Immune Modulation to Enhance Bone Healing—A New Concept to Induce Bone Using Prostacyclin to Locally Modulate Immunity

Abstract

Within an aging population, fracture incidences will rise and with the augmented risks of impaired healing the overall risk of delayed bone regeneration will substantially increase in elderly patients. Thus, new strategies to rescue fracture healing in the elderly are highly warranted. Modulating the initial inflammatory phase toward a reduced pro-inflammation launches new treatment options for delayed or impaired healing specifically in the elderly. Here, we evaluated the capacity of the prostacyclin analog Iloprost to modulate the inflammatory phase toward a pro-regenerative milieu using in vitro as well as in vivo model systems. In vitro , Iloprost administration led to a downregulation of potential unfavorable CD8+ cytotoxic T cells as well as their pro-inflammatory cytokine secretion profile. Furthermore, Iloprost increased the mineralization capacity of osteogenic induced mesenchymal stromal cells through both direct as well as indirect cues. In an in vivo approach, Iloprost, embedded in a biphasic fibrin scaffold, decreased the pro-inflammatory and simultaneously enhanced the anti-inflammatory phase thereby improving bone healing outcome. Overall, our presented data confirms a possible strategy to modulate the early inflammatory phase in aged individuals toward a physiological healing by a downregulation of an excessive pro-inflammation that otherwise would impair healing. Further confirmation in phase I/II trials, however, is needed to validate the concept in a broader clinical evaluation.

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“…The close interaction between the immune system and bone healing is well documented. In the emerging research field of osteoimmunology, the early inflammatory phase of healing is a promising target for immunomodulatory approaches to enhance bone healing [113]. Even though the role of immune cells and cytokines in bone healing has been recognized for 20 years now, and EStim has been used to treat bone fractures even longer, little is known about the effects of EStim on immune cells during bone healing.…”

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“…On the other hand, the role of the adaptative immune system also seems to be relevant for tissue healing and regeneration [ 24 ]. Recent research shows that lower levels of pro-inflammatory cytokines secreted by CD8+ T stimulate the new bone formation by MSC and bone healing [ 42 ]. In addition, it is known that CD4+CD25+FOXP3+ regulatory (Treg) cells are essential modulators of the immune response, being able to suppress the inflammatory response and allow reparative processes to stop some forms of autoimmune diseases [ 5 , 30 ].…”

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“…Although previous data suggests that a certain degree of inflammation is essential for bone regeneration, a persistent or unregulated inflammatory stage is detrimental to bone regeneration. 28 For example, as evidenced in our previous study the proinflammatory cytokine interleukin 1 beta was extensively expressed in the large delayed healing defects. 20 Therefore, in this study we describe the simple modification of a PCL scaffold to regulate inflammation and enhance osteogenesis.…”