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© 2018, Nature Publishing Group. All rights reserved. Continuous glucose monitors (CGMs), used by patients with diabetes mellitus, can autonomously track fluctuations in blood glucose over time. However, the signal produced by CGMs during the initial recording period following sensor implantation contains substantial noise, requiring frequent recalibration via finger-prick tests. Here, we show that coating the sensor with a zwitterionic polymer, found via a combinatorial chemistry approach, significantly reduces signal noise and improves CGM performance. We evaluated the polymer-coated sensors in mice as well as in healthy and diabetic non-human primates, and show that the sensors accurately record glucose levels without the need for recalibration. We also show that the coated sensors significantly abrogated immune responses, as indicated by histology, fluorescent whole-body imaging of inflammation-associated protease activity and gene expression of inflammation markers. The polymer coating may allow CGMs to become standalone measuring devices., This work was supported by the Leona M. and Harry B. Helmsley Charitable Trust Foundation (2015PG-T1D063), Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063), and National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), and through a generous gift from the Tayebati Family Foundation. J.C.D was supported by JDRF postdoctoral fellowship (Grant 3-PDF-2015-91-A-N). J.O. is supported by the National Institutes of Health (NIH/NIDDK) R01DK091526 and the Chicago Diabetes Project. X.X. was supported by the 100 Talents Program of Sun Yat-Sen University (76120-18821104) and 1000 Talents Youth Program of China and would like to acknowledge financial support from the National Natural Science Foundation of China (Grant No.51705543, 61771498 and 31530023) and Science and Technology Program of Guangzhou, China (Grant No. 20180310097). And, of extreme importance, the authors thank the Histology and Whole Animal Imaging cores for use of resources (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT).

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency., National Institutes of Health (U.S.) (Grant EB000244), National Institutes of Health (U.S.) (Grant EB000351), National Institutes of Health (U.S.) (Grant DE013023), National Institutes of Health (U.S.) (Grant CA151884)

The surface modification of implantable biomaterials with zwitterionic phosphorylcholine polymer is demonstrated through mussel-mimetic catecholamine polymer thin films. Using this method, the surfaces of alginate hydrogel microspheres and polystyrene microbeads, a model material known to produce robust foreign body responses and fibrosis, are successfully modified to reduce the tissue reaction by reducing the fibrosis in immunocompetent C57BL/6J mice. Keywords: alginate; dopamine; fibrosis; foreign body response; zwitterionic polymers, National Institutes of Health (U.S.) (Grant F32DK101335)

Implantable sensors that detect biomarkers in vivo are critical for early disease diagnostics. Although many colloidal nanomaterials have been developed into optical sensors to detect biomolecules in vitro, their application in vivo as implantable sensors is hindered by potential migration or clearance from the implantation site. One potential solution is incorporating colloidal nanosensors in hydrogel scaffold prior to implantation. However, direct contact between the nanosensors and hydrogel matrix has the potential to disrupt sensor performance. Here, we develop a hollow-microcapsule-based sensing platform that protects colloidal nanosensors from direct contact with hydrogel matrix. Using microfluidics, colloidal nanosensors were encapsulated in polyethylene glycol microcapsules with liquid cores. The microcapsules selectively trap the nanosensors within the core while allowing free diffusion of smaller molecules such as glucose and heparin. Glucose-responsive quantum dots or gold nanorods or heparin-responsive gold nanorods were each encapsulated. Microcapsules loaded with these sensors showed responsive optical signals in the presence of target biomolecules (glucose or heparin). Furthermore, these microcapsules can be immobilized into biocompatible hydrogel as implantable devices for biomolecular sensing. This technique offers new opportunities to extend the utility of colloidal nanosensors from solution-based detection to implantable device-based detection. Keywords: biomolecular sensing; Microcapsules; microfluidic fabrication; nanosensors, Juvenile Diabetes Research Foundation International (Award 17-2013-507)

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response., Leona M. and Harry B. Helmsley Charitable Trust (3-SRA-2014-285-M-R), United States. National Institutes of Health (EB000244), United States. National Institutes of Health (EB000351), United States. National Institutes of Health (DE013023), United States. National Institutes of Health (CA151884), United States. National Institutes of Health (P41EB015871-27), National Cancer Institute (U.S.) (P30-CA14051)

Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis., American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, National Science Foundation (U.S.), Massachusetts Institute of Technology. Presidential Fellowship

The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions., Juvenile Diabetes Research Foundation International (Grant 17-2007-1063), Leona M. and Harry B. Helmsley Charitable Trust (Grant 09PG-T1D027), National Institutes of Health (U.S.) (Grant EB000244), National Institutes of Health (U.S.) (Grant EB000351), National Institutes of Health (U.S.) (Grant DE013023), National Institutes of Health (U.S.) (Grant CA151884), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), Tayebati Family Foundation, Juvenile Diabetes Research Foundation International (Postdoctoral Fellowship Grant 3-2013-178), United States. Dept. of Defense. Congressionally Directed Medical Research Programs (Postdoctoral Fellowship Grant W81XWH-13-1-0215)

In vivo implantation of sterile materials and devices results in a foreign body immune response leading to fibrosis of implanted material. Neutrophils, one of the first immune cells to be recruited to implantation sites, have been suggested to contribute to the establishment of the inflammatory microenvironment that initiates the fibrotic response. However, the precise numbers and roles of neutrophils in response to implanted devices remains unclear. Using a mouse model of peritoneal microcapsule implantation, we show 30–500 fold increased neutrophil presence in the peritoneal exudates in response to implants. We demonstrate that these neutrophils secrete increased amounts of a variety of inflammatory cytokines and chemokines. Further, we observe that they participate in the foreign body response through the formation of neutrophil extracellular traps (NETs) on implant surfaces. Our results provide new insight into neutrophil function during a foreign body response to peritoneal implants which has implications for the development of biologically compatible medical devices., Mazumdar-Shaw International Oncology Fellowship, Juvenile Diabetes Research Foundation International (Grant 17-2007-1063), Leona M. and Harry B. Helmsley Charitable Trust (Grant 09PG-T1D027), National Institutes of Health (U.S.) (Grant EB000244), National Institutes of Health (U.S.) (Grant EB000351), National Institutes of Health (U.S.) (Grant DE013023), National Institutes of Health (U.S.) (Grant CA151884)

Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings., National Institutes of Health (U.S.) (U54‐CA151884), National Institutes of Health (U.S.) (R01‐DE016516‐06), National Institutes of Health (U.S.) (EB000244)

Ion cyclotron resonance heating is the primary auxiliary heating on the Alcator C-Mod tokamak and is commonly used on other devices, and is planned for use on ITER. The RF-power density on C-Mod is above 5 MW m−3 providing for a unique opportunity to study wave–particle effects in the high RF power per particle regime. Minority heating produces a highly energetic tail in the minority distribution function which is measured using a compact neutral particle analyser. In this paper, we present the measurements of the fast-ion spectrum between 200 and 2 MeV, compiled over an entire experimental campaign. We also estimate the effective tail temperatures for the fast-ion distribution. We find that the fast-ion distribution is less energetic and less dense with increasing electron density; is more energetic with increasing plasma current; and is more dense but has no measurable change in energy with increasing RF power. Some possible explanations for these findings are discussed., United States. Dept. of Energy (Award DE-FC02-99ER54512)

In the Alcator C-Mod tokamak, strong, steady-state variations of molybdenum density within a flux surface are routinely observed in plasmas using hydrogen minority ion cyclotron resonant heating. In/out asymmetries, up to a factor of 2, occur with either inboard or outboard accumulation depending on the major radius of the minority resonance layer. These poloidal variations can be attributed to the impurity's high charge and large mass in the neoclassical parallel force balance. The large mass enhances the centrifugal force, causing outboard accumulation while the high charge enhances ion-impurity friction and makes impurities sensitive to small poloidal variations in the plasma potential. Quantitative comparisons between existing parallel high-Z impurity transport theories and experimental results for r/a < 0.7 show good agreement when the resonance layer is on the high-field side of the tokamak but disagree substantially for low-field side heating. Ion-impurity friction is insufficient to explain the experimental results, and the accumulation of impurity density on the inboard side of flux surface is shown to be driven by a poloidal potential variation due to magnetic trapping of non-thermal, cyclotron heated minority ions. Parallel impurity transport theory is extended to account for cyclotron effects and shown to agree with experimentally measured impurity density asymmetries., United States. Dept. of Energy (Agreement DE-FC02-99ER54512), United States. Dept. of Energy. Office of Fusion Energy Sciences (Postdoctoral Research Program)

This paper reports on new experiments at Alcator C-Mod that were performed in order to investigate the long-standing, unresolved discrepancy between Thomson scattering (TS) and electron cyclotron emission (ECE) measurements of electron temperature in high temperature tokamak plasmas. Ion cyclotron range of frequency (ICRF) heating is used to produce high temperature conditions where the type of TS-ECE discrepancy observed in the past at JET and TFTR should become observable. At Alcator C-Mod, plasmas with Te(0) up to 8 keV are obtained using ion cyclotron resonance heating (ICRH), ICRF mode conversion heating and a combination of the two heating methods in order to explore the hypothesis that the presence of ICRH-generated fast ions may be related to the discrepancy. In all high temperature cases, the TS and ECE measurements of electron temperature agree to within experimental uncertainties. We find no evidence for the type of discrepancy reported at JET and TFTR. These results show that the TS-ECE discrepancy does not depend on high temperatures alone and also that the presence of ICRH-generated fast ions is insufficient to cause the TS-ECE discrepancy., United States. Dept. of Energy (DE-FC02-99ER54512)