Periodic Reporting for period 4 - SBR (SMART BONE REGENERATION)
Reporting period: 2024-01-01 to 2024-12-31
Demographic change and age-linked conditions such as osteoporosis and related fragility fractures pose a significant burden on the European healthcare systems. According to the International Osteoporosis Foundation, the annual healthcare costs associated with fractures and impaired healing are expected to increase by 23% by the year 2030. Current clinical practice for the treatment of large bone defects (i.e. cases in which at least 3 cm of bone is missing) involves either the technique of bone transport (distraction osteogenesis) or the induced membrane technique (Masquelet technique). In bone transport, following a breakage (osteotomy) of the bone away from the site of the bone defect and using a fine wire fixator, the bone is pulled away (towards the defect site). Such an approach is demanding and also associated with complications such as failure of the metal work, infection and failure of consolidation of the regenerate bone. The Masquelet technique requires a two-step approach; implantation of the cement spacer in the bone defect (first stage), and removal of the cement spacer in six weeks’ time and filing-up the void left with autologous bone graft along with MSCs and bone composites such as Hydroxyapatide etc (second stage).
The main advantage of the SBR approach is the reduction from a two-step to a novel singlestep surgical procedure for regeneration of large bone defects, healing of non-unions and complex fractures. This will relieve the burden on the patients (not have to undergo a second procedure with all the associated risks), and also reduce the costs on the health care system as a whole. SBR (Smart Bone Regeneration) aims to develop a single stage less invasive technique designed to complement existing clinical practices.
The SBR bone regenerative solution will reduce the risk of post-operative complications such as infection and failure of consolidation of the regenerate bone. A reduction of the overall cost and recovery time for patients with large bone defects and reduced burden for families and caretakers will be achieved.
The main advantage of the SBR approach is the reduction from a two-step to a novel singlestep surgical procedure for regeneration of large bone defects, healing of non-unions and complex fractures. This will relieve the burden on the patients (not have to undergo a second procedure with all the associated risks), and also reduce the costs on the health care system as a whole. SBR (Smart Bone Regeneration) aims to develop a single stage less invasive technique designed to complement existing clinical practices.
The SBR bone regenerative solution will reduce the risk of post-operative complications such as infection and failure of consolidation of the regenerate bone. A reduction of the overall cost and recovery time for patients with large bone defects and reduced burden for families and caretakers will be achieved.
During the timeframe of SBR, after determining the optimal specifications of the smart implant and its components, a lot of work was carried out to produce the different components: The design, geometry and materials of the different parts of the implant have been selected and second generation prototypes have been prepared and tested.
In particular:
-Several parts of the SBR smart implant (SIM), consisting of the implant scaffold, sensors and materials incorporating the bioactive substances, have been designed and manufactured and further evaluated in vitro for their mechanical properties, degradation rates, performance, and biocompatibility.
-optimal methods were selected for the incorporation of bioactive substances into SIM parts.
After studying the samples obtained from the pilot studies on animals:
-The scaffold was increased in diameter. The extensions were inclined as their screw holes would be overlapped in such a way that they would be fixed by means of a single screw. The locking mechanism was optimized and made more effective.
-The sensors were developed and optimized (their connection cable was increased in length and covered with a thick layer of silicone to make it more rigid and avoid fiber fatigue; better shielding of the battery was applied and it was fixed in a robust frame for stapling on the fascia latta), and their performance and signal transmission capability was tested.
Biocompatibility both in vitro and in vivo was evaluated and confirmed through histological studies. The surgical technique was finalized and the double plate concept was mechanically tested on cadaveric sheep femur bones, and final in vivo efficacy studies were carried out in large animals.
Conclusions:
Series of in vitro studies proved the efficacy of: (i) The selected method for growth factor integration onto the SIM (electrospun-fiber-encapsulated-liposomal growth factors) to permit SIM sterilization (without loss of bioactivity) and additionally to retain and prolong the bioactivities of the growth factors. (ii) The FTY720 bioactive lipid, especially in its liposomal form, to promote reprogramming of L929 fibroblasts into osteoblasts, a novel finding deserving future exploitation. (iii) AAVs for the expression of growth factors involved in bone regeneration in transduced e.g. mesenchymal stromal cells and (iv) the development of a novel transduction enhancer for AAV.
From the final in vivo studies for the efficacy of the proposed method, we concluded:(i) That the animal model, including osteotomy and surgical technique (double plate fixation), proved to be very effective and mechanically sound. And (ii) That from a histological point of view, the osseointegration, and bridging of the defect were satisfactory, proportional to the amount of bone graft, and with good biocompatibility.
Therefore, the primary goal of the project to bridge the large bone defect in one stage of surgery, as opposed to the two-stage procedure of the Masquelet technique, is achievable.
Remaining challenges include: (i) The determination of the exact contribution of each growth factor type (liposomal, AAVs) in the in vivo study; (ii)The determination of the degradation rate of the scaffold in vivo and, if necessary, use PLLA with faster degradation rate., and (iii) Optimising the robustness and functionality of sensors.
SBR results such as the scaffold, the sensors and the bioactive’s integration have been published in 6 OA publications and in total partners have disseminated the project and their findings in more than 50 scientific conferences, exhibitions, and trade fairs. At the same time, partners have made sure to align dissemination activities with their exploitation ones, always safeguarding potential IP generated in the project. Partners will continue to negotiate joint ownership shares where applicable and to pursue the valorisation of the project results beyond the project runtime and to bring them into their application in health care for the treatment of large bone defects.
In particular:
-Several parts of the SBR smart implant (SIM), consisting of the implant scaffold, sensors and materials incorporating the bioactive substances, have been designed and manufactured and further evaluated in vitro for their mechanical properties, degradation rates, performance, and biocompatibility.
-optimal methods were selected for the incorporation of bioactive substances into SIM parts.
After studying the samples obtained from the pilot studies on animals:
-The scaffold was increased in diameter. The extensions were inclined as their screw holes would be overlapped in such a way that they would be fixed by means of a single screw. The locking mechanism was optimized and made more effective.
-The sensors were developed and optimized (their connection cable was increased in length and covered with a thick layer of silicone to make it more rigid and avoid fiber fatigue; better shielding of the battery was applied and it was fixed in a robust frame for stapling on the fascia latta), and their performance and signal transmission capability was tested.
Biocompatibility both in vitro and in vivo was evaluated and confirmed through histological studies. The surgical technique was finalized and the double plate concept was mechanically tested on cadaveric sheep femur bones, and final in vivo efficacy studies were carried out in large animals.
Conclusions:
Series of in vitro studies proved the efficacy of: (i) The selected method for growth factor integration onto the SIM (electrospun-fiber-encapsulated-liposomal growth factors) to permit SIM sterilization (without loss of bioactivity) and additionally to retain and prolong the bioactivities of the growth factors. (ii) The FTY720 bioactive lipid, especially in its liposomal form, to promote reprogramming of L929 fibroblasts into osteoblasts, a novel finding deserving future exploitation. (iii) AAVs for the expression of growth factors involved in bone regeneration in transduced e.g. mesenchymal stromal cells and (iv) the development of a novel transduction enhancer for AAV.
From the final in vivo studies for the efficacy of the proposed method, we concluded:(i) That the animal model, including osteotomy and surgical technique (double plate fixation), proved to be very effective and mechanically sound. And (ii) That from a histological point of view, the osseointegration, and bridging of the defect were satisfactory, proportional to the amount of bone graft, and with good biocompatibility.
Therefore, the primary goal of the project to bridge the large bone defect in one stage of surgery, as opposed to the two-stage procedure of the Masquelet technique, is achievable.
Remaining challenges include: (i) The determination of the exact contribution of each growth factor type (liposomal, AAVs) in the in vivo study; (ii)The determination of the degradation rate of the scaffold in vivo and, if necessary, use PLLA with faster degradation rate., and (iii) Optimising the robustness and functionality of sensors.
SBR results such as the scaffold, the sensors and the bioactive’s integration have been published in 6 OA publications and in total partners have disseminated the project and their findings in more than 50 scientific conferences, exhibitions, and trade fairs. At the same time, partners have made sure to align dissemination activities with their exploitation ones, always safeguarding potential IP generated in the project. Partners will continue to negotiate joint ownership shares where applicable and to pursue the valorisation of the project results beyond the project runtime and to bring them into their application in health care for the treatment of large bone defects.
Innovative approaches were developed, which will have applications in:
• New animal model for bone defect (osteotomy and double plate fixation method) able to fill the gap in one stage of surgery.
• New biocompatible and bioabsorbable scaffolding.
• Non-invasive monitoring of the bone regeneration process.
• New methods for delivery or in situ production of bioactive substances to accelerate bone healing.
In addition to the smart bone regeneration implant, we havedeveloped several new technologies and products that will have general applications in tissue regeneration and the treatment of numerous related pathologies, thus having a high socio-economic impact and broad societal implications.
• New animal model for bone defect (osteotomy and double plate fixation method) able to fill the gap in one stage of surgery.
• New biocompatible and bioabsorbable scaffolding.
• Non-invasive monitoring of the bone regeneration process.
• New methods for delivery or in situ production of bioactive substances to accelerate bone healing.
In addition to the smart bone regeneration implant, we havedeveloped several new technologies and products that will have general applications in tissue regeneration and the treatment of numerous related pathologies, thus having a high socio-economic impact and broad societal implications.