Review Article Open Access
Clinically Relevant Imaging of Transplanted Pancreatic Islet Cells
Dian R. Arifin
Department of Chemistry, Towson University, Baltimore, Maryland, USA
*Corresponding author:

Dian R. Arifin, Department of Chemistry, Towson University, Baltimore, Maryland, USA; E-mail: @

Received: 01 May, 2017; Accepted: 24 May, 2017; Published: 02 June, 2017
Citation: Dian R. Arifin. (2017) Clinically Relevant Imaging of Transplanted Pancreatic Islet Cells. SOJ Surg 4(2):1-4.
Abstract
Transplantation of pancreatic islet cells has shown exciting potential for normalizing the blood glucose levels of diabetic patients and those suffering from chronic pancreatitis. The underlying causes of transplant failure and variations in success rate however are poorly understood. At present, islets are transplanted via minimally-invasive infusion into a “black box,” that is the fate of islets after infusion into patients is not known. A promising approach uses medical imaging technology to monitor, study and evaluate islet grafts during transplantation and in situ in a clinically relevant and non-invasive fashion, hence offering a means to apply timely medical intervention in the case of therapy failure and to improve the long-term outcome of islet transplantation. This review focuses on advancements in clinical imaging of transplanted islets as well as the limitations and advantages of each imaging modality.
Introduction
Transplantation of pancreatic islet cells has shown exciting potential for normalizing the blood glucose levels of type I and severe type II diabetic patients and those suffering from chronic pancreatitis. Unlike daily insulin injections, transplanted islets can response to elevation of systemic blood glucose levels in a proportional and rapid manner, therefore removing any adverse effects due to inaccurate doses of insulin. Although human islet isolation and subsequent transplantation following the Edmonton protocol had been undergoing multiple trials in the clinics, the percentages of recipients achieving insulin independence, the period of insulin independence and the health complications accompanying islet transplantation significantly varied between clinics and trials [1-6]. The underlying causes of therapy failure and variations in success rate are poorly understood.

At present, islets are transplanted via minimallyinvasive infusion into a “black box,” that is the fate of islets after infusion into patients is not known. Conventional methods of analyzing insulin, c-peptide and glucose levels in the blood samples are inadequate since the results are influenced by physiological changes and these methods can only detect islet death or impaired function only after the events. A promising approach uses medical imaging technology to monitor, study and evaluate islet grafts during transplantation and in situ in a clinically relevant and non-invasive fashion. Moreover, ability to track islets ensures that islets are delivered to the correct target areas. Such approach may also enable temporal and spatial study of islet grafts, hence offering a means to apply timely medical intervention in the case of therapy failure and to improve the long-term outcome of islet transplantation. This review focuses on advancements in clinical imaging of transplanted islets as well as the limitations and advantages of each imaging modality.
Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET)
SPECT and PET are nuclear medicine imaging modalities commonly used to study metabolic processes in the body. Both scanners detect radioactive materials as “hot spots”, providing high sensitivity and good resolution with almost no background interference. A SPECT or PET scan is typically combined with anatomical images from MRI or CT/X-ray imaging. SPECT directly detects gamma radiation emitted by radioisotopes, whereas PET detects pairs of gamma rays emitted indirectly by a positronemitting radiotracers [7]. PET offers higher sensitivity and better spatial resolution than SPECT. However, SPECT radiotracers and gamma scanning equipment are less expensive than PET. SPECT radiotracers have longer decay time than those of PET, thus allowing a longer observation window. In addition, PET is less accessible than SPECT since a cyclotron is required to produce PET radiotracers and an immediate transport from the production site to the imaging site is necessary due to the rapid decay time of PET radioisotopes. For islet imaging, SPECT or PET radiotracers are designed to target and label islets in vivo with high specificity. SPECT radiotracer [123I]-iodobenzamide (IBZM) and [111In]-exendin-3 target dopamine 2 receptor and glucagon like peptide-1 receptor, respectively, which are expressed on islet cells. Islets engrafted in rats could be serially imaged by SPECT for 4-10 weeks after infusion of [123I]-IBZM or [111In]-exendin-3. Imaging of individual islets was a possibility due to its high detection sensitivity [8-10]. In addition, SPECT may facilitate quantification of volume or mass of islet grafts as SPECT signal correlated linearly with islet volume or mass. This method therefore can potentially be used for in situ, non-invasive and serial quantification of islet viability in vivo as dead islets are degraded and cleared by the recipient’s body and can be detected as signal loss.

The PET counterparts include [177Lu]-DO3A-VSCys40- exendin-4 and [18F]-TTCO-Cys40-exendin-4 - both targeting glucagon like peptide-1 receptor- and [18F]-L-3,4- dihydroxyphenylalanine(DOPA), targeting dopaminergic metabolic pathway present in islets [11-13]. Transplanted islets in mice could be visualized by PET after infusion of said radiotracers. As PET signal correlated with the number of islet grafts, PET scan may be used for in vivo quantification of islets. An alternative method was to label islets with 18F-fluorodeoxyglucose (FDG) ex vivo prior to transplantation [14]. Although labeled islets engrafted in rats could be imaged by PET, the observation window was short (within hours) and islets had be transplanted as soon as the labeling process was completed due to the rapid decay time of PET radioisotope.

The downside of SPECT and PET modality is the use of a radioisotope which may be toxic to the patients as well as the islets themselves. The facility to produce radiotracers is costly and is not available near small clinics and in remote areas. Moreover, the specificity of the radiotracers to exclusively label islets in vivo requires improvements.
Magnetic Resonance Imaging (MRI)
MRI is a medical imaging technique that can provide a 3D anatomical information of a patient’s whole body with an excellent soft tissue contrast and a spatial resolution close to the size of a single cell [7]. MRI manipulation is mostly performed on water protons (1H), taking advantages of its abundance in human and animal bodies. To impart 1H MRI-visibility, islets were labeled with carbon nanotubes, commercial super paramagnetic iron oxide nanoparticles, such as Endorem, Ferucarbotran and Ferumoxytol, or gadolinium-based contrast agent ex vivo before transplantation [15-19]. Many studies geared toward functionalization of iron oxide nanoparticles to enhance efficiency of islet labeling are in progress [20-23]. Likewise, novel MRI protocol to improve detection of iron oxide-labeled islets is currently being developed and tested in human patients [24].

Longitudinal imaging of iron oxide-labeled islets by 1H MRI as dark (hypointense) entities had been successfully demonstrated in murine models up to 2-8 weeks, in nonhuman primate models as well as in patients up to 10 months post-transplantation [15,17,22, 25, 18]. MRI of islets labeled with gadoliniumbased contrast agents showed visibility as bright (hyperintense) signals in vitro although in vivo detection was inconclusive [19]. Iron oxide and gadolinium-based contrast agents do not degrade over time, thus offering long shelf-lives and stable signal intensity as long as the contrast agents are retained by islets [7].

MRI for quantification of islet grafts and predicting therapy success orfailure remains a challenge [26]. Recent findings however are promising. In murine models, a correlation between the total area of visualized islets and the transplanted islet mass was observed [16]. Disappearance of MRI signals was associated with the loss of islet graft function in nonhuman primates and in patients [25,18]. Efficient islet labeling to achieve high detection sensitivity – particularly in clinical applications - is still an issue, necessitating an improvement in labeling protocol and contrast agent. Labeled islets appeared under MRI scanner as dark (hypointense) or bright (hyperintense) signals against black and white tissue background which may lead to misinterpretation of data. Furthermore, a MRI scanner is very expensive, making it less accessible.
Ultrasound Imaging (US)
Ultrasonography is safe, fast and the most inexpensive clinical imaging modality. The equipment is portable, therefore suitable for bed-side uses, and is available in small clinics. Recent work reported that transplanted islets could be detected as hyperechoic signals in mice by high-frequency ultrasonography (HF-US) as well as in a human patient by clinical ultrasonography [27,28]. In murine study, islet volume calculated by the HF-US device correlated with numbers of transplanted islets, while islets rejected by the host immune system were imaged as hypoechoic areas [27]. Individual islets inside a patient’s portal vein could be visualized by intraoperative US with a central frequency of 7.5 MHz [28]. These data demonstrated a potential for in vivo monitoring, prediction of transplant rejection and quantification of islets grafts by US. In addition, US imaging does not require islets to be labeled, hence eliminating any potential toxicity caused by contrast agents. This modality however can only image a specific area of the body, necessitating prior knowledge of the location of transplanted islets. Islets grafts appeared as dark entities, and thus may be difficult to be differentiated from the black and white tissue background.
A Hybrid of Imaging and Encapsulation Method
A multifunctional approach is encapsulation of islets inside labeled, semi-permeable, spherical biomatrix. The biomatrix provides a 3D supportive environment for the islets while acting as a physical barrier to protect transplanted islets against invasion of the immune system. Islet encapsulation allows indirect labeling of transplants by labeling the biomatrix instead of the islets which may reduce the contrast agent’s potential cytotoxity to the islets themselves. The volume of the biomatrix allows higher concentration of contrast agents to be used which in turns improve the detection sensitivity of the transplants. MRI, X-ray and US-compatible encapsulated islets have been developed up to date. Encapsulated islets labeled with iron oxide nanoparticles and engrafted into various transplantation sites in swine models were visible under a clinical 1.5T MRI scanner [29]. Microcapsules synthesized using barium or labeled with gold nanoparticles could be imaged by CT/X-ray scanner or X-ray phase contrast imaging in rodents [30-32]. Those labeled with gadolinium-gold nanoparticles and engrafted into murine models can be imaged in a trimodal fashion - simultaneously by MRI, CT/X-ray and ultrasonography –and thus combining the advantages of each imaging modality [33]. Due to its high detection sensitivity, this hybrid approach offers the potential of individual capsule imaging in vivo, i.e. individual islet imaging since each capsule enclosed approximately one islet. However, immune rejection caused by the biomatrix itself is an issue and efforts to develop a biocompatible material for encapsulation are in progress [29].

Despite advancements in islet labeling protocol and imaging technology, clinical imaging of transplanted islets remains an experimental method which requires further research in contrast agent toxicity, stability of contrast agents or imaging signals over the observation period, detection sensitivity and reliable methods for in vivo quantification of islet grafts.
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