RESUMEN
For implantable sensors to become a more viable option for continuous glucose monitoring strategies, they must be able to persist in vivo for periods longer than the 3- to 7-day window that is the current industry standard. Recent studies have attributed such limited performance to tissue reactions resulting from implantation. While in vivo biocompatibility studies have provided much in the way of understanding histology surrounding an implanted sensor, little is known about how each constituent of the foreign body response affects sensor function. Due to the ordered composition and geometry of implant-associated tissue reactions, their effects on sensor function may be computationally modeled and analyzed in a way that would be prohibitive using in vivo studies. This review both explains how physiologically accurate computational models of implant-associated tissue reaction can be designed and shows how they have been utilized thus far. Going forward, these in silico models of implanted sensor behavior may soon complement in vivo studies to provide valuable information for improved sensor designs.
Asunto(s)
Técnicas Biosensibles/instrumentación , Glucemia/análisis , Prótesis e Implantes/efectos adversos , Técnicas Biosensibles/métodos , Reacción a Cuerpo Extraño/etiología , Humanos , Sistemas de Infusión de Insulina , Modelos TeóricosRESUMEN
The erroneous and unpredictable behavior of percutaneous glucose sensors just days following implantation has limited their clinical utility for diabetes management. Recent research has implicated the presence of adherent inflammatory cells as the key mitigating factor limiting sensor functionality in this period of days post-implantation. Here we present a novel in vitro platform to mimic the cell-embedded provisional matrix that forms adjacent to the sensor immediately after implantation for the focused investigation of the effects of early stage tissue response on sensor function. This biomimetic surrogate is formed by imbibing fibrin-based gels with physiological densities of inflammatory RAW 264.7 macrophages. When surrounding functional sensors, macrophage-embedded fibrin gels contribute to sensor signal declines that are similar in both shape and magnitude to those observed in previous whole blood and small animal studies. Signal decline in the presence of gels is both metabolically-mediated and sensitive to cell type and activation. Computational modeling of the experimental setup is also presented to validate the design by showing that the cellular glucose uptake parameters necessary to achieve such experimental declines align well with literature values. Together, these data suggest this in vitro provisional matrix surrogate may serve as an effective screening tool for testing the biocompatibility of future glucose sensor designs.
Asunto(s)
Técnicas Biosensibles , Glucemia/análisis , Fibrina/química , Geles/química , Inflamación/etiología , Macrófagos/inmunología , Prótesis e Implantes/efectos adversos , Células 3T3 , Animales , Materiales Biocompatibles/química , Técnicas Biosensibles/instrumentación , Línea Celular , Células Inmovilizadas/citología , Células Inmovilizadas/inmunología , Inflamación/inmunología , Macrófagos/citología , RatonesRESUMEN
BACKGROUND: Tissue response to indwelling glucose sensors remains a confounding barrier to clinical application. While the effects of fully formed capsular tissue on sensor response have been studied, little has been done to understand how tissue interactions occurring before capsule formation hinder sensor performance. Upon insertion in subcutaneous tissue, the sensor is initially exposed to blood, blood borne constituents, and interstitial fluid. Using human whole blood as a simple ex vivo experimental system, the effects of protein accumulation at the sensor surface (biofouling effects) and cellular consumption of glucose in both the biofouling layer and in the bulk (metabolic effects) on sensor response were assessed. METHODS: Medtronic MiniMed SofSensor glucose sensors were incubated in whole blood, plasma-diluted whole blood, and cell-free platelet-poor plasma (PPP) to analyze the impact of different blood constituents on sensor function. Experimental conditions were then simulated using MATLAB to predict the relative impacts of biofouling and metabolic effects on the observed sensor responses. RESULTS: Protein biofouling in PPP in both the experiments and the simulations was found to have no interfering effect upon sensor response. Experimental results obtained with whole and dilute blood showed that the sensor response was markedly affected by blood borne glucose-consuming cells accumulated in the biofouling layer and in the surrounding bulk. CONCLUSIONS: The physical barrier to glucose transport presented by protein biofouling does not hinder glucose movement to the sensor surface, and the consumption of glucose by inflammatory cells, and not erythrocytes, proximal to the sensor surface has a substantial effect on sensor response and may be the main culprit for anomalous sensor behavior immediately following implantation.
Asunto(s)
Incrustaciones Biológicas , Automonitorización de la Glucosa Sanguínea/instrumentación , Glucemia/análisis , Simulación por Computador , Glucosa/metabolismo , Inflamación/metabolismo , Modelos Biológicos , Transporte Biológico/fisiología , Humanos , Inflamación/etiología , Inflamación/patología , Leucocitos/ultraestructura , Valor Predictivo de las Pruebas , Prótesis e Implantes/efectos adversos , Tejido Subcutáneo/metabolismo , Tejido Subcutáneo/patologíaRESUMEN
Little is known mechanistically about why implanted glucose sensors lag behind blood glucose levels in both the time to peak sensor response and the magnitude of peak sensor response. A mathematical model of glucose transport from capillaries through surrounding tissue to the sensor surface was constructed to address how different aspects of the tissue affect glucose transport to an implanted sensor. Physiologically relevant values of capsule diffusion coefficient, capsule porosity, cellular glucose consumption, capsule thickness, and subcutaneous vessel density were used as inputs to create simulated sensor traces that mimic experimental instances of time lag and concentration attenuation relative to a given blood glucose profile. Using logarithmic sensitivity analysis, each parameter was analyzed to study the effect of these variables on both lag and attenuation. Results identify capsule thickness as the strongest determinant of sensor time lag, while subcutaneous vessel density and capsule porosity had the largest effects on attenuation of glucose that reaches the sensor surface. These findings provide mechanistic insight for the rational design of sensor modifications that may alleviate the deleterious consequences of tissue effects on implanted sensor performance.
Asunto(s)
Técnicas Biosensibles/métodos , Glucosa/farmacocinética , Animales , Transporte Biológico , Técnicas Biosensibles/instrumentación , Difusión , Glucosa/química , Cinética , Microvasos/metabolismo , Modelos Biológicos , Prótesis e Implantes , RatasRESUMEN
Surfaces decorated with high affinity ligands can be used to facilitate rapid attachment of endothelial cells; however, standard equilibrium cell detachment studies are poorly suited for assessing these initial adhesion events. Here, a dynamic seeding and cell retention method was used to examine the initial attachment of perfusing human umbilical vein endothelial cells (HUVECs) to bare Teflon-AF substrates, substrates pre-adsorbed with fibronectin alone, or substrates co-pre-adsorbed with two dual-function cell-adhesion ligands: biotinylated fibronectin (bFN) and RGD-streptavidin mutant (RGD-SA). Cell attachment was evaluated as a function of cell trypsinization (integrin digestion), surface protein formulation, and cell perfusion rate. Surfaces co-pre-adsorbed with bFN and RGD-SA showed the highest density of attached cells after 8 min of perfusion and the highest percent retention when subjected to shear flow at 60 dynes/cm2 for 2 min. Surfaces with no ligand treatment showed the lowest cell attachment and retention under flow in all cases. HUVECs trypsinized with mild 0.025% trypsin/ethylenediaminetetraacetic acid (EDTA) showed greater cell adhesion after perfusion and higher percent retention after shear flow than those trypsinized using harsher 0.05% trypsin/EDTA. The preferential affinities of the two dual-function ligands for alpha5beta1 and alphavbeta3 integrins were also examined by surface plasmon resonance (SPR) spectroscopy. The dynamic cell seeding studies confirmed that the dual-function ligand system promotes HUVEC adhesion and retention at short time points when tested using a perfusion assay. SPR studies showed that the two ligands exhibited equal affinity for both alpha5beta1 and alphavbeta3 integrins but that the combined ligands bound more total integrins than the two ligands tested separately.
Asunto(s)
Antineoplásicos/farmacología , Biotina/farmacología , Células Endoteliales/metabolismo , Fibronectinas/farmacología , Oligopéptidos/farmacología , Estreptavidina/farmacología , Venas Umbilicales/metabolismo , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/citología , Humanos , Ligandos , Politetrafluoroetileno/química , Venas Umbilicales/citologíaRESUMEN
The field of biomaterials has begun to focus upon materials strategies for modulating the immune response. While certain approaches appear promising, they are currently limited to isolated facets of inflammation process. It is well documented that both bacteria and viruses have highly developed methods for evading the immune system, providing inspiration for a more biomimetic approach to materials design. This review presents the immune evasive tactics employed by viruses and bacteria, and offers suggestions for future directions that apply these principles to design of immune evasive biomaterials.