Development of injectable citrate-based bioadhesive bone implants

Abstract

Injectable bone implants have been widely used in bone tissue repairs including the treatment of comminuted bone fractures (CBF). However, most injectable bone implants are not suitable for the treatment of CBF due to their weak tissue adhesion strengths and minimal osteoinduction. Citrate has been recently reported to promote bone formation through enhanced bioceramic integration and osteoinductivity. Herein, a novel injectable citrate-based mussel-inspired bioadhesive hydroxyapatite (iCMBA/HA) bone substitute was developed for CBF treatment. iCMBA/HA can be set within 2–4 minutes and the as-prepared (wet) iCMBA/HA possess low swelling ratios, compressive mechanical strengths of up to 3.2±0.27 MPa, complete degradation in 30 days, suitable biocompatibility, and osteoinductivity. This is also the first time to demonstrate that citrate supplementation in osteogenic medium and citrate released from iCMBA/HA degradation can promote the mineralization of osteoblastic committed human mesenchymal stem cells (hMSCs). In vivo evaluation of iCMBA/HA in a rabbit comminuted radial fracture model showed significantly increased bone formation with markedly enhanced three-point bending strength compared to the negative control. Neovascularization and bone ingrowth as well as highly organized bone formation were also observed showing the potential of iCMBA/HA in treating CBF.

Nanospherical arabinogalactan proteins are a key component of the high-strength adhesive secreted by English ivy

“…Subsequent Ca 2+ -driven cross-linking among carboxyl groups of the uronic acid residues within the AGPs and the pectic acids in the extracellular space favors the cohesion of the adjacent AGP-rich nanoparticles, gives rise to the generation of an adhesive film (24,31,38), further aids in the curing progress of the exuded adhesive, and eventually realizes the adhesive function at the interface by restraining the relative movement of the adventitious roots and the corresponding substrates. Throughout these procedures, the AGP-rich ivy nanoparticles also possess the capacity to permeate irregularities present on the substrates owing to their rough surfaces in most cases, resulting in a strong mechanical interlocking at the interface and further ensuring an ideal adhesive action (26,39,40,(42)(43)(44)(45)(46). In addition to the calcium-dependent electrostatic interactions and mechanical interlocking, the van der Waals force is also evidenced to be involved in the curing process, as interpreted in our previous study (56).…”

“…(H) A schematic drawing of the Ca 2+ -driven crosslinking among carboxyl groups of uronic acid residues within the AGPs and the pectic acids. (26,(39)(40)(41)(42)(43)(44). Analogous to a series of conventional glues, to accomplish adhesion at the interface, the sticky exudates derived from English ivy should initially wet the surface, a spreading motion capable of driving an intimate and extensive contact over the substrates.…”

“…Apart from the wetting activity favored by the low intrinsic viscosity of the AGP-rich ivy nanoparticles, as a typical structural adhesive, in principle, a curing step is required for the ivy-derived adhesive to create sufficient cohesive strength within the exudate, aiding in the formation of strong adhesion strength at the interface (26,(39)(40)(41)(42)(43)(44). Commonly, curing (hardening) of adhesives arises from water evaporation and/or chemical cross-linking (26,(39)(40)(41)(42)(43)(44).…”

“…Apart from the wetting activity favored by the low intrinsic viscosity of the AGP-rich ivy nanoparticles, as a typical structural adhesive, in principle, a curing step is required for the ivy-derived adhesive to create sufficient cohesive strength within the exudate, aiding in the formation of strong adhesion strength at the interface (26,(39)(40)(41)(42)(43)(44). Commonly, curing (hardening) of adhesives arises from water evaporation and/or chemical cross-linking (26,(39)(40)(41)(42)(43)(44). Notably, in the earlier studies, morphological descriptions with respect to the drying process involved in the curing of botanic adhesives derived from the adventitious roots of English ivy (18), and the climbing organs of analogous plants (15), have substantially advanced our understanding of the relevant molecular events regulating the adhesive action in the plant kingdom.…”

“…To evaluate the behavior of the prepared adhesive composites, the adhesion strength of this reconstructed adhesive was examined by both the lap joint shear strength test and the tensile strength test, two strategies that have been extensively applied to quantitatively assess bioadhesives (Fig. 6A) (42,43,(57)(58)(59). The variation in shear strength of the prepared adhesive constructs was monitored over time to reflect the curing progress.…”