Minimally Processed Adipose-Derived Stem Cells Increase Union Rates in a Murine Model of Irradiated Mandibular Fracture Repair: Enhancing the Translational Application of Cell Based Therapeutics
Kavitha Ranganathan, MD, Jeremy V. Lynn, N/A, Kevin Urlaub, BS, Noah S. Nelson, BS, Alex Donneys, MD, Lauren Buchman, N/A, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Purpose: Cell-based therapeutics represent a critically important component of regenerative medicine and tissue engineering methodologies, as these techniques inherently possess the requisite machinery for tissue growth and differentiation. More specifically, adipose-derived stem cells (ASCs) have been studied extensively throughout the past several decades due to their multipotent potential, distinct biomarkers, and relative ease of harvest. Despite the immense potential of ASCs to enhance bone regeneration, the Food and Drug Administration (FDA) remains hesitant to approve ASC-based therapies given the consistent need for scaffolds, onerous processing techniques, and requirement of cell culture. The purpose of this study is to define the optimal method of administration of ASCs that will most readily mitigate the deleterious effect of radiation therapy (XRT) on bone healing during fracture repair while maintaining compliance with FDA guidelines; this will consequently maximize the translational applicability and clinical adoption of such therapies.
Methods: Forty-four male Lewis rats were randomly divided into four groups: control, XRT, ASC, and minimally processed ASC (MP-ASC). Excluding the control group, all rats received a fractionated dose of 35Gy of radiation, and all groups underwent subsequent mandibular osteotomy. The ASC group was treated with cultured ASCs, while the MP-ASC group received non-cultured ASCs. More specifically, for both groups, ASCs were harvested from the inguinal fat pads of isogenic Lewis rats. Cultured ASCs were processed, plated, and achieved confluence within 10-12 days. These cells were subsequently implanted into the osteotomy site at passage two. In the MP-ASC treated group, ASCs were harvested, centrifuged, and immediately implanted into the osteotomy site without the need for cell culture. After animals were sacrificed on post-operative day 40, gross pathology and MicroCT analysis were utilized to determine union rates and the quality of the bony regenerate within the osteotomy site.
Results: The implantation of MP-ASCs significantly increased union rates compared to XRT alone based on MicroCT results and pathology (60% vs. 15%). Although MP-ASC administration resulted in slightly decreased union rates compared to cultured ASCs (60% vs. 100%), the quality of bone regenerated was similar between the groups based on bone mineral density (687.25±92.02 vs. 619.64±42.5; p=0.17.) and bone volume fraction (0.755±0.097 vs. 0.721±0.057; p=0.75). The implantation of cultured ASCs resulted in similar union rates as non-radiated mandible fracture sites (100% vs. 100%).
Conclusions: Mesenchymal stem cells (MSCs) are adult stem cells with immense potential to enhance bone healing and regeneration following injury. This study identifies the ability of MP-ASCs, a minimally processed type of MSCs, to enhance bone regeneration in the absence of cell culture. With these results in mind, additional studies are required to further maximize the osteogenic potential of ASCs while also maintaining adherence to FDA regulations that mandate the minimal processing of tissues prior to implantation.
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