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"An, Duo"
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A bioinspired scaffold for rapid oxygenation of cell encapsulation systems
Inadequate oxygenation is a major challenge in cell encapsulation, a therapy which holds potential to treat many diseases including type I diabetes. In such systems, cellular oxygen (O
2
) delivery is limited to slow passive diffusion from transplantation sites through the poorly O
2
-soluble encapsulating matrix, usually a hydrogel. This constrains the maximum permitted distance between the encapsulated cells and host site to within a few hundred micrometers to ensure cellular function. Inspired by the natural gas-phase tracheal O
2
delivery system of insects, we present herein the design of a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O
2
diffusivity than hydrogels. We incorporate the scaffold into a bulk hydrogel containing cells, which facilitates rapid O
2
transport through the whole system to cells several millimeters away from the device-host boundary. A computational model, validated by in vitro analysis, predicts that cells and islets maintain high viability even in a thick (6.6 mm) device. Finally, the therapeutic potential of the device is demonstrated through the correction of diabetes in immunocompetent mice using rat islets for over 6 months.
Cell encapsulation into biomaterials for transplantation is currently limited by inadequate oxygenation. Here the authors present a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels and demonstrate correction of diabetes in immunocompetent mice using rat islets for over 6 months.
Journal Article
Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation
Foreign body reaction (FBR) to implanted biomaterials and medical devices is common and can compromise the function of implants or cause complications. For example, in cell encapsulation, cellular overgrowth (CO) and fibrosis around the cellular constructs can reduce the mass transfer of oxygen, nutrients and metabolic wastes, undermining cell function and leading to transplant failure. Therefore, materials that mitigate FBR or CO will have broad applications in biomedicine. Here we report a group of zwitterionic, sulfobetaine (SB) and carboxybetaine (CB) modifications of alginates that reproducibly mitigate the CO of implanted alginate microcapsules in mice, dogs and pigs. Using the modified alginates (SB-alginates), we also demonstrate improved outcome of islet encapsulation in a chemically-induced diabetic mouse model. These zwitterion-modified alginates may contribute to the development of cell encapsulation therapies for type 1 diabetes and other hormone-deficient diseases.
Cellular overgrowth and fibrosis in the foreign body response can compromise the function of transplanted cells. Here, the authors report on the zwitterionically modified alginates for the encapsulation of cells to reduce cellular overgrowth and demonstrate application in mice, dogs and pigs.
Journal Article
Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes
Cell encapsulation has been shown to hold promise for effective, long-term treatment of type 1 diabetes (T1D). However, challenges remain for its clinical applications. For example, there is an unmet need for an encapsulation system that is capable of delivering sufficient cell mass while still allowing convenient retrieval or replacement. Here,we report a simple cell encapsulation design that is readily scalable and conveniently retrievable. The key to this design was to engineer a highly wettable, Ca2+-releasing nanoporous polymer thread that promoted uniform in situ cross-linking and strong adhesion of a thin layer of alginate hydrogel around the thread. The device provided immunoprotection of rat islets in immunocompetent C57BL/6 mice in a short-term (1-mo) study, similar to neat alginate fibers. However, the mechanical property of the device, critical for handling and retrieval, was much more robust than the neat alginate fibers due to the reinforcement of the central thread. It also had facile mass transfer due to the short diffusion distance. We demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 mo as well as in immunodeficient SCID-Beige mice using human islets for 4 mo. We further showed, as a proof of concept, the scalability and retrievability in dogs. After 1 mo of implantation in dogs, the device could be rapidly retrieved through a minimally invasive laparoscopic procedure. This encapsulation device may contribute to a cellular therapy for T1D because of its retrievability and scale-up potential.
Journal Article
Engineering transferrable microvascular meshes for subcutaneous islet transplantation
The success of engineered cell or tissue implants is dependent on vascular regeneration to meet adequate metabolic requirements. However, development of a broadly applicable strategy for stable and functional vascularization has remained challenging. We report here highly organized and resilient microvascular meshes fabricated through a controllable anchored self-assembly method. The microvascular meshes are scalable to centimeters, almost free of defects and transferrable to diverse substrates, ready for transplantation. They promote formation of functional blood vessels, with a density as high as ~220 vessels mm
-2
, in the poorly vascularized subcutaneous space of SCID-Beige mice. We further demonstrate the feasibility of fabricating microvascular meshes from human induced pluripotent stem cell-derived endothelial cells, opening a way to engineer patient-specific microvasculature. As a proof-of-concept for type 1 diabetes treatment, we combine microvascular meshes and subcutaneously transplanted rat islets and achieve correction of chemically induced diabetes in SCID-Beige mice for 3 months.
The success of engineered tissue depends on the integration of a dense vascular network to supply nutrients and remove waste products. Here the authors design high density microvascular meshes made through an anchored self-assembly mechanism, and use these meshes to support subcutaneous pancreatic islet survival in a mouse diabetes model.
Journal Article
Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity
Consumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of β cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse β cell failure in patients with diabetes.
High-energy diet triggers mild β cell proliferation to compensate for peripheral insulin resistance. Qi and colleagues show that TLR2 and TLR4 inhibit the diet-induced replication of β cells in mice and humans.
Journal Article
Engraftment of human induced pluripotent stem cell-derived hepatocytes in immunocompetent mice via 3D co-aggregation and encapsulation
Cellular therapies for liver diseases and
in vitro
models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum-H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in
immunocompromised
animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in
immunocompetent
mice by pre-engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and α1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H and may be applicable to many stem cell-based therapies.
Journal Article
Mass production of shaped particles through vortex ring freezing
A vortex ring is a torus-shaped fluidic vortex. During its formation, the fluid experiences a rich variety of intriguing geometrical intermediates from spherical to toroidal. Here we show that these constantly changing intermediates can be ‘frozen’ at controlled time points into particles with various unusual and unprecedented shapes. These novel vortex ring-derived particles, are mass-produced by employing a simple and inexpensive electrospraying technique, with their sizes well controlled from hundreds of microns to millimetres. Guided further by theoretical analyses and a laminar multiphase fluid flow simulation, we show that this freezing approach is applicable to a broad range of materials from organic polysaccharides to inorganic nanoparticles. We demonstrate the unique advantages of these vortex ring-derived particles in several applications including cell encapsulation, three-dimensional cell culture, and cell-free protein production. Moreover, compartmentalization and ordered-structures composed of these novel particles are all achieved, creating opportunities to engineer more sophisticated hierarchical materials.
The evolution of vortex flow exhibits a rich spectrum of complicated geometries. Here, An
et al
. utilize these features to control and mass produce inorganic and organic particles via an electrospraying process, whereby the shape of vortex rings translates into particles during a freezing process.
Journal Article
Preparation and Characterization of Silk Fibroin-Based Hybrid Vascular Tissue Engineering Film
Patients suffering from cardiovascular disease lack suitable stent. In this study, a new polymeric composite material was prepared by incorporating various concentrations of gamma-glycidoxypropyltrimethoxysilane (GPTMS) into silk fibroin (SF), aiming at achieving a novel composite film with superior mechanical and biological properties, in order to match the requirement of cardiovascular tissue engineering stents. Fourier transform infrared spectroscopy (FTIR) analysis showed that GPTM could promote SF to transform from the original alpha helix and random coil/extension chain conformation to the beta-folded conformation. Tensile experiment indicated tensile strength and breaking elongation of SF/GPTMS hybrid film reach the maximum with 20% GPTMS content. Within a certain range, the water drop contact angle of SF/GPTMS hybrid film is positively correlated with the content of GPTMS. Endothelial cells (ECs) are best grown on hybrid SF/GPTMS hybrid film with 20% GPTMS content.
Journal Article
Preparation and Characterization of Oligopeptide/M-Pluronic F127 Composite Membranes
In the present study, oligopeptide (TEA) and modified Pluronic F127 (M-Pluronic F127) with different mass fraction composited by intermolecular forces. And the oligopeptide/M-Pluronic F127 composite membranes were prepared and investigated. The structural parameters of the membranes were characterized by fourier transform-infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) measurements. It was found that there had strong interaction between TEA and M-Pluronic F127 and the composite films with different proportions had different surface morphology and thermal stability. The characteristics of the membranes were related to the significant changes of the self-assembly behavior of the TEA modified by M-Pluronic F127.
Journal Article