Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates.

Host recognition and immune-mediated foreign body response 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 knockout 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, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates.

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.

Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion.

BACKGROUND AND PURPOSE: The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. METHODS: A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. RESULTS: Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). CONCLUSIONS: A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy.

High-resolution image-guided WEB aneurysm embolization by high-frequency optical coherence tomography.

BACKGROUND: High-frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging technique capable of assessing device-vessel interactions at spatial resolution approaching 10 µm. We tested the hypothesis that adequately deployed Woven EndoBridge (WEB) devices as visualized by HF-OCT lead to higher aneurysm occlusion rates. METHODS: In a leporine model, elastase-induced aneurysms (n=24) were treated with the WEB device. HF-OCT and digital subtraction angiography (DSA) were performed following WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion (0-present, 1-absent) and malapposition (0-malapposed, 1-neck apposition >50%) were binary coded. A device was considered 'adequately deployed' by HF-OCT and DSA if apposed and non-protruding. Aneurysm healing on DSA was reported using the 4-point WEB occlusion score: A or B grades were considered positive outcome. Neointimal coverage was quantified on HF-OCT images at 12 weeks and compared with scanning electron microscopy (SEM). RESULTS: Adequate deployment on HF-OCT correlated with positive outcome (P=0.007), but no statistically significant relationship was found between good outcome and adequate deployment on DSA (P=0.289). Absence of protrusion on HF-OCT correlated with a positive outcome (P=0.006); however, malapposition alone had no significant relationship (P=0.19). HF-OCT showed a strong correlation with SEM for the assessment of areas of neointimal tissue (R²=0.96; P<0.001). More neointimal coverage of 78%±32% was found on 'adequate deployment' cases versus 31%±24% for the 'inadequate deployment' cases (P=0.001). CONCLUSION: HF-OCT visualizes features that can determine adequate device deployment to prognosticate early aneurysm occlusion following WEB implantation and can be used to longitudinally monitor aneurysm healing progression.

In situ decellularization of a large animal saccular aneurysm model: sustained inflammation and active aneurysm wall remodeling.

OBJECTIVE: To investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation. METHODS: 18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks. Every 2 weeks, three of the rabbits (two elastase + SDS, one control) underwent MRI, followed by contrast injection with myeloperoxidase (MPO)-sensing contrast agent. MRI was repeated 3 hours after contrast injection and the enhancement ratio (ER) was calculated. Following MRI, aneurysms were explanted and subjected to immunohistopathology. RESULTS: During follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (p<0.001). The width of SDS-treated aneurysms increased significantly in comparison with the elastase aneurysms (47% vs 20%, p<0.001). Image analysis of thin sections showed infiltration of MPO-positive cells in decellularized aneurysms and surroundings through the 12-week observation period while control tissue had 5-6 times fewer cells present 2 weeks after aneurysm creation. Immunohistochemistry demonstrated the presence of MPO-positive cells surrounding decellularized lesions at early time points. MPO-positive cells were found in the adventitia and in the thrombi adherent to the aneurysm wall at later time points. CONCLUSIONS: In situ decellularization of a large animal model of saccular aneurysms reproduces features of unstable aneurysms, such as chronic inflammation (up to 12 weeks) and active aneurysm wall remodeling, leading to continued growth over 8 weeks.

Longitudinal Monitoring of Flow-Diverting Stent Tissue Coverage After Implant in a Bifurcation Model Using Neurovascular High-Frequency Optical Coherence Tomography.

BACKGROUND: Tissue growth over covered branches is a leading cause of delayed thrombotic complications after flow-diverter stenting (FDS). Due to insufficient resolution, no imaging modality is clinically available to monitor this phenomenon. OBJECTIVE: To evaluate high-frequency optical coherence tomography (HF-OCT), a novel intravascular imaging modality designed for the cerebrovascular anatomy with a resolution approaching 10 microns, to monitor tissue growth over FDS in an arterial bifurcation model. METHODS: FDS were deployed in a rabbit model (n = 6), covering the aortic bifurcation. The animals were divided in different groups, receiving dual antiplatelet therapy (DAPT) (n = 4), aspirin only (n = 1), and no treatment (n = 1). HF-OCT data were obtained in vivo at 3 different time points in each animal. For each cross-sectional image, metal and tissue coverage of the jailed ostium was quantified. Scanning electron microscopy images of harvested arteries were subsequently obtained. RESULTS: Good quality HF-OCT data sets were successfully acquired at implant and follow-up. A median value of 41 (range 21-55) cross-sectional images were analyzed per ostium for each time point. Between 0 and 30 d after implant, HF-OCT analysis showed a significantly higher ostium coverage when DAPT was not given. After 30 d, similar growth rates were found in the DAPT and in the aspirin group. At 60 d, a coverage of 90% was reached in all groups. CONCLUSION: HF-OCT enables an accurate visualization of tissue growth over time on FDS struts. The use of FDS in bifurcation locations may induce a drastic reduction of the jailed-branch ostium area.

Acute Thrombus Burden on Coated Flow Diverters Assessed by High Frequency Optical Coherence Tomography.

PURPOSE: The implantation of flow diverters requires administration of dual anti-platelet therapy, posing the potential for complications. The p48MW HPC (phenox, Bochüm, Germany) hydrophilic-coated flow diverting stent is designed to be anti-thrombotic, thus opening the potential for single anti-platelet therapy. We deploy a novel intravascular high-resolution imaging technique, high-frequency optical coherence tomography (HF-OCT), to study in an animal model the acute thrombus formation on coated p48MW devices versus uncoated control devices. METHODS: Three pigs were implanted with 4 flow diverters each, two test hydrophilic-coated devices, and two control uncoated devices (p48MW). Each pig was treated with a different anti-platelet regime: no anti-platelet therapy, aspirin only, aspirin and clopidogrel. Twenty minutes after the flow diverter was implanted, an HF-OCT data set was acquired. Acute clot formed on the flow diverter at each covered side branch was measured from the HF-OCT slices. Factors considered to be important were the device type (pHPC versus bare metal), aspirin, clopidogrel, and vessel location. A linear model was constructed from the significant factors. RESULTS: Both coating (p < 0.001) and aspirin (p = 0.003) were significantly related to reduction in clot burden, leading to an approximate 100-fold and 50-fold reduction in clot, respectively. CONCLUSIONS: This study shows the power of HF-OCT not only in the detection of clot but also the quantification of clot burden. In an animal model, the pHPC-coated p48MW significantly reduced acute thrombus formation over jailed side branches as compared to the bare metal p48MW that was nearly eliminated when combined with aspirin administration.

A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy.

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated.

Microcatheter navigation through the clot: does size matter?

BACKGROUND: Despite high recanalization rates achieved with endovascular treatment of acute ischemic strokes, around 50% of eligible patients will not achieve a good outcome. Parameters that may determine patient outcomes include: time from puncture to recanalization, the collateral status, the anesthesia regimen, blood pressure management, and distal emboli. Characterization of distal emboli generated during mechanical thrombectomy has been performed in previous studies. OBJECTIVE: To further investigate the risk of distal embolization associated with microcatheter navigation across the clot. METHODS: A contrast-enhanced clot analog was used in an in vitro model that mimicked a middle cerebral artery occlusion within a complete circle of Willis vascular replica. The clot was crossed with one of the following microcatheters: Pro18, XT-27 or 3MAX. The emboli generated during the procedure were collected and measured. RESULTS: The use of Pro18 and XT-27 resulted in a significant reduction of visible particles (size ≥500 µm) as compared with the 3MAX catheter (P<0.003). For the size range between 8 and 200 µm, there was a trend for Pro18 to generate fewer particles (-18%) than XT-27 but without statistical significance (P>0.05). In comparison with previously published data, acquired under the same conditions, it was found that the clot crossing maneuver accounts approximately for 12% of the total number of small emboli (<200 µm) induced during a stent retriever-mediated mechanical thrombectomy procedure via a balloon guide catheter. CONCLUSIONS: The clot crossing maneuver has a significant effect on the total number of small particles induced during mechanical thrombectomy. Smaller microcatheter sizes should be favored when possible.

Robotic Assisted MRI-Guided Interventional Interstitial MR-Guided Focused Ultrasound Ablation in a Swine Model.

BACKGROUND: Ablative lesions are current treatments for epilepsy and brain tumors. Interstitial magnetic resonance (MR) guided focused ultrasound (iMRgFUS) may be an alternate ablation technique which limits thermal tissue charring as compared to laser therapy (LITT) and can produce larger ablation patterns nearer the surface than transcranial MR guided focused ultrasound (tcMRgFUS). OBJECTIVE: To describe our experience with interstitial focused ultrasound (iFUS) ablations in swine, using MR-guided robotically assisted (MRgRA) delivery. METHODS: In an initial 3 animals, we optimized the workflow of the robot in the MR suite and made modifications to the robotic arm to allow range of motion. Then, 6 farm pigs (4 acute, 2 survival) underwent 7 iMRgFUS ablations using MRgRA. We altered dosing to explore differences between thermal dosing in brain as compared to other tissues. Imaging was compared to gross examination. RESULTS: Our work culminated in adjustments to the MRgRA, iMRgFUS probes, and dosing, culminating in 2 survival surgeries; swine had ablations with no neurological sequelae at 2 wk postprocedure. Immediately following iMRgFUS therapy, diffusion-weighted imaging, and T1 weighted MR were accurate reflections of the ablation volume. T2 and fluid-attenuated inversion-recovery (FLAIR) images were accurate reflections of ablation volume 1-wk postprocedure. CONCLUSION: We successfully performed MRgRA iFUS ablation in swine and found intraoperative and postoperative imaging to correlate with histological examination. These data are useful to validate our system and to guide imaging follow-up for thermal ablation lesions in brain tissue from our therapy, tcMRgFUS, and LITT.

Platelet decoys inhibit thrombosis and prevent metastatic tumor formation in preclinical models.

Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation. Platelet decoys inhibited aggregation and adhesion of platelets on thrombogenic surfaces in vitro, which could be immediately reversed by the addition of normal platelets; in vivo in a rabbit model, pretreatment with platelet decoys inhibited arterial injury-induced thromboembolism. Decoys also interfered with platelet-mediated human breast cancer cell aggregation, and their presence decreased cancer cell arrest and extravasation in a microfluidic human microvasculature on a chip. In a mouse model of metastasis, simultaneous injection of the platelet decoys with tumor cells inhibited metastatic tumor growth. Thus, our results suggest that platelet decoys might represent an effective strategy for obtaining antithrombotic and antimetastatic effects.

Communicating malapposition of flow diverters assessed with optical coherence tomography correlates with delayed aneurysm occlusion.

BACKGROUND: Optical coherence tomography (OCT) is a high resolution intravascular imaging method that allows visualization of flow diverter struts and the vessel wall. In this study, malapposition of the flow diverter that continues into the neck of the aneurysm, named communicating malapposition (CM), was investigated as a potential factor for delayed aneurysm healing. METHODS: 40 New Zealand White rabbits underwent elastase induced aneurysm creation, and were subsequently assigned to one of four treatment groups based on flow diverter type and administration of antiplatelet therapy. All animals underwent post device deployment balloon angioplasty and subsequent OCT to assess device/vessel apposition. The incidence of CM seen on OCT was assessed with a binary scoring system: 0-CM present; 1-CM absent. At 30 days, DSA was acquired to assess aneurysm healing. Aneurysm healing on terminal DSA was measured using a previously developed 5 point scale, with a score of 3 or 4 considered a positive outcome. RESULTS: All animals were grouped into a single cohort for analysis as no difference in the rate of CM or healing was seen in the four treatment groups. Significant interaction between the absence of CM and a positive outcome was confirmed by Fisher exact test (P=0.0034). Angioplasty was shown to treat 33% of the cases of CM seen at implant, and these treated cases overwhelmingly had a positive outcome (P<0.001). CONCLUSION: The use of OCT to assess CM of flow diverters has been shown to be predictive of the 30 day healing rate of an animal model of aneurysms.

Acute thrombus formation on phosphorilcholine surface modified flow diverters.

PURPOSE: Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED). METHODS: Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent. RESULTS: Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p<0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198). CONCLUSION: In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.

Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia.

BACKGROUND: Optical coherence tomography (OCT) is a high-resolution, intra-vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED). METHODS: In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline - cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations. RESULTS: OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r2=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED. CONCLUSION: OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates.

In situ tissue engineering: endothelial growth patterns as a function of flow diverter design.

BACKGROUND: Vascular remodeling in response to implantation of a tissue engineering scaffold such as a flow diverter (FD) leads to the cure of intracranial aneurysms. We hypothesize that the vascular response is dependent on FD design, and CD34+ progenitor cells play an important role in the endothelialization of the implant. METHODS: Sixteen rabbit aneurysms were randomly treated with two different single-layer braided FDs made of cobalt-chrome alloys. The FD-48 and FD-72 devices had 48 and 72 wires, respectively. Aneurysm occlusion rate was assessed during the final digital subtraction angiogram at 10, 20, 30, and 60 days (n=2 per device per time point). Implanted vessels were analyzed with scanning electron microscopy for tissue coverage, endothelialization, and immuno-gold labeling for CD34+ cells. RESULTS: Complete aneurysm occlusion rates were similar between the devices; however, complete or near complete occlusion was more frequently observed in aneurysms with neck ≤4.2 mm (p=0.008). Total tissue coverage at 10 days over the surface of the FD-48 and FD-72 devices was 56.4±11.6% and 76.6±3.6%, respectively. Endothelial cell growth over the surface was time-dependent for the FD-72 device (Spearman's r=0.86, p=0.013) but not for the FD-48 device (Spearman's r=-0.59, p=0.094). The endothelialization score was marginally correlated with the distance from the aneurysm neck for the FD-48 device (Spearman's r=1, p=0.083) but not for the FD-72 device (Spearman's r=0.8, p=0.33). CD34+ cells were present along the entirety of both devices at all time points. CONCLUSIONS: This study gives preliminary evidence that temporal and spatial endothelialization is dependent on FD design. Circulating CD34+ progenitor cells contribute to endothelialization throughout the healing process.

Quantitative assessment of device-clot interaction for stent retriever thrombectomy.

PURPOSE: Rapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device-clot interaction as a potential mechanism for efficient embolectomy. METHODS: Two different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF). RESULTS: The CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004-0.007). CONCLUSIONS: This study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot-device integration increased in both clot models by waiting 5 min.

Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-ß cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-ß cells. SC-ß cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

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.

Neutrophil Responses to Sterile Implant Materials.

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.