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 to 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 5-fold 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 by simply tuning their spherical dimensions.

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in diabetic patients1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but are limited by the adverse effects of lifetime immunosuppression and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose responsive mature β-cells derived from human embryonic stem cells; called SC-β, these cells may represent an unlimited human cell source for pancreas replacement therapy4. Strategies to address the immunosuppression concern include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier5,6. However, clinical implementation has been challenging due to host immune responses to implant materials7. Here, we report the first long term glycemic correction of a diabetic, immune-competent animal model with human SC-β cells. SC-β cells were encapsulated with alginate-derivatives capable of mitigating foreign body responses in vivo, and implanted into the intraperitoneal (IP) space of streptozotocin-treated (STZ) C57BL/6J mice. These implants induced glycemic correction until removal at 174 days without any immunosuppression. Human C-peptide concentrations and in vivo glucose responsiveness demonstrate therapeutically relevant glycemic control. Implants retrieved after 174 days contained viable insulin-producing cells.

Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higheraffinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency.vaccination kinetics | antigen retention | humoral response | computational immunology | germinal center formation S ubunit vaccines based on recombinant protein antigens combined with adjuvants can safely elicit protective humoral immune responses in humans, and they have become a cornerstone of modern public health (1, 2). Recent advances in structure-based vaccine design (3, 4) and progress in the development of adjuvants that are safe and effective for prophylactic vaccines (5) have helped drive the field. However, several challenges remain: A number of protein vaccines, such as candidate vaccines against HIV and malaria, have tended to elicit short-lived immunity (6, 7). In HIV, broadly neutralizing antibodies (BNAbs) isolated from infected patients are generally characterized by high degrees of somatic hypermutation (SHM) (8), but methods to generate such highly mutated antibodies by vaccination remain unknown. SHM occurs in germinal centers (GCs) within lymphoid organs, and data from animal models demonstrate a critical role for follicular helper T cells in the induction of GCs and promotion of affinity maturation (9, 10). To date, methods to promote Tfh generation and long-lived germinal centers during vaccination remain unclear (11-15). Much attention has focused on the use of adjuvants to promote affinity maturation, but it remains unclear if adjuvants alone can provide the necessary immunological driving forces for promoting extensive affinity maturation (16).During acute infections, which often provoke robust germinal center responses and durable humoral immunity, microorganism replication typically occurs over the course of one to several weeks (17-19). During this time, recognition of molecular danger signals contained within the pathogen sustains stimulation of the innate immune system, and a continuous supply of antigen is provided to the adaptive immune system. In contrast to these patterns of antigen and inflammatory cues during infection, typical subunit vaccines...

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient1–6. 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.

Host recognition and immune-mediated foreign body response (FBR) to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knock out and CXCL13 neutralization. Interestingly, Colony Stimulating Factor-1 Receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer, and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, ROS production, and phagocytosis. Our results indicate targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

BackgroundGiven the protracted nature of the crisis in Syria, the large noncommunicable disease (NCD) caseload of Syrian refugees and host Lebanese, and the high costs of providing NCD care, the implications for Lebanon’s health system are vast.ObjectiveThe aim of this study was to evaluate the effectiveness of treatment guidelines and a mobile health (mHealth) app on quality of care and health outcomes in primary care settings in Lebanon.MethodsA longitudinal cohort study was implemented from January 2015 to August 2016 to evaluate the effectiveness of treatment guidelines and an mHealth app on quality of care and health outcomes for Syrian and Lebanese patients in Lebanese primary health care (PHC) facilities.ResultsCompared with baseline record extraction, recording of blood pressure (BP) readings (−11.4%, P<.001) and blood sugar measurements (−6.9%, P=.03) significantly decreased following the implementation of treatment guidelines. Recording of BP readings also decreased after the mHealth phase as compared with baseline (−8.4%, P=.001); however, recording of body mass index (BMI) reporting increased at the end of the mHealth phase from baseline (8.1%, P<.001) and the guidelines phase (7.7%, P<.001). There were a great proportion of patients for whom blood sugar, BP, weight, height, and BMI were recorded using the tablet compared with in paper records; however, only differences in BMI were statistically significant (31.6% higher in app data as compared with paper records; P<.001). Data extracted from the mHealth app showed that a higher proportion of providers offered lifestyle counseling compared with the counseling reported in patients’ paper records (health diet counseling; 77.3% in app data vs 8.8% in paper records, P<.001 and physical activity counseling and 59.7% in app vs 7.1% in paper records, P<.001). There were statistically significant increases in all four measures of patient-provider interaction across study phases. Provider inquiry of medical history increased by 16.6% from baseline following guideline implementation and by 28.2% from baseline to mHealth implementation (P<.001). From baseline, patient report of provider inquiry regarding medication complications increased in the guidelines and mHealth phases by 12.9% and 59.6%, respectively, (P<.001). The proportion of patients reporting that providers asked other questions relevant to their illness increased from baseline through guidelines implementation by 27.8% and to mHealth implementation by 66.3% (P<.001). Follow-up scheduling increased from baseline to the guidelines phase by 20.6% and the mHealth phase by 39.8% (P<.001).ConclusionsResults from this study of an mHealth app in 10 PHC facilities in Lebanon indicate that the app has potential to improve adherence to guidelines and quality of care. Further studies are necessary to determine the effects of patient-controlled health record apps on provider adherence to treatment guidelines, as well as patients’ long-term medication and treatment adherence and disease control.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled release formulations for local antiinflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sitessubcutaneous, intraperitoneal and intramuscular. In particular incorporation of GW2580, a Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor, into a range of devices including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and musclestimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials. Implanted biomedical devices are an integral part of modern therapeutics, playing key roles in many clinical applications including neural interfacing 1 , monitoring vital signs 2 , pacemakers 3 , controlled drug release 4 , scaffolds for tissue reconstruction 5 , vascular stenting, cell encapsulation and transplantation 6. While the immunological response to materials can be therapeutic, for example with particulate vaccines 7 , some device materials, including polysaccharides, polymers, ceramics, and metals 8 , can induce host immune-mediated foreign body and rejection responses This response can lead to fibrotic encapsulation, and in some cases, reduced efficacy or failure 8-12. Current approaches for long-term maintenance of biomedical device implant biocompatibility often involve broad-spectrum antiinflammatories 13. Short-term steroid or anti-fibrotic drug delivery can transiently inhibit inflammatory cell recruitment as well as improve protein secretion of immuno-isolated cellular grafts 14,15. However, many anti-inflammatory drugs have multiple targets and differential effects in vivo, and associated toxicity 13,16. In particular, macrophages are known to be key mediators of the immune response to implanted biomaterials 8-10. Recently it was shown that the implant-induced foreign body response can be inhibited through selective targeting of the monocyte/macrophage-expressed colony stimulating factor-1 (CSF1R) receptor 10. Importantly, while macrophage numbers in the IP space as well as Farah et al.

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 fingerprick 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 polymer-coated sensors significantly abrogated immune responses to the sensor, 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.