3D printing at the macroscale has evolved from making plastic prototypes to the production of high-performance functional metal parts for industries such as medical and aerospace. By contrast, MEMS devices today are produced in large quantities using semiconductor manufacturing processes. However, the semiconductor manufacturing paradigm is not cost-effective for producing customized MEMS devices in small to medium volumes (tens to thousands of units per year), and related applications are difficult to address efficiently. 3D printing of functional MEMS devices could play an important role in filling this gap. Here, we discuss recent advances in 3D- printed functional MEMS, addressing the challenges of economical customization at smaller production volumes.

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.

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.

Microelectromechanical systems (MEMS) offer powerful solutions for drug delivery where biological barriers limit the potential of advanced therapeutics. This thesis demonstrates how unorthodox applications of microfabrication techniques can create novel platforms to overcome drug delivery challenges, enhancing the delivery of potent and fragile biologics.

The first part of this work focuses on implantable systems. An ultrasonically actuated micro-implant is presented, which exploits mechanical resonance not for sensing but for the selective, on demand destruction of reservoir membranes. This enables remotely triggered drug release without onboard power or electronics. Building on this, a miniaturized ultrasonic energy harvester is developed, integrating a high-performance, bulk piezoelectric material (PZT-5H) via a novel low-temperature bonding process, creating a robust power source for future active implants.

The second part explores two-photon polymerization (2PP) to fabricate complex 3D microstructures for non-invasive delivery. First, rolling ultra-miniaturized microneedle spheres (RUMS) are introduced. Unlike traditional flat microneedle patches, these 3D particles are suspended in topical formulations to gently and repeatedly disrupt the skin’s stratum corneum, enabling the effective transdermal delivery of biologics. Second, a micro-swirl nozzle, a design typically found in internal combustion or agricultural applications, has been developed to aerosolize fragile biologics. This geometry generates a fine mist suitable for deep lung deliverythrough a low-shear mechanism, preserving the integrity of sensitive payloads like lipid nanoparticle (LNP)-encapsulated mRNA.

Collectively, this work showcases a versatile approach to biomedical engineering, where the precise control of micro-scale geometry and physics is leveraged to solve persistent challenges in therapeutic delivery.

Mikroelektromekaniska system (MEMS) erbjuder nya effektiva lösningar för läkemedelstillförsel där biologiska barriärer hindrar den kliniska potentialen hos avancerade terapier. Denna avhandling visar hur oortodoxa tillämpningar av mikrofabrikationstekniker kan skapa nya plattformar för att överkomma läkemedelstillförsel utmaningar och förbättra tillförsel av potenta och ömtåliga biologiska läkemedel.

Den första delen av detta arbete fokuserar på implanterbara system. Ett ultraljudsaktiverat mikroimplantat presenteras som utnyttjar mekanisk resonans, inte för avkänning, utan för selektiv, on-demand destruktion av reservoarmembran. Detta möjliggör fjärrstyrd läkemedelsfrisättning utan någon inbyggd strömförsörjning eller elektronik. Baserat på samma teknik har en miniatyriserad ultraljudsenergiuppsamlare utvecklats. Den integrerar ett högpresterande, bulk-piezoelektriskt material (PZT-5H) via en ny lågtemperaturbindningsprocess, vilket skapar en robust strömkälla för framtida aktiva implantat.

Den andra delen utav arbetet utforskar tvåfotonpolymerisation (2PP) för att tillverka komplexa 3D-mikrostrukturer för icke-invasiv läkemedelstillförsel. Först introduceras rullande ultraminiatyriserade mikronålssfärer (RUMS). Till skillnad från traditionella platta mikronålsplåster är dessa 3D-partiklar suspenderade i topiska formuleringar för att skonsamt och upprepat bryta hudens hornlager, vilket möjliggör effektiv leverans av biologiska läkemedel genom huden av. Vidare har ett mikrovirvelmunstycke, en design som vanligtvis återfinns i förbränningsmotorer eller i jordbrukstillämpningar, utvecklats för att aerosolisera ömtåliga biologiska läkemedel. Geometrin hos munstycket genererar en fin dimma som är lämplig för djup lungadministrering genom en lågskjuvningsmekanism. Detta bevarar integriteten hos läkemedel med känsliga laster såsom lipid nanopartikel (LNP)-inkapslat mRNA.

Sammantaget visar detta arbete användbara och mångsidiga tillvägagångssätt inom medicinsk teknik, där precis kontroll av mikroskalig geometri och fysik utnyttjas för att lösa svåra utmaningar inom läkemedelstillförsel.

We demonstrate a low-temperature fabricated MEMS-based piezoelectric ultrasonic energy harvester with enhanced device performance. Compared to state-of-the-art, our work uses a low-temperature bonding method, which ensures the integrated piezoelectric material undergoes prominently lower temperatures (≤ 85 °C) throughout the whole fabrication process. Due to this, bulk PZT-5H, a material with superior piezoelectric properties, could be used in this type of application for the first time. The method guarantees the device fabrication temperature well below the PZT-5H Curie temperature (225 °C) and preserves its piezoelectricity to the greatest extent. As a result, devices fabricated using the proposed method achieve higher performance than the devices prepared by the MEMS fabrication method using BCB bonding. The root-mean-square voltage and the average power outputs at the frequency (170 kHz) where maximum voltage and power outputs were observed were improved by 38 % and 92 %, respectively.

The functional area of silicon-based microelectromechanical systems (MEMS) devices often occupies only a fraction of the actual silicon area of the chip. As the chip cost directly scales with the total chip area, there is an incentive to reduce the chip to the smallest possible size. However, handling such diminutive devices poses challenges that industry-standard packaging cannot solve. Here, the world's smallest spray nozzle chip for drug delivery to the lung is manufactured and packaged and how magnetic assembly combined with microfluidic glue fixation can overcome this barrier for diminutive MEMS devices is demonstrated. The spray nozzle chips have a circular footprint with a diameter of 280 µm and feature a nickel coating on their conical sidewall, allowing magnetic manipulation. The chips are assembled and sealed into plastic substrates using a three-step gluing process guided by capillary action and activated by heat. Assembly speeds of up to 147 chips per minute are demonstrated and fabrication to packaging and functional operation of this device is shown for the target application.

Large-molecule pharmaceuticals offer new treatment options for severe lung disease. However, delivering these drugs to the lung is challenging due to the elevated shear rates during the aerosolization process. So far, this has prevented an application in portable inhalers, holding back the portable use of biopharmaceuticals for drug delivery. We demonstrate that a micro swirl nozzle can aerosolize fragile biopharmaceuticals in an aqueous solution. Shear rate simulations of the nozzle unit indicate orders of magnitude in shear rate reduction compared with conventional aqueous aerosolization units. Catalase protein can survive the aerosolization process at up to 50 bar without significant degradation. The protein further remains enzymatically active after the spray event.

Using an in-vitro model, we present the delivery of more complex and fragile mRNA structures (Nanoluc mRNA) at high concentrations when encapsulated in solid lipid nanoparticles (LNPs) or Extracellular vesicles (EVs). These vesicles maintain their capability to pass the cell wall in in-vitro cell cultures, leading to an expression of the encapsulated protein structure within the celll. Micro swirl nozzles can enable the portable delivery of large molecule pharmaceuticals and bring new treatment options to patients who have so far had to rely on stationary devices.