Hydrogel based sensor arrays (2 × 2) with perforated piezoresistive diaphragms for metabolic monitoring (in vitro).

This report details the first experimental results from novel hydrogel sensor array (2 × 2) which incorporates analyte diffusion pores into a piezoresistive diaphragm for the detection of hydrogel swelling pressures and hence chemical concentrations. The sensor assembly was comprised of three components, the active four sensors, HPMA/DMA/TEGDMA (hydroxypropyl methacrylate (HPMA), N,N-dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA)) hydrogel, and backing plate. Each of the individual sensors of the array can be used with various hydrogels used to measure the presence of a number of stimuli including pH, ionic strength, and glucose concentrations. Ideally, in the future, these sensors will be used for continuous metabolic monitoring applications and implanted subcutaneously. In this paper and to properly characterize the sensor assembly, hydrogels sensitive to changes ionic strength were synthesized using hydroxypropyl methacrylate (HPMA), N,N-dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA) and inserted into the sensor assembly. This hydrogel quickly and reversibly swells when placed environments of physiological buffer solutions (PBS) with ionic strengths ranging from 0.025 to 0.15 M, making it ideal for proof-of-concept testing and initial characterization. The assembly was wire bonded to a printed circuit board and coated with 3 ± 0.5 µm of Parylene-C using chemical vapor deposition (CVD) to protect the sensor and electrical connections during ionic strength wet testing. Two versions of sensors were fabricated for comparison, the first incorporated diffusion pores into the diaphragm, and the second used a solid diaphragm with perforated backing plate. This new design (perforated diaphragm) was shown to have slightly higher sensitivity than solid diaphragm sensors with separate diffuse backing plates when coupled with the hydrogel. The sensitivities for the 1 mm × 1 mm, 1.25 mm × 1.25 mm, 1.5 mm × 1.5 mm perforated diaphragm sensors were 53.3 ± 6.5, 171.7 ± 8.8, and 271.47 ± 27.53 mV/V-M, respectively. These results show that perforations in the diaphragm can be used not only to allow the diffusion of analyte into the cavity but to increase mechanical stress in the piezoresistive diaphragm, thereby increasing sensor output signal. The time constants for swelling (τswelling) and contracting (τcontracting) were calculated by fitting the sensor output half cycles to an exponential growth function. We found that the sensors' response was initially retarded during the preliminary hydrogel conditioning period then improved after 3-5 cycles with values of approximately 9 and 7 min for τswelling and τcontracting. For all sensors tested τswelling > τcontracting. This may be due to the increased loading on the hydrogel from the diaphragm during the swelling process. During contraction the diaphragm aids the hydrogel by reversibly applying mechanical pressure and therefore reducing τcontracting. Long term stability testing showed the sensors remained functional for upwards of 2 weeks in the test phosphate buffer solution (PBS).

Local release of masitinib alters in vivo implantable continuous glucose sensor performance.

Continuous glucose monitoring (CGM) sensors are often advocated as a clinical solution to improve long-term glycemic control in the context of diabetes. Subcutaneous sensor inflammatory response, fouling and fibrous encapsulation resulting from the host foreign body response (FBR) reduce sensor sensitivity to glucose, eventually resulting in sensor performance compromise and device failure. Several combination device strategies load CGM sensors with drug payloads that release locally to tissue sites to mitigate FBR-mediated sensor failure. In this study, the mast cell-targeting tyrosine kinase inhibitor, masitinib, was released from degradable polymer microspheres delivered from the surfaces of FDA-approved human commercial CGM needle-type implanted sensors in a rodent subcutaneous test bed. By targeting the mast cell c-Kit receptor and inhibiting mast cell activation and degranulation, local masitinib penetration around the CGM to several hundred microns sought to reduce sensor fibrosis to extend CGM functional lifetimes in subcutaneous sites. Drug-releasing and control CGM implants were compared in murine percutaneous implant sites for 21 days using direct-wire continuous glucose reporting. Drug-releasing implants exhibited no significant difference in CGM fibrosis at implant sites but showed relatively stable continuous sensor responses over the study period compared to blank microsphere control CGM implants.

Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kit(w-Sh) murine model.

Mast cells (MCs)_are recognized for their functional role in wound-healing and allergic and inflammatory responses - host responses that are frequently detrimental to implanted biomaterials if extended beyond acute reactivity. These tissue reactions impact especially on the performance of sensing implants such as continuous glucose monitoring (CGM) devices. Our hypothesis that effective blockade of MC activity around implants could alter the host foreign body response (FBR) and enhance the in vivo lifetime of these implantable devices motivated this study. Stem cell factor and its ligand c-KIT receptor are critically important for MC survival, differentiation and degranulation. Therefore, an MC-deficient sash mouse model was used to assess MC relationships to the in vivo performance of CGM implants. Additionally, local delivery of a tyrosine kinase inhibitor (TKI) that inhibits c-KIT activity was also used to evaluate the role of MCs in modulating the FBR. Model sensor implants comprising polyester fibers coated with a rapidly dissolving polymer coating containing drug-releasing degradable microspheres were implanted subcutaneously in sash mice for various time points, and the FBR was evaluated for chronic inflammation and fibrous capsule formation around the implants. No significant differences were observed in the foreign body capsule formation between control and drug-releasing implant groups in MC-deficient mice. However, fibrous encapsulation was significantly greater around the drug-releasing implants in sash mice compared to drug-releasing implants in wild-type (e.g. MC-competent) mice. These results provide insights into the role of MCs in the FBR, suggesting that MC deficiency provides alternative pathways for host inflammatory responses to implanted biomaterials.