Often caused by trauma or tumor removal, large bone defects frequently result in delayed or non-union. The current gold standard for treatment is autograft. However, due to limitations, such as the size and location of the defect, these cannot always be utilized. A common alternative to autograft is the use of BMP-2 with a collagen scaffold, however, this treatment is limited by numerous side effects. In recent years, genetic materials such as microRNAs (miRNAs) have offered possible alternative therapies. MiRNAs are small non-coding RNA molecules that generally range from 20-24 nucleotides, serve as repressors of gene expression, and are involved in a wide range of biological activities. Their functions can be inhibited or upregulated by delivering antagomiRs or miRNA mimics, respectively. Two miRNAs involved in bone regeneration are of particular interest in this study, miR-26a and miR-133a. Previous studies demonstrated miR-26a is involved in osteoblastic differentiation and miR-133 is a negative regulator of Runx2, the key transcription factor of osteogenesis. Therefore, we hypothesized the delivery of miR-26a and antagomiR-133a will increase bone formation in critical-sized bone defects. The research outlined in this thesis investigates the healing efficacy of these genetic cargos delivered by novel peptide nanoparticles, RALA, soak loaded into a collagen-hydroxyapatite scaffold. vi To test this hypothesis, scaffolds soak-loaded with RALA/microRNA were implanted into calvarial defects in Wistar Rats. The defects were then left to heal for 8 weeks and were longitudinally monitored using micro-computed tomography (μCT). At 8 weeks, rats were euthanized and calvaria tissue was harvested for histological analysis. The μCT data demonstrates that the scaffolds with microRNAs show promise as a novel therapy for bone defects. The histological analysis showed the treatments promote healing by normal bone formation activity. While there was no statistical difference (p ≥ 0.11276) between groups for the healing variables, this is believed to be due to the small sample size and low power (60%). All of the miRNA treatment groups had samples with considerably higher healing responses than the gene-free group. In conclusion, the findings of this study support the use of this cell-free implant system as a potential novel clinical therapy, as an alternative to bone grafting, for treating large bone defects.
| Identifer | oai:union.ndltd.org:UMASS/oai:scholarworks.umass.edu:masters_theses_2-2205 |
| Date | 18 March 2022 |
| Creators | Ferreira, Cole J |
| Publisher | ScholarWorks@UMass Amherst |
| Source Sets | University of Massachusetts, Amherst |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Masters Theses |
| Rights | http://creativecommons.org/licenses/by/4.0/ |
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