A systematic review and meta-analyses on animal models used in bone adhesive research.

Currently, steel implants are used for osteosynthesis of (comminuted) fractures and intra-articular bone defects. These osteosyntheses can sometimes be complicated procedures and can have several drawbacks including stress shielding of the bone. A bone glue might be a safe and effective alternative to current materials. Despite numerous animal studies on bone adhesives, no such material is clinically applied yet. We have conducted a systematic review to summarize the evidence in experimental animal models used in research on bone adhesive materials for trauma and orthopedic surgery. Additionally, we analysed the efficacy of the different bone adhesives for different experimental designs. A heterogeneity in experimental parameters including animal species, defect types, and control measurements resulted in a wide variety in experimental models. In addition, no standard outcome measurements could be identified. Meta-analysis on bone regeneration between adhesive treatment and nonadhesive treatment showed a high heterogeneity and no statistically significant overall effect (M: -0.71, 95% confidence interval [CI]: -1.63-0.21, p = 0.13). Besides, currently there is not enough evidence to draw conclusions based on the effectiveness of the individual types of adhesives or experimental models. A positive statistically significant effect was found for the adhesive treatment in comparison with conventional osteosynthesis materials (M: 2.49, 95% CI: 1.20-3.79, p = 0.0002). To enhance progression in bone adhesive research and provide valuable evidence for clinical application, more standard experimental parameters and a higher reporting quality in animal studies are needed. Statement of Clinical Significance: Current materials restoring anatomical alignments of bones have several drawbacks. A (biodegradable) adhesive for fixating bone defects can be a treatment breakthrough. Although numerous bone adhesives have been researched, most seemed to fail at the preclinical stage. An overview in this field is missing. This systematic review highlights the relevant parameters for design of experimental bone adhesive studies. It demonstrates evidence regarding benefit of bone adhesives but also that the quality of reporting and the risk of bias in studies need to be improved. The results will aid in designing better quality animal studies for bone adhesive research with higher translational value.

Bone-Adhesive Hydrogels Based on Dual Crosslinked Poly(2-oxazoline)s.

The development of bone glues based on bone-adhesive hydrogels to allow for facile bone fracture fixation remains a major challenge. Herein, dual crosslinked hydrogels that combine tunable stiffness, ductility, and self-healing capacity are successfully synthesized. The resulting double network hydrogel is formed by chemical crosslinking of N-hydroxysuccinimide-functionalized poly(2-oxazoline)s(POx-NHS)"?> with amine-functionalized poly(2-oxazoline)s, and physical crosslinking of alendronate-functionalized poly(2-oxazoline)s (POx-Ale) with calcium ions in solution. The use of an excess of alendronate-functionalized POx-Ale polymers also ensures affinity toward calcium cations in the mineral phase of bone, thereby rendering these hydrogels adhesive to bone. The mechanical and bone-adhesive properties of these novel hydrogels are superior to commercially available fibrin sealants. Moreover, hydrogels retain their bone-adhesive properties under wet conditions. Although the dual crosslinked hydrogels swell considerably, they are stable upon immersion in phosphate-buffered saline (up to 12 d) and even in ethylenediaminetetraacetic acid solution. The enhanced mechanical and bone-adhesive properties of these hydrogels, as well as their in vitro stability, indicate that they have much application potential as bone-adhesive glues.

Bone-adhesive barrier membranes based on alendronate-functionalized poly(2-oxazoline)s.

To create a novel generation of barrier membranes with bone-adhesive properties, three-component membranes were successfully developed using a solvent-free approach by combining an occlusive polyester backing layer with a bone-adhesive fibrous gelatin carrier impregnated with calcium-binding alendronate-functionalized poly(2-oxazoline)s (POx-Ale). The mechanical properties of these novel membranes were similar to other commercially available barrier membranes. In contrast, the adhesion of our membranes towards bone was by far superior (i.e. 62-fold) compared to conventional commercially available Bio-Gide® membranes. Moreover, alendronate-functionalized membranes retained their bone-adhesive properties under wet conditions in phosphate-buffered saline (PBS) solutions with and without collagenase. Finally, the in vitro degradation of the membranes was studied by monitoring their weight loss upon immersion in PBS solutions with and without collagenase. The membranes degraded in a sustained manner, which was accelerated by the presence of collagenase due to enzymatic degradation of the carrier. In conclusion, our results show that surface functionalization of barrier membranes with alendronate moieties renders them adhesive to bone. As such, the biomaterials design strategy presented herein opens up new avenues of research on bone-adhesive membranes for guided bone regeneration.

Alendronate-Functionalized Poly(2-oxazoline)s with Tunable Affinity for Calcium Cations.

A library of poly(2-oxazoline)s functionalized with controllable amounts of alendronate, hydroxyl, and carboxylic acid side groups was successfully synthesized to create novel polymers with tunable affinity for calcium cations. The affinity of alendronate-containing polymers for calcium cations was quantified using isothermal titration calorimetry. Thermodynamic measurements revealed that the Ca2+-binding affinity of these polymers increased linearly with the amount of alendronate functionalization, up to values (KCa2+ = 2.4 × 105 M-1) that were about 120-fold higher than those for previously reported polymers. The calcium-binding capacity of alendronate-functionalized poly(2-oxazoline)s was exploited to form robust hydrogel networks cross-linked using reversible physical bonds. Oscillatory rheology showed that these hydrogels recovered more than 100% of their initial storage modulus after severe network destruction. The versatile synthesis of alendronate-functionalized polymers and their strong and tunable affinity for calcium cations render these polymers promising candidates for various biomedical applications.