Event
PhD Dissertation - Eman Mirdamadi
Monday, April 7, 2025
1:00 p.m.
AJC 5104 (5th floor conference room)
Rachel Chang
301 405 8268
rachel53@umd.edu
Title: Engineering Biologically Inspired Tissue Hybrids Towards Treating Patient And Defect-Site-Specific Bone Defects
Committee members:
Dr. Tao Lowe, Chair
Dr. John Fisher
Dr. Kimberly Stroka
Dr. Masahiro Iwamoto
Dr. Isabel Lloyd, Dean's Representative
Abstract:
There are over 150 million new bone fractures globally each year with treatments projecting to cost 17 billion USD by 2030 as the population is aging. While bone is a highly vascularized tissue capable of self-healing, many bone defects take months to heal, leading to an overall decreased quality of life. In addition, there are other bone defects incapable of self-healing all together, which are termed critical sized bone defects (CSBDs) which require highly invasive surgical treatment. To treat bone defects, bone grafts are commonly used during defect reconstruction but are either scarce or lack the essential growth factors and shaping capabilities for mature bone formation. To enhance endogenous bone healing, growth factors can be delivered locally to a defect site. However, their short half-lives and high costs make these compounds challenging to deliver to induce a therapeutic response without the risk of side-effects. To address these current challenges, bone tissue engineering and drug delivery hybrid strategies seek to design a safe and efficacious regenerative bone implant that provides in situ osteoconduction, osteoinduction, and osseointergration. However, many of these novel solutions require sophisticated methods and materials to manufacture, making such bone implants infeasible to translate clinically and to scale. Therefore, there is an unmet need to develop a hybrid engineered bone implant and nanotechnology solution utilizing mainly clinically acceptable materials and facile fabrication methods to achieve a translational solution for bone defect regeneration. To this end, the objective of this dissertation is to 3D-print polycaprolactone-allograft (PCL-ALLO) constructs coated with bone morphogenetic protein-2 (BMP-2)-loaded nanogels (BNGs) to regenerate bone defects. BMP-2 was loaded into nanogels composed of poly(N-isopropylacrylamide)-dextran-poly(lactate-2-hydroxyethyl-methacrylate) by UV-emulsion polymerization. The presented fabrication strategy, using a commercial fused deposition modeling (FDM) printer can produce bone constructs with interconnected pores ranging from 250-750 µm while encapsulating up to 30 wt % allograft. Despite allograft encapsulation, the PCL-allograft (PCL-ALLO) hybrid are mechanically stiff like native bone. In addition, the constructs and nanogels are biocompatible while the constructs can enable strong nanogel localization and adherence. BMP-2 released from nanogels remained bioactive and sustained its release for over 2 months. Additionally, 30 wt% ALLO in the composite constructs demonstrated enhancements of nanogel adhesion by 180%, and dental pulp stem cell (DPSC) metabolic activity by 30% after a week in culture compared to their PCL alone counterparts. The accumulated degraded byproducts of PCL-ALLO constructs, after 6 months, also demonstrated minimal cytotoxicity to DPSCs. By incorporating BNGs into PCL-ALLO constructs with 30 wt% ALLO, additive effects on early osteoblast conversion marker alkaline phosphatase (ALP) were apparent in various osteogenic inducing cell lines including Mouse preosteoblasts (MC3T3s) and human derived mesenchymal stem cells (hMSCs) as early as 7 days. Finally, allograft and BMP-2-loaded nanogels played important roles in increasing construct cellular penetration and mineralization in rodent heterotopic and critical-sized calvarial defect models. Completion of the project will have a significant impact on creating clinically translatable bone implants for patient-specific and defect-specific bone regeneration.
