The successful translation of tissue engineering therapies into clinical application that will benefit veterans requires overcoming a number of technical, biological and surgical challenges. The volume of tissue that can be engineered is limited by the extent to which stable blood vessels can be stimulated to form. An extensive, stable blood supply is required to meet mass transport demands in the new tissues and most methods are optimized for engineering tissues in small volume pre-clinical models. We have shown that implantation of a chamber containing model tissue engineering therapies against the periosteum can lead to the generation of three-dimensional vascularized bone of clinically appropriate shape and volume.4 This technique has been translated into clinical application but required an autologous source of bone for the chamber components. Broad application of this approach requires the identification of alternative, non- autologous tissue sources. Tissue engineering has the potential to provide alternative sources for chamber components. In our previous MERIT grant we investigated and optimized the design of porous hydrogel scaffolds for vascularized tissue formation. In the previous cycle we developed techniques for polymer synthesis and design, evaluated vascularization and cellular response to these biomaterial scaffolds in vitro, in vivo, and in silico, and investigated new imaging techniques for the evaluation of tissue engineering strategies. These studies illustrate our ability to promote and influence vascular ingrowth into engineered tissues. Challenges remain in regards to achieving vascular ingrowth sufficient for engineering large volumes of bone, coordinating vascularization and bone formation and engineering complex structures suitable for clinical application. The broad goals of this proposal are to 1) investigate and optimize the design of biosignal-embedded poly(ethylene glycol)-based hydrogels for engineering vascularized bone and 2) apply these materials for engineering vascularized bone for reconstruction of large, complex craniofacial defects. In order to achieve our goals we will complete the following specific aims: Objective 1: Investigate and optimize the generation of gradients scaffolds for stimulating vascularized tissue invasion into porous hydrogels. Objective 2: Investigate porous hydrogel systems for coordination of vascularization and bone formation in porous hydrogels in vitro and in vivo. Objective 3: Develop topological optimization methods for applying the clinically-translatable large animal model to engineer vascularized bone of appropriate volume and structure for clinical application. This is an ambitious proposal focused on the optimization of techniques that will bring new reconstructive techniques closer to the clinic.

Public Health Relevance

Since World War II, improvements in battlefield armor and medicine has resulted in significantly enhanced survival following battlefield trauma to the head and neck region. When combined with the increased in blast injury resulting from improvised explosive devices (IEDs) in current conflicts (Operation Enduring Freedom (OEF) / Operation Iraqi Freedom (OIF)), more veterans are requiring the complex and multi-stage procedures required for craniofacial reconstruction. Traumatic craniofacial wounds present some of the greatest challenges to reconstructive surgeons. Engineering living bone replacements in shapes and volumes relevant to clinical application would have a significant impact on veterans' populations.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000418-05
Application #
8814103
Study Section
Surgery (SURG)
Project Start
2009-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Edward Hines Jr VA Hospital
Department
Type
DUNS #
067445429
City
Hines
State
IL
Country
United States
Zip Code
60141
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Zivkovic, Lada; Akar, Banu; Roux, Brianna M et al. (2017) Investigation of DNA damage in cells exposed to poly (lactic-co-glycolic acid) microspheres. J Biomed Mater Res A 105:284-291
Somo, Sami I; Khanna, Omaditya; Brey, Eric M (2017) Alginate Microbeads for Cell and Protein Delivery. Methods Mol Biol 1479:217-224
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Appel, Alyssa A; Ibarra, Veronica; Somo, Sami I et al. (2016) Imaging of Hydrogel Microsphere Structure and Foreign Body Response Based on Endogenous X-Ray Phase Contrast. Tissue Eng Part C Methods 22:1038-1048
Ibarra, Veronica; Appel, Alyssa A; Anastasio, Mark A et al. (2016) This paper is a winner in the Undergraduate category for the SFB awards: Evaluation of the tissue response to alginate encapsulated islets in an omentum pouch model. J Biomed Mater Res A 104:1581-90
Appel, Alyssa A; Larson, Jeffery C; Jiang, Bin et al. (2016) X-ray Phase Contrast Allows Three Dimensional, Quantitative Imaging of Hydrogel Implants. Ann Biomed Eng 44:773-81
Köllmer, Melanie; Appel, Alyssa A; Somo, Sami I et al. (2015) Long-Term Function of Alginate-Encapsulated Islets. Tissue Eng Part B Rev :

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