Current insights on the regenerative potential of the periosteum: Molecular, cellular, and endogenous engineering approaches

Abstract

While century old clinical reports document the periosteum's remarkable regenerative capacity, only in the past decade have scientists undertaken mechanistic investigations of periosteum's regenerative potential. Here we outline three presentations from a 2012 Orthopaedic Research Society Workshop which reviewed the current state of the art in molecular, cellular and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential and translational therapies as well as engineering solutions inspired by the periosteum's remarkable regenerative capacity. First, we highlight the development of the periosteum and its role in bone repair, noting that the entire population of osteoblasts within periosteum, and at endosteal and trabecular bone surfaces within the bone marrow, derive from the embryonic perichondrium. Secondly, we underscore the role of periosteum derived cells in postnatal bone healing and regeneration; cells of the periosteum contribute more to formation of cartilage and bone within the callus during fracture healing than do cells of the bone marrow or endosteum, which not migrate out of the bone marrow compartment. Furthermore, a current healing paradigm regards the activation, expansion and differentiation of periosteal stem/progenitor cells as an essential step in building a template for subsequent neovascularization, bone formation and remodeling. Thirdly, the periosteum comprises a complex, composite structure, providing a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. The periosteum's advanced, "smart" material properties change depending on the mechanical, chemical and biological state of the tissue. Understanding periosteum development, progenitor cell-driven initiation of periosteum's endogenous tissue building capacity, as well as the complex structure-function relationships of periosteum as an advanced material are important for harnessing and engineering ersatz materials to mimic the periosteum's remarkable regenerative capacity.

Unraveling macrophage contributions to bone repair

“…These cells then initiate a cascade of growth factors and inflammatory cytokine and chemokine production that facilitate the recruitment of inflammatory immune cells (granulocytes and inflammatory monocyte/ macrophages) that combat infection and phagocytose debris and dead cell remnants. 25 During this inflammatory event, expansion/recruitment of mesenchymal stem/progenitor/precursor cells (be they from local or more distant locations 26 ) occurs and this is followed by replacement of the hematoma with a vascularized fibrous connective tissue, known as granulation tissue. 25 Macrophages are present during the inflammatory phase of fracture healing in both humans 27 and animals.…”

“…At this point, healing mechanisms diverge either toward direct bone deposition by intramembranous ossification (rigidly stabilized fractures) or toward periosteal callus formation via endochondral ossification (nonrigid fixation). In both cases, vital events are mesenchymal stem/progenitor/precursor cell recruitment/expansion (from distant or local pools 26 ) and subsequent induction of osteoblastogenesis or chondrogenesis, respectively. Data from animal models support the fact that macrophages are present within repair-associated tissues during this early anabolic phase with potentially sustained presence of robust numbers of macrophages during rigidly stabilized fixation compared with nonrigid repair scenarios.…”

Skeletal Blood Flow in Bone Repair and Maintenance

“…This line of reasoning was bolstered by a careful histological examination of vasculature following fracture that nicely demonstrated the periosteal callus alone has extensive new vessel formation (69). Additionally, a body of experimental work has shown that the presence or absence of the periosteum significantly affects the healing response (70). Finally, recent work has demonstrated that invading blood vessels in the periosteal fracture callus are intimately associated with osteoblast precursors (71).…”

Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation

“…The early inflammatory phase of fracture healing, which is characterised by a complex interaction between immune cells, resident tissue cells and pro-and antiinflammatory cytokines and chemokines, is thought to initiate the repair cascade by attracting mesenchymal progenitor cells locally, including from the periosteum (Colnot et al, 2012) and the bone marrow (Taguchi et al, 2005 ). There is evidence suggesting that circulating MSC are physiologically recruited to the fracture site and contribute to osteogenesis (Kumagai et al, 2008), implying that increasing their numbers in the blood circulation by intravenous administration may support fracture repair.…”