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
) delivery is ...limited to slow passive diffusion from transplantation sites through the poorly O
-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
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
diffusivity than hydrogels. We incorporate the scaffold into a bulk hydrogel containing cells, which facilitates rapid O
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.
Islet encapsulation Ernst, Alexander Ulrich; Wang, Long-Hai; Ma, Minglin
Journal of materials chemistry. B, Materials for biology and medicine,
11/2018, Letnik:
6, Številka:
42
Journal Article
Recenzirano
This review focuses on recent engineering advances in islet encapsulation technologies. β cell replacement therapy in the form of allogeneic naked islet transplantation has become an established ...treatment for type 1 diabetes mellitus (T1DM). However, some limitations still impact the broad applicability and long-term efficacy of the procedure, including shortage of donor islets, the need for lifelong immunosuppression, and restriction to the most vulnerable patients. Islet encapsulation promises to overcome these constraints by providing a selectively permeable barrier between host and therapeutic tissues. While tremendous progress has been made and the clearing of key translational hurdles appears to be near, many challenges need to be addressed before this technology platform can enter the clinic. Here, we summarize the research in this area and seek to identify the outstanding challenges in translating islet encapsulation technology to human patients.
Review of emerging advances and persisting challenges in the engineering and translation of islet encapsulation technologies.
Cell replacement therapy is emerging as a promising treatment platform for many endocrine disorders and hormone deficiency diseases. The survival of cells within delivery devices is, however, often ...limited due to low oxygen levels in common transplantation sites. Additionally, replacing implanted devices at the end of the graft lifetime is often unfeasible and, where possible, generally requires invasive surgical procedures. Here, the design and testing of a modular transcutaneous biphasic (BP) cell delivery device that provides enhanced and unlimited oxygen supply by direct contact with the atmosphere is presented. Critically, the cell delivery unit is demountable from the fixed components of the device, allowing for surgery‐free refilling of the therapeutic cells. Mass transfer studies show significantly improved performance of the BP device in comparison to subcutaneous controls. The device is also tested for islet encapsulation in an immunocompetent diabetes rodent model. Robust cell survival and diabetes correction is observed following a rat‐to‐mouse xenograft. Lastly, nonsurgical cell refilling is demonstrated in dogs. These studies show the feasibility of this novel device for cell replacement therapies.
A refillable transcutaneous cell encapsulation device is reported. Inspired by the biphasic physiology of the cornea, the device achieves elevated oxygen levels by direct contact with the atmosphere and provides environmental protection by application of a perfluorinated oil‐infused polymer nanomembrane. Diabetes correction is accomplished in mice and nonsurgical cell refilling is achieved in dogs.
Type 1 diabetes (T1D) is a disease characterized by the loss of glycemic control following the immune-mediated destruction of the insulin-secreting β-cells, which reside in pancreatic cell clusters ...known as islets. Presently, insulin administration is the primary method of treatment for T1D. However, secondary complications and the requirement for constant attention render insulin therapy imperfect. The intraportal infusion of allogeneic islets, or more recently stem cell-derived β-cell clusters, have demonstrated the potential for more robust glycemic control. Nevertheless, intraportal islet therapy is constrained in applicability because it requires the co-administration of immunosuppressive drugs. Encapsulating insulin-secreting cells in a hydrogel-based system which prevents immune interference but allows free transport of nutrients and therapeutics promises to overcome these limitations and would constitute a bioartificial pancreas. Unfortunately, encapsulation demands that the cells are physically separated from the host circulation, introducing mass transport challenges. This thesis aims first to quantify those constraints, especially that of oxygen---what is likely the limiting nutrient---and then evaluates three strategies proposed to overcome them. First, a computational platform is developed to evaluate bioartificial pancreas devices, accounting for their intrinsic stochastic properties. We find that device potency is strikingly sensitive to variance in the size distributions of the encapsulated cell clusters. We also determine that large cell payloads and devices are required to provide clinical benefit. A novel accounting of the therapeutic cell mass, adjusted for oxygen-limited potency, is then proposed. Subsequently, an approach which enables the maintenance of a continuous gas phase within hydrogels is described, which increases the oxygen permeability in such systems significantly. The second approach proposes a system by which the cellular waste product carbon dioxide is recycled into oxygen in situ through an "inverse-breathing" chemical reaction in a physically separated encapsulation system. The final chapter explores the benefit of vascularizing the host site before device implantation. Characterizations using electron paramagnetic resonance oxygen imaging confirm model predictions that all three systems elevate graft oxygenation. Studies in mice demonstrate that all three strategies improve diabetes correction in comparison to suitable controls. Cumulatively, this work contributes to overcoming mass transport limitations in encapsulated cell therapy for T1D.
Cell encapsulation represents a promising therapeutic strategy for many hormone-deficient diseases such as type 1 diabetes (T1D). However, adequate oxygenation of the encapsulated cells remains a ...challenge, especially in the poorly oxygenated subcutaneous site. Here, we present an encapsulation system that generates oxygen (O
) for the cells from their own waste product, carbon dioxide (CO
), in a self-regulated (i.e., "inverse breathing") way. We leveraged a gas-solid (CO
-lithium peroxide) reaction that was completely separated from the aqueous cellular environment by a gas permeable membrane. O
measurements and imaging validated CO
-responsive O
release, which improved cell survival in hypoxic conditions. Simulation-guided optimization yielded a device that restored normoglycemia of immunocompetent diabetic mice for over 3 months. Furthermore, functional islets were observed in scaled-up device implants in minipigs retrieved after 2 months. This inverse breathing device provides a potential system to support long-term cell function in the clinically attractive subcutaneous site.
2016 Alexander Honold, Christine Lubkoll, Ernst Osterkamp, Ulrich Raulff / Alexander Honold, Christine Lubkoll, Ernst Osterkamp, Ulrich Raulff
2016
eBook
Das Jahrbuch der Deutschen Schillergesellschaft ist ein literaturwissenschaftliches Periodikum, das vorwiegend Beiträge zur deutschsprachigen Literatur von der Aufklärung bis zur Gegenwart ...veröffentlicht. Diese Zeitspanne entspricht den Sammelgebieten des Deutschen Literaturarchivs Marbach, das von der Deutschen Schillergesellschaft getragen wird. Arbeiten zu Schiller sind besonders willkommen, bilden aber nur einen Teil des Spektrums.
2018 Alexander Honold, Christine Lubkoll, Steffen Martus, Sandra Richter / Alexander Honold, Christine Lubkoll, Ernst Osterkamp, Ulrich Raulff
2018
eBook
Das Jahrbuch der Deutschen Schillergesellschaft ist ein literaturwissenschaftliches Periodikum, das vorwiegend Beiträge zur deutschsprachigen Literatur von der Aufklärung bis zur Gegenwart ...veröffentlicht. Diese Zeitspanne entspricht den Sammelgebieten des Deutschen Literaturarchivs Marbach, das von der Deutschen Schillergesellschaft getragen wird. Arbeiten zu Schiller sind besonders willkommen, bilden aber nur einen Teil des Spektrums.
3H‐Phosphaallenes, R−P=C=C(H)C−R’ (3), are accessible in a multigram scale on a new and facile route and show a fascinating chemical reactivity. BH3(SMe2) and 3 a (R=Mes*, R’=tBu) afforded by ...hydroboration of the C=C bonds of two phosphaallene molecules an unprecedented borane (7) with the B atom bound to two P=C double bonds. This compound represents a new FLP based on a B and two P atoms. The increased Lewis acidity of the B atom led to a different reaction course upon treatment of 3 a with H2B‐C6F5(SMe2). Hydroboration of a C=C bond of a first phosphaallene is followed in a typical FLP reaction by the coordination of a second phosphaallene molecule via B−C and P−B bond formation to yield a BP2C2 heterocycle (8). Its B−P bond is short and the B‐bound P atom has a planar surrounding. Treatment of 3 a with tBuLi resulted in deprotonation of the β‐C atom of the phosphaallene (9). The Li atom is bound to the P atom as demonstrated by crystal structure determination, quantum chemical calculations and reactions with HCl, Cl‐SiMe3 or Cl‐PtBu2. The thermally unstable phosphaallene Ph−P=C=C(H)‐tBu gave a unique trimeric secondary product by P−P, P−C and C−C bond formation. It contains a P2C4 heterocycle and was isolated as a W(CO)4 complex with two P atoms coordinated to W (15).
Renewed interest: 3H‐Phosphaallenes are highly functional compounds with a fascinating perspective in various chemical transformations. Hydroboration of the C=C bond afforded a BP2 FLP or a BP2C2 heterocycle and deprotonation yielded a reactive Li phosphide. A new secondary product was obtained by trimerisation of a sterically low shielded phosphaallene via P−P, P−C and C−C bond formation.
The Al/P‐based frustrated Lewis pair (FLP) Mes2P−C(AltBu)2=C(H)Ph (1; Mes=mesityl) reacted as an efficient two‐electron reductant with benzil to afford a cis‐enediolate that was coordinated to the ...FLP through P−O and Al−O bonds and the formation of a seven‐membered heterocycle (2). The phosphorus atom is oxidised from +III to +V. Similar heterocycles (3 a to 3 f) were formed if 1 was treated with various enones (acrolein, acrylate, acrylamide). The resulting enolates are bound to the FLP through P−C and Al−O bonds. Cyclopropenone gave an adduct (4) with the C=O bond coordinated by P and Al. Ynones gave a fascinating variety of different structures. 1,3‐Diphenylprop‐2‐yn‐1‐one afforded a remarkable allene‐type moiety with two cumulated C=C bonds (5); 3‐hexyn‐2‐one yielded a ligand with two conjugated C=C bonds by C−H bond activation at the carbonyl methyl group (7); and 4‐(trimethylsilyl)‐3‐butyn‐2‐one reacted by C−H bond cleavage, formation of an enolate group with a terminal C=C bond, and shift of the proton to the P atom (8). The C≡C bond was not affected. Allene compound 5 rearranged at elevated temperature and in daylight through the formation of a tricyclic compound by C−H bond activation and C−C bond formation. DFT calculations on this unusual rearrangement suggest insertion of the central allene C atom into the C−H bond of a methyl group and the intermediate formation of a C3 ring.
Polarising reactants: An Al/P‐based frustrated Lewis pair (FLP) reacted as an effective two‐electron reductant towards α,β‐unsaturated carbonyl compounds. Coordination of the O atoms to Al polarised the substrates and facilitated the attack of P at the β position, with formation of seven‐membered heterocycles (see scheme). An allenic ligand showed C−H bond activation and rearrangement to a tricyclic compound probably via a three‐membered cyclic transition state.
The trilithium compound 1,3-PhMe2Si–C(Li)C(H)2C6H3Li (2b) reacted with BCl3, AlCl3, or GaCl3 by salt elimination to yield dinuclear heptacyclic compounds (4). Two tridentate tricarbanionic ligands ...coordinate two B, Al, or Ga atoms and adopt a helical arrangement of the ligands around a central E2 unit. The unusual structures comprise E2C2 heterocycles with two 3c–2e (three-center–two-electron) E–C–E bonds and two C atoms of aromatic rings in the bridging positions. While such a bonding situation is well-documented in Al chemistry, it is rare for B and Ga compounds. Insight into the bonding situation of the molecules is provided by DFT calculations.
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