Heterogeneous toroidal spiral particles for islet encapsulation.

Transplantable cell encapsulation systems present a promising approach to deliver a therapeutic solution from hormone-producing cells for the treatment of endocrine diseases like type 1 diabetes. However, the development of a broadly effective and safe transplantation system has been challenging. While some current micro-sized capsules have been optimized for adequate nutrient and metabolic transport, they lack the robustness and retrievability for the clinical safety translation that macro-devices may offer. An existing challenge to be addressed in the current macro-devices is their configuration which may lead to unsatisfactory mass transfer. Here, we design and characterize a millimeter-size particle system of poly-ethylene glycol (PEG) featuring internal toroidal spiral channels, called toroidal spiral particles (TSPs). The characteristic internal structure of the TSPs allows for large encapsulation capacity and large surface area available to all the encapsulated cell mass for effective molecular diffusion. The polymeric matrix renders the particle flexible yet robust for safe transplantation and retrieval. We demonstrate the feasibility of fabricating these particles with various polymer compositions, while optimizing their mechanical properties as well as glucose and insulin permeability. Encapsulation of islets of Langerhans is achieved with high loading capacity (∼160 IEQ per TSP) and excellent cell viability. TSP-encapsulated islets showed similar glucose-stimulated insulin secretion to the naked islets. Preliminary biocompatibility of the TSPs on naïve C57BL/6 mice shows minimal inflammatory response after 4-week transplantation into the intraperitoneal (IP) space. Long-term therapeutic efficacy of encapsulated islets needs to be confirmed in diabetic rodent models in the future, while determining minimal mass required to reverse diabetes. However, we believe from the in vitro favorable results and the TSPs' unique design that TSPs may provide a safe, effective method to transplant and retrieve therapeutic cells for type 1 diabetes treatment and may also be applicable for other cell therapies.

Impeded Molecular Reorganization by Polyethylene Glycol Conjugation Revealed by X-ray Reflectivity and Diffraction Measurements.

Polyethylene glycol (PEG) coatings have been widely applied in pharmaceutical and biomedical systems to prevent nonspecific protein absorption, increase vesicle blood circulation time, and sustain drug release. This study systematically investigated the planar interfacial organization of phospholipid monolayers containing various amounts of PEG conjugations before and after enzyme-catalyzed degradation of the lipids using X-ray reflectivity and grazing incidence X-ray diffraction techniques. Results showed that attaching PEG to the headgroup of the lipids up to 15 mol % had limited effects on molecular packing of the lipid monolayers in the condensed phase at the gas-liquid interface and negligible effects on the enzyme adsorption to the interface. After enzyme-catalyzed degradation, equimolar fatty acids and lyso PC were generated. The fatty acids together with the subphase Ca2+ self-assembled into highly organized multilayer domains at the interface. The X-ray measurements unambiguously revealed that the densely packed PEG markedly hindered microphase separation and formation of the palmitic acid-Ca2+ complexes.

Heterogeneous Polymeric Particles Encapsulating Human T cells for Controlled Activation, Proliferation, and Delivery.

We report a particulate cell delivery platform, toroidal spiral particles (TSPs), for continuous cell activation, expansion, and local sustained release. Biocompatible TSPs, generated by a self-assembly process of polymeric droplet sedimentation in an aqueous solution and subsequent polymer solidification, possess many engineering design flexibilities to manipulate the microenvironment of the cells to control cell proliferation, migration, and release kinetics. These millimeter-size particles with desired mechanical and physicochemical properties may be potentially used for adoptive cellular therapy (ACT) delivery by a minimally invasive procedure to the tumor mass.

In Situ Measurements of Polymer Micellization Kinetics with Millisecond Temporal Resolution.

Utilizing synchrotron small-angle X-ray scattering (SAXS) integrated with a microfluidic device, micellization kinetics of a diblock co-polymer, poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL) was measured in situ with millisecond temporal and micrometer spatial resolution. The evolutionary regimes of polymer micellization - nucleation, fusion, and insertion were directly observed. The five-inlet microfluidic device provided steady continuous mixing of the polymer solution and the antisolvent. Solvent replacement was mainly dominated by lateral diffusion across the hydrodynamically focused central layer, whose thickness could be precisely designed and manipulated from mass balance of the partitioning streams. Knowing the micellization kinetics of the polymers is essential for design and optimization of self-assembled polymeric nanostructures. The technique of integrating SAXS with microfluidic devices can be translatable to other systems for a breadth of applications.

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin.

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

Effects of trimethylaluminium and tetrakis(ethylmethylamino) hafnium in the early stages of the atomic-layer-deposition of aluminum oxide and hafnium oxide on hydroxylated GaN nanoclusters.

We calculate the interactions of two atomic layer deposition (ALD) reactants, trimethylaluminium (TMA) and tetrakis(ethylmethylamino) hafnium (TEMAH) with the hydroxylated Ga-face of GaN clusters when aluminum oxide and hafnium oxide, respectively, are being deposited. The GaN clusters are suitable as testbeds for the actual Ga-face on practical GaN nanocrystals of importance not only in electronics but for several other applications in nanotechnology. We find that TMA spontaneously interacts with hydroxylated GaN; however it does not follow the atomic layer deposition reaction path unless there is an excess in potential energy introduced in the clusters at the beginning of the optimization, for instance, using larger bond lengths of various bonds in the initial structures. TEMAH also does not interact with hydroxylated GaN, unless there is an excess in potential energy. The formation of a Ga-N(CH3)(CH2CH3) bond during the ALD of HfO2 using TEMAH as the reactant without breaking the Hf-N bond could be the key part of the mechanism behind the formation of an interface layer at the HfO2/GaN interface.