Therapeutic strategies that can deliver bioactive signals at different times during tissue formation are essential for the regeneration of complex tissues such as a mature vasculature. During normal wound healing, the events that lead to mature blood vessel formation result from a series of tightly regulated events, which occur sequentially upon environmental changes. As a result, for the generation of mature and stable blood vessels more than one bioactive signal is needed and these signals are needed at different times. This proposal focuses on the design, synthesis and testing (in vitro and in vivo) of a non- viral gene delivery strategy that can deliver multiple DNA sequentially. In our approach, a two component, enzymatically degradable hydrogel composed of a micro porous (5-pore) slow degrading hydrogel and nano-porous (n-pore) fast degrading hydrogel will be used deliver encapsulated DNA nanoparticles at different times.
Aim 1 will explore the design and synthesize two component hydrogel scaffolds that can release DNA nanoparticles at two different rates in vitro and in vivo.
Aim 2 will explore the ability of the optimized two-component hydrogels to result in temporally controlled gene transfer in vitro and in vivo.
Aim 3 will explore the hypothesis that within the wound-healing environment our two-component hydrogel system can release the encapsulated pro-angiogenic polyplexes and growth factors at different rates and result in enhanced angiogenesis and subsequent wound healing.

Public Health Relevance

Angiogenesis, the formation of new blood vessels, represents a pressing clinical need for the treatment of ischemic wounds and is a major obstacle in the translation of tissue-engineered constructs. One major limitation in the generation of mature blood vessels is the inability to deliver therapeutic molecules at the necessary times. This proposal aims to design a gene delivery strategy that can deliver DNA (the therapeutic) at the required times for angiogenesis to take places by using hydrogel scaffolds that are degraded at different rates.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110592-02
Application #
8320041
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Skarlatos, Sonia
Project Start
2011-08-15
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$352,277
Indirect Cost
$102,277
Name
University of California Los Angeles
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zhu, Suwei; Segura, Tatiana (2016) Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis. Ann Biomed Eng 44:1983-92
Zhu, Suwei; Nih, Lina; Carmichael, S Thomas et al. (2015) Enzyme-Responsive Delivery of Multiple Proteins with Spatiotemporal Control. Adv Mater 27:3620-5
Lam, Jonathan; Carmichael, S Thomas; Lowry, William E et al. (2015) Hydrogel design of experiments methodology to optimize hydrogel for iPSC-NPC culture. Adv Healthc Mater 4:534-9
Siegman, Shayne; Truong, Norman F; Segura, Tatiana (2015) Encapsulation of PEGylated low-molecular-weight PEI polyplexes in hyaluronic acid hydrogels reduces aggregation. Acta Biomater 28:45-54
Tokatlian, Talar; Cam, Cynthia; Segura, Tatiana (2015) Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model. Adv Healthc Mater 4:1084-91
Griffin, Donald R; Weaver, Westbrook M; Scumpia, Philip O et al. (2015) Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat Mater 14:737-44
Cam, Cynthia; Zhu, Suwei; Truong, Norman F et al. (2015) Systematic evaluation of natural scaffolds in cutaneous wound healing. J Mater Chem B Mater Biol Med 3:7986-7992
Nowak-Sliwinska, Patrycja; Segura, Tatiana; Iruela-Arispe, M Luisa (2014) The chicken chorioallantoic membrane model in biology, medicine and bioengineering. Angiogenesis 17:779-804
Lam, Jonathan; Truong, Norman F; Segura, Tatiana (2014) Design of cell-matrix interactions in hyaluronic acid hydrogel scaffolds. Acta Biomater 10:1571-80
Cam, Cynthia; Segura, Tatiana (2014) Chemical sintering generates uniform porous hyaluronic acid hydrogels. Acta Biomater 10:205-13

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