Subcutaneous Interstitial Fluid Research Articles

Clinical Utility of Bioimpedance Analysis for Upper Limb Lymphedema with Surgical Treatment.

Background: In lymphedema, the accumulation of subcutaneous interstitial fluid is the most characteristic feature. Bioimpedance analysis (BIA) is a promising technique to measure the amount of body components using a noninvasive method. In this study, we determined the clinical significance of BIA parameters in upper limb lymphedema with surgical treatment such as lymphovenous anastomosis or vascularized lymph node transfer. Methods and Results: A single-center retrospective study using a multifrequency BIA. Perioperative BIA parameters such as extracellular water ratio or fat-free mass (FFM) ratio and limb volume defined as percentage of excess volume (PEV) were measured. The relationships between the magnitude of change in PEV and BIA parameters during surgery were evaluated. Out of 48 unilateral lymphedema patients, 46 were female and the average age was 55.4 years. PEV and all BIA parameters showed a significant decrease after surgery (p < 0.001). There were significant correlations between ΔPEV and the degree of changes in all BIA parameters. ΔFFM ratio showed the highest correlation with the amount of change in PEV (r = 0.599, p < 0.001). Conclusion: BIA parameters correlated well with the volume change after surgery. BIA could be useful as a quick and easy tool for follow-up after lymphedema surgery.

A high-performance wearable microneedle sensor based on a carboxylated carbon nanotube-carbon nanotube composite electrode for the simultaneous detection of uric acid and dopamine

Uric acid (UA) and dopamine (DA) are crucial biomarkers in the human body. However, there is limited research on detecting UA or DA in subcutaneous interstitial fluid (SISF), and no studies on their simultaneous detection in SISF. Here, we developed an electrochemical microneedle sensor based on the carboxylated carbon nanotubes/multiwalled carbon nanotubes (CCNT/CNT) composite electrode for the simultaneous detection of UA and DA. Highly carboxylated CCNT was prepared and mixed with CNT and organosilicon-modified acrylic resin to form the CCNT/CNT composite. The carboxyl functional groups of CCNT enhance the electrode’s adsorption of UA and DA, while CNT improves electron conduction. The sensor achieves a wide linear detection range for UA (5–600 μM) with high sensitivity (7.13 μA μM−1 cm−2) and linearity (R2 = 0.994), as well as a wide linear range for DA (2–200 μM) with high sensitivity (13.31 μA μM−1 cm−2) and linearity (R2 = 0.994). The sensor achieved simultaneous detection of DA and UA in artificial interstitial fluid (ISF), with sensitivity and linearity remaining nearly unchanged compared to that in PBS, and is not affected by high levels of ascorbic acid (AA). Finally, the sensor successfully detected changes in UA levels in ISF of subjects before and after alcohol consumption in vivo, demonstrating its practical application capabilities. This study presents a practical strategy for detecting human biomarkers characterized by low cost, easy fabrication and excellent performance of electrode materials, and a well-designed microneedle sensor preparation scheme, making it highly promising for further research extension.

Pharmacokinetics, Dose-Proportionality, and Tolerability of Intravenous Tanespimycin (17-AAG) in Single and Multiple Doses in Dogs: A Potential Novel Treatment for Canine Visceral Leishmaniasis.

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50-250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h μg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 μg/mL and 6850 ± 469 μg/mL × h in plasma and 736 ± 294 μg/mL and 7382 ± 1357 μg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.

Prediction of subcutaneous drug absorption - Characterization of subcutaneous interstitial fluids as a basis for developing biorelevant in vitro models

Unlike orally administered drugs, the absorption profile of subcutaneously injectable drugs in humans is difficult to predict from preclinical studies. Since the subcutaneous interstitial fluid (ISF) is the first fluid interacting with the administered formulation before the respective drug is absorbed, it could critically affect bioavailability. The aim of the present study was to gain a better understanding of the similarities and differences of ISF of different species. For this purpose, ISF was isolated from subcutaneous tissues of five preclinical animal species, i.e., mice, rats, minipig, landrace pig, non-human primates, and humans, using a centrifugation method, and characterized with respect to its major constituents and physicochemical properties. The results show trends between animal species, with ISF from non-human primates differing significantly from that of the other preclinical species for most parameters analyzed and showing similarities to ISF of human origin. Although from a statistical point of view it will be necessary to further increase the existing data sets, the presented data provide valuable information for the development of biorelevant in vitro models to predict the in vivo performance of subcutaneously administered formulations, as they provide fundamental information for the design of biorelevant ISF media for both preclinical species and humans.

Fred J Boyd Oration 2021

Fred J Boyd Oration 2021

Pre-cooling with ingesting a high-carbohydrate ice slurry on thermoregulatory responses and subcutaneous interstitial fluid glucose during heat exposure

The purpose of this study was to compare the effects of ingesting ice slurries with two different carbohydrate contents on body temperatures and the subcutaneous interstitial fluid glucose level during heat exposure. Seven physically active men underwent one of three interventions: the ingestion of 7.5 g/kg of a control beverage (CON: 26°C), a normal-carbohydrate ice slurry (NCIS: −1°C), or a high-carbohydrate ice slurry (HCIS: −5°C). The participants were monitored for a 120-min period that included 10 min of rest, 25 min of exposure to the experimental cooling intervention (during which the beverage was ingested), and 85 min of seated rest in a climate chamber (36°C, 50% relative humidity). The rectal temperature in the HCIS and NCIS trials was lower than that in the CON trial from 40 to 75 min. The infrared tympanic temperature was also lower in the HCIS and NCIS trials than in the CON trial from 20 to 50 min, whereas the deep thigh or mean skin temperatures were not significantly different among the three groups. From 90 to 120 min, the subcutaneous interstitial fluid glucose level in the NCIS trial was lower than that at 65 min; however, reductions were not seen in the HCIS and CON trials. These findings suggest that both HCIS ingestion and conventional NCIS ingestion were effective cooling strategies for reducing thermal strain, while HCIS ingestion may also enable a higher subcutaneous interstitial fluid glucose level to be maintained, ensuring an adequate supply of required muscle substrates.

Liposuction in cancer-related lower extremity lymphedema: an investigative study on clinical applications

BackgroundLymphedema is a progressive, noncurable condition consisting of increases in subcutaneous fat and interstitial fluid in the limbs and fibrosis during later stages. The disease most commonly affects the limbs following injury to or removal of the lymph nodes. The aim of this study was to investigate the therapeutic outcomes of liposuction for cancer-related lower extremity lymphedema.MethodsSixty-two patients with cancer-related lymphedema in the unilateral lower extremity were recruited for this study, and all patients underwent liposuction. The volume of hemorrhage and lipids, the operation time, and the volume changes of the affected extremity were compared by applying the t tests, and the subjective feelings of patients were compared with the chi-square tests.ResultsThe total lipid volume was 2539 ± 1253.5 ml, and the hemorrhage volume was 828 ± 311.8 ml. For the comparison of objective indices, (1) the percent volume differences (PVDs) before surgery, intraoperatively, and at the 3-month follow-up were 5.5 ± 12.2 vs. 11.6 ± 18.4 vs. 43.2 ± 23.7, P < 0.05, respectively; (2) greater lipid volumes and higher liposuction rates were observed for female patients, as was a smaller volume of hemorrhage; (3) greater hemorrhage volumes were observed in patients with a history of recurrent erysipelas; and (4) greater lipid volumes and liposuction rates (LRs) and smaller hemorrhage volumes were observed for stage II than for stage III patients.ConclusionsLiposuction is an effective therapy for cancer-related lower extremity lymphedema. Sex, stage, and recurrent erysipelas history influence the course and effect of liposuction.

Role of Flash Glucose Monitoring System in Diabetic Patients with Chronic Liver Disease

Background: Diabetic patients show serious complications of chronic liver disease. The monitoring of glucose in diabetic patients with chronic liver disease is very challenging. Generally, the glycaemic control monitoring in chronic liver disease patients is the same as in a person who does not have any liver disease. Flash glucose monitoring system is a way to measure glucose levels of body without pricking the body. It is an innovative method of measuring glucose levels. A flash glucose monitor is a small sensor. This sensor is a small sticky chip and is attached on the skin of the arm. One side of the chip has a small needle that goes inside the skin. It records glucose levels throughout day and night continuously. Levels of glucose can be assessed whenever wanted. Materials and Methods: The study was conducted in the Medical Ward 1, Bahawal Victoria Hospital, Bahawalpur and the Department of Pathology, Quaid-e-Azam Medical College, Bahawalpur from 1st January 2018 to June 2020. Freestyle Libre Sensor flash glucose monitoring system (by CoolPlus Medical) was used to measure glucose of subcutaneous interstitial fluid. The disposable sensor was applied to the back of the arm for up to 14 days. Sensor is calibrated by the factory with no automatic alarms. Results: We noticed that the results of the patients who had co-existing disease of chronic hepatitis and diabetes mellitus had same results of glucose readings when measured by flash glucose monitoring system and by finger prick for glucose measurement by glucometer. Conclusion: Flash glucose monitoring system is way better than self monitoring blood glucose method by glucometer in diabetic patients with chronic liver disease. Keywords: Diabetes, glucose, monitoring, chronic liver disease, complications

Microdialysis sampling to monitor target-site vancomycin concentrations in septic infants: a feasible way to close the knowledge gap

This work is dedicated to the memory of Hartmut Derendorf (1953–2020), a pioneer of modern pharmacokinetics and valued mentor of this project.Objectives: Septic infants/neonates need effective antibiotic exposure, but dosing recommendations are challenging as the pharmacokinetics in this age are highly variable. For vancomycin, which is used as a standard treatment, comprehensive pharmacokinetic knowledge especially at the infection site is lacking. Hence, an exploratory clinical study was conducted to assess the feasibility and safety of microdialysis sampling for vancomycin monitoring at the target site.Methods: Nine infants/neonates with therapeutic indications for vancomycin treatment were administered 15 mg/kg as 1-hour infusions every 8–24 hours. Microdialysis catheters were implanted in the subcutaneous interstitial space fluid of the lateral thigh. Samples were collected every 30 minutes over 24 hours, followed by retrodialysis for catheter calibration. Prior in vitro investigations have evaluated impact factors on relative recovery and retrodialysis.Results: In vitro investigations showed the applicability of microdialysis for vancomycin monitoring. Microdialysis sampling was well tolerated in all infants/neonates (23–255 days) without major bleeding or other adverse events. Pharmacokinetic profiles were obtained and showed plausible vancomycin concentration-time courses.Conclusions: Microdialysis as a minimally invasive technique for continuous longer-term sampling is feasible and safe in infants/neonates. Interstitial space fluid profiles were plausible and showed substantial interpatient variation. Hence, a larger microdialysis trial is warranted to further characterise the pharmacokinetics and variability of vancomycin at the target site and ultimately improve vancomycin dosing in these vulnerable patients.

Glucose control using an artificial pancreas in a severe COVID-19 patient on extracorporeal membrane oxygenation: a case report

The usefulness and safety of continuous glucose monitoring (CGM) systems in adult patients with severe coronavirus disease (COVID-19) have been reported. Using CGM might reduce the exposure patients and healthcare workers to COVID-19 and limit the use of personal protective equipment during the pandemic. CGM devices measure glucose in the subcutaneous interstitial fluid, but the accuracy of this technique has not been established in critically ill patients. The artificial pancreas, STG-55 (Nikkiso, Tokyo), is a closed-loop device that conducts continuous blood glucose monitoring using a peripheral vein. We used the STG-55 for glucose control in a 60-year-old woman with severe COVID-19 admitted to the intensive care unit. Due to severe respiratory failure, the patient was intubated, and extracorporeal membrane oxygenation was introduced. Because she had hyperglycemia despite high-dose intravenous insulin therapy, we decided to use STG-55 for glucose control. The STG-55 safely titrated the insulin infusion and monitored glucose levels. Fifty-six hours after adopting the STG-55, it was removed because the blood sampling failed. No episodes of hypoglycemia were observed despite deep sedation during this period. In conclusion, this case demonstrates the potential utility of an artificial pancreas in patients with severe COVID-19.

Clinic-on-a-Needle Array toward Future Minimally Invasive Wearable Artificial Pancreas Applications.

In order to reduce medical facility overload due to the rise of the elderly population, modern lifestyle diseases, or pandemics, the medical industry is currently developing point-of-care and home medical device systems. Diabetes is an incurable and lifetime disease, accountable for a significant mortality and socio-economic public health burden. Thus, tight glucose control in diabetic patients, which can prevent the onset of its late complications, is of enormous importance. Despite recent advances, the current best achievable management of glucose control is still inadequate, due to several key limitations in the system components, mainly related to the reliability of sensing components, both temporally and chemically, and the integration of sensing and delivery components in a single wearable platform, which is yet to be achieved. Thus, advanced closed-loop artificial pancreas systems able to modulate insulin delivery according to the measured sensor glucose levels, independently of patient supervision, represent a key requirement of development efforts. Here, we demonstrate a minimally invasive, transdermal, multiplex, and versatile continuous metabolites monitoring system in the subcutaneous interstitial fluid space based on a chemically modified SiNW-FET nanosensor array on microneedle elements. Using this technology, ISF-borne metabolites require no extraction and are measured directly and continuously by the nanosensors. Due to their chemical sensing mechanism, the nanosensor response is only influenced by the specific metabolite of interest, and no response is observed in the presence of potential exogenous and endogenous interferents known to seriously affect the response of current electrochemical glucose detection approaches. The 2D architecture of this platform, using a single SOI substrate as a top-down multipurpose material, resulted in a standard fabricated chip with 3D functionality. After proving the ability of the system to act as a selective multimetabolites sensor, we have implemented our platform to reach our main goal for in vivo continuous glucose monitoring of healthy human subjects. Furthermore, minor adjustments to the fabrication technique allow the on-chip integration of microinjection needle elements, which can ideally be used as a drug delivery system. Preliminary experiments on a mice animal model successfully demonstrated the single-chip capability to both monitor glucose levels as well as deliver insulin. By that, we hope to provide in the future a cost-effective and reliable wearable personalized clinical tool for patients and a strong tool for research, which will be able to perform direct monitoring of clinical biomarkers in the ISF as well as synchronized transdermal drug delivery by this single-chip multifunctional platform.

A sensitive in vitro performance assay reveals the in vivo drug release mechanisms of long-acting medroxyprogesterone acetate microparticles.

Today, a growing number of subcutaneously administered depot formulations enable continuous delivery of poorly soluble compounds over a longer time period. The modified liberation is considered to be a rate-limiting step in drug absorption and thus impacts therapeutic efficacy and product safety. In the present approach, a mechanism-based pharmacokinetic model of the commercial microparticle formulation depo-subQ provera 104™ (Sauter mean diameter of 5.08±1.63µm) was established. The model was verified using human pharmacokinetic data from three different clinical trials. Further, the effects of drug release, injection site and patient population on the pharmacokinetic profile were investigated. For this purpose, the drug release was assessed using the novel dispersion releaser technology, whereby a biorelevant medium reflecting major characteristics of the subcutaneous tissue (including ion background, buffer capacity and protein concentration) was used. The established model provided an effective prediction of the key pharmacokinetic parameters, including Cmax, Tmax and AUCall. Only in presence of 55% of fetal bovine serum (using a novel simulated subcutaneous interstitial fluid), the release assay was capable to discriminate between microparticles before and after storage.

69-LB: A Wearable Microneedle Array Sensor Shows High Correlation between Dermal Glucose and Venous Blood Glucose

Objective: Current continuous glucose monitors (CGM) measure glucose in the subcutaneous interstitial fluid (ISF). Previous ex vivo research with hypodermic needles has shown that glucose in the dermal ISF is highly correlated to venous glucose with little or no lag time. However, this methodology is not viable for continuous measurement. In this study, we have developed and tested a wearable microneedle array sensor for continuous in situ measurement of glucose in the dermal ISF. A dermal CGM could be applied without an introducer needle and without pain during application. Methods: In this study the microneedle array sensor was tested against venous glucose measured every 15 minutes from a YSI analyzer in 8-hour sessions over 2 days (Phase One) and 5-7 days (Phase Two). Results: Five participants without diabetes and 10 participants with diabetes were recruited for phase One and 10 participants with diabetes were recruited for phase Two. A high degree of linear correlation (R2 ≥ 0 .90) between the microneedle array measured dermal ISF glucose and venous glucose was observed. The figure shows the linear correlation (A) and temporal profile (B) for one microneedle array sensor over 8 hours. Conclusions: A wearable microneedle array measuring dermal ISF glucose can accurately track glucose values. The study demonstrated early human feasibility of a CGM based on microneedle sensing of dermal ISF. Disclosure P.P. Samant: Employee; Self; Biolinq. M.P. Christiansen: Research Support; Self; Abbott, Ascensia Diabetes Care, Biolinq, Dexcom, Inc., Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Medtronic, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi-Aventis, Senseonics, ViroMed Laboratories, Xeris Pharmaceuticals, Inc. S. Sattayasamitsathit: None. A. Campbell: None. T.A. Peyser: Consultant; Self; Insulet Corporation. Employee; Self; Biolinq. J.R. Windmiller: Employee; Self; Biolinq. J.R. Tangney: Board Member; Self; Biolinq. R. Lal: Consultant; Self; Abbott, Biolinq. N.C. Bhavaraju: Employee; Self; Biolinq.

Nanochannel-driven rapid capture of sub-nanogram level biomarkers for painless preeclampsia diagnosis

Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome recognized as the leading cause of maternal and fetal morbidity and mortality worldwide. Painful blood-collection procedures or low accuracy of non-invasive approaches require faster, patient-friendly, and more sensitive diagnostic technologies. Here we report a painless, highly sensitive detection platform using nanoporous microneedles (nMNs) that enables rapid capture of biomarkers present at sub-nanogram levels. The highly porous nanostructures on the nMN surface were prepared by anodization of aluminum MN and then functionalized by immobilization of capture antibodies to detect target biomarkers based on an immunoassay method. The immuno-functionalized nMN array demonstrated rapid capture of an estrogen (E2) biomarker for PE following a 1-min incubation and exhibited a concentration-dependent change in fluorescence intensity over the E2 range of 0.5 ng mL−1 to 1000 ng mL−1 after treatment with fluorescence-detection antibodies. Remarkably, the nMN patch selectively detected sub-nanogram-levels of E2 in subcutaneous interstitial fluid from rats with increased diagnostic accuracy as compared with commercial immunoassay kits. This bio-functionalized nMN platform showed improved biosensing capability for multiple PE-related biomarkers, including hormones and proteins. Furthermore, this painless method demonstrated efficacy as a point-of-need diagnostic platform using portable smartphone-based fluorescence microscope to obtain fluorescence images of biomarker-captured nMN arrays.

Basics and use of continuous glucose monitoring (CGM) in diabetes therapy

Abstract Background For a long time, self-monitoring of blood glucose (SMBG) was widely viewed as the essential glucose measurement procedure in the therapy of insulin-treated people with diabetes. With increasing accuracy and simplified handling of continuous glucose monitoring (CGM) systems, this evolving technology challenges and at least partly replaces SMBG systems. Content Sensors of all currently available CGM systems measure glucose levels in the subcutaneous interstitial fluid for 6–14 days. The only available implantable sensor facilitates a measurement span of up to 6 months. Depending on the used system, glucose levels are either shown in real time (rtCGM systems) or after scanning (iscCGM systems). Functions such as alerts, alarms and trend arrows and data presentation encourage independent self-management of diabetes therapy. The high frequency of glucose data and the multitude of existing functions require an extensive training of people with diabetes and their caregivers. Summary CGM systems provide a much more detailed picture of glycemia in people with diabetes. Educated patients can use these data to react adequately to their glucose levels and therefore avoid hypoglycemic and hyperglycemic events. Studies showed that glycated hemoglobin (HbA1c) levels and hypoglycemic events can be significantly reduced by frequent use of CGM systems.

Continuous glucose monitoring can disclose glucose fluctuation in advanced Parkinsonian syndromes.

Continuous glucose monitoring (CGM) is a method to examine glucose concentration in subcutaneous interstitial fluid sequentially. CGM can disclose glucose fluctuation (GF), which can be unrecognized in routine blood tests. A limited number of studies suggest advanced Parkinsonian syndromes (PS) is at risk of GF, however, the report of CGM in PS is scarce. We performed CGM for 72 h in 11 nondiabetic patients with advanced PS. The etiology was Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies. All participants were bedridden, elderly (≥65 year-old), and receiving enteral nutrition. The retrospective data was obtained after the removal of CGM device. In the glucose concentration, 9 (81.8%) participants showed nocturnal decline (≤70 mg/dL; 4 of them reached recordable limit of 40 mg/dL), and 6 (54.5%) participants showed remarkable elevation (≥200 mg/dL) postprandially. In the majority, these abnormalities were difficult to predict from routine blood tests. Standard deviation and mean of sequential glucose concentration were higher than those in precedent reports of young or middle-aged healthy controls. CGM in nondiabetic and elderly patients with advanced PS can disclose GF, with features of nocturnal decline and/or postprandial remarkable elevation of glucose concentration. Owing to limitations such as small sample size, heterogeneity of etiology, and retrospectivity of CGM data, further investigations are required.

Prevention of Surgical Site Infections and Biofilms: Pharmacokinetics of Subcutaneous Cefazolin and Metronidazole in a Tumescent Lidocaine Solution.

Tumescent anesthesia antibiotic delivery (TAAD) consists of subcutaneous infiltration of antibiotic(s) dissolved tumescent lidocaine anesthesia. Tumescent lidocaine anesthesia contains lidocaine (≤ 1 g/L), epinephrine (≤ 1 mg/L), sodium bicarbonate (10 mEq/L) in 0.9% saline. Our aim was to measure cefazolin and metronidazole concentrations over time in subcutaneous tumescent interstitial fluid (TISF) after TAAD, in serum after TAAD and after intravenous antibiotic delivery (IVAD). We hypothesize that the pharmacokinetic/pharmacodynamic profiles of TAAD + IVAD are superior to IVAD alone for the prevention of surgical site infections and biofilms. Concentrations of cefazolin and metronidazole in TISF and serum following TAAD and in serum following IVAD were compared in 5 female volunteers. Subjects received cefazolin or cefazolin plus metronidazole by IVAD alone and by TAAD alone. One subject also received concomitant IVAD and TAAD of these 2 antibiotics. Sequential samples of serum or subcutaneous TISF were assayed for antibiotic concentration. Cefazolin (1 g) by TAAD resulted in an area under the curve of the concentration-time profile and a maximum concentration (Cmax) in subcutaneous tissue that were 16.5 and 5.6 times greater than in serum following 1 g by IVAD. Metronidazole (500 mg) by TAAD resulted in an area under the curve and Cmax that were 8.1 and 24.7 times greater in TISF, than in serum after 500 mg by intravenous delivery. IVAD + TAAD resulted in superior antibiotic concentrations to IVAD alone. TAAD + IVAD produced superior antibiotic bioavailability in both subcutaneous interstitial fluid and serum compared with IVAD alone. There was no evidence that TAAD of cefazolin and metronidazole poses a significant risk of harm to patients.

Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients

ObjectiveTo identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. MethodsProteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. ResultsGalectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p<0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p<0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p<0.05) and increased by overfeeding (p<0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p<0.05) but this was independent of the insulin signal. ConclusionProteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes.

A continuous glucose monitoring device by graphene modified electrochemical sensor in microfluidic system.

This paper presents a continuous glucose monitoring microsystem consisting of a three-electrode electrochemical sensor integrated into a microfluidic chip. The microfluidic chip, which was used to transdermally extract and collect subcutaneous interstitial fluid, was fabricated from five polydimethylsiloxane layers using micromolding techniques. The electrochemical sensor was integrated into the chip for continuous detection of glucose. Specifically, a single-layer graphene and gold nanoparticles (AuNPs) were decorated onto the working electrode (WE) of the sensor to construct a composite nanostructured surface and improve the resolution of the glucose measurements. Graphene was transferred onto the WE surface to improve the electroactive nature of the electrode to enable measurements of low levels of glucose. The AuNPs were directly electrodeposited onto the graphene layer to improve the electron transfer rate from the activity center of the enzyme to the electrode to enhance the sensitivity of the sensor. Glucose oxidase (GOx) was immobilized onto the composite nanostructured surface to specifically detect glucose. The factors required for AuNPs deposition and GOx immobilization were also investigated, and the optimized parameters were obtained. The experimental results displayed that the proposed sensor could precisely measure glucose in the linear range from 0 to 162 mg/dl with a detection limit of 1.44 mg/dl (S/N = 3). The proposed sensor exhibited the potential to detect hypoglycemia which is still a major challenge for continuous glucose monitoring in clinics. Unlike implantable glucose sensors, the wearable device enabled external continuous monitoring of glucose without interference from foreign body reaction and bioelectricity.

In Vivo Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis.

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) was significantly higher than the median ISF AUC0-24 (340.4 versus 141.1 mg · h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (Cmax and Cmin) showed a significant correlation with the fluconazole plasma exposure (Cmax, R(2) = 0.86, P < 0.0001; Cmin, R(2) = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.