Sub‐clinical dose of bone morphogenetic protein‐2 does not precipitate rampant, sustained inflammatory response in bone wound healing

Abstract

Large bone injuries, defects, and chronic wounds present a major problem for medicine. Several therapeutic strategies are used clinically to precipitate bone including a combination therapy delivering osteoinductive bone morphogenetic protein 2 (rhBMP‐2) via an osteoconductive scaffold (absorbable collagen sponge [ACS], i.e., INFUSE). Adverse side effects reportedly associated with rhBMP2 administration include rampant inflammation and clinical failures. Although acute inflammation is necessary for proper healing in bone, inflammatory cascade dysregulation can result in sustained tissue damage and poor healing. We hypothesized that a subclinical dose of rhBMP2 modeled in the murine calvarial defect would not precipitate alterations to inflammatory markers during acute phases of bone wound healing. We utilized the 5 mm critical size calvarial defect in C57BL6 wild‐type mice which were subsequently treated with ACS and a subclinical dose of rhBMP2 shown to be optimal for healing. Three and 7‐day postoperative time points were used to assess the role that rhBMP‐2 plays in modulating inflammation vs. ACS alone by cytokine array and histological interrogation. Data revealed that rhBMP‐2 delivery resulted in substantial modulation of several markers associated with inflammation, most of which decreased to levels similar to control by the 7‐day time point. Additionally, while rhBMP‐2 administration increased macrophage response, this peptide had a little noticeable effect on traditional markers of macrophage polarization (M1‐iNOS, M2‐Arg1). These results suggest that rhBMP‐2 delivered at a lower dose does not precipitate rampant inflammation. Thus, an assessment of dosing for rhBMP‐2 therapies may lead to better healing outcomes and less surgical failure.

rhBMP2 alone does not induce macrophage polarization towards an increased inflammatory response

“…It remains unexplained why rhBMP2 might drive the observed patient responses, but these data suggest the peptide alone is not likely solely responsible. What is still very much up for debate is the supraphysiological doses used in human therapies that are difficult to mimic in culture and in preclinical models (Durham et al, 2018a;Grey et al, 2019;Herberg et al, 2014;Krishnan et al, 2017;Zara et al, 2011). As rhBMP2 is thought to act in a feedback loop where the delivered peptide is cleared within 24-48 hours and then the endogenous system begins to make more bone growth factors in response at that site (Kim et al, 2014;Lissenberg-Thunnissen et al, 2011;Tsuji et al, 2006), future research should interrogate the delivered doses of rhBMPs in clinical scenarios.…”

“…Our group and others have been focused on the pathway of effect for delivery of rhBMP2 using preclinical surgical models (Durham et al, 2018a;Durham et al, 2018b;Grey et al, 2019;Herberg et al, 2017;Herberg et al, 2014;Howie et al, 2018a;Howie et al, 2018b). Within our models, we have been relatively unable to replicate the side effect of rampant inflammation that is described in the clinical literature case studies.…”

“…Within our models, we have been relatively unable to replicate the side effect of rampant inflammation that is described in the clinical literature case studies. In fact, much of our preclinical data has even suggested that not only does rhBMP2 not precipitate an abnormal inflammatory response to injury, in some conditions it may even act in an anti-inflammatory manner (Durham et al, 2018a;Grey et al, 2019). These data precipitated our focus on rhBMP2 in the inflammatory axis.…”

Simultaneous Regeneration of Bone and Nerves Through Materials and Architectural Design: Are We There Yet?

“…[236] Large doses applied to fracture sites to improve treatment efficacy may induce inflammatory reaction, neoplasia and ectopic bone formation at unwarranted sites. [237] Small Molecules: They are natural/synthetic molecules with low molecular weight (<1 kDa) that regulate cell and tissue functions with high stability. [112] Often uncharged or hydrophobic, they readily penetrate the phospholipid bilayer of cell membranes.…”

“…[ 236 ] Large doses applied to fracture sites to improve treatment efficacy may induce inflammatory reaction, neoplasia and ectopic bone formation at unwarranted sites. [ 237 ]…”