocompatibility within brain tissue. Typically, neural implants are identified as foreign entities by the patient's immune system, triggering persistent inflammation and severe adverse effects. In this study, we investigate the host response in mouse brain tissue of implanted microscale constructs measuring 0.1 x 0.1 x 1 mm3 fabricated from common microfabrication materials. Magnetic Resonance Imaging (MRI) analysis reveals rapid recovery of brain parenchyma at 6 week interval post-implantation, accompanied by negligible or mild adverse immune responses during the experimental period. Histological assessments and cell marker stainings targeting astroglia, macrophages, and microglia demonstrate minimal impacts of the microconstructs on mouse brain tissue throughout the 24-week implantation period. Our findings indicate that untethered microimplants of this scale may have potential applications in medical technology and medical treatment for various brain diseases. In summary, this study supports the development of potentially biocompatible brain microimplants that could be useful for the long-term management of chronic brain disorders.

MEMS-based piezoelectric ultrasonic energy harvesters (PUEH) have become one of the most promising options for replacing or transferring energy to batteries in medical implants, where device miniaturization and power optimization are needed. Among the most commonly used piezoelectric materials in PUEH, lead zirconate titanate (PZT) is widely acknowledged for its excellent piezoelectric properties, good stability, and low cost. However, the performance of PZT degrades when the processing temperature approaches and exceeds half of its Curie temperature Tc, limiting its application. Here, we demonstrate a highly miniaturized, low-temperature fabricated MEMS-based PUEH with an effective ultrasound harvesting area of 0.79 mm2 and an effective device volume of 0.35 mm3. The low-temperature adhesive epoxy bonding ensures the temperature throughout the entire fabrication process remains below 85°C, which preserves the properties of the integrated piezoelectric material to the greatest extent. This allows the use of bulk PZT-5H, a material that possesses superior piezoelectric properties, but has a relatively low Tc, to enhance device performance. Our device outputs a root-mean-square (RMS) voltage of 0.62 V and an RMS power of 0.19 mW on a 2 kΩ resistive load at an optimum operating frequency of 200 kHz, with a reception distance of 20 mm in water and input acoustic power intensity of 178 mW/cm2. The proposed design and fabrication technique enable our device to achieve the smallest effective size among the reported MEMS-based PUEH while still being capable of powering up numerous implantable medical devices and being compatible with various commercially available power management units. [2024-0081]

Topical drug delivery offers a localized and patient-friendly method for treating skin diseases and subcutaneous lesions. However, the outermost skin barrier - the stratum corneum (SC) - hinders the delivery of large molecules such as biopharmaceuticals. This study introduces rolling ultraminiaturized microneedle spheres (RUMS) as a novel solution that enables topical delivery of messenger RNA (mRNA) without the need for chemical enhancers or techniques like electroporation, iontophoresis, or microneedle patches. RUMS are engineered spherical microparticles that gently roll over the skin, creating numerous micropores while minimizing tissue damage. In ex vivo porcine skin experiments, 25 RUMS generated approximately 4,500 pores within 10 seconds, achieving penetration depths of around 20 micrometers and increasing skin permeability by up to 100-fold. In vivo studies in mice showed that combining RUMS with topical doxycycline led to a ~50% tumor size reduction within two weeks and full recovery by four weeks. In contrast, doxycycline or RUMS alone offered limited therapeutic benefit. Rapid skin healing was observed due to the small pore size. Additionally, topical delivery of lipid nanoparticle-encapsulated luciferase (luc)-encoding mRNA was successfully demonstrated in mice. Overall, use of RUMS presents a simple, painless, and potentially well-tolerated technique for enabling transdermal topical delivery of biologics.

Large-molecule pharmaceuticals can offer new treatment options for severe lung diseases. However, their effective delivery to the lungs is challenged by the high-shear forces generated during the aerosolization process. These forces can degrade sensitive biomolecules, limiting their compatibility with portable inhalers and, consequently, restricting the use of biopharmaceuticals in portable drug delivery systems. Here, we demonstrate that micro-swirl nozzles can effectively aerosolize fragile biopharmaceuticals in aqueous solutions. Computational shear rate simulations of the nozzle design show that it produces low shear conditions suitable for the gentle aerosolization of sensitive pharmaceuticals. We demonstrate the aerosolization of encapsulated large molecules using a swirl nozzle integrated into a portable soft-mist inhaler. Catalase protein endures the aerosolization process at pressures up to 50 bar without notable degradation, retaining enzymatic activity post-spray event. We demonstrate the successful in vitro delivery of both mRNA and proteins encapsulated in lipid nanoparticles (LNPs) and extracellular vesicles (EVs), respectively. These vesicles maintain their structural integrity and cellular uptake capabilities in vitro, facilitating intracellular expression of the delivered biomolecules. Finally, we validate the successful in vivo administration pulmonary delivery and expression of LNP-encapsulated mRNA in pigs. This study highlights the potential of micro swirl nozzles to enable portable delivery of large-molecule therapeutics, offering new treatment options for patients who previously relied on stationary, and complex delivery systems.