Bioactive lipid coating of bone allografts directs engraftment and fate determination of bone marrow-derived cells in rat GFP chimeras

Abstract

Bone grafting procedures are performed to treat wounds incurred during wartime trauma, accidents, and tumor resections. Endogenous mechanisms of repair are often insufficient to ensure integration between host and donor bone and subsequent restoration of function. We investigated the role that bone marrow-derived cells play in bone regeneration and sought to increase their contributions by functionalizing bone allografts with bioactive lipid coatings. Polymer-coated allografts were used to locally deliver the immunomodulatory small molecule FTY720 in tibial defects created in rat bone marrow chimeras containing genetically-labeled bone marrow for monitoring cell origin and fate. Donor bone marrow contributed significantly to both myeloid and osteogenic cells in remodeling tissue surrounding allografts. FTY720 coatings altered the phenotype of immune cells two weeks post-injury, which was associated with increased vascularization and bone formation surrounding allografts. Consequently, degradable polymer coating strategies that deliver small molecule growth factors such as FTY720 represent a novel therapeutic strategy for harnessing endogenous bone marrow-derived progenitors and enhancing healing in load-bearing bone defects.

Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches

“…Das et al proceeded to evaluate the in situ regulation capacity of FTY720-coated allografts towards multiple marrow-derived cells in a rat critical size segmental tibial defect model. The bone allografts, coated with a mixture of FTY720 and PLGA, achieved improved integration with the surrounding tissue, new bone formation and neovascularisation, via local immune regulation enhancing the angiogenesis–osteogenesis coupling in bone repair [ 119 ]. In another study, researchers locally delivered FTY720 using murine basement membrane-based hydrogel (Matrigel) and human trabecular bone allografts to improve bone regeneration conditions in both models of endochondral and intramembranous ossification.…”

Controlling Arteriogenesis and Mast Cells Are Central to Bioengineering Solutions for Critical Bone Defect Repair Using Allografts

“…For example, polymer-coated allografts were used to locally deliver an analog of sphingosine-1-phosphate (S1P), a bioactive sphingolipid growth factor that plays physiological roles in immune cell trafficking, vascular network formation and maturation, and osteogenic activities. This S1P-coated allograft was shown to enhance tibia [ 15 , 16 ] and cranial bone defect regeneration [ 16 ]. In the same manner, we have explored strategies for revitalizing allografts by local gene transfer of angiogenic, osteogenic and remodeling factors via freeze-dried recombinant adeno-associated virus [ 17 , 18 , 19 , 20 ].…”

Optic Nerve Lipidomics Reveal Impaired Glucosylsphingosine Lipids Pathway in Glaucoma

“…There is a possibility that remodeling of load-bearing tissues contributes to changes in lipid profiles. Experience from other fields and empirical estimates do not suggest that large changes compared to fraction in total lipids due to such changes render gross total lipid amount changes 47–50. Again, specific lipid species may provide insight into changes attributable to these factors.…”