Detecting and Monitoring Hydrogels with Medical Imaging

Abstract

Hydrogels, water-swollen polymer networks, are being applied to numerous biomedical applications, such as drug delivery and tissue engineering, due to their potential tunable rheologic properties, injectability into tissues, and encapsulation and release of therapeutics. Despite their promise, it is challenging to assess their properties in vivo and crucial information such as hydrogel retention at the site of administration and in situ degradation kinetics are often lacking. To address this, technologies to evaluate and track hydrogels in vivo with various imaging techniques have been developed in recent years, including hydrogels functionalized with contrast generating material that can be imaged with methods such as X-ray computed tomography (CT), magnetic resonance imaging (MRI), optical imaging, and nuclear imaging systems. In this review, we will discuss emerging approaches to label hydrogels for imaging, review the advantages and limitations of these imaging techniques, and highlight examples where such techniques have been implemented in biomedical applications.

Keywords: biomedical imaging; computed tomography; contrast agents; fluorescence imaging; hydrogels; magnetic resonance imaging.

Figure 1.

Schematic of various strategies to image hydrogels. This figure was created with BioRender.com.

Figure 2.

(A) Transverse CT images of a rat during the week after receiving radiopaque hydrogel treatments. (B) 3D reconstructions of CT images of a rat after treatment with the radiopaque hydrogel at the indicated time points. This figure is reproduced with permission from ref . Copyright 2017 Elsevier.

Figure 3.

(A) Illustration of the formation of the self-healing hydrogel. (B) MRI image of rat after subcutaneous injection of hydrogels. (C) Transverse cross sections of pseudocolored MR images of rat after subcutaneous injection of hydrogels at different time-points. This figure is reproduced with permission from ref . Copyright 2013 Royal Society of Chemistry.

Figure 4.

(A) Principles of CEST for hydrogel imaging. Hydrogels can be differentiated based on their dominant exchangeable proton groups. (B) CEST maps and corresponding T₂-weighted MRI images from a dithiobis(ethylamine) (DTEA)-cross-linked HA hydrogel over time. (C) Quantification of CEST signal from the corresponding images over different time courses. Panel A is reproduced with permission from ref . Copyright 2015 American Chemical Society. Panels B and C are reproduced with permission from ref . Copyright 2018 Elsevier.

Figure 5.

(A) Structure of the pemetrexed-peptide conjugate, which (B) serves as a CEST probe with a chemical shift of 5.2 ppm and (C) self-assembles into a filamentous hydrogel as the concentration increases. (D) Monitoring the diffusion of the hydrogel by MRI (top) and CEST at 5.2 ppm (bottom) before and 2 h or 5 h postinjection in brain tumor. This figure is reproduced with permission from ref . Copyright 2017 American Chemical Society.

Figure 6.

(A) Photograph before (left) and after (right) gelation of the ICG loaded melittin-based hydrogel and (B) its ICG release profile. (C) Visualization by photoacoustic imaging of the ICG loaded melittin-based hydrogel (red) and solution of free ICG (green) after intratumoral injection. (D) NIR fluorescence monitoring of the biodistribution of the hydrogel (top) compared to free ICG solution (bottom) at various time points postinjection (5 min, 3 h, 24 h). This figure is reproduced with permission from ref . Copyright 2017 American Chemical Society.

Figure 7.

(A) Schematic of the strategy of dual-channel fluorescence imaging for the in vivo assessment of brain tissue ingrowth and hydrogel scaffold degradation. (B) Fluorescent hydrogel and brain tissue targeted contrast agent Ox1 were administered to the animal. Dual-channel imaging was performed 1-h postinjection. Brain tissue ingrowth (red) and hydrogel (green) degradation can be observed in the merged image. This figure is reproduced with permission from ref . Copyright 2019 Ivyspring International Publisher.

Figure 8.

Left panel (L): overview SPECT/CT scan of mice. SPECT signal from ¹¹¹In in the kidney and bladder is indicated with arrows. Middle panel (M): the different treatment conditions indicated by the dashed circles in the SPECT/CT scans to the right. Right panel (R): representative SPECT/CT images for mice under different treatment conditions. Green arrows indicate that the activities of hydrogels leaked away from the wound area but stayed close to the site of application. This figure is reproduced with permission from ref . Copyright 2013 Royal Society of Chemistry.

Figure 9.

(A) 2D greyscale ultrasound images of rat thigh with silk hydrogel implants. The echogenicity increased over time (a–f). (B) CEUS imaging of the hydrogel implants at different time points (a–e). More microbubbles infused into the gel matrix over time, indicating the progression of neovascularization. Red arrows indicate the outline of hydrogel implants. This figure is reproduced with permission from ref . Copyright 2015 John Wiley and Sons.