Cell And Molecular Tissue Engineering LLC — Department of Health and Human Services SBIR Phase I: NIDDK

Description

An overarching factor in the development of any successfulartificial pancreassystem is the advancement of a highly accurate and long lived glucose sensorwithout the need for numerous recalibrationsFrequentlyimplantable glucose sensors demonstrate insufficient reliability with respect to performanceaccuracy and response timewhich is thought to be the result of poor biocompatibilityCentral to these complications is the failure of these sensors to successfully integrate into surrounding tissueIn factone of the major paradigms of modern glucose sensor technology is thatif the sensor is not biocompatibleit will not lastGenerallypoor sensor performance has been attributed to the triad of inflammationfibrosisand vessel regressionsensor induced tissue reactionsSITRThis failure is the result of initial chronic inflammationtissue destructionand intense scarring induced by the sensori esensor induced tissue reactionsThis class of implant induced tissue reactions is referred to as foreign body reactionsFBRThese FBRs are driven by activated pro inflammatory macrophagesM MQThussuppressing Mmacrophage function is key to overcoming SITR FBR and the associated complicationsPreventing the early onset of FBR is central to promoting successful integration of sensor into tissuei eingrowth of fibro vascular tissuerather than intense scaring resulting in a wide range of complicationsPrevious efforts to overcome SITR have generally focused on the usage of synthetic polymer coatingsdrugsbut with limited successIn additiona variety of sensor coatingsboth synthetic and biologic in naturehave been usedbut with limited successIn the present applicationwe propose to develop and validate a new generation of biologically active exosome based sensor coatings that will suppress macrophage function and thereby prevent sensor induced FBRinflammation and fibrosisin so doingenhancing successful sensor integration into surrounding tissueTo achieve this goalwe propose to utilize microvesiclesi eexosomesfrom anti inflammatory cellse gregulatory T cellsTregThese exosomes will be incorporated into basement membrane matricesand utilized as bioactive sensor coatingswhich will suppress sensor induced inflammationfibrosisas well as promote tissue regeneration at sensor implantation sitesIf these bioactive exosome based coatingsi eExo Matricesare successful in suppressing macrophage activation and enhancing sensor integration in vivoin the futurePhaseSBIRthese exosomes will be analyzed forcargocompositione gRNADNA and proteinPrevious studies of exosome cargo have demonstrated that the microRNAs in microvesicles exosomes are powerfulcell re programmersand synthetic miRNAs are being developed into cutting edge therapiesUsing this informationin the futurewe will developdesigner exosomesusing genetically engineered exosomes from antiinflammatory andamppro wound healing cellsultimately leading to the development ofsynthetic exosomesfor uses in Exo MatricesWe anticipate the miRNAs will likely be the key exosome cargo component that will suppress macrophage function during SITR FBRand will be the foundation for future artificial synthetic exosomeswhich will be used in our Exo Matrices coatings of sensors!Narrative The present application focuses on the development of a new generation of glucose sensor coatings that have the ability to control tissue bio reactions induced by implantable glucose sensorsThese matrices are comprised of exosomes isolated from anti inflammatory cellsRegulatory T cellswhich are added to our existing glucose sensor coatingsdesignated as Exo Matricesand used to suppress inflammatory reactions induced by the sensor in vivoWe hypothesize that the antiinflammatory effect of these Exo Matrices will improve sensor accuracy and lifespan in vivo