JiYong Lee

Microneedles (MNs) offer a minimally invasive approach for transdermal drug delivery, with dissolving MNs gaining popularity due to their biodegradability and controlled release properties. However, challenges such as air void formation in MNs, rigid base substrates and difficulties in multi-drug delivery limit their effectiveness. Here, we introduce a vacuum-assisted direct ink writing (DIW) method to fabricate high-strength, void-free, heterogeneous MN (hetero-MN) meshes. This approach enables precise control of drug composition and release kinetics within a single MN patch whose base substrate can be designed to have desired patterns and flexibility. We developed hetero-MN meshes with PLGA MNs for sustained release and HA MNs for rapid delivery, loaded with rhodamine B and fluorescein isothiocyanate-dextran as model drugs. The optimised MNs demonstrated reliable penetration in porcine skin, with HA MNs delivering drugs within an hour and PLGA MNs sustaining release over 40 days. Customisable hetero-MN designs highlight DIW printing as a promising platform for advanced multi-drug delivery applications.

Devising an approach to deterministically position organisms can impact various fields such as bioimaging, cybernetics, cryopreservation, and organism-integrated devices. This requires continuously assessing the locations of randomly distributed organisms to collect and transfer them to target spaces without harm. Here, an aspiration-assisted adaptive printing system is developed that tracks, harvests, and relocates living and moving organisms on target spaces via a pick-and-place mechanism that continuously adapts to updated visual and spatial information about the organisms and target spaces. These adaptive printing strategies successfully positioned a single static organism, multiple organisms in droplets, and a single moving organism on target spaces. Their capabilities are exemplified by printing vitrification-ready organisms in cryoprotectant droplets, sorting live organisms from dead ones, positioning organisms on curved surfaces, organizing organism-powered displays, and integrating organisms with materials and devices in customizable shapes. These printing strategies can ultimately lead to autonomous biomanufacturing methods to evaluate and assemble organisms for a variety of single and multi-organism-based applications.

Microneedle (MN)-based electrochemical biosensors enable minimally invasive and in situ monitoring of biomolecules from interstitial fluid (ISF) that is strongly correlated to their concentrations in the blood. When an array of MNs is used as either working or counter electrodes for electrochemical sensing, it is often difficult to have narrow spacing between them and this can lead to poor measurement accuracy due to increased resistance, low sensitivity, and slow response time. This study aims to develop a method to fabricate independently functioning MN electrodes with narrow intervals between them for high precision electrochemical sensing. A mixture of photocurable polymer (SU-8) and single-wall carbon nanotubes (SWCNTs) was optimized for pressure-assisted transfer (PAT) molding and electrical conductivity. Single composite MNs were molded by PAT molding, and then attached on pre-patterned electrodes. After the 'mold-and-place' of the composite MN structures, plasma etching and electropolymerization of PEDOT:PSS were performed to enhance the electrochemical activity. Prussian blue (PB) and glucose oxidase (GOx) were electrodeposited on surface-treated MNs to enable glucose detection. MN electrodes showed limit of detection (LOD) at 0.225 mM and linearity up to 20 mM. Finally, MN electrodes were constructed on a flexible polyimide film and demonstrated the feasibility of detecting glucose in an in vivo mouse study.

Devising an approach to deterministically position organisms could impact various fields such as bioimaging, cybernetics, cryopreservation, and organism-integrated devices. This requires continuously assessing the locations of randomly distributed organisms to collect and transfer them to target spaces without harm. Here we developed an aspiration-assisted adaptive printing system that tracks, harvests, and relocates living and moving organisms on target spaces via a pick-and-place mechanism that continuously adapts to updated visual and spatial information about the organisms and target spaces. These adaptive printing strategies successfully positioned a single static organism, multiple organisms in droplets, and a single moving organism on target spaces. Their capabilities were exemplified by printing vitrification-ready organisms in cryoprotectant droplets, sorting live organisms from dead ones, positioning organisms on curved surfaces, organizing organism-powered displays, and integrating organisms with materials and devices in customizable shapes. These printing strategies could ultimately lead to autonomous biomanufacturing methods to evaluate and assemble organisms for a variety of single and multi-organism-based applications.

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations. [Display omitted] •Sequential release of sirolimus and rosuvastatin as a silk-fibroin microneedle device.•Drug released via external vascular device suitably absorbed into localized lesion.•Perivascular device is promising intensive drug delivery to the lesion.•Strategy to prevent IH through the understanding of key signaling pathways at each stage.•The safety of drug toxicity by delivering the drug to the target lesion rather than by systemic diffusion.

Wireless Wearables In article number 2302256, John A. Rogers, Ralph G. Nuzzo, Yonggang Huang, and co‐workers report a miniaturized, wireless mechanoacoustic sensor, encapsulated with a self‐healing, dynamic covalent elastomer, embedded with chemistries that provide colorimetric responses, strain‐adaptive stiffening, and thermal insulation properties relevant to the safety of wireless, skin‐interfaced bioelectronic device use and operation. These multifunctional materials design strategies can immediately apply to wide ranging classes of devices, and also inspire the development of additional, complementary materials strategies for safe operation of bioelectronic systems.

Atherosclerosis is one of the severe cardiovascular diseases in which blood vessels lose elasticity and the lumen narrows. If atherosclerosis worsens, it commonly leads to acute coronary syndrome (ACS) due to the rupture of vulnerable plaque or aortic aneurysm. As the mechanical properties of vascular tissues vary from their conditions, measuring the vascular stiffness of an inner blood vessel wall may be applied to the accurate diagnosis of atherosclerotic symptoms. Therefore, early mechanical detection of vascular stiffness is highly needed for immediate medical attention for ACS. Even with conventional examination methods such as intravascular ultrasonography and optical coherence tomography, several limitations still remain that make it difficult to directly determine the mechanical properties of the vascular tissue. As piezoelectric materials convert mechanical energy to electricity without an external power source, a piezoelectric nanocomposite could be utilized as a balloon catheter-integrated mechanical sensor on its surface. Here, we present piezoelectric nanocomposite micropyramid balloon catheter (p-MPB) arrays for measuring vascular stiffness. We study the structural characterization and feasibility of p-MPB as endovascular sensors by conducting finite element method analyses. Also, multifaceted piezoelectric voltages are measured by compression/release tests, in vitro vascular phantom tests, and ex vivo porcine heart tests to confirm that the p-MPB sensor properly operates in blood vessels.

Cardiovascular diseases can be prevented in advance by noninvasive and continuous real-time measurement of blood pressure using a wearable sensor. Among many recent developments, piezoelectric sensors demonstrate the possibility to monitor blood pressure continuously without relying on an external energy input. However, most of the piezoelectric-sensor research focuses on the property enhancement of piezoelectric materials without systematic investigations of how sensor performance is influenced by the microgeometry and electrode configuration of piezoelectric sensor. Herein, the micropyramid-assisted piezoelectric film (MPF) sensors are designed and constructed and their performances are investigated both experimentally and by finite-element modeling (FEM) simulations. The sensor signal that is strongly coupled to both stress amplification and capacitance change because of the micropyramids and electrode configuration is identified. After comparing the different designs of MPF sensors, it is confirmed that polydimethylsiloxane micropyramids covered with the highly compliant Ecoflex show the highest sensitivity. The MPF sensor shows the sensitivity of 685 mV N-1 in a range between 50 and 400 mN. MPF sensors are attached to the wrist and neck to measure pulse pressure signals. Using the pulse pressure signals and linear regression, blood pressures are estimated and compared with the values measured with a commercial cuff device.

We investigated the role of a sirolimus-embedded silk microneedle (MN) wrap as an external vascular device for drug delivery efficacy, inhibition of neointimal hyperplasia, and vascular remodeling. Using dogs, a vein graft model was developed to interpose the carotid or femoral artery with the jugular or femoral vein. The control group contained four dogs with only interposed grafts; the intervention group contained four dogs with vein grafts in which sirolimus-embedded silk-MN wraps were applied. After 12-weeks post-implantation, 15 vein grafts in each group were explanted and analyzed. Vein grafts applied with the rhodamine B-embedded silk-MN wrap showed far higher fluorescent signals than those without the wrap. The diameter of vein grafts in the intervention group decreased or remained stable without dilatation; however, it increased in the control group. The intervention group had femoral vein grafts with a significantly lower mean neointima-to-media ratio, and had vein grafts with an intima layer showing a significantly lower collagen density ratio than the control group. In conclusion, sirolimus-embedded silk-MN wrap in a vein graft model successfully delivered the drug to the intimal layer of the vein grafts. It prevented vein graft dilatation, avoiding shear stress and decreasing wall tension, and it inhibited neointimal hyperplasia.

Although autologous vein grafting is essential, the high vein failure rate and specific clinical interventions are not clear, so a potential treatment is critically needed; thus, complex analyses of the relationship between pathobiological and physiological processes in preclinical are essential. The interposition of the femoral vein was performed in a canine model. Maximized expansion and velocity were measured at 8 weeks post-implantation, and a relative decrease was observed at 12 weeks. However, NI formation and NI/Media ratio significantly increased time dependently, and differences between the mechanical properties were observed. Additionally, RhoA-mediated TNF-α induced by rapid structural changes and high shear stress was confirmed. After adaptation to the arterial environment, vascular remodeling occurred by SMC proliferation and differentiation, apoptosis and autophagy were induced through YAP activity without vasodilation and RhoA activity. Our results show that understanding pathobiological processes in which time-dependent physiological changes contribute to vein failure can lead to a potential strategy. Graphical abstract The implanted vein graft within the arterial environment undergoes pathobiological processes through RhoA and YAP activity, leading to pathophysiological changes.