Two in One: Use of Divalent Manganese Ions as Both Cross-Linking and MRI Contrast Agent for Intrathecal Injection of Hydrogel-Embedded Stem Cells

Abstract

Cell therapy is a promising tool for treating central nervous system (CNS) disorders; though, the translational efforts are plagued by ineffective delivery methods. Due to the large contact surface with CNS and relatively easy access, the intrathecal route of administration is attractive in extensive or global diseases such as stroke or amyotrophic lateral sclerosis (ALS). However, the precision and efficacy of this approach are still a challenge. Hydrogels were introduced to minimize cell sedimentation and improve cell viability. At the same time, contrast agents were integrated to allow image-guided injection. Here, we report using manganese ions (Mn2+) as a dual agent for cross-linking alginate-based hydrogels and magnetic resonance imaging (MRI). We performed in vitro studies to test the Mn2+ alginate hydrogel formulations for biocompatibility, injectability, MRI signal retention time, and effect on cell viability. The selected formulation was injected intrathecally into pigs under MRI control. The biocompatibility test showed a lack of immune response, and cells suspended in the hydrogel showed greater viability than monolayer culture. Moreover, Mn2+-labeled hydrogel produced a strong T1 MRI signal, which enabled MRI-guided procedure. We confirmed the utility of Mn2+ alginate hydrogel as a carrier for cells in large animals and a contrast agent at the same time.

Advances in Algin and Alginate-Hybrid Materials for Drug Delivery and Tissue Engineering

“…The developed AHM showed improved cell viability and a lack of immune response. The Mn 2+ -labeled AHM produced a strong T1 MRI signal [ 87 ]. The AHM also showed its potential in neuro-regenerative applications.…”

Towards clinical translation of ‘second-generation’ regenerative stroke therapies: hydrogels as game changers?

“…HA) [30,31] or contrast agents (e.g. manganese ions for alginate) [32] will help guide further development of space conforming [32] and biodegradation [30] as well as the precision of injection into the stroke cavity. Most preclinical stroke studies use healthy young male adult rodents whereas human stroke is usually complicated by age and multi-morbidities in both sexes [33] in which host tissue-hydrogel interactions are underexplored (Table 1).…”

“…Coupled with their absorptive capacity [87], these properties make alginate-based hydrogels very effective as wound dressings, with the ability to absorb wound exudate and promote tissue repair [89]. In addition to being non-toxic [32,87], alginate-based hydrogels do not elicit an inflammatory response in vivo [32] and their easy administration make alginate-based hydrogels a promising and effective payload delivery vehicle for pharmacological compounds and regenerative stem cells [90]. Chitosan in generated by the deacetylation of chitin, a natural polysaccharide obtained from the exoskeletons of crustaceans, insects and fungi [91].…”

The legacy of mRNA engineering: A lineup of pioneers for the Nobel Prize

“…149 Because hydrogels can be labeled and imaged relatively quickly, they offer seamless precision for procedures. 150 RNA viruses capitalize on the ability of nucleoproteins to package mRNA. It has been shown that, under some circumstances, transmembrane proteins can interact and package other mRNA-bearing RNA-packaging signals in the form of virus-like particles.…”