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Introduction: The management of long bone critical-size defects leading to nonunion remains a major clinical orthopaedic challenge. Mesenchymal stem cell (MSC)-based therapies are promising strategies for bone healing of critical-size defects. Preliminary studies suggested that implantation of Interleukin-4 (IL-4) overexpressing MSCs within a gelatin microribbon (µRB) scaffold during the early stage could enhance bone healing in a murine long bone critical-size defect model. However, in the scenario of nonunion due to a critical-sized bone defect, it is unknown if delayed treatment during the chronic inflammatory phase could enhance bone healing. In the current study, we examined whether IL-4 overexpressing murine MSCs could facilitate bone healing of acute and chronic bone defects in younger and older mice.
Methodology: All the animal experiment protocols were approved by Stanford’s Administrative Panel on Laboratory Animal Care (APLAC). 10-12 week-old and 18-month-old male and female BALB/c mice were used to generate a 2-mm critical-size diaphyseal bone defect in the right femur stabilized with an external fixation device. The defect sites were untreated (Empty group) or implanted with 2-mm long cylindrical µRB scaffolds encapsulated with MSCs (MSC group) or IL-4 overexpressing MSCs (IL-4-MSC group) initially or 4 weeks after the creation of the bone defect. Six weeks (acute defect) or 10 weeks (chronic defect) after the primary surgery, mice were euthanized, and femurs were collected for µCT scan. The original and final lengths of the defects were measured based on the µCT images for each case. The defect healing was defined as the original length- final length. The Region of Interest (ROI) was set as a box of 3 mm × 3 mm × original length covering the defect site for analysis of tissue mineral content. One-way ANOVA with Bonferroni’s post hoc tests were conducted for the multiple statistical comparisons among groups. The difference was considered significant when the p-value was < 0.05. Comprehensive histomorphometric examination was also performed of retrieved specimens.
Results: Using the acute bone defect model, both young male and female mice showed a significant decrease in defect size and increased tissue mineral content in the IL-4 MSCs group, compared to the Sc+MSCs group. Thus, the scaffold with IL-4 MSCs showed very promising results in younger mice with acute defects. However, the results in older mice proved to be more challenging; neither Sc+MSCs nor IL-4 MSCs enhanced healing of the bone defects. Nonunions persisted in all older mice, irrespective of gender and time.
Conclusion/Significance: There is an unmet clinical need for more efficacious strategies and treatment modalities for healing of both acute and chronic critical size bone defects, especially in older patients in whom bone graft from the iliac crest is often insufficient in quality and quantity. In our experiments, scaffolds with IL-4 over-expressing MSCs were more successful in healing of acute defects in younger male and female animals, than unaltered MSCs. However, these treatments were insufficient for healing of more challenging long bone defects in older animals. Other strategies must be pursued to facilitate bone healing in the elderly.
20941834866
