Swellable Biopolymer Composite Microneedle Patch for Pain-Free Collection of Interstitial Fluid to Analyze Multiple Biomolecules.

Sampling of interstitial fluid (ISF) using microneedle (MN) patch offers a pain-free minimally invasive alternative to syringe needle-based blood sample collection. However, there is a challenge in the development of MN patch that provides swelling behavior with sufficient mechanical strength for skin penetration. Here, we report fabrication of MN patch made of biopolymer composite containing iota-carrageenan, gelatin, and polyethylene glycol. Calcium chloride was used as a crosslinker to improve mechanical strength. MN patch was characterized for integrity, swelling behavior, mechanical strength, aspiration of fluid from agarose gel, and the excised porcine ear skin. An array of 361 MNs was able to aspirate 36 ± 5 and 14 ± 1 µL fluid after application in agarose gel matrix and the ex vivo porcine skin model, respectively. MN patch applied in vivo rat model for 30 min resulted in the collection of ISF containing 267 ± 128 mg/dL, 24 ± 13 mg/dL, and 0.6 ± 0.4 mIU/mL of glucose, uric acid and thyroid stimulating hormone (TSH), respectively. The concentration of glucose, uric acid, and TSH in rat blood was found to be 199 ± 47 mg/dL, 8.4 ± 6 mg/dL, and 1.1 ± 0.6 mIU/mL at the same time. Furthermore, MN patch applied on the forearm of 10 healthy human volunteers for 30 min was able to aspirate 32 ± 14 µL of ISF. The concentration of glucose, uric acid, and TSH determined from ISF samples of human volunteers was 64 ± 25 mg/dL, 4.2 ± 4.1 mg/dL, and 0.16 ± 0.08 mIU/mL, respectively. The visual analogue scale (VAS) pain score after MN application was lower compared with hypodermic syringe needle insertion. Taken together, biopolymer composite-based swellable MN patch can be developed for collection of ISF for simultaneous determination of multiple biomolecules in a minimally invasive manner.

An Invisible Dermal Nanotattoo-Based Smart Wearable Sensor for eDiagnostics of Jaundice.

Despite substantial progress in the diagnosis of jaundice/hyperbilirubinemia as the most common disease and cause of hospitalization of newborns, on the eve of Industry/Healthcare 5.0, the development of accurate and reliable wearable diagnostic sensors for noninvasive smart monitoring of bilirubin (BIL) is still in high demand. Aiming to fabricate a smart wearable sensor for early diagnosis of neonatal jaundice and its therapeutic monitoring, we here report a fluorescent dermal nanotattoo that further coupled with an IoT-integrated wearable optoelectronic reader for minimally invasive, continuous, and real-time monitoring of BIL in interstitial fluid. Selective recovery of quenched fluorescence of the dermal tattoo sensor, composed of biocompatible dissolving/hydrogel microneedles loaded with fluorescent carbon quantum dots, upon blue light exposure used for jaundice phototherapy was utilized for highly selective BIL sensing. The fascinating features of our developed smart wearable tattoo sensor and its successful results with high correlation with blood BIL results make it a highly promising sensor for easy, minimally invasive, reliable, and smart eDiagnostics and continuous therapeutic eMonitoring of jaundice and other BIL-induced diseases at the point of care. We envision that the developed nanotattoo sensing bioplatform will inspire the development of future smart tattoo sensors in various diagnostic and monitoring scenarios.

Microneedle sensors for dermal interstitial fluid analysis.

The rapid advancement in personalized healthcare has driven the development of wearable biomedical devices for real-time biomarker monitoring and diagnosis. Traditional invasive blood-based diagnostics are painful and limited to sporadic health snapshots. To address these limitations, microneedle-based sensing platforms have emerged, utilizing interstitial fluid (ISF) as an alternative biofluid for continuous health monitoring in a minimally invasive and painless manner. This review aims to provide a comprehensive overview of microneedle sensor technology, covering microneedle design, fabrication methods, and sensing strategy. Additionally, it explores the integration of monitoring electronics for continuous on-body monitoring. Representative applications of microneedle sensing platforms for both monitoring and therapeutic purposes are introduced, highlighting their potential to revolutionize personalized healthcare. Finally, the review discusses the remaining challenges and future prospects of microneedle technology.

Synovial fluid does not retard fluid exudation during stress-relaxation of immature bovine cartilage.

Interstitial fluid load support (FLS) is a dominant mechanism of lubrication in cartilage, producing a low friction coefficient while enhancing the tissue's load bearing capabilities. Due to its viscosity, synovial fluid (SF) may retard loss of FLS by slowing the exudation of interstitial fluid from the cartilage. This study tested this hypothesis by comparing the stress-relaxation (SRL) response of immature bovine articular cartilage immersed either in phosphate buffered saline (PBS) or in healthy mature bovine SF, under unconfined compression (fluid exudation across cut lateral tissue boundary) and indentation testing (fluid exudation across articular surface). To investigate the influence of diffusion of SF molecular constituents into cartilage, the effect of incubation time in SF on SRL was also investigated. The SRL response in unconfined compression was not significantly different in PBS versus SF when compared directly (p = 0.98) and had a slope ofm = 1.00 ± 0.04 (R2 = 0.989 ± 0.007). Samples tested in PBS exhibited characteristic relaxation times, τPBS=42.6 ± 5.3 s andτSF = 40.8 ± 4.7 s, that were not significantly different (p = 0.40). Incubation time of 24 h in SF resulted in no significant difference in the SRL response (p = 0.39, m=1.03 ± 0.12; R2=0.983 ± 0.011, andτPBS = 43.4 ± 10.7 s versusτSF = 41.5 ± 4.8 s, p = 0.59). Indentation testing showed some statistically significant, but functionally insignificant, difference in SRL responses in PBS versus SF with a slope ofm = 0.958 ± 0.060 (R2 = 0.957 ± 0.020, p = 0.029, andτPBS = 16.9 ± 2.6 s versusτSF = 19.4 ± 3.3 s, p = 0.073). Based on these results, we reject the hypothesis that healthy SF can retard the loss of FLS in cartilage due to its viscosity.

Minimally invasive detection of buprenorphine using a carbon-coated 3D-printed microneedle array.

A machine learning-assisted 3D-printed conducting microneedle-based electrochemical sensing platform was developed for wireless, efficient, economical, and selective determination of buprenorphine. The developed microneedle array-based sensing platform used 3D printing and air spray coating technologies for rapid and scalable manufacturing of a conducting microneedle surface. Upon optimization and understanding of the electrode stability, redox behavior, and electrochemical characteristics of as-prepared conducting microneedle array, the developed electrochemical platform was investigated for monitoring different levels of buprenorphine in the artificial intestinal fluid and found to be highly sensitive and selective towards buprenorphine for a wide detection range from 2 to 140 µM, with a low limit of detection of 0.129 µM. Furthermore, to make the sensing platform user accessible, the experimentally recorded sensing data was used to train a machine learning model and develop a web application for the numerical demonstration of buprenorphine levels at the point of site. Finally, the proof-of-concept study demonstrated that by advancing our prevailing 3D printing and additive manufacturing techniques, a low-cost, user-accessible, and compelling wearable electrochemical sensor could be manufactured for minimally invasive determination of buprenorphine in interstitial fluid.

A microfluidic in vitro method predicting the fate of peptide drugs after subcutaneous administration.

For many biopharmaceuticals, subcutaneous (sc) administration is the only viable route. However, there is no in vitro method available accurately predicting the absorption profiles of subcutaneously injected pharmaceuticals. In this work, we show that a recently developed microfluidics method for interaction studies (MIS) has the potential to be useful in this respect. The method utilises the responsiveness of polyelectrolyte microgel networks to oppositely charged molecules as a means to monitor the interaction between peptides and hyaluronic acid (HA), a major constituent of the subcutaneous extracellular matrix. We use the method to determine parameters describing the strength of interaction between peptide and HA as well as the peptide's aggregation tendency and transport properties in HA networks. The results from MIS studies of the peptide drugs exenatide, pramlintide, vancomycin, polymyxin B, lanreotide, MEDI7219 and AZD2820 are compared with results from measurements with the commercially available SCISSOR system and in vivo absorption and bioavailability data from the literature. We show that both MIS and SCISSOR reveal differences in the peptides' diffusivity and tendency to aggregate in the presence of HA. We show that MIS is particularly good at discriminating between peptides forming aggregates stabilised by non-electrostatic forces in the presence of HA, and peptides forming complexes stabilised by electrostatic interactions with HA. The method provides two parameters that can be used to quantify the peptides' aggregation tendency, the one describing the peptide packing density in complexes with HA and the other the apparent diffusivity upon release in a medium of physiological ionic strength and pH. The order of the peptides when ranked by increasing binding strength at pH 7.4 determined with MIS is shown to be in agreement with the order when ranked by the apparent 1st order absorption rate constant (ka) after sc administration in humans: lanreotide (Autogel) < exenatide (IRF) < AZD2820 < pramlintide < lanreotide (IRF) (IRF: Immediate release formulation). A correlation is found between the 1st order release rate constant determined with SCISSOR and ka for lanreotide (Autogel), exenatide and AZD2820. A mechanism relating the magnitude of ka to the peptides' charge is proposed.

Lateral Flow-Based Skin Patch for Rapid Detection of Protein Biomarkers in Human Dermal Interstitial Fluid.

Rapid diagnostic tests (RDTs) offer valuable diagnostic information in a quick, easy-to-use and low-cost format. While RDTs are one of the most commonly used tools for in vitro diagnostic testing, they require the collection of a blood sample, which is painful, poses risks of infection and can lead to complications. We introduce a blood-free point-of-care diagnostic test for the rapid detection of protein biomarkers in dermal interstitial fluid (ISF). This device consists of a lateral flow immunochromatographic assay (LFIA) integrated within a microfluidic skin patch. ISF is collected from the skin using a microneedle array and vacuum-assisted extraction system integrated in the patch, and transported through the lateral flow strip via surface tension. Using this skin patch platform, we demonstrate in situ detection of anti-tetanus toxoid IgG and SARS-CoV-2 neutralizing antibodies, which could be accurately detected in human ISF in <20 min. We envision that this device can be readily modified to detect other protein biomarkers in dermal ISF, making it a promising tool for rapid diagnostic testing.

Active CNS delivery of oxycodone in healthy and endotoxemic pigs.

BACKGROUND: The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. METHODS: This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. RESULTS: Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood-brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. CONCLUSIONS: This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings.

Silver Nanoclusters-Decorated Porous Microneedles Coupling Duplex-Specific Nuclease-Assisted Signal Amplification for Sampling and Detection of MicroRNA in Interstitial Fluid.

MicroRNAs (miRNAs) in dermal interstitial fluid (ISF) have recently been recognized as clinically promising biomarkers for the diagnosis and prognosis of cancer. However, the detection poses significant challenges, primarily due to the low abundance of miRNAs and the limitations of current sampling techniques. To address this issue, we develop novel porous microneedles (PMNs) array-based sensor composed of poly(vinyl alcohol) porous hydrogel and DNA-templated silver nanoclusters (AgNCs) to facilitate the enrichment and highly sensitive detection of ISF miRNA. Leveraging the capillary action facilitated by its unique porous structure and the swelling properties of the hydrogel, the PMNs array can efficiently extract 2.7 ± 0.3 mg of ISF within 5 min. Additionally, the interconnected pores within the PMNs array contribute to an increased specific surface area, thereby offering a convenient platform for the decoration of DNA-templated AgNCs. The immobilized large amount of AgNCs effectively capture the target miRNA from the extracted ISF, resulting in miRNA-induced fluorescence quenching of AgNCs. Subsequently, the introduction of the duplex-specific nuclease leads to the cleavage of DNA in DNA-RNA heteroduplexes, which release miRNA to interact with other AgNCs. This process of target recycling triggers a further reduction in fluorescence intensity, thereby enabling sensitive detection of the low-abundant miRNA down to 1.6 pM. Both in vitro and in vivo experiments validate the efficacy of the AgNCs immobilized PMNs array for the detection of miRNA biomarkers in ISF within minutes. These results indicate that the proposed PMNs array-based sensor holds great potential for the development of noninvasive personalized diagnostic strategies.

Pressure loading regulates the stemness of liver cancer stem cells via YAP/BMF signaling axis.

Cancer stem cells (CSCs) are considered the major cause of the occurrence, progression, chemoresistance/radioresistance, recurrence, and metastasis of cancer. Increased interstitial fluid pressure (IFP) is a key feature of solid tumors. Our previous study showed that the distribution of liver cancer stem cells (LCSCs) correlated with the mechanical heterogeneity within liver cancer tissues. However, the regulation of liver cancer's mechanical microenvironment on the LCSC stemness is not fully understood. Here, we employed a cellular pressure-loading device to investigate the effects of normal IFP (5 mmHg), as well as increased IFP (40 and 200 mmHg) on the stemness of LCSCs. Compared to the control LCSCs (exposure to 5 mmHg pressure loading), the LCSCs exposed to 40 mmHg pressure loading exhibited significantly upregulated expression of CSC markers (CD44, EpCAM, Nanog), enhanced sphere and colony formation capacities, and tumorigenic potential, whereas continuously increased pressure to 200 mmHg suppressed the LCSC characteristics. Mechanistically, pressure loading regulated Yes-associated protein (YAP) activity and Bcl-2 modifying factor (BMF) expression. YAP transcriptionally regulated BMF expression to affect the stemness of LCSCs. Knockdown of YAP and overexpression of BMF attenuated pressure-mediated stemness and tumorgenicity, while YAP-deficient and BMF-deletion recused pressure-dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression.

Hydrogel Capacitors Based on MoS2 Nanosheets and Applications in Glucose Monitoring.

Non-invasive/minimally invasive continuous monitoring of blood glucose and blood glucose administration have a high impact on chronic disease management in diabetic patients, but the existing technology is yet to achieve the above two purposes at the same time. Therefore, this study proposes a microfluidic microneedle patch based on 3D printing technology and an integrated control system design for blood glucose measurement, and a drug delivery control circuit based on a 555 chip. The proposed method provides an improved preparation of a PVA-PEG-MoS2 nanosheet hydrogel, making use of its dielectric properties to fabricate a microcapacitor and then embedding it in a microfluidic chip. When MoS2 nanosheets react with interstitial liquid glucose (and during the calibration process), the permittivity of the hydrogel is changed, resulting in changes in the capacitance of the capacitor. By converting the capacitance change into the square-wave period change in the output of the 555 chip with the control circuit design accordingly, the minimally invasive continuous measurement of blood glucose and the controlled release of hypoglycemic drugs are realized. In this study, the cross-linking structure of MoS2 nanosheets in hydrogel was examined using infrared spectroscopy and scanning electron microscopy (SEM) methods. Moreover, the critical doping mass fraction of MoS2 nanosheets was determined to be 2% via the measurement of the dielectric constant. Meanwhile, the circuit design and the relationship between the pulse cycle and glucose concentration is validated. The results show that, compared with capacitors in series, the microcapacitors embedded in microfluidic channels can be connected in parallel to obtain better linearized blood glucose measurement results.

Role of arterial blood glucose and interstitial fluid glucose difference in evaluating microcirculation and clinical prognosis of patients with septic shock: a prospective observational study.

BACKGROUND: Microcirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA-I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock. METHODS: The present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA-I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA-I interval was analyzed. RESULTS: A total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6-16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9-40), of whom 18 died during ICU stay. The GA-I levels were negative correlation with CRT (r = 0.369, P < 0.001), Lac (r = -0.269, P < 0.001), skin mottling score (r=-0.223, P < 0.001), and were positively associated with urine volume (r = 0.135, P < 0.05). The ICU mortality rate of patients with septic shock presenting GA-I ≤ 0.30 mmol/L and ≥ 2.14 mmol/L was significantly higher than that of patients with GA-I at 0.30-2.14 mmol/L [65.2% vs. 15.0%, odds ratio (OR) = 10.625, 95% confidence interval (CI): 2.355-47.503]. CONCLUSION: GA-I was correlated with microcirculation parameters, and with differences in survival. Future studies are needed to further explore the potential impact of GA-I on microcirculation and clinical prognosis of septic shock, and the bedside monitoring of GA-I may be beneficial for clinicians to identify high-risk patients.

Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway.

Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the "window period" characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing (RNA-seq) and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the Ras homologue family member A (RhoA)/Rho-associated protein kinase (ROCK) signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.

High incidence of low interstitial fluid glucose among type 2 diabetes patients with chronic kidney disease (CKD) despite adhering to appropriate glycated haemoglobin targets-has time come for robust integration of interstitial fluid glucose targets into glycaemic guidelines?

AIM: We aim to compare the burden of Level 1 (<4 mmol/L) and Level 2 (<3 mmol/L) hypoglycaemia between type 2 diabetes (T2D) patients with and without chronic kidney disease (CKD). METHODS: T2D subjects with and without CKD (eGFR<60 mL/min/1.73 m2) were recruited from a tertiary-care hospital. Subjects wore the Freestyle Libre-Pro sensor for 2 weeks. The number of hypoglycaemic events and intra-day difference in Level 1 and 2 hypoglycaemias were compared between the cohorts. RESULTS: We recruited 134 subjects: 74 with CKD (44 M:30F) and 60 without CKD (36 M:24F), with no difference in HbA1c between the two cohorts (66 ± 20 vs 64 ± 16 mmol/mol, p = 0.529). The CKD cohort had increased level 1 (OR 1.73, p = 0.011), level 2 hypoglycaemias (OR 2.16, p = 0.002), and glycaemic variability than the non-CKD cohort (35.3 ± 9.5 vs 32.3 ± 6.8%). The CKD cohort had more level 2 hypoglycaemia events nocturnally compared to day at 1.9 ± 3.1 vs. 1.4 ± 2.5 events/person within the two week sensor wearing period (p = 0.022), whereas there was no significant intra-day difference in the number of such events within the non-CKD cohort. CONCLUSIONS: The CKD cohort has a greater burden of hypoglycaemia despite being treated to similar HbA1c targets. The greater number of nocturnal events warrants safety concern. Interstitial fluid glucose targets should be incorporated into the glycaemic guidelines for T2D patients with CKD.

A novel neuroprotective method against ischemic stroke by accelerating the drainage of brain interstitial fluid.

Ischemic stroke is a leading cause of death and disability worldwide. Inflammatory response after stroke determines the outcome of ischemic injury. A recent study has reported an efficient method, epidural arterial implantation (EAI), for accelerating interstitial fluid (ISF) drainage, which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space (ECS). In this study, the method of EAI was modified (m-EAI) to control its function of accelerating the ISF drainage at different time points following ischemic attack. The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion (tMCAO) rat model. The results demonstrated the accumulation of IL-1ß, IL-6, and TNF-α was significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats, accompanied with decreased infarct volume and improved neurological function. This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS. Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.

Defining the Spatial Resolution of Analyte Recovery during Microperfusion-Based Sampling of Brain Parenchyma.

The unique architecture of the brain and the blood-brain barrier imposes challenges for the measurement of parenchyma-derived biomarkers that prevent sufficient understanding of transient neuropathogenic processes. One solution to this challenge is direct sampling of brain interstitial fluid via implanted microperfusion probes. Seeking to understand spatial limitations to microperfusion in the brain, we employed computational fluid dynamics modeling and empirical recovery of fluorescently labeled dextrans in an animal model. We found that dextrans were successfully recovered via microperfusion over a 6 h sampling period, especially at probes implanted 2 mm from the dextran infusion point relative to probes implanted 5 mm from the injection site. Experimental recovery was consistently around 1% of simulated, suggesting that this parameter can be used to set practical limits on the maximal tissue concentration of proteins measured in microperfusates and on the spatial domain sampled by our multimodal microperfusion probe.

Influence of interstitial fluid pressure, porosity, loading magnitude, and anisotropy in cortical bone adaptation.

Adaptive elasticity in cortical bone has traditionally been modeled using Strain Energy Density (SED). Recent studies have highlighted the importance of interstitial fluid in bone adaptation, yet no research has quantified the role of interstitial fluid pressure and its effects, specifically incorporating both SED and interstitial fluid pressure in the adaptation process. This study introduces a novel formulation combining theory of porous media and theory of adaptive elasticity that considers both SED and interstitial fluid's pressure in cortical bone adaptation. The formulation is solved using ANSYS Fluent and a MATLAB script, and sensitivity analyses were conducted, analyzing various porosities, loading magnitudes, anisotropic properties of cortical bone, and involvement coefficients of interstitial fluid's pressure. This study reveals that bones with different vascular porosities (PV) tend to achieve similar density distributions under uniform loading over time. This highlights the significant role of interstitial fluid pressure in accelerating the convergence to optimal bone properties, especially in specimens with larger PV porosities. The findings emphasize the importance of fluid pressure in bone remodeling, aligning with previous studies. Furthermore, this study demonstrates that considering transversely isotropic material properties can significantly alter the remodeling configuration compared to isotropic material properties. This highlights the importance of accurately representing the anisotropic nature of cortical bone in models to better predict its adaptive responses. However, aspects such as fluid density variations and bone geometry changes remain unexplored, suggesting directions for future research. Overall, this research enhances the understanding of cortical bone adaptation and its mechanical interactions.

Development of an electrochemical biosensor for non-invasive cholesterol monitoring via microneedle-based interstitial fluid extraction.

In this study, we present the development of an innovative electrochemical biosensor integrated into a microneedle-based system for non-invasive and sensitive quantification of cholesterol levels in interstitial fluid (ISF). The biosensor employs a graphene-based electrode with a polyelectrolyte interlayer to immobilize cholesterol oxidase (ChOx), enabling selective cholesterol detection. Graphene oxide is electrochemically reduced to form a conductive layer, and PANI is chosen as the optimal polyelectrolyte for ChOx immobilization. The biosensor's performance is thoroughly evaluated, demonstrating excellent sensitivity, stability, and selectivity. Furthermore, the biosensor is successfully applied to skin-mimicking agarose gel and porcine skin, showcasing its potential for real-world interstitial fluid extraction and cholesterol monitoring. The integrated microneedle-based system offers a promising approach for non-invasive monitoring of cholesterol levels, with implications for personalized healthcare diagnostics.

Glucose detection: In-situ colorimetric analysis with double-layer hydrogel microneedle patch based on polyvinyl alcohol and carboxymethyl chitosan.

Skin interstitial fluid (ISF) has emerged as a significant reservoir of biomarkers for disease diagnosis and prevention. Microneedle (MN) patches are regarded as an optimal platform for ISF extraction from the skin due to their non-invasive nature. However, challenges such as prolonged sampling durations and complex detection procedures impede timely metabolic analysis. In this investigation, we amalgamated MN technology with immobilized enzyme technology to fabricate a dual-layer MN patch integrating sampling and detection functionalities, thereby enabling in-situ colorimetric detection of hyperglycemia. The tip layer of the patch, comprising polyvinyl alcohol/carboxymethyl chitosan (PVA/CMCS) MN, was synthesized utilizing a chemical crosslinking approach for the first time, with glucose oxidase (GOx) being incorporated. The hydrophilicity of CMCS expedited the extraction process, facilitating the retrieval of approximately 10 mg of ISF within 10 min. The backing layer consisted of an immobilized polyvinyl alcohol-chitosan-horseradish peroxidase (PVA-CS-HRP) hydrogel film loaded with 3,3', 5,5'-tetramethylbenzidine (TMB). Incorporating macromolecular polymer PVA and CS for HRP immobilization addressed the issue of poor stability associated with traditional natural enzymes, thereby enhancing the sensitivity of the reaction system. The in-situ colorimetric sensor facilitated minimally invasive ISF extraction and swift conversion of glucose levels into detectable color changes.

Sliding Microneedle - Lateral flow immunoassay strip device for highly sensitive biomarker detection in interstitial fluid.

Diabetes is a chronic disease with significant complications, necessitating regular treatment and checkups, which can be costly and time-consuming for patients. To address this, we developed the Sliding Microneedle (MN)-Lateral flow immunoassay strip (LFIAs) device that combines the advantages of MNs and LFIAs to detect IL-6, an independent biomarker for diabetes complications. This device offers rapid and highly sensitive detection of IL-6 by extracting interstitial fluid (ISF) through MNs and transferring it to LFIAs. The stainless MN, embedded in the 3D-printed Sliding MN-LFIAs device, was inserted into the skin at a 20° angle, minimizing blood contamination risk. With a filter paper attached to the MN surface, the device collected 4.65 ± 0.05 µL of ISF containing IL-6 within 90 s. The ISF was then transferred to the LFIAs using a running buffer. After a 15-min reaction, silver enhancement (SE) treatment was applied, allowing for the highly sensitive and specific detection of IL-6 at 102 pg/mL concentrations. The Sliding MN-LFIAs device successfully distinguished between normal and diabetic rat models, demonstrating its potential as an effective tool for detecting diabetes complications quickly and affordably.