Abstract
pH is a critical indicator of bone physiological function and disease status; however, noninvasive and real-time sensing of bone pH in vivo has been a challenge. Here, we synthesized a bone pH sensor by labeling alendronate with the H+-sensitive dye fluorescein isothiocyanate (Aln-FITC). Aln-FITC showed selective affinity for hydroxyapatite (HAp) rather than other calcium materials. An in vivo biodistribution study showed that Aln-FITC can be rapidly and specifically delivered to rat bones after caudal vein injection, and the fluorescence lasted for at least 12 h. The fluorescence intensity of Aln-FITC binding to HAp linearly decreased when the pH changed from 6 to 12. This finding was further confirmed on bone blocks and perfused bone when the pH changed from 6.8 to 7.4, indicating unique pH-responsive characteristics in the bone microenvironment. Aln-FITC was then preliminarily applied to evaluate the changes in bone pH in a nude mouse acidosis model. Our results demonstrated that Aln-FITC might have the potential for minimally invasive and real-time in vivo bone pH sensing in preclinical studies of bone healing, metabolism, and cancer mechanisms.
Highlights
PH plays an important role in bone homeostasis [1,2,3,4], and disruption of bone pH is associated with tumors, inflammation, fractures, and hypoxia [1, 2, 4, 5]
The Mass spectrometry (MS) confirmed the molecular weight of Aln-fluorescein isothiocyanate (FITC) as 636.85, which is consistent with the theoretical value of Aln-FITC, indicating a successful synthesis
We found that the average fluorescence intensity linearly decreased (R2 = 0:95467) at pH values of 6.8 (57:61 ± 6:42), 7.0 (50:13 ± 5:30), 7.2 (43:25 ± 2:67), and 7.4 (31:78 ± 6:12), and the loss of fluorescence was more obvious in the thin part of the bone blocks than in the thick part, indicating that the change started from the bone surface
Summary
PH plays an important role in bone homeostasis [1,2,3,4], and disruption of bone pH is associated with tumors, inflammation, fractures, and hypoxia [1, 2, 4, 5]. Real-time sensing of bone pH can provide valuable information for diagnosis and research, but delivery of the sensor is challenged by hard and solid cortical bone [6]. A pH-responsive hydrogel-based implanted sensor with a metal pin was developed, where the pH data could be collected by a series of X-rays [9]. These sensors were all constrained by their expensive devices, low spatial resolution, and invasive surgery. To overcome these limitations, we assumed that a good bone pH sensor should be easy to fabricate, easy to deliver, and sensitive to real-time pH changes
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