Gluing Living Bone Using a Biomimetic Bioadhesive: From Initial Cut to Final Healing

Abstract

Osteoporotic fractures are a growing issue due to the increasing incidence of osteoporosis worldwide. High reoperation rates in osteoporotic fractures call for investigation into new methods in improving fixation of osteoporotic bones. In the present study, the strength of a recently developed bone bioadhesive, OsStictm, was evaluated in vivo using a novel bone core assay in a murine animal model at 0, 3, 7, 14, 28, and 42 days. Histology and micro-CT were obtained at all time points, and the mean peak pull-out force was assessed on days 0–28. The adhesive provided immediate fixation to the bone core. The mean peak bone core pull-out force gradually decreased from 6.09 N (σ 1.77 N) at day 0 to a minimum of 3.09 N (σ 1.08 N) at day 7, recovering to 6.37 N (σ 4.18 N) by day 28. The corresponding fibrin (Tisseel) control mean peak bone core pull-out characteristic was 0.27 N (σ 0.27 N) at day 0, with an abrupt increase from 0.37 N (σ 0.28) at day 3, 6.39 N (σ 5.09 N) at day 7, and continuing to increase to 11.34 N (σ 6.5 N) by day 28. The bone cores failed either through core pull-out or by the cancellous part of the core fracturing. Overall, the adhesive does not interrupt healing with pathological changes or rapid resorption. Initially, the adhesive bonded the bone core to the femur, and over time, the adhesive was replaced by a vascularised bone of equivalent quality and quantity to the original bone. At the 42 day time point, 70% of the adhesive in the cancellous compartment and 50% in the cortical compartment had been replaced. The adhesive outwith the bone shell was metabolized by cells that are only removing the material excess with no ectopic bone formation. It is concluded that the adhesive is not a physical and biochemical barrier as the bone heals through the adhesive and is replaced by a normal bone tissue. This adhesive composition meets many of the clinical unmet needs expressed in the literature, and may, after further preclinical assessments, have potential in the repair of bone and osteochondral fragments.

Cytocompatibility and Bioactive Ion Release Profiles of Phosphoserine Bone Adhesive: Bridge from In Vitro to In Vivo

“…The initial screening criterion was neutral pH extracts (between pH 6–8) and rapid initial setting times (2–5 min). Formulations #29, #34, and #35 were also included because they were evaluated in prior or ongoing in vivo studies [ 4 , 5 ], and have a high bond strength to calcified or soft tissues [ 5 , 24 ].…”

“…In vitro testing of acidic cements has, until now, been largely impossible without curing samples for days to weeks, as well as repeated rinsing to deplete excess ions [ 33 , 43 ]. PMCs with extract pH as low as 5.7 and 2.8 (#29 [ 4 ] and #36 [ 4 ], respectively, and #35 [ 24 ]) are histocompatible in vivo [ 4 ], while, in vitro, these formulations would likely be cytotoxic due to pH and ion related effects. Most importantly, regardless of the pH or whether extracts were cytocompatible, most PMCs discs produced a thick carpet of precipitated crystals within 6 h of incubation in media.…”

“…Likewise, in vivo, based on the results of the present study, we would expect thin layers of PMCs to release 50–200% high concentrations of calcium, phosphorus, and silicon during the first 24 h of in situ curing, compared to in vitro studies that use “prefabricated” samples. We have previously reported that PMCs degrade slowly ex vivo (10% mass loss over 4 weeks [ 5 ], with much faster degradation when implanted in bone in vivo (50–75% volume changed to bone within 12 weeks in rodents [ 24 ], or within 52 weeks in rabbits [ 13 ]) and negligable degradation in vivo when PMCs are implanted in tissues that lack mineral resorbing cells [ 4 ]. Taking into account cell mediated resorption, the ion release profiles are expected to be even higher in vivo, chronically, than we can detect using in vitro methods.…”

“…The purpose of this study was to collect preliminary data, where no other data exist, on ion release and cell response under conditions that mimic the actual in vivo condition. An in vivo study has recently been completed [ 24 ] in rodents, and one is ongoing in sheep, evaluating in-situ curing PMCs with identical dimensions as in this study (approximately 1–2 mm diameter). The fluid exchange and sample preparation conditions for these in vivo studies are expected to closely mirror the test conditions of this study.…”

“…Ex vivo studies have shown faster remodeling of phosphoserine modified cements (PMCs) compared to unmodified aTCP cement, where modified cements rapidly transform into brushite rather than slowly transforming into hydroxyapatite [ 4 , 5 ]. In vivo studies have shown osteointegration and histocompatibility of phosphoserine cements [ 4 , 17 , 21 , 24 ], where the tissue healing response is improved without pathological inflammation, and is remodelled into new bone rapidly [ 5 ]. Early studies on PMCs used cements with much lower concentrations of phosphoserine (1–5 wt%), and CPCs with phosphoserine stimulated higher bone remodeling and bone formation in rats [ 18 ] and accelerated the resorption of calcium phosphate cements in mini pigs [ 17 ].…”