Engineering Immunological Functions with Biomaterials

Synthetic materials such as biodegradable polymeric particles and hydrogels have revolutionized the traditional fields of drug delivery and biopharmaceuticals. Yet, application of these new materials and engineering techniques remain largely unexplored in immunological studies. My research goal is to develop synthetic biomaterials that can regulate immunological functions and use this system to design new vaccines and immunotherapies. During this presentation, I will highlight my past research efforts in drug delivery, polymer synthesis, immunology, and cellular and tissue engineering, and I will discuss how these engineering technologies will be applied to augment immunological functions for development of novel medical treatments, including vaccines against infectious diseases and immunotherapies for cancers.

As currently licensed vaccine adjuvants are inadequate in eliciting protective immunity against cancer or intracellular pathogens such as malaria or HIV, there is a great interest in new vaccine technologies that can potently activate humoral and cellular immune responses.  Toward this goal, I have developed a novel synthetic vaccine platform based on interbilayer-crosslinked multilamellar vesicles (ICMVs) and demonstrated their efficacy in a malaria model. ICMVs were formed by fusing liposomes into multilamellar vesicles and subsequent crosslinking of adjacent lipid headgroups across lipid bilayers within multilamellar vesicles. These particles exhibited substantially enhanced protein antigen loading and extended drug release kinetics compared with traditional drug delivery vehicles (e.g. liposomes and polymeric particles). Crosslinking of lipid bilayers enhanced stability of particles in serum, allowing efficient delivery of cargo antigens to antigen-presenting cells. ICMVs encapsulating model antigen ovalbumin and FDA-approved adjuvant elicited potent antibody and CD8+ T cell responses in vivo, comparable to those for strong viral vector vaccines. With the goal of translating these results to an infectious disease, the potency of ICMVs was examined in a malaria model. ICMVs carrying a malaria antigen and adjuvant elicited robust humoral immune responses with high-avidity antibody titers lasting more than a year. Particle immunization also led to prominent germinal center formation in lymph nodes, accompanied with increased, partially explaining the long-lasting and high-avidity antibody titers elicited by particle immunizations. These results highlight the potential of synthetic vaccines based on biomaterials in vaccinations against infectious diseases.

In addition to particulate systems, scaffolds and hydrogels are another mode of drug delivery for biological pharmaceuticals. During my graduate work, I developed synthetic, biomimetic hydrogels, designed to undergo protease-mediated degradation. Unlike protein-based extracellular matrix gels isolated from natural sources, synthetic gels based on polymers can be precisely designed/modified to change their biophysical and biochemical properties for manipulation of drug release kinetics and cellular behaviors. With the main goal of inducing and sustaining therapeutic angiogenesis for wound healing and tissue engineering applications, rational design of hydrogels were pursued: changes in polymer structures, photolithographic micropatterning of biological drugs within hydrogels, and co-culture system with stem cells led to fabrication of hydrogels that were robustly vascularized with newly formed blood vessels integrated with hosts' vasculature in vivo.

References

1.        Moon JJ, Suh H, Bershteyn A, Stephan MT, Liu H, Huang B, Sohail M, Luo S, Um SH, Chiu W, and Irvine DJ. Interbilayer-crosslinked multilamellar vesicles for potent humoral and cellular immune responses, 10, 243-251, 2011, Nature Materials.             

- Featured by Nature Materials: News and Views, 10, 166-68, 2011, and Nature Biotech: Research Highlights, 29, 330, 2011.

2.        Stephan MT, Moon JJ, Um SH, Bershteyn A, and Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles, 16, 1035-41, 2010, Nature Medicine.

3.        Moon JJ, Suh H, Luo S, Yadava A, and Irvine DJ. Induction and maintenance of robust immune responses against Plasmodium vivax malaria using interbilayer-crosslinked multilamellar vesicles. (In preparation).

4.        Moon JJ, Suh H, Yadava A, and Irvine DJ. Vaccination with polymeric nanoparticles vaccines incorporating toll-like receptor agonists generates potent immune responses against Plasmodium viva malaria. (In preparation).

5.        Moon JJ, Saik JE, Poche RA, Leslie-Barbick JE, Lee SH, Smith AA, Dickinson ME, and West JL. Biomimetic hydrogels with pro-angiogenic properties, 31, 3840-3847, 2010, Biomaterials.

6.        Moon JJ, Hahn MS, Kim I, Nsiah BA, and West JL. Micropatterning of poly(ethylene glycol) diacrylate hydrogels with biomolecules to regulate and guide endothelial morphogenesis, 15, 579-585, 2009, Tissue Engineering.

7.        Hu Y, Atukorale PU, Lu JJ, Moon JJ, Um SH, Cho EC, Wang Y, Chen J, and Irvine DJ. Cytosolic delivery mediated via electrostatic surface binding of protein, virus, or siRNA cargos to pH-responsive core-shell gel particles, 10, 756-765, 2009, Biomacromolecules.

8.        Leslie-Barbick JE, Moon JJ, and West JL. Covalently-Immobilized Vascular Endothelial Growth Factor Promotes Endothelial Cell Tubulogenesis in Poly(ethylene glycol) Diacrylate Hydrogels, 20, 1763-1779, 2009, Journal of Biomaterials Science.

9.        Moon JJ, and West JL. Vascularization of engineered tissues: approaches to promote angiogenesis in biomaterials, 8, 300-310, 2008, Current Topics in Medicinal Chemistry.

10.    Lee SH*, Moon JJ*, and West JL. Three-dimensional micropatterning of bioactive hydrogels via two-photon laser scanning photolithography for guided 3D cell migration, 29, 2962-2968, 2008, Biomaterials.

11.    Gobin AM*, Moon JJ*, and West JL. EphrinA I-targeted nanoshells for photothermal ablation of prostate cancer cells, 3, 351-358, 2008, International Journal of Nanomedicine.

12.    Moon JJ, Lee SH, and West JL. Synthetic biomimetic hydrogels incorporated with ephrin-A1 for therapeutic angiogenesis, 8, 42-49, 2007, Biomacromolecules.

13.    Lee SH, Moon JJ, Miller JS, and West JL. Poly(ethylene glycol) hydrogels conjugated with a collagenase-sensitive fluorogenic substrate to visualize collagenase activity during three-dimensional cell migration, 28, 3163-3170, 2007, Biomaterials.

14.    Hahn MS, Taite LJ, Moon JJ, Rowland MC, Ruffino KA, and West JL. Photolithographic patterning of polyethylene glycol hydrogels, 27, 2519-2524, 2006, Biomaterials.

15.    Lee P, Lin R, Moon J, and Lee LP. Microfluidic alignment of collagen fibers for in vitro cell culture, 8, 35-41, 2006, Biomedical Microdevices.

16.    DeLong SA, Moon JJ, and West JL. Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration, 26, 3227-3234, 2005, Biomaterials.

17.    Lee SH, Miller JS, Moon JJ, and West JL. Proteolytically degradable hydrogels with a fluorogenic substrate for studies of cellular proteolytic activity and migration, 21, 1736-1741, 2005, Biotechnol Progr.

18.    Moon JJ, Matsumoto M, Patel S, Lee L, Guan JL, and Li S. Role of cell surface heparan sulfate proteoglycans in endothelial cell migration and mechanotransduction, 203, 166-176, 2005, J Cell Physiol. (selected as a cover)

19.    Li S, Moon JJ, Miao H, Jin G, Chen BP, Yuan S, Hu Y, Usami S, and Chien S. Signal transduction in matrix contraction and the migration of vascular smooth muscle cells in three-dimensional matrix, 40, 378-388, 2003, J. Vasc Res.

                                                          *Authors contributed equally