(3da) 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