This work represents a biomaterials-based biomedical engineering research program integrated with immunology directed toward tolerance. Specifically, this project focuses on the engineering of technologies to provide personalized high-throughput screening of immune cell response to microparticle-based vaccines, using a limited number of cells. Microparticle-based vaccine systems can, in vivo, deliver antigen and relevant immuno- modulatory factors to targeted phagocytic cell population, specifically, dendritic cells, a key immune regulator. Typical assessment of a tolerance-inducing vaccine relies on testing one formulation at a time, hoping to uncover a single factor capable of generating long-lived immune tolerance. However, multiple critical signals are likely to combine to promote robust, enduring antigen-specific tolerance. A lack of understanding of the interactions between different immunomodulatory factors, and the lack of an efficient means to test large numbers of combinations of factors represents a significant blockade for the development of new vaccine technologies. In order to overcome this barrier, we are developing a high-throughput cell-based microarray approach for the testing of microparticles incorporating multiple components targeted to dendritic cells, a key antigen presenting cell type. Our preliminary data indicates that the unique high- throughput in vitro platform we are developing is feasible, and that in vitro screening of microparticle formulations can be useful for suggesting in vivo responses to injected microparticles. Our long-term test-bed application is the prevention of type-1 diabetes in a diabetic mouse model by injection of microparticles. We are optimizing multi- component particle formulations to direct DCs toward a tolerogenic phenotype and the induction of regulatory T-cells for antigen-specific immune suppression. Our miniaturized technology requires only small numbers of cells, taking steps toward the development of personalized vaccines.
We are rapidly in vitro assessing and optimizing antigen-delivering, immuno-modulatory microparticles as an injectable microparticle-based vaccine, intended for targeted uptake in vivo by dendritic cells for future studies for the treatment of type 1 diabetes. Our in vitro system consists of fabricating cell-based microarrays of immune cells for high-throughput screening of microparticle formulations, and formulations will be assessed for their ability to generate immune cell phenotypes which have been linked to the induction of antigen-specific tolerance. This miniaturized approach uses only a small number of cells, and moves toward the development of personalized vaccines, which may be screened for a patient's specific immune cell response.
|Fernando, Lawrence P; Lewis, Jamal S; Evans, Brian C et al. (2018) Formulation and characterization of poly(propylacrylic acid)/poly(lactic-co-glycolic acid) blend microparticles for pH-dependent membrane disruption and cytosolic delivery. J Biomed Mater Res A 106:1022-1033|
|Yang, Lirong; Bracho-Sanchez, Evelyn; Fernando, Lawrence P et al. (2017) Poly(2-propylacrylic acid)/poly(lactic-co-glycolic acid) blend microparticles as a targeted antigen delivery system to direct either CD4+ or CD8+ T cell activation. Bioeng Transl Med 2:202-211|
|Acharya, Abhinav P; Carstens, Matthew R; Lewis, Jamal S et al. (2016) A cell-based microarray to investigate combinatorial effects of microparticle-encapsulated adjuvants on dendritic cell activation. J Mater Chem B 4:1672-1685|
|Yoon, Young Mee; Lewis, Jamal S; Carstens, Matthew R et al. (2015) A combination hydrogel microparticle-based vaccine prevents type 1 diabetes in non-obese diabetic mice. Sci Rep 5:13155|
|Lewis, Jamal S; Dolgova, Natalia V; Zhang, Ying et al. (2015) A combination dual-sized microparticle system modulates dendritic cells and prevents type 1 diabetes in prediabetic NOD mice. Clin Immunol 160:90-102|
|Carstens, Matthew R; Fisher, Robert C; Acharya, Abhinav P et al. (2015) Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells. Proc Natl Acad Sci U S A 112:8732-7|
|Han, Chul; Choe, Se-Woon; Kim, Yong Hwan et al. (2014) VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 17:823-830|
|Lewis, Jamal S; Roy, Krishnendu; Keselowsky, Benjamin G (2014) Materials that harness and modulate the immune system. MRS Bull 39:25-34|
|Lewis, Jamal S; Roche, Chris; Zhang, Ying et al. (2014) Combinatorial delivery of immunosuppressive factors to dendritic cells using dual-sized microspheres. J Mater Chem B 2:2562-2574|
|Acharya, Abhinav P; Lewis, Jamal S; Keselowsky, Benjamin G (2013) Combinatorial co-encapsulation of hydrophobic molecules in poly(lactide-co-glycolide) microparticles. Biomaterials 34:3422-30|