Significance: Personalized medicine requires the tracking of an individual’s metabolite levels over time to detect anomalies and evaluate the body’s response to medications. Implanted sensors offer effective means to continuously monitor specific metabolite levels, provided they are accurate, stable over long time periods, and do no harm.
Aim: Four types of hydrogel embedded with pH-sensitive sensors were evaluated for their accuracy, sensitivity, reversibility, longevity, dynamic response, and consistency in static versus dynamic conditions and long-term storage.
Approach: Raman spectroscopy was first used to calibrate the intensity of pH-sensitive peaks of the Raman-active hydrogel sensors in a static pH environment. The dynamic response was then assessed for hydrogels exposed to changing pH conditions within a flow cell. Finally, the static pH response after 5 months of storage was determined.
Results: All four types of hydrogels allowed the surface-enhanced Raman spectroscopy (SERS) sensors to respond to the pH level of the local environment without introducing interfering signals, resulting in consistent calibration curves. When the pH level changed, the probes in the gels were slow to reach steady-state, requiring several hours, and response times were found to vary among hydrogels. Only one type, poly(2-hydroxyethyl methacrylate) (pHEMA), lasted five months without significant degradation of dynamic range.
Conclusions: While all hydrogels appear to be viable candidates as biocompatible hosts for the SERS sensing chemistry, pHEMA was found to be most functionally stable over the long interval tested. Poly(ethylene glycol) hydrogels exhibit the most rapid response to changing pH. Since these two gel types are covalently cross-linked and do not generally degrade, they both offer advantages over sodium alginate for use as implants.
Point-of-care (PoC) devices are gaining more attention due to their rapid readout times, low cost and reduced system complexity. The use of these devices to aid in health outcomes, particularly of populations that lack access to centralized healthcare, is essential to improving quality of life. Broad fluorescence background presents a major issue in Raman detection with suppression techniques being employed to prevent signal crosstalk. The presented spectroscopic platform splits the Raman and fluorescence signal onto separate detectors in order in minimize crosstalk and to extract useful information from each optical signal. Separate illumination sources were utilized to selectively excite either Raman or fluorescence emission. The developed spectroscopic platform was designed using off-the-shelf components with small form factor and ultimately the capacity for low cost being the primary selection criteria. The platform enables multimodal detection of Raman signal over a spectral range of 900 – 2000 cm-1 with a resolution of 2 nm, coupled with monitoring the average fluorescence emission intensity. The ratio of the two signals is compared in order to quantify the concentration of target molecules present. The optical system was assembled on a portable optical breadboard and calibrated using an Argon emission lamp. The multimodal functionality was validated using Raman reporter (4-MBA) tagged gold nanoparticles in solution with unbound fluorophores (fluorescein). Results showed an increase in both the Raman and fluorescence signals as the concentration of each was increased from 5-55 μM.
Now that a fully-implantable, continuous glucose monitor has received FDA approval, optical techniques other than fluorescence will seek to overcome the limited lifetimes resulting from photobleaching. Using plasmonic nanoparticles, we present the potential of reversible SERS-active sensing assays to function as long-term implantable sensors. The assays offer high selectivity and specificity of analyte detection and concentration without loss of emission intensity over time due to photodestruction. These assays are encapsulated in microdomains bounded by polyelectrolyte multilayers (PEMs), permeable to the target but impermeable to proteins. The microdomains are stabilized in hydrogels for biocompatibility and longevity. This study characterizes the performance of pH-sensitive Raman probes in three different hydrogels in a simulated in vivo environment with changing pH over time.
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