High throughout technologies has already significantly revolutionized fields such as genomics, proteomics, and drug discovery and formulation. This technology can similarly revolutionize the development of biomaterials for tissue engineering applications. A fundamental component of this proposal is to apply and advance our fully automated, high throughput discovery methods to push hESC tissue engineering closer towards clinical applications. Two key remaining limitations of existing hESC and iPSC methods are 1) the low efficiency and long time associated with stem cell differentiation into functional cell types such as chondrocytes and osteoblasts, and 2) suboptimal performance (e.g. mechanical properties, biocompatibility) of existing degradable materials used for tissue engineering. As such, we propose to develop both high throughput strategies to rapidly optimize the production of homogenous populations of key cell populations and degradable biomaterials that provide for improved cellular performance and low inflammation. Accordingly our specific aims are:
Aim1. Develop efficient, rapid methods to differentiate human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into homogenous populations of craniofacial cells. We will use high-throughput approaches on hESC and iPSC cells to identify the optimal combinations of soluble (growth factor and small molecules), and insoluble factors (synthetic polymer surfaces) capable of committing ES cells to craniofacial precursor cells and fully committed osteogenic and chondrogenic cells.
Aim 2 : Develop biodegradable, non-inflammatory and mechanically appropriate 3D scaffold systems that can effectively deliver craniofacial cells to the site of injury. High-throughput libraries of hyaluronic acid (cartilage) and poly(2-amino ester) (bone) polymers will be synthesized and assessed for ability to form gels or solid porous scaffolds, respectively. Favorable materials will then be evaluated for either chondrocyte or bone cell compatibility.
Aim 3 : Assess performance of tissue engineered constructs developed in Aim 1 and 2 to generate cartilage and bone in vivo. Small animal model will be used to test osteogenesis in a cranial critical sized defect, while chondrogenesis will be evaluated subcutaneously.
We believe that this technology can similarly revolutionize the development of biomaterials for tissue engineering applications. A fundamental component of this proposal is to apply and advance our fully automated, high throughput discovery methods to push hESC and iPSC tissue engineering closer towards craniofacial clinical applications.
|Dong, Yizhou; Dorkin, J Robert; Wang, Weiheng et al. (2016) Poly(glycoamidoamine) Brushes Formulated Nanomaterials for Systemic siRNA and mRNA Delivery in Vivo. Nano Lett 16:842-8|
|Yin, Hao; Bogorad, Roman L; Barnes, Carmen et al. (2016) RNAi-nanoparticulate manipulation of gene expression as a new functional genomics tool in the liver. J Hepatol 64:899-907|
|Luo, X; Wang, W; Dorkin, J R et al. (2016) Poly(glycoamidoamine) brush nanomaterials for systemic siRNA delivery in vivo. Biomater Sci 5:38-40|
|Appel, Eric A; Tibbitt, Mark W; Webber, Matthew J et al. (2015) Self-assembled hydrogels utilizing polymer-nanoparticle interactions. Nat Commun 6:6295|
|White, Kevin; Lu, Yu; Annis, Sofia et al. (2015) Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med 7:695-713|
|Sydlik, Stefanie A; Jhunjhunwala, Siddharth; Webber, Matthew J et al. (2015) In vivo compatibility of graphene oxide with differing oxidation states. ACS Nano 9:3866-74|
|Appel, Eric A; Larson, Benjamin L; Luly, Kathryn M et al. (2015) Non-cell-adhesive substrates for printing of arrayed biomaterials. Adv Healthc Mater 4:501-5|
|Jhunjhunwala, Siddharth; Aresta-DaSilva, Stephanie; Tang, Katherine et al. (2015) Neutrophil Responses to Sterile Implant Materials. PLoS One 10:e0137550|
|Patel, Asha K; Celiz, Adam D; Rajamohan, Divya et al. (2015) A defined synthetic substrate for serum-free culture of human stem cell derived cardiomyocytes with improved functional maturity identified using combinatorial materials microarrays. Biomaterials 61:257-65|
|Bogorad, Roman L; Yin, Hao; Zeigerer, Anja et al. (2014) Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice. Nat Commun 5:3869|
Showing the most recent 10 out of 70 publications