Thesis
Drug delivery for bone tissue engineering mediated by three-dimensional biomimetic scaffolds
University of Iowa
Master of Science (MS), University of Iowa
Spring 2023
DOI: 10.25820/etd.007295
Abstract
Critical-sized bone defects remain an unmet clinical challenge due to the shortcomings of current treatments. Autologous bone grafts are considered the gold standard treatment for bone regeneration of critical-sized defects; yet they are associated with many complications and limitations related to bone harvesting, such as donor site morbidity, high cost, and limited availability. Biomaterial-based tissue engineering strategies offer a promising alternative to autologous bone grafts. However, a challenge arises when attempting to effectively deliver bioactive factors(drugs)/cells from three-dimensional (3D) tissue engineering scaffolds. To address this challenge, I have developed two kinds of biomimetic scaffolds based on natural and synthetic polymers with distinct drug delivery techniques. 3D printing is emerging as a promising scaffold fabrication tool due to its low cost, high degree of customization, and standardization. However, conventional 3D printing is unable to fabricate nanosized structures and also has severely limited bioactive factors/cells delivery capabilities. My first strategy utilizes nanomaterials to functionalize 3D printed polycaprolactone (PCL) scaffolds by incorporating localized drug delivery and a nanofibrous structure. While PCL is an FDA approved synthetic polymer for bone repair, its hydrophobic and bioinert nature necessitate modifications. Polydopamine (PDA), a natural mussel inspired polymer, can coat the pre-modified (neat) PCL scaffolds to increase collagen binding. Collagen provides the nanofibrous structure present in bone’s extra cellular matrix (ECM) that enhances cell attachment. Finally, nanoclay is incorporated into the collagen gel for prolonged and sustained drug delivery. Nanoclay is a nanomaterial with drug binding capabilities due to its unique 2D structure and charged surfaces. By combining these materials to create a drug delivery system and an osteoconductive environment, I developed a scaffold primed for bone regeneration.
Gelatin, a natural polymer formed from denatured collagen, serves as the basis for fabricating 3D gelatin nanofibrous scaffolds (GF). This scaffold possesses a unique nanofibrous and interconnected macroporous structure created through the thermally induced phase separation and porogen leaching (TIPS+P) method. Although its collagen-mimicking nanofibrous structure is appealing for osteogenesis, its limited drug-binding capacity impedes its success in bone regeneration. Heparin, a naturally occurring glycosaminoglycan, can facilitate sustained release of growth factors mainly through its strong negative charge. However, heparin’s capacity to facilitate drug release by functionalizing GF scaffolds is less studied. I hypothesized heparin will be able to control drug release from the GFH scaffold and subsequently increase bone regeneration. Therefore, the GF scaffold is further modified through chemically crosslinking it with heparin (GFH). To investigate the potential of the GFH scaffold, I tested the effects of heparin-conjugation on the physical structure and bioactivity of the scaffold in addition to the binding and release of bone morphogenetic protein 2 (BMP2).
Similar methods were used to investigate both scaffolds’ structure, drug delivery abilities, and osteogenic potential. Scanning electron, fluorescent and confocal microscopy imaged the morphology of the scaffolds as well as their interaction with pre-osteoblast MC3T3-E1 cells. The in vitro results with MC3T3-E1 cells supported the ability of the scaffolds to increase the activity of osteogenic differentiation marker alkaline phosphatase (ALP) and improve matrix mineralization. The findings presented in this study provide strong evidence that nanoclay and heparin enabled drug binding/sustained release are effective and versatile techniques for distinct 3D scaffolds with promising potential for tissue engineering applications.
Details
- Title: Subtitle
- Drug delivery for bone tissue engineering mediated by three-dimensional biomimetic scaffolds
- Creators
- Jessica Faber
- Contributors
- Hongli Sun (Advisor)Edward Sander (Committee Member)Kristan Worthington (Committee Member)Huojun Cao (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Biomedical Engineering
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007295
- Publisher
- University of Iowa
- Number of pages
- x, 74 pages
- Copyright
- Copyright 2023 Jessica Faber
- Language
- English
- Date submitted
- 04/19/2023
- Date approved
- 06/30/2023
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 61-71).
- Public Abstract (ETD)
When bone injury surpasses a critical size, it is unable to heal without medical treatment. Bone grafts harvested from the patient's pelvic bone are currently considered the top treatment; however, they often are accompanied by complications or limitations due to bone harvesting. Biomaterial-based tissue engineering is emerging as a potential alternative, but these materials often are unable to deliver the bioactive factors (drugs) or cells necessary for bone regeneration. This thesis investigates two unique 3D scaffolds that integrate drug delivery techniques into their biomimetic structure for increased bone regeneration.
The first scaffold is a modified 3D printed scaffold that incorporated nanoclay, a nanomaterial, to facilitate drug delivery through its unique 2D structure and charged surfaces. While the 3D printed polycaprolactone (PCL) scaffolds are low cost and biocompatible, they lack bone regeneration capacity. Therefore, natural polymers collagen and polydopamine were incorporated to fabricate a biomimicking structure. The second scaffold coupled heparin to gelatin to create a porous and nanofibrous biomimetic structure. Heparin is a natural molecule with strong drug-binding potential. Similar methods were used to investigate the structure, drug delivery, and osteogenic potential of the two scaffolds. Various forms of microscopy were used to assess the morphology and cell integration abilities of the scaffolds. Bone formation potential was evaluated using in vitro cell culture. The results indicated that both drug delivery methods have high bone regeneration potential. In future studies, an in vivo cranial defect mouse model could be used to further validate these drug delivery techniques.
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
- Record Identifier
- 9984425314902771
Metrics
10 Record Views