Borden, M. A. | bioRxiv Science

bioRxiv2020

Contrast-enhanced sonography with biomimetic lung surfactant nanodrops

Nanodrops comprising a perfluorocarbon liquid core can be acoustically vaporized into echogenic microbubbles for ultrasound imaging. Packaging the microbubble in its condensed liquid state provides distinct advantages, including in situ activation of the acoustic signal, longer circulation persistence, and the advent of expanded diagnostic and therapeutic applications in pathologies which exhibit compromised vasculature. One obstacle to clinical translation is the inability of the limited surfactant present on the nanodrop to encapsulate the greatly expanded microbubble interface, resulting in ephemeral microbubbles with limited utility. In this study, we examine a biomimetic approach to stabilizing an expanding gas surface by employing the lung surfactant replacement, Beractant. Lung surfactant contains a suite of lipids and surfactant proteins that provides efficient shuttling of material from bilayer folds to the monolayer surface. We therefore hypothesized that Beractant would improve stability of acoustically vaporized microbubbles. To test this hypothesis, we characterized Beractant surface dilation mechanics and revealed a novel biophysical phenomenon of rapid interfacial melting, spreading and re-solidification. We then harnessed this unique spreading capability to increase the stability and echogenicity of microbubbles produced after acoustic droplet vaporization for in vivo ultrasound imaging. Such biomimetic lung surfactant-stabilized nanodrops may be useful for applications in ultrasound imaging and therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/367235v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b6b2f4org.highwire.dtl.DTLVardef@9eb8b7org.highwire.dtl.DTLVardef@71364corg.highwire.dtl.DTLVardef@a3c41d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing {beta}-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of {beta}-cell mass at T1D onset. There are limited methods to track the progression of insulitis and {beta}-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phasechange agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D. SignificanceThere is a need for imaging methods to detect type1 diabetes (T1D) progression prior to clinical diagnosis. T1D is a chronic disease that results from autoreactive T cells infiltrating the islet of Langerhans and destroying insulin-producing {beta}-cells. Overt disease takes years to present and is only diagnosed after significant {beta}-cells loss. As such, the possibility of therapeutic intervention to preserve {beta}-cell mass is hampered by an inability to follow pre-symptomatic T1D progression. There are immunotherapies that can delay T1D development. However identifying at risk individuals, and tracking whether therapeutic interventions are impacting disease progression, prior to T1D onset, is lacking. A method to detect insulitis and {beta}-cell mass decline would present an opportunity to guide therapeutic treatments to prevent T1D.

bioengineering↗