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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Gene and Drug Delivery Systems Study Section (GDD)
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Lapham, Cheryl K
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University of Florida
Biomedical Engineering
Schools of Engineering
United States
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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