Biocompatibility evaluation of sol-gel coatings for subcutaneously implantable glucose sensors

The objective of the current investigation is to determine the soft-tissue biocompatibility of sol-gel matrices which can be used to optimize the properties of implantable glucose sensors. The biocompatibility of sol-gel matrices with heparin, dextran sulphate, Nafion, polyethylene glycol, and polystyrene sulphonate was examined in vitro in simulated body fluid and with cell culture experiments using human dermal fibroblasts. Finally, an in vivo study was performed. Therefore, sol-gel coated polystyrene discs were inserted subcutaneously in the back of rabbits. After 4 and 12 weeks, the implants with surrounding tissue were retrieved and processed histologically. In simulated body fluid, the formation of a granular calcium phosphate precipitate was observed. Cell proliferation on polyethylene glycol, Nafion, and heparin coated substrates was comparable to control samples and significantly higher than on dextran sulphate and polystyrene sulphate coated substrates. Light microscopic evaluation of the retrieved in vivo samples showed a fair tissue reaction to all materials. Histomorphometric analysis demonstrated that there were no differences in tissue response to the different sol-gel coatings. In conclusion, sol-gel matrices exhibit a fair biocompatibility both in vitro and in vivo. These results will form the basis for further research into the real merits of sol-gel coatings in optimizing the properties of subcutaneously implantable glucose sensors.     

Characterization of porous,dexamethasone-releasing polyurethane coatings for glucose sensors

Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue–sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue–sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.     

Influence of inflammatory cells and serum on the performance of implantable glucose sensors

The objective of this investigation was to evaluate the influence of polymorphonuclear granulocytes on the performance of uncoated and cellulose acetate/Nafion coated amperometric glucose sensors in vitro. The response of these sensors was also investigated in serum. Uncoated and coated sensors showed lower sensitivities to glucose, with a significant drift in sensor output upon exposure to serum or leukocytes. Although the use of a coating resulted in higher sensitivity, the progressive loss of output was not completely prevented. Stimulated granulocytes were shown to excrete components, probably catalase and myeloperoxidase, which consumed the hydrogen peroxide formed by the oxidation of glucose. In addition, adsorbed serum proteins formed a diffusional barrier for glucose. Furthermore, serum was found to contain low-molecular weight components that alone inhibited glucose oxidase activity. Based on preliminary electrochemical results, we postulate that rabbit serum contains oxidizing substrates that compete with molecular oxygen for the acceptance of electrons from the oxidized enzyme. Consequently, future efforts should be aimed at elucidating the mechanisms involved in the interference of unknown serum components with electron transfer. In addition, further investigations have to be performed to develop an outer membrane that minimizes protein adsorption as well as the actions of inflammatory cells.     

Parylene-on-oil packaging for long-term implantable pressure sensors

This paper reports and analyzes the feasibility study of a parylene-on-oil encapsulation packaging method of pressure sensors targeted for long-term implantation. Commercial barometric digital-output pressure sensors are enclosed in silicone oil and then encapsulated in situ with parylene-C or –D (PA-C, PA-D) chemical vapor deposition. Experimentally, sensors encapsulated with 30,000 cSt silicone oil and 27 μm PA-D show good performance for 6 weeks in 77 °C saline with >99 % of original sensitivity, corresponding to an extrapolated lifetime of around 21 months in 37 °C saline. This work shows that, with proper designs, such a packaging method can preserve the original pressure sensor sensitivity without offset, validated throughout accelerated lifetime tests. In experiments, wires on the prototypes are used for external electronics but it is found that they contributed to early failures, which would be absent in real wireless versions, indicating a potential for even longer lifetimes. Finally, a verified model is presented to predict the pressure sensor sensitivity of parylene-on-oil packaging with and without the presence of a bubble in the oil.     

Macrophage embedded fibrin gels: An in vitro platform for assessing inflammation effects on implantable glucose sensors

The erroneous and unpredictable behavior of percutaneous glucose sensors just days following implantation has limited their clinical utility for diabetes management. Recent research has implicated the presence of adherent inflammatory cells as the key mitigating factor limiting sensor functionality in this period of days post-implantation. Here we present a novel in vitro platform to mimic the cell-embedded provisional matrix that forms adjacent to the sensor immediately after implantation for the focused investigation of the effects of early stage tissue response on sensor function. This biomimetic surrogate is formed by imbibing fibrin-based gels with physiological densities of inflammatory RAW 264.7 macrophages. When surrounding functional sensors, macrophage-embedded fibrin gels contribute to sensor signal declines that are similar in both shape and magnitude to those observed in previous whole blood and small animal studies. Signal decline in the presence of gels is both metabolically-mediated and sensitive to cell type and activation. Computational modeling of the experimental setup is also presented to validate the design by showing that the cellular glucose uptake parameters necessary to achieve such experimental declines align well with literature values. Together, these data suggest this in vitro provisional matrix surrogate may serve as an effective screening tool for testing the biocompatibility of future glucose sensor designs.     

In vitro and in vivo characterization of porous poly-L-lactic acid coatings for subcutaneously implanted glucose sensors

The purpose of this study was to test the hypothesis that porous poly-L-lactic acid (PLLA) sensor coatings reduce fibrosis and promote blood microvessel formation in tissue adjacent to the sensor surface. Porous PLLA coatings were produced using ammonium bicarbonate as the gas foaming/salt leaching agent, and deployed on functional and nonfunctional sensors. The porous coatings minimally affected sensor accuracy and response rate in vitro. Three-week subcutaneous rat studies of nonfunctional glucose sensors showed the anticipated effect of porous coatings enhancing vascularity and decreasing collagen deposition. In contrast, percutaneous functional sensors with and without porous coatings showed no significant difference in terms of histology or sensor response. In spite of the observation that texturing increases the vascularity of the tissue that surrounds implanted sensors, other factors such as the additional mechanical stresses imposed by percutaneous tethering may override the beneficial effects of the porous coatings.     

An Universal packaging technique for low-drift implantable pressure sensors

Monitoring bodily pressures provide valuable diagnostic and prognostic information. In particular, long-term measurement through implantable sensors is highly desirable in situations where percutaneous access can be complicated or dangerous (e.g., intracranial pressure in hydrocephalic patients). In spite of decades of progress in the fabrication of miniature solid-state pressure sensors, sensor drift has so far severely limited their application in implantable systems. In this paper, we report on a universal packaging technique for reducing the sensor drift. The described method isolates the pressure sensor from a major source of drift, i.e., contact with the aqueous surrounding environment, by encasing the sensor in a silicone-filled medical-grade polyurethane balloon. In-vitro soak tests for 100 days using commercial micromachined piezoresistive pressure sensors demonstrate a stable operation with the output remaining within 1.8 cmH₂O (1.3 mmHg) of a reference pressure transducer. Under similar test conditions, a non-isolated sensor fluctuates between 10 and 20 cmH₂O (7.4–14.7 mmHg) of the reference, without ever settling to a stable operation regime. Implantation in Ossabow pigs demonstrate the robustness of the package and its in-vivo efficacy in reducing the baseline drift.     

Conductive hydrogels with tailored bioactivity for implantable electrode coatings

The development of high-resolution neuroprosthetics has driven the need for better electrode materials. Approaches to achieve both electrical and mechanical improvements have included the development of hydrogel and conducting polymer composites. However, these composites have limited biological interaction, as they are often composed of synthetic polymers or non-ideal biological polymers, which lack the required elements for biorecognition. This study explores the covalent incorporation of bioactive molecules within a conducting hydrogel (CH). The CH was formed from the biosynthetic co-hydrogel poly(vinyl alcohol)–heparin and the conductive polymer (CP), poly(3,4-ethylene dioxythiophene). Adhesive biomolecules sericin and gelatin were covalently incorporated via methacrylate crosslinking within the CH. Electrical properties of the bioactive CH were assessed, and it was shown that the polar biomolecules improved charge transfer. The bioactivity of heparin within the hybrid assessed by examining stimulation of B-lymphocyte (BaF3) proliferation showed that bioactivity was retained after electropolymerization of the CP through the hydrogel. Similarly, incorporation of sericin and gelatin in the CH promoted neural cell adhesion and proliferation, with only small percentages (⩽2 wt.%) required to achieve optimal results. Sericin provided the best support for the outgrowth of neural processes, and 1 wt.% was sufficient to facilitate adhesion and differentiation of neurons. The drug delivery capability of CH was shown through incorporation of nerve growth factor during polymer fabrication. NGF was delivered to the target cells, resulting in outgrowth of neural processes. The CH system is a flexible technology platform, which can be tailored to covalently incorporate bioactive protein sequences and deliver mobile water-soluble drug molecules.     

Electrochemical platinum coatings for improving performance of implantable microelectrode arrays

The formation and properties of electrochemical platinum films grown on platinum contacts contained in implantable flexible microelectrodes were investigated. The resulting platinum deposits were obtained by applying cyclic voltammetry to baths containing concentrations around 70 mM of chloroplatinic acid. A pre-activation step was necessary before the platinum-electroplating step in order to achieve good adhesive properties. The benefits of this process were ascribed to higher corrosion resistance, lower impedance and improved adhesion to the sputtered platinum. These improvements can make the application of this electrochemical technique highly useful for increasing the lifetime of implantable microelectrode arrays, such as cuff structures (IEEE Trans. Biomed. Eng. 40 (1993) 640). These medical devices, obtained by semiconductor technology could be used for selective stimulation of nerve fascicles, although, poor long-term performance has been achieved with them. The dissolution rate for platinum thin-film microelectrodes under fixed corrosion test conditions was 38.8 ng/C. Lower rates were observed for electroplated microelectrodes, obtaining a dissolution rate of 7.8 ng/C under analogous experimental ageing conditions. The corrosion behaviour of the electroplated platinum during stimulation experimental conditions was estimated by electrochemical impedance spectroscopy.     

植入式实验动物血糖动态监测装置的设计

目的 设计、研制一种用于实验动物的全植入式血糖浓度检测系统,通过一次植入手术可获得实验动物自然状态下经无线方式传输的动态血糖监测数据.方法 监测系统包括植入体和体外接收端两部分.植入体尺寸设计为11.5 mm×16.0 mm×5.0 mm,不超过实验大鼠体积的1/10.以SOF-SENSOR植入式葡萄糖传感器及其外围三电极伏安测量电路为核心,采用锂电池和稳压芯片构建供电,测量数据通过CC2540低功耗蓝牙系统芯片无线传输至体外.植入体外层包裹医用硅胶材料,以保护电路和提高植入体生物相容性.结果 体外验证实验表明,本系统可在2～34 mmol/L范围较准确地测量葡萄糖浓度(r=0.996 7),平均标准误差为0.193 mmol/L,灵敏度为9.24 nM(mmol/L),能够满足设计要求.结论 植入式实验动物血糖动态监测装置体积小,适合植入.体外血糖测量验证实验表明本装置的血糖测量范围、准确性、灵敏度及标准误差等均能满足设计要求.此装置有望为糖尿病病理和药效学研究提供重要的技术支持.     

Plasma application of protective polymer-powder coatings to ultrasonic sensors

The failure of medical ultrasonic transducers caused by abrasion of the surface layer of the piezoelectric element is an urgent problem. Application of polymer-powder materials by spraying in an electrostatic field is the most convenient method for restoring the working properties of ultrasonic sensors. It provides more effective control of coating thickness, which is important for compliance to the requirements for transmission, reflection, and absorption of ultrasonic waves used in the piezoelectric transducer. A method of plasma coating application for the restoration of defective medical ultrasound probes is presented in this work. Results of the study of physical and mechanical properties of the coatings are discussed.     

植入式葡萄糖传感器膜材料壳聚糖与Nafion的组织相容性比较

背景：壳聚糖是天然高分子多糖,可单独或者与其他材料复合制作敷料、药物、基因载体、生物涂层、组织工程支架、传感器膜材料等。 目的：了解壳聚糖作为植入式葡萄糖传感器膜材料的组织相容性,并与Nafion膜进行对比。 方法：制备壳聚糖膜并对其理化性质进行表征,比较壳聚糖膜皮下植入与肌肉植入、Nafion膜肌肉植入的生物相容性。 结果与结论：壳聚糖膜的厚度、溶胀率、表观密度等理化参数可以通过浓度、铸膜液体积来控制;壳聚糖膜能生物降解,63 d皮下植入的降解率为(17.0±9.9)%,说明壳聚糖的体内降解速度较慢。壳聚糖膜皮下植入引起的炎症反应较肌肉植入重,63 d后形成的纤维包膜比肌肉植入要厚(P < 0.05);肌肉植入Nafion与壳聚糖膜引起材料周围纤维包膜厚度差异无显著性意义(P > 0.05),两者均在15 d以后趋于稳定。证明壳聚糖膜能生物降解,与Nafion膜均有较好的组织相容性。     

Characterization of a CMOS sensing core for ultra-miniature wireless implantable temperature sensors with application to cryomedicine

In effort to improve thermal control in minimally invasive cryosurgery, the concept of a miniature, wireless, implantable sensing unit has been developed recently. The sensing unit integrates a wireless power delivery mechanism, wireless communication means, and a sensing core—the subject matter of the current study. The current study presents a CMOS ultra-miniature PTAT temperature sensing core and focuses on design principles, fabrication of a proof-of-concept, and characterization in a cryogenic environment. For this purpose, a 100 μm × 400 μm sensing core prototype has been fabricated using a 130 nm CMOS process. The senor has shown to operate between −180 °C and room temperature, to consume power of less than 1 μW, and to have an uncertainty range of 1.4 °C and non-linearity of 1.1%. Results of this study suggest that the sensing core is ready to be integrated in the sensing unit, where system integration is the subject matter of a parallel effort.     

Preliminary evaluation of implantable MOSFET radiation dosimeters

In this paper, we report on measurements performed on a new prototype implantable radiation detector that uses metal-oxide semiconductor field effect transistors (MOSFETs) designed for in vivo dosimetry. The dosimeters, which are encapsulated in hermetically sealed glass cylinders, are used in an unbiased mode during irradiation, unlike other MOSFET detectors previously used in radiotherapy applications. They are powered by radio frequency telemetry for dose measurements, obviating the need for a power supply within each capsule. We have studied the dosimetric characteristics of these MOSFET detectors in vitro under irradiation from a 60Co source. The detectors show a dose reproducibility generally within 5% or better, with the main sources of error being temperature fluctuations occurring between the pre- and post-irradiation measurements as well as detector orientation. A better temperature-controlled environment leads to a reproducibility within 2%. Our preliminary in vitro results show clearly that true non-invasive in vivo dosimetry measurements are feasible and can be performed remotely using telemetric technology.     

The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions

Members of the Bcl-2 family are crucial integrators of survival and death signals in higher eukaryotes. Although recent studies have provided novel and quite unexpected insights into the mechanisms by which these proteins might issue life permits or death sentences in cells, we are still on the way to fully understand their modes of action. This review provides a snapshot on where we are on this journey and how we may exploit our knowledge on this family of proteins to unveil the mysteries of immune regulation.     

Implantable glucose sensors: comparison between in vitro and in vivo kinetics

This study was aimed at validating the in vitro estimated response characteristics of implanted glucose oxidase/H2O2 electrodes with respect to their in vivo function. Monoexponential non-linear regression analysis of sensor current vs. time curves in response to square alterations in glucose concentration gave response times T95 of between 1 and 5 min. Non-primed glucose infusions were applied to dogs with these electrodes implanted subcutaneously. The simultaneously monitored in vivo data were subjected to non-linear regression analysis. The time constants T of increases or decreases after starting or ending the glucose load were (mean +/- SEM) 53 +/- 10 and 26 +/- 4 min (significant difference, p less than 0.05) in sensor current, 28 +/- 8 and 15 +/- 2 min (NS) in whole blood, and 26 +/- 5 and 18 +/- 2 min (NS) in plasma. The in vivo kinetic patterns of sensors were not related to their in vitro response times. Non-linear regression analysis of in vitro responses of glucose sensors under clearly defined conditions is recommended as a basis for further studies. The physiological delay in the subcutaneous glucose system needs more attention in this field of research.     

In vitro characterization of vascular endothelial growth factor and dexamethasone releasing hydrogels for implantable probe coatings

Anti-fouling hydrogel coatings, copolymers of 2-hydroxyethyl methacrylate, 1-vinyl-2-pyrrolidinone, and polyethylene glycol, were investigated for the purpose of improving biosensor biocompatibility. These coatings were modified to incorporate poly(lactide-co-glycolide) (PLGA) microspheres in order to release dexamethasone (DX) and/or vascular endothelial growth factor (VEGF). DX and VEGF release kinetics from microspheres, hydrogels, and microspheres embedded in hydrogels were determined in 2-week and 1-month studies. Overall, monolithic, non-degradable hydrogel drug release had an initial burst followed by release at a significantly lower amount. Microsphere drug release kinetics exhibited an initial burst followed by sustained release for 1 month. Embedding microspheres in hydrogels resulted in attenuated drug delivery. VEGF release from embedded microspheres, 1.1+/-0.3 ng, was negligible compared to release from hydrogels, 197+/-33 ng. After the initial burst from DX-loaded hydrogels, DX release from embedded microspheres was similar to that of hydrogels. The total DX release from hydrogels, 155+/-35 microg, was greater than that of embedded microspheres, 60+/-6 microg. From this study, hydrogel sensor coatings should be prepared incorporating VEGF in the hydrogel and DX either in the hydrogel or in DX microspheres embedded in the hydrogel.     

半侧上颌骨缺损赝复体修复固位方案的生物力学评价

目的 对3种单侧上颌骨缺损赝复体修复方式——卡环固位、一根/两根颧种植与卡环联合固位进行生物力学评价。方法 基于CT扫描数据建立正常人颅骨的三维有限元模型,通过三维有限元法计算分析3种重建模型中上颌复合体的应力分布,综合比较赝复体、基牙、卡环、种植体、颧骨的应力水平。结果 单一的卡环固位,基牙应力峰值达130.7 MPa,赝复体产生位移4.439 mm,卡环应力峰值达452.4 MPa,健侧眶缘应力为23.32 MPa;加入一根颧种植后,卡环应力减小至118.1 MPa,基牙应力峰值为31.12 MPa,健侧眶缘应力仅为5.387 MPa。两根颧种植体固位方式下,颧骨应力由66.11 MPa减小到48.12 MPa;颧种植体上的最大应力也由500.2 MPa降至313.8 MPa。 结论 颧种植与卡环联合固位,颌面骨骼应力分布更符合咬合力传导规律。研究结果将为人体上颌单侧缺损重建方案设计和优化提供重要参考数据。