The long term objective of this research is to develop tissue engineering strategies for the understanding and treatment of craniofacial abnormalities. This proposal is both hypothesis and design driven. We will investigate tissue development of cells from mouse models of the craniofacial abnormality Apert syndrome. We hypothesize that mutant cells from the FGFR2 knock-in Apert mouse model developed by the co-Pi will develop tissue and respond to growth factors in a significantly different manner compared to normal cells when grown in monolayer or in three dimensional (3D) hydrogel scaffolds. Furthermore, we hypothesize that when the normal and mutant cells are cocultured in multilayered hydrogel scaffolds, proliferation, tissue development, and growth factor response will change. The design driven portion of the proposal will develop a clinically practical strategy for repair of craniofacial defects, in iatrogenic defects and in the disease mouse model, using cell encapsulation technologies developed by the lab. To test these hypotheses and design the repair system the following specific aims will be investigated:
Specific aim 1. Investigate cell behavior and tissue development of cells isolated from FGFR2 knock-in mouse model of Apert Syndrome. Specifically this aim will address 1.) chondrogenesis and osteogenesis of cells from a Fgfr2+/S252W mouse model of Apert Syndrome, compared to cells from normal siblings and an immortalized, clonal mouse mesenchymal stem cell line. Cells from a.) the long bone and b.) the cranium will be evaluated in 2D monolayer and 3D hydrogel scaffolds in vitro.
Specific aim 2. Investigate cell behavior and tissue development of mutant and normal cells in response to growth factors and co-culture. Specifically this aim will address 1.) response of mutant and normal cells to musculoskeletal-related growth factors in 2D and 3D hydrogel culture, and 2.) apply a novel 3D bilayered hydrogel system to coculture normal and mutant cells to determine the effects of coculture on cell behavior and tissue development of normal and mutant cells.
Specific aim 3. Determine in vivo function of mutant and normal cells in craniofacial models. Specifically, tissue development in 1.) iatrogenic mouse cranial defects and 2.) congenital defects in Apert Syndrome will be evaluated using cells embedded in hydrogels. Normal and mutant mouse cell lines will be used in addition to a clonally-derived mouse mesenchymal stem cell line. Tissue development will be assessed by radiographic and histological analyses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016887-04
Application #
7652360
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$381,324
Indirect Cost
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Reid, Branden; Gibson, Matthew; Singh, Anirudha et al. (2015) PEG hydrogel degradation and the role of the surrounding tissue environment. J Tissue Eng Regen Med 9:315-8
Kochhar, Amit; Wu, Iwen; Mohan, Raja et al. (2014) A comparison of the rheologic properties of an adipose-derived extracellular matrix biomaterial, lipoaspirate, calcium hydroxylapatite, and cross-linked hyaluronic acid. JAMA Facial Plast Surg 16:405-9
Hwang, Nathaniel S; Varghese, Shyni; Lee, H Janice et al. (2013) Biomaterials directed in vivo osteogenic differentiation of mesenchymal cells derived from human embryonic stem cells. Tissue Eng Part A 19:1723-32
Beck, Jennifer N; Singh, Anirudha; Rothenberg, Ashley R et al. (2013) The independent roles of mechanical, structural and adhesion characteristics of 3D hydrogels on the regulation of cancer invasion and dissemination. Biomaterials 34:9486-95
Reid, Branden; Afzal, Junaid M; McCartney, Annemarie M et al. (2013) Enhanced tissue production through redox control in stem cell-laden hydrogels. Tissue Eng Part A 19:2014-23
Zhan, Jianan; Singh, Anirudha; Zhang, Zhe et al. (2012) Multifunctional aliphatic polyester nanofibers for tissue engineering. Biomatter 2:202-12
Wu, Iwen; Nahas, Zayna; Kimmerling, Kelly A et al. (2012) An injectable adipose matrix for soft-tissue reconstruction. Plast Reconstr Surg 129:1247-57
Li, Hanwei; Feng, Felicia; Bingham 3rd, Clifton O et al. (2012) Matrix metalloproteinases and inhibitors in cartilage tissue engineering. J Tissue Eng Regen Med 6:144-54
Hwang, Nathaniel S; Varghese, Shyni; Li, Hanwei et al. (2011) Regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells in PEG-ECM hydrogels. Cell Tissue Res 344:499-509
Strehin, Iossif; Nahas, Zayna; Arora, Karun et al. (2010) A versatile pH sensitive chondroitin sulfate-PEG tissue adhesive and hydrogel. Biomaterials 31:2788-97

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