Long term monitoring of oxygen concentrations at the level of biomedical implants, and optimizing its availability are key issues in diagnostics, tissue engineering and biotechnology. Recent advances in the use of EPR detectable, oxygen-sensitive probes with excellent sensitivity, accuracy and remote accessibility, opened a new era of opportunity for real-time monitoring of oxygenation in vivo. However, for many applications these probes need to be encapsulated behind a semi-permeable membrane. We developed a nanofilter-limited, implantable model device with dual EPR-based oxygen sensor and drug delivery capabilities, and we tested its capacity to track oxygenation in a tissue engineered construct containing bone marrow progenitor cells. Using a quantitative model of oxygen diffusion in the vicinity of implants, we also demonstrated that our oxygen sensor provides a proportional relationship between the reported local pO2 and microvascular density, supported by in situ observations at the end of the experiment. Furthermore, we synthesized a novel class of biomaterials, incorporating by electrospinning the EPR sensitive nano-crystals directly into a poly-caprolactone microfibrillar scaffold. Using EPR imaging, we showed the in vivo distribution of oxygen within this scaffold and found that the determined average pO2 was compatible with its subcutaneous location. In addition, we demonstrated the capacity of this scaffold to support proliferation and endothelial differentiation of bone marrow progenitor cells. Here we propose to further validate, improve the design and expand the applications of this device. This project will take into consideration, besides the development of the device and the logistics of its use, also the design of its interface with the tissue, with the goal to develop a tool for studying and optimizing implant oxygenation as dependent on nearby neovascularization.
Specific Aims : 1. Determine oxygenation within tissue engineering constructs as dependent on their vascularization. 2. Test the hypothesis that oxygenation within a filter-limited implant is sensitive to pharmacological modulation of nearby angiogenesis. 3. Demonstrate that stimulation of neovascularization in peri-implant space using tissue engineering methods could also improve implant oxygenation. The progress in the use of implanted oxygen probes will be readily translated into novel clinical applications such as monitoring available oxygen in tissue engineering constructs, with improved perfusion, optimized cell encapsulation, or better functioning of oxygen or glucose sensors.

Public Health Relevance

We propose to develop a method and an implantable device for minimally invasive, in vivo monitoring of local oxygen concentrations in biomedical implants. These will be useful for monitoring oxygenation in oxygen- dependent sensors, in encapsulated cells, in tissue engineering constructs, and for other branches of regenerative medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Lee, Albert
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Moldovan, Nicanor I; Anghelina, Mirela; Varadharaj, Saradhadevi et al. (2014) Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction. J Am Heart Assoc 3:e000471
Jain, Harsh Vardhan; Moldovan, Nicanor I; Byrne, Helen M (2012) Modeling stem/progenitor cell-induced neovascularization and oxygenation around solid implants. Tissue Eng Part C Methods 18:487-95
Guan, Jianjun; Wang, Feng; Li, Zhenqing et al. (2011) The stimulation of the cardiac differentiation of mesenchymal stem cells in tissue constructs that mimic myocardium structure and biomechanics. Biomaterials 32:5568-80