Diamagnetic chemical exchange saturation transfer (diaCEST) affords magnetic resonance imaging of extracellular matrix hydrogel implantation in a rat model of stroke

Abstract

Extracellular matrix (ECM) is widely used as an inductive biological scaffold to repair soft tissue after injury by promoting functional site-appropriate remodeling of the implanted material. However, there is a lack of non-invasive analysis methods to monitor the remodeling characteristics of the ECM material after implantation and its biodegradation over time. We describe the use of diamagnetic chemical exchange saturation transfer (CEST) magnetic resonance imaging to monitor the distribution of an ECM hydrogel after intracerebral implantation into a stroke cavity. In vitro imaging indicated a robust concentration-dependent detection of the ECM precursor and hydrogel at 1.8 and 3.6 ppm, which broadly corresponded to chondroitin sulfate and fibronectin. This detection was robust to changes in pH and improved at 37 °C. In vivo implantation of ECM hydrogel into the stroke cavity in a rat model corresponded macroscopically to the distribution of biomaterial as indicated by histology, but mismatches were also evident. Indeed, CEST imaging detected an endogenous “increased deposition”. To account for this endogenous activity, pre-implantation images were subtracted from post-implantation images to yield a selective visualization of hydrogel distribution in the stroke cavity and its evolution over 7 days. The CEST detection of ECM returned to baseline within 3 days due to a decrease in fibronectin and chondroitin sulfate in the hydrogel. The distribution of ECM hydrogel within the stroke cavity is hence feasible in vivo, but further advances are required to warrant a selective long-term monitoring in the context of biodegradation.

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

“…To assess the presence, location and volume of tissue loss, MCAo rats were anesthetized with isoflurane (4% induction, 1% maintenance) and scanned using a T 2 -weighted spin-echo MRI sequence (TR = 6000 ms, TE = 8 ms, 8 Averages, FOV 30x30 mm, 128x128 matrix, 42 slices at 0.5 mm thickness) on a horizontal bore 9.4 T Varian scanner 10 days post-infarction [30]. …”

“…Lesion-equivalent volumes of solubilized ECM (72-246 μL) were injected into the ventral posterior region of the cavity to displace and drain the less dense necrotic debris from the most dorsal part of the lesion [25]. We have previously demonstrated that a precise neurosurgical planning is required for these large volume injections to avoid misplacement or leaching of material into the lateral ventricles, but also to avoid damage to structures in the path of injection [25, 30]. Injection of ECM hydrogel (n=11) was controlled using a frame mounted injection pump (World Precision Instruments, USA) at a constant speed of 10 μL/min until the total volume was delivered (7-25 min).…”

“…To determine the long-term structure-function relationship of ECM hydrogel and peri-infarct host tissue, we investigated an ECM preparation (8 mg/mL) that is retained inside the stroke cavity to provide structural support [25, 30], but also provides a strong signaling environment to recruit large numbers of host cells that can promote structural remodeling of the material [26]. The objective of the present study was to evaluate if this hydrogel formulation of ECM (i.e.…”

Accomplishments and challenges in stem cell imaging in vivo

“…A novel approach, described by Mukherjee et al, uses aquaporin 1 (AQP1) which increases transmembrane water transport in transfected cells, and therefore water diffusion rates, increasing contrast on diffusion-weighted MRI [79]. The use of agents that enable chemical exchange saturation transfer (CEST) have become valuable tools for the detection of biomarkers such as temperature and pH [80,81], and have also been used to monitor the distribution of an extracellular hydrogel matrix after in vivo implantation [82].…”

EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging

“…By applying a selective radiofrequency irradiation to the mobile protons, the induced saturation is transferred to the bulk water protons, thus inducing a reduction of the water signal . Several natural molecules and polymers (glucose, glycogen, glycosaminoglycan, sialic acid, gelatin) have already been exploited as MRI-CEST contrast agents, since these molecules have precedence of use with human exposure (Chan et al, 2012;Jin et al, 2017;Liang et al, 2015;Ling et al, 2008;Shinar et al, 2014;van Zijl et al, 2007;Walker-Samuel et al, 2013). Also metabolites, drugs and polypeptides/proteins have been investigated to demonstrate their capability to generate contrast within this approach Bar-Shir et al, 2014;Cai et al, 2015;Haris et al, 2012;Liu et al, 2016;Longo et al, 2014a;McMahon et al, 2008;Zaiss et al, 2013).…”