Proresolving nanomedicines activate bone regeneration in periodontitis.
Therapies to reverse tissue damage from osteolytic inflammatory diseases are limited by the inability of current tissue-engineering procedures to restore lost hard and soft tissues. There is a critical need for new therapeutics in regeneration. In addition to scaffolds, cells, and soluble mediators necessary for tissue engineering, control of endogenous inflammation is an absolute requirement for success. Although significant progress has been made in understanding natural resolution of inflammation pathways to limit uncontrolled inflammation in disease, harnessing the biomimetic properties of proresolving lipid mediators has not been demonstrated. Here, we report the use of nano-proresolving medicines (NPRM) containing a novel lipoxin analog (benzo-lipoxin A4, bLXA4) to promote regeneration of hard and soft tissues irreversibly lost to periodontitis in the Hanford miniature pig. In this proof-of-principle experiment, NPRM-bLXA4 dramatically reduced inflammatory cell infiltrate into chronic periodontal disease sites treated surgically and dramatically increased new bone formation and regeneration of the periodontal organ. These findings indicate that NPRM-bLXA4 is a mimetic of endogenous resolving mechanisms with potent bioactions that offers a new therapeutic tissue-engineering approach for the treatment of chronic osteolytic inflammatory diseases.
Center for Periodontology, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA tvandyke@forsyth.org.
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Van Dyke
Center for Periodontology, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
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Hasturk
Center for Periodontology, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
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Kantarci
Center for Periodontology, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
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Freire
Center for Periodontology, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA.
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Nguyen
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Dalli
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Serhan
D016301:Alveolar Bone Loss / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D000539:Alveolar Process / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D040761:Biomimetic Materials / Q000627:therapeutic use; D001861:Bone Regeneration / Q000187:drug effects*; D055113:Chronic Periodontitis / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003739:Dental Cementum / Q000187:drug effects / Q000473:pathology; D012534:Dental Scaling / Q000379:methods; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000097:blood / Q000627:therapeutic use; D005260:Female; D007091:Image Processing, Computer-Assisted / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods; D044045:Lipoxins / Q000097:blood / Q000627:therapeutic use*; D050997:Nanomedicine; D049329:Nanostructures / Q000627:therapeutic use*; D010012:Osteogenesis / Q000187:drug effects; D010513:Periodontal Ligament / Q000187:drug effects / Q000473:pathology; D010514:Periodontal Pocket / Q000188:drug therapy / Q000601:surgery; D011897:Random Allocation; D016745:Root Planing / Q000379:methods; D013524:Surgical Flaps / Q000601:surgery; D013552:Swine; D013556:Swine, Miniature; D055114:X-Ray Microtomography / Q000379:methods
D000893:Anti-Inflammatory Agents; D044045:Lipoxins; D004281:Docosahexaenoic Acids; C562252:benzo-lipoxin A4
bacteremia; cardiovascular disease; lipoxins; periodontal disease; resolution of inflammation; resolvins