Repetitive abdominal pain in a reproductive-aged woman.

We report a young woman with ileocecal endometriosis who presented with repeated abdominal pain. Under hormonal effects, the endometrium may proliferate and cause bleeding in the bowel wall, leading to cyclical abdominal pain. When recurring abdominal pain is observed in reproductive-aged women, physicians should always be aware of gastrointestinal endometriosis.

A case of hemorrhagic shock due to intercostal artery injury that occurred during initial trauma care with multiple displaced rib fractures and traumatic head injury.

Rib fractures can cause injury to some organs. We herein report a case of hemorrhagic shock due to intercostal artery injury that occurred during initial trauma care (ITC) treated by resuscitative thoracotomy (RT) and transcatheter arterial embolization (TAE) with multiple displaced rib fractures (RFs) and traumatic head injury (THI). A man in his 50s who was injured in a traffic accident was transferred to our institution by helicopter for emergency medical treatment. He underwent left thoracic drainage on site. On admission, he was diagnosed with multiple RF, THI, pelvic fracture and right humerus fracture. His D-dimer and fibrin degradation products (FDP) level were extremely elevated. However, contrast enhance CT (CECT) revealed no extravasation. At 2 h after arrival, massive hemorrhaging from his thoracic tube suddenly occurred and his blood pressure decreased to approximately 40s mmHg. CECT performed after volume resuscitation and massive transfusion revealed extravasation from the intercostal artery. Because his blood pressure could not be maintained by massive transfusion, we performed RT and TAE followed by RT. He then received intensive care and several surgical procedures were performed, including craniotomy for removal of hematoma, rib fixation and humerus fixation. He was transferred to another hospital for rehabilitation on day 63, with a GCS of 15. Hemorrhagic shock due to intercostal artery injury may occur at any time from arrival in cases with displaced RF, especially when complicated by THI.

Biorthogonal click chemistry on poly(lactic-co-glycolic acid)-polymeric particles.

Biodegradable polymeric materials are a key area of investigation in drug delivery and disease treatment. This is due to their proven clinical potential for payload protection, responsivity, and surface modification imparted by the versatile array of polymers available for their formulation. Here, we employ a novel biodegradable azide containing polymer in the formulation of polymeric nanoparticles and show that these particles can then be functionalized, with biorthogonal click reactions, to alter their surface appearance and their ability to interact with biological systems.

Nanogels as imaging agents for modalities spanning the electromagnetic spectrum.

In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents.

Short Soluble Coumarin Crosslinkers for Light-Controlled Release of Cells and Proteins from Hydrogels.

Materials that degrade or dissociate in response to low power light promise to enable on-demand, precisely localized delivery of drugs or bioactive molecules in living systems. Such applications remain elusive because few materials respond to wavelengths that appreciably penetrate tissues. The photocage bromohydroxycoumarin (Bhc) is efficiently cleaved upon low-power ultraviolet (UV) and near-infrared (NIR) irradiation through one- or two-photon excitation, respectively. We have designed and synthesized a short Bhc-bearing crosslinker to create light-degradable hydrogels and nanogels. Our crosslinker breaks by intramolecular cyclization in a manner inspired by the naturally occurring ornithine lactamization, in response to UV and NIR light, enabling rapid degradation of polyacrylamide gels and release of small hydrophilic payloads such as an ∼10 nm model protein and murine mesenchymal stem cells, with no background leakage.

Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent.

Clinically approved small-molecule magnetic resonance imaging (MRI) contrast agents are all rapidly cleared from the body and offer weak signal enhancement. To avoid repeated administration of contrast agent and improve signal-to-noise ratios, agents with stronger signal enhancement and better retention in tumors are needed. Therefore, we focused on hydrogels because of their excellent water accessibility and biodegradability. Gadolinium (Gd)-chelating cross-linkers were incorporated into self-assembled pullulan nanogels to both impart magnetic properties and to stabilize this material that has been extensively studied for medical applications. We show that these Gd-chelating pullulan nanogels (Gd-CHPOA) have the highest reported relaxivity for any hydrogel-based particles and accumulate in the 4T1 tumors in mice at high levels 4 h after injection. This combination offers high signal enhancement and lasts up to 7 days to delineate the tumor clearly for longer imaging time scales. Importantly, this long-term accumulation does not cause any damage or toxicity in major organs up to three months after injection. Our work highlights the clinical potential of Gd-CHPOA as a tumor-imaging MRI contrast agent, permitting tumor identification and assessment with a high signal-to-background ratio.

Nanogels from metal-chelating crosslinkers as versatile platforms applied to copper-64 PET imaging of tumors and metastases.

Metals are essential in medicine for both therapy and diagnosis. We recently created the first metal-chelating nanogel imaging agent, which employed versatile, reproducible chemistry that maximizes chelation stability. Here we demonstrate that our metal chelating crosslinked nanogel technology is a powerful platform by incorporating (64)Cu to obtain PET radiotracers. Polyacrylamide-based nanogels were crosslinked with three different polydentate ligands (DTPA, DOTA, NOTA). NOTA-based nanogels stably retained (64)Cu in mouse serum and accumulated in tumors in vivo as detected by PET/CT imaging. Measurement of radioactivity in major organs ex vivo confirmed this pattern, revealing a high accumulation (12.3% ID/g and 16.6% ID/g) in tumors at 24 and 48 h following administration, with lower accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). Nanogels accumulated even more efficiently in metastases (29.9% and 30.4% ID/g at 24 and 48 h). These metal-chelating nanogels hold great promise for future application as bimodal PET/MRI agents; chelation of ß-emitting radionuclides could enable radiation therapy.

Collective activation of MRI agents via encapsulation and disease-triggered release.

An activation mechanism based on encapsulated ultrasmall gadolinium oxide nanoparticles (Gd oxide NPs) in bioresponsive polymer capsules capable of triggered release in response to chemical markers of disease (i.e., acidic pH, H2O2) is presented. Inside the hydrophobic polymeric matrices, the Gd oxide NPs are shielded from the aqueous environment, silencing their ability to enhance water proton relaxation. Upon disassembly of the polymeric particles, activation of multiple contrast agents generates a strong positive contrast enhancement of >1 order of magnitude.

Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.

Iron oxide nanoparticle-based magnetic resonance method to monitor release kinetics from polymeric particles with high resolution.

A new method to precisely monitor rapid release kinetics from polymeric particles using super paramagnetic iron oxide nanoparticles, specifically by measuring spin-spin relaxation time (T(2)), is reported. Previously, we have published the formulation of logic gate particles from an acid-sensitive poly-ß-aminoester ketal-2 polymer. Here, a series of poly-ß-aminoester ketal-2 polymers with varying hydrophobicities were synthesized and used to formulate particles. We attempted to measure fluorescence of released Nile red to determine whether the structural adjustments could finely tune the release kinetics in the range of minutes to hours; however, this standard technique did not differentiate each release rate of our series. Thus, a new method based on encapsulation of iron oxide nanoparticles was developed, which enabled us to resolve the release kinetics of our particles. Moreover, the kinetics matched the relative hydrophobicity order determined by octanol-water partition coefficients. To the best of our knowledge, this method provides the highest resolution of release kinetics to date.

An extracellular MRI polymeric contrast agent that degrades at physiological pH.

Macromolecular contrast agents have the potential to assist magnetic resonance imaging (MRI) due to their high relaxivity, but are not clinically useful because of toxicity due to poor clearance. We have prepared a biodegradable ketal-based polymer contrast agent which is designed to degrade rapidly at physiological pH by hydrolysis, facilitating renal clearance. In vitro, the agent degraded more rapidly at lower pH, with complete fragmentation after 24 h at pH 7.4. In vitro relaxivity measurements showed a direct correlation between molecular weight and relaxivity. We compared our polymer contrast agent with commercially available Magnevist in vivo by MRI imaging, as well as measuring the Gd concentration in blood. Our results show that our polymer contrast agent gives a higher contrast and intensity in the same organs and areas as Magnevist and is cleared from the blood at a similar rate. We aim to improve our polymer contrast agent design to develop it for use as a MRI contrast agent, and explore its use as a platform for other imaging modalities.