The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages

Abstract

Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug loaded constructs significantly enhanced SDF1α mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects.

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis

“…Moreover, owing to its lipophilic nature, FTY720 can exert pharmacological effects directly across the bloodebrain barrier and on resident cells of the CNS [17]. PCL, semi crystalline aliphatic polyester, is a commonly used biomaterial due its biodegradability, biocompatibility and benign drug permeability [18]. Because PCL has a distinct advantage of not giving rise to an acidic microenvironment upon degradation, it has been widely utilized in a broad range of diverse biomedical applications including delivery of bioactive molecules and as scaffolds for nerve regeneration [19].…”

Radiological assessment of bioengineered bone in a muscle flap for reconstruction of a critical-size mandibular defect

“…Bone bioengineering using biomaterial, bioactive molecules and autogenous stem cells have been studied extensively and variable rates of success are reported [3][4][5]. Other studies have investigated various ways to induce angiogensesis and arteriogenesis which are essential for the bone regeneration process [6,7]. The applications of vascular endothelial growth factors (VEGF), angiogenic proteins and hypoxia induced factor1a to improve vascularity at the surgical site have also been reported [8][9][10].…”

Sutures Possess Strong Regenerative Capacity for Calvarial Bone Injury

“…Studies based on long bone fracture models indicate that resident stem or progenitor cells collaborate with macrophages and circulating blood cells to orchestrate a complex signaling cascade leading to tissue regeneration and remodeling [1][2][3]. Craniofacial bones are different from long bones in their developmental origins and osteogenic programs and structures: craniofacial bones are flat and developed mainly through intramembranous osteogenesis instead of endochondral ossification.…”