What a Real Bone Glue Would Have to Do: The 2023 Bench-to-Bedside Review of Bone Adhesives (Bingol et al.)

"Bone adhesive materials: From bench to bedside" is a review by Hatice B. Bingol, Johan C.M.E. Bender, Joost A. Opsteen and Sander C.G. Leeuwenburgh. The corresponding author is at Radboudumc. It was received in December 2022, accepted in March 2023 and collected in the April 2023 issue. It does not mention Bone-02 or its developers. What it offers this dossier is an independent yardstick: a definition of what a bone glue must achieve, a catalogue of the materials tried so far, and a warning about how bond-strength numbers are measured. Its central verdict is blunt. According to the authors, no commercial product yet qualifies as a "true" bone adhesive that meets all the requirements.

Why surgeons want a glue at all

The case for a glue begins with what is wrong with metal hardware. Plates, pins and screws do not degrade, so the authors note that taking them out means another operation. They also tie metal fixation to infection risk and to refractures caused by stress shielding, and say it handles tiny fragments and fractures close to joints badly. A glue the body eventually absorbs would make the removal operation unnecessary. A glue that is liquid when applied and then sets would also bond across the whole fracture surface rather than at a few points, as a pin does, which the authors suggest could reduce stress-shielding refractures too. All of this is put forward as the field's aim, not as something any product has delivered. The press material on Bone-02 shares two of these motivations: avoiding a second surgery to remove implants, and the need to bond in a wet, blood-rich site (see Bone Adhesive (Bio-Glue)).

The requirements list

The authors observe that the field has no agreed definition of a bone adhesive and supply their own. Its first and hardest demand is a bond that forms in a wet surgical site, in reasonable time, strong enough to carry load, whether it joins bone to bone or bone to an implant. Its second demand pulls the other way: the material, which must be biocompatible, should eventually disappear, degrading into harmless products at a rate that keeps pace with new bone. From this the review derives practical requirements, which can be sorted by the questions a reader would ask:

• Will it stick where there is blood? Adhesion has to stay strong when the bone is moist and bleeding.
• Will it last? The bond has to survive several weeks to months of both steady and repeated loading, and its strength must remain predictable while the material is being broken down.
• Is it safe? Both the material and whatever it degrades into must be nontoxic and biocompatible.
• Can a surgeon use it? Preparation and application must be easy and fit within a clinically acceptable time.
• Can it be made and sold? It must be manufacturable, sterilisable, stable in storage and cost-effective.

For a single number, the review cites Weber and Chapman: 200 kPa is the minimum bond strength for effective clinical fixation. They reported that fixation could not be achieved below that level.

Three families of material

The review sorts candidate adhesives into natural polymers, synthetic polymers and inorganic cements. Its running text and Table 1 supply the history and strength figures for each, while Table 2 condenses each family into a short status line. Among the materials it covers:

• Fibrin glue has been in clinical use for decades. It received a CE mark in 1982 and FDA approval in 1998. Its measured adhesion to bone is only 5–17 kPa (bovine cancellous) and 11 kPa (porcine cortical), so it is limited to fragments that bear no load.
• Gelatin–resorcinol–formaldehyde systems reach about 200 kPa, but the authors say aldehyde toxicity means they are no longer widely used.
• Cyanoacrylates give very high laboratory values, up to 12100 kPa for N-butyl-2-cyanoacrylate on compact bovine bone. The review lists heat release when they set, brittleness and toxic breakdown products. It calls their use for fracture fixation still controversial.
• Polyurethanes have a history of clinical setbacks. "Ostamer" in the late 1950s produced poor adhesion and complications. "Kryptonite", a castor-oil polyurethane with calcium carbonate, went through a 55-patient pilot randomised trial in sternal closure. The review reports that it was later withdrawn from the market after losing strength and stiffness at body temperature.
• PMMA bone cement holds by mechanical interlocking, not by bonding to bone, and does not degrade.
• Phosphoserine-modified calcium phosphate cements, including "Tetranite" (phosphoserine with tetracalcium phosphate) and "OsStic" (phosphoserine with α-tricalcium phosphate), are described as showing high bone adhesion strength relevant to clinical practice. Those figures come from bench tests: above 1000 kPa for Tetranite joining porcine bone, and about 2500–4000 kPa for OsStic on bovine cortical bone cured in liquid for 24 hours. The supporting in vivo work so far is in animals, and the authors say more detailed clinical investigation of safety and performance is still needed.

What nature-inspired glues have shown so far

The section most relevant to an oyster-inspired product covers adhesives modelled on marine and insect glues. These include mussel DOPA chemistry, sandcastle-worm coacervates, caddisfly silk, barnacle cement and a frog secretion. The review explains the proposed catechol chemistry: hydrogen bonding, binding to metal ions, and cross-linking after oxidation. It also notes that the mussel mechanism is not yet fully understood. For polymers carrying these bioinspired groups, the authors' summary is sober. Bond strengths are relatively low next to conventional synthetic adhesives. Most work only measures adhesion to bone outside the body. There are few preclinical studies, and the status line reads "No clinical study yet." Oysters do not appear among the organisms the review discusses (on oyster cement itself, see Oyster Cement).

Why bond-strength numbers are hard to compare

The review's main methodological point is that bone adhesion testing has no standard. That is why Table 1 records, for every number, the test type (pull-off, lap shear, tear-off), the substrate (bovine, porcine, chicken or human cadaver bone, cortical or cancellous, sometimes aluminium) and the curing and storage conditions. The differences are large. Glutaraldehyde-crosslinked chitosan measured 200 ± 60 kPa dry but 24 ± 3.6 kPa wet. Lactide-methacrylate composites ranged from 3100–13900 kPa dry down to 300–7700 kPa humid. PMMA gave 1010 kPa on cancellous bone but 350 kPa on compact bone. The authors list the missing standard tests as a major barrier, alongside wet adhesion, scaling up production and market approval.

Reading Bone-02's press figures against this benchmark

The review's framework makes some limits of the Bone-02 coverage concrete (see Bone Glue Claims vs. Evidence: Press Numbers, Patent Abstracts and the Absence of Primary Data). The press-reported shear strength of about 0.5 MPa equals 500 kPa. That is above the 200 kPa clinical threshold the review cites. But a strength figure alone cannot be placed on the review's scale. The reader also needs the test geometry, the bone type, and whether the joint was wet or dry, and for how long. The review shows these factors can change results by an order of magnitude, and the press reports give none of them. The review's other requirements are durability over weeks to months, degradation matched to healing, nontoxic by-products, sterilisation and storage. The documents in this dossier offer no data on any of them. None of this shows that Bone-02 fails. It shows how much evidence a bone glue would need before it could be called the product the review says does not yet exist.

Further reading

• Bone Adhesive (Bio-Glue)
• Bone-02
• Lin Xianfeng and Bone-02: Oyster-Inspired Bone Glue — The source archive Press-and-Patent Dossier