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Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that results from autoreactive T cells destroying insulin-producing pancreatic beta (β) cells. The development of T1DM is associated with the deficiency of co-inhibitory immune checkpoint ligands (e.g., PD-L1, CD86, and Gal-9) in β cells. Here, a new translational approach based on metabolic glycoengineering and bioorthogonal click chemistry, which bioengineers β cells with co-inhibitory immune checkpoint molecules that induce antigen-specific immunotolerance and reverse early-onset hyperglycemia is reported. To achieve this goal, a subcutaneous injectable acellular pancreatic extracellular matrix platform for localizing the bioengineered β cells while creating a pancreas-like immunogenic microenvironment, in which the autoreactive T cells can interface with the β cells, is devised.

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of a novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80 to 85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.

The cooling system of a plastic injection mould is important as it affects the quality and productivity of the polymeric components or assemblies. Contemporary cooling channel design is confined to simple configurations of straight-drilled coolant passageway around the mould insert. Undesirable defects resulted during injection moulding, such as warpage, are inevitable. The application of rapid tool (RT) based on solid freeform fabrication (SFF) technologies with conformal cooling channel (CCC) design has provided a profound opportunity in quality improvement of polymeric components. In this study, a novel design of variable radius conformal cooling channel (VRCCC) is proposed to achieve better uniform cooling performance. Thermal-FEA and melt flow analysis are used to validate the method.

Nowadays, with the advances of Finite Element Analysis (FEA) packages, some of the engineering and design problems such as stress or thermal deformation can be successfully solved. These are convenient for better incorporating the design constraints of various tasks such as injection molded parts, or rapid prototyping and tooling. Mesh generation is the major step of finite element method for numerical computation. Common types of mesh include triangulation or tetrahedralization. During the mesh generation process, we always find difficulty in the formation of a uniform, non-conformal mesh. The undesirable mesh will adversely influence the accuracy and meshing time of the model. This paper will, thus, propose an effective approach to extend to threedimensional (3D) mesh generation by octree balancing method so as to adjust the mesh pattern. In this paper, the implementation of octree balancing will be explained and illustrated with real life example. The proposed method includes three main steps. Problematic unbalanced octants will be detected and Steiner points will be added as appropriate before the tetrahedral mesh generation. The balanced octree will form good tetrahedral meshes for further analysis. Then the balanced and unbalanced meshes will be compared for efficiency and accuracy for mesh generation.

Optical coherence tomography (OCT) is a modern high resolution subsurface medical imaging technique. Herein we describe: (i) the synthesis of a thiophene-functionalized oligo(ethylene glycol) methacrylate (OEGMA)-based statistical copolymer, denoted poly(2TMOI–OEGMA); (ii) the preparation of sterically-stabilized polypyrrole (PPy) nanoparticles of approximately 60 nm diameter; (iii) the evaluation of these nanoparticles as a NIR-absorbing optical contrast agent for high-resolution OCT imaging. We show that poly(2TMOI–OEGMA)-stabilized PPy nanoparticles exhibit similar optical properties to poly(vinyl alcohol) (PVA)-stabilized PPy nanoparticles of comparable size prepared using commercially available PVA. Spectroscopic measurements and Mie calculations indicate that both types of PPy nanoparticles strongly absorb NIR radiation above 1000 nm, suggesting their potential use as OCT contrast agents. In vitro OCT studies indicate that both types of PPy nanoparticles reduce NIR backscattering within homogeneous intralipid tissue phantoms, offering almost identical contrast performance in this medium. However, PVA-stabilized PPy nanoparticles became colloidally unstable when dispersed in physiological buffer and immersed in a solid biotissue phantom and hence failed to generate a strong contrast effect. In contrast, the poly(2TMOI–OEGMA)-stabilized PPy nanoparticles remained well-dispersed and hence exhibited a strong rapid onset contrast effect within the biotissue phantom under identical physiological conditions. Ex vivo studies performed on excised chicken and porcine skin tissue demonstrated that topical administration of a low concentration of poly(2TMOI–OEGMA)-stabilized PPy nanoparticles rapidly enhances OCT image contrast in both cases, allowing key tissue features to be readily identified.

We report on a photothermal modulation detection scheme developed using a swept source-based optical coherence tomography (OCT) system centred at 1300nm. Photothermal detection is an improved technique for studying the contrast properties of exogenous contrast agents such as highly absorbing polypyrrole (PPy) nanoparticles used for OCT imaging. The swept source based OCT system has a wavelength sweep rate of 10 kHz which is used for the phase modulation detection of various concentrations of PPy nanoparticles. PPy nanoparticles have been recently reported to be a promising candidate for OCT imaging owing to their strong NIR absorption from 700–1300nm. Phase-sensitive detection of the photothermal modulation signal is achieved using a pumped 975 nm laser beam at 80Hz and 160Hz for varying concentrations of PPy nanoparticles dispersed in 2% Intralipid phantom. A phase-sensitive detection system is realised by carrying out the phase calibration using the back reflections obtained from the coverslip used with the sample. This study provides quantitative support for the use of PPy nanoparticles as a potential biocompatible contrast agent in OCT imaging.

A near-infrared (NIR) absorbing contrast agent based on polypyrrole nanoparticles is described. Quantitative optical coherence tomography studies on tissue phantoms and Mie scattering calculations indicate their potential application for early-stage cancer diagnosis.