Periodic Reporting for period 2 - BoneFix (BoneFix: A Paradigm Shift in Fracture Fixations via On-Site Fabrication of Bone Restoration Patches)
Período documentado: 2022-04-01 hasta 2023-09-30
The socioeconomic cost of bone fractures is rapidly increasing, along with the age of Europe’s population. The WHO estimates that the total number of osteoporosis-related fractures in EU patients will rise to 4.5 million in 2025, which translates to 8.5 incidents per minute. The standard-of-care for treating complex or unstable bone fractures is open reduction internal fixation (ORIF) with metal plates and screws. Unfortunately, their rigid design, which only allows for minimal contouring, makes them poor fixators for fractures on thin, fragile, inaccessible and shattered bone. Clinics require expensive inventories of plates to treat a myriad of fractures. The incompatibility of the plates with surrounding soft tissues can create post-surgical problems such as stress-shielding and soft-tissue adhesions, which may necessitate re-operations and the removal of the implant. Reconstruction of the fracture site may also require autologous bone transplants resulting in higher costs, longer rehabilitation periods and an increased chance of infections.
Our solution is BoneFix, a combination of light-curable, polymer-based technologies which allow for the personalized treatment of bone fractures. BoneFix consists of three domains: (i) an injectable bone scaffold hydrogel, for treating critical sized bone voids, (ii) a topological fixation patch, for stabilizing the fracture throughout the healing process, and (iii) an anti-bacterial hydrogel coating, for protecting against surgical site infections. The domains are applied to the fracture site and shaped to fit the unique geometry and mechanical requirements of the fracture before being cured on demand via high energy visible light initiated thiol-ene coupling chemistry. Collectively, these domains form a Bone Restoration Patch (BRP), a customizable, universal solution for fractures. These domains are formulated from state-of-the-art libraries of biocompatible, biodgradable monomers, multi-functional dendritic polymers and linear polycarbonates, together with ceramic fillers, resulting in materials that can accommodate the stability, bone regenerative and anti-bacterial conditions required for successful bone healing. The BRPs will be thoroughly evaluated by stakeholders to assess relevant properties, both in vitro and in vivo using relevant animal models. The ultimate goal is to cement a new disruptive technology and a paradigm shift in clinical interventions of bone fractures in which BoneFix heals, fixates and protects complex fractures which are unsuitable for metal plating.
Our solution is BoneFix, a combination of light-curable, polymer-based technologies which allow for the personalized treatment of bone fractures. BoneFix consists of three domains: (i) an injectable bone scaffold hydrogel, for treating critical sized bone voids, (ii) a topological fixation patch, for stabilizing the fracture throughout the healing process, and (iii) an anti-bacterial hydrogel coating, for protecting against surgical site infections. The domains are applied to the fracture site and shaped to fit the unique geometry and mechanical requirements of the fracture before being cured on demand via high energy visible light initiated thiol-ene coupling chemistry. Collectively, these domains form a Bone Restoration Patch (BRP), a customizable, universal solution for fractures. These domains are formulated from state-of-the-art libraries of biocompatible, biodgradable monomers, multi-functional dendritic polymers and linear polycarbonates, together with ceramic fillers, resulting in materials that can accommodate the stability, bone regenerative and anti-bacterial conditions required for successful bone healing. The BRPs will be thoroughly evaluated by stakeholders to assess relevant properties, both in vitro and in vivo using relevant animal models. The ultimate goal is to cement a new disruptive technology and a paradigm shift in clinical interventions of bone fractures in which BoneFix heals, fixates and protects complex fractures which are unsuitable for metal plating.
Alkene and thiol functionalized dendritic-linear-dendritic (DLD) polymers, monomers, and polycarbonates have been synthesized by KTH for use in the BoneFix formulations. Multiple bone scaffold hydrogels were created by mixing different thiol crosslinkers with an alkene-functionalized DLD. By changing the length and valency of the crosslinkers the physical properties of the hydrogels, such as the modulus and degree of swelling, could be tuned. UiB investigated the in vitro cytocompatibility and osteodifferentiation of the hydrogels. Two of the formulations were promising, in that they were cytocompatible and stable enough in the culture medium to allow for their analysis. One formulation, was identified as the preferred formulation and was subsequently functionalized with hydroxyapatite, which resulted in good osteoconductivity in vitro. The capacity of this formulation for supporting bone regeneration is currently being investigated in an in vivo critical sized defect model in rodents. In addition, UiB has begun exploring the 3D printability of the different hydrogel formulations.
The inconsistent adhesive strength of the primers developed at KTH resulted in the use of metal screws for attaching the fixation patch to the bone. This approach allows for the same shapeability as the original fixation patch, but with the reliability of screw anchorage to the bone. The biomechanics of the fixation patch were evaluated on fracture models in synthetic bones, animal bones and human cadaver specimens through a close collaboration between ARI and RegionH. Screw attachment allowed for the evaluation of the biomechanics of the patch without confounding influences from the inconsistent primer. Results from a variability study involving six surgeons showed that the fixation patch approach was simple to learn and highly reproducible between surgeons. Fractures stabilized with the fixation patch were capable of withstanding bending loads due to early-stage rehabilitation exercises in a human cadaver hand study. The patch will next be evaluated along with the bone scaffold hydrogel in an in vivo sheep model commencing in January 2024. The antibacterial hydrogel has also been formulated at KTH from alkene-functionalized cationically charged DLDs. The hydrogel's cytotoxicity and antibacterial activity against different bacteria strains was investigated.
MINES have been developing degradable 3D printed poly(lactic) acid (PLA) membranes, which have been combined with the fixation patch composite and characterized mechanically and structurally. The PLA membranes were compared to non-degradable poly(ethylene terephthalate) (PET) meshes. The PLA membranes could be rapidly impregnated with the composite, which suggested the possibility of pre-impregnation of the membrane with composite which would reduce the implantation time of the fixation patch. Additionally, the 3D printing parameters of the PLA membranes allowed for the creation of self-folding membranes.
Throughout the project, the website (bonefix.org) has acted as the main communication platform for the project activities. The consortium has generated news items for the website which are also shared on LinkedIn and X. With the maturity of the domain 1 and 3 hydrogels, BMB has together with KTH and UiB developed prototype kits for storing and mixing the hydrogels, along with instructions for use and training videos on their handling and application. Prototype kits of the fixation patch have been shared with several partners in the consortium. BMB have been actively contacting key stakeholders within manufacturing, clinical and investment scope to build the foundation for the exploitation of BoneFix project results.
The inconsistent adhesive strength of the primers developed at KTH resulted in the use of metal screws for attaching the fixation patch to the bone. This approach allows for the same shapeability as the original fixation patch, but with the reliability of screw anchorage to the bone. The biomechanics of the fixation patch were evaluated on fracture models in synthetic bones, animal bones and human cadaver specimens through a close collaboration between ARI and RegionH. Screw attachment allowed for the evaluation of the biomechanics of the patch without confounding influences from the inconsistent primer. Results from a variability study involving six surgeons showed that the fixation patch approach was simple to learn and highly reproducible between surgeons. Fractures stabilized with the fixation patch were capable of withstanding bending loads due to early-stage rehabilitation exercises in a human cadaver hand study. The patch will next be evaluated along with the bone scaffold hydrogel in an in vivo sheep model commencing in January 2024. The antibacterial hydrogel has also been formulated at KTH from alkene-functionalized cationically charged DLDs. The hydrogel's cytotoxicity and antibacterial activity against different bacteria strains was investigated.
MINES have been developing degradable 3D printed poly(lactic) acid (PLA) membranes, which have been combined with the fixation patch composite and characterized mechanically and structurally. The PLA membranes were compared to non-degradable poly(ethylene terephthalate) (PET) meshes. The PLA membranes could be rapidly impregnated with the composite, which suggested the possibility of pre-impregnation of the membrane with composite which would reduce the implantation time of the fixation patch. Additionally, the 3D printing parameters of the PLA membranes allowed for the creation of self-folding membranes.
Throughout the project, the website (bonefix.org) has acted as the main communication platform for the project activities. The consortium has generated news items for the website which are also shared on LinkedIn and X. With the maturity of the domain 1 and 3 hydrogels, BMB has together with KTH and UiB developed prototype kits for storing and mixing the hydrogels, along with instructions for use and training videos on their handling and application. Prototype kits of the fixation patch have been shared with several partners in the consortium. BMB have been actively contacting key stakeholders within manufacturing, clinical and investment scope to build the foundation for the exploitation of BoneFix project results.
As a revolutionary alternative to the current standard-of-care fixators, the development of BoneFix is expected to have significant impacts for (i) scientific research, by demonstrating the vast potential of thiol-ene coupling based biomedical technologies; (ii) the healthcare industry, by providing surgeons with a highly customizable and tissue friendly alternative to ORIF plating, which will allow them to treat a wider variety of fracture types while reducing the need for reoperations; and (iii) society as a whole, by providing enhanced quality of life to patients suffering from fractures by reducing rehabilitation times and the incidence of post-surgical complications. Furthermore, our multi-disciplinary consortium will lay the foundation for a rich, Euro-centric, innovative ecosystem which will drive the BoneFix technology towards commercialization.
This project aims to create a paradigm shift in clinical interventions of bone fractures, in which thiol-ene chemistry based bone restoration patches heal, fixate and protect complex fractures, providing surgeons with unparalleled freedom to personalize the bone restoration treatment to the specific needs of the fracture.
This project aims to create a paradigm shift in clinical interventions of bone fractures, in which thiol-ene chemistry based bone restoration patches heal, fixate and protect complex fractures, providing surgeons with unparalleled freedom to personalize the bone restoration treatment to the specific needs of the fracture.