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Green and robust approaches towards dual-purpose dendritic adhesives: Novel minimally invasive methodologies for bone fracture fixation applications

Periodic Reporting for period 1 - DendroBAP (Green and robust approaches towards dual-purpose dendritic adhesives: Novel minimally invasive methodologies for bone fracture fixation applications)

Reporting period: 2015-08-01 to 2017-07-31

Addressing a major problem. Considering the growing population, an increasing number of severe bone fracture cases can be foreseen worldwide. Severe fractures are typically fixated with rigid metal or polymer implants, which have an excellent mechanical strength but also a great number of limitations, such as the need for drilling on the bone, the use of open surgery with general anesthesia, or the common occurrence of post-operative complications. In any case, such treatments come with heavy socioeconomic costs, in the form of physical and mental stress for patients, prolonged hospital stays and an increased economic burden on society.

State-of-the-art solutions. To replace the current gold standard metal-based implant with a polymer-based bone adhesive, a number of critical requirements appear, such as an excellent cytocompatibility and adhesion to both wet and dry surfaces among others. Unfortunately, all medically approved soft-tissue and dental adhesives are all promising bone adhesives that have failed one or several of the above mentioned criteria. A promising alternative is the Fiber Reinforced Adhesive Patch reported by Malkoch and coworkers (WO 2011048077 A2 20110428). Nevertheless, several challenges were ahead of this technology in order to become a real alternative to metal-based implants, such as the unmet adhesion strength to wet bone, the high intensity UV source and the medically questionable E-glass fibres.

Objectives of the project. The main objective of DendroBAP project was to overcome fundamental obstacles in the treatment of complicated bone fractures by cementing a ground-breaking concept in fracture fixation: Bone Adhesive Patches (BAPs). The refined patches were foreseen to address the challenges of the state-of-the-art BAPs and become a proof-of-concept for a viable alternative to metal implants in fracture fixation. If successful, a new era of personalized surgery of bone fractures will be unfolded.

Conclusions of the action. The technology developed during the DendroBAP project has overcome current issues on adhesive systems for hard tissue diseases. DendroBAP has enabled a high strength adhesive fixation method functioning in physiologically wet environments such as at the bone surface. The patch components – i) dendritic primer layer, ii) adhesive and iii) fiber selectively and on-demand solidify to BAPs via physiologically benign reactions. The developed patches provided support for the traumatized area within minutes of application, independent of position and complexity of the fracture.
"Overview of the results.
The DendroBAP project enabled the identification of a new bone fixation concept which can make the current metal implants obsolete. The methodology relies on Bone Adhesive Patches (BAPs) prepared selectively and on-demand in the fracture site.
Dendritic primers are the key. Aiming to increase the adhesion strength towards wet bone, a primer component was designed comprising a dual functionality capable of adhering to bone and crosslinking with the adhesive resin. From the extensive library of nanomaterials, dendritic primers displaying phosphonic acid moieties unlocked a new phase in the BAP development enabling an excellent adhesion to wet bone when used as primer coatings.
New generation of adhesive patches. The refined BAP concept is the state-of-the-art of adhesives for bone fixations and takes into consideration the surgical feasibility i.e. (1) a primer coating based on a dendritic molecule with phosphonic acid yielding extraordinary strong adhesion to bone substrates and that also efficiently binds to (2) a multicomponent adhesive composite comprising a two-components triazine glue, ca 50 wt% hydroxyapatite (HA) fillers and three layers of biomedically approved poly(ethylene terephthalate) (PET) fiber sheets relying on a (3) bottom-up formation from the fracture site accomplished via high energy visible light (HEV) curing provided by a dental lamp. The components are connected by the HEV-promoted Off-Stoichiometric Thiol-Ene Chemistry (OSTEC) strategy developed in house. The new patches outperform all commercially available adhesives for bone related fixations and Kuaray’s dental self-etching primer and adhesive SE Bond Clearfil™.
Getting closer to the clinic. As part of a collaborative project outside the scope of this action, a first preclinical study conducted by Research Institutes of Sweden and Karolinska Institute on the femur of rat models has revealed that these new generation BAPs can be applied by hand surgeons with great freedom within 20 minutes. The initial results elucidated that the patches do indeed only topologically fixate the fractures with no interference with the bone tissue during regeneration. NAMSA GLP evaluations and histology after 5 weeks in vivo also showed that the patch is non-toxic and non-genotoxic. Finally, the patches were found to be intact after 5 weeks in vivo without any trace of biodegradability.

Exploitation and dissemination.
During the course of an Exploitation Strategy Seminar for the DendroBAP project, several Key Exploitable Results (KER) were identified. The most advanced KER which it has been included in the international patent application A composition comprising thiol, alkene and phosphonic acid containing compounds for use as a primer for adhesion improvement (PCT/EP2017/077350). The transition towards tangible impact creation will be performed by the start-up company Biomedical Bonding AB, where the fellow participates as board member and Chief Operations Officer.
The main results from the project are included in two scientific articles. ""High-performance thiol-ene composites unveils a new era of adhesives suited for bone repair"" (Advanced Functional Materials 2018, doi: 10.1002/adfm.201800372 ) and “Multifunctional primers for bone fracture fixation” (under preparation). A fruitful dissemination among relevant actors in the field – researchers, surgeons and industrial partners- was performed during the workshop “Next generation adhesives and surgical methodologies for fracture fixation and bone restoration applications”, organized by the project coordinators. Further dissemination of the project results to a broader audience was accomplished in the 5th International Symposium on Biomedical Applications of Dendrimers (Denmark, 2016) and the NanoMedNorth Annual Meeting and Focus Seminar (Denmark, 2016).

Going beyond state-of-the-art of the scientific breakthrough Fiber Reinforced Adhesive Patches, a new generation of patches was developed that addressed the challenges of its predecessor. Successfully, the proposed patches and their surgical methodologies can now be considered as a viable alternative and further development ought to alter the course of personalized treatment of bone fractures, ultimately increasing the quality of life for patients, reducing rehabilitation time and the overall healthcare costs. Moreover, from a surgeon’s point-of-view, the ability of tailoring the BAPs to suit the shape of the bone, unlike today´s metal plates, and the shift from open surgery to minimally invasive techniques is of great interest as it would minimize the risk of infection after fracture fixation and only require local anesthesia.
Dendritic primers enable the bonding of adhesive resins to difficult substrates such as wet bone
Bone Adhesive Patch (BAP) fixating a bovine femur fracture