Periodic Reporting for period 1 - Bio-TUNE (Fine tune of cellular behavior: multifunctional materials for medical implants)
Reporting period: 2020-01-01 to 2022-12-31
In biomaterials science, it is well accepted that improving implant biointegration with surrounding tissues is a major goal. However, implant surfaces that facilitate cell adhesion and proliferation may also favor colonization of bacterial cells. Infection of biomaterials and subsequent biofilm formation can be catastrophic and significantly reduce patient quality of life, representing an emerging concern in healthcare. Conversely, efforts towards inhibiting bacterial colonization may negatively affect host tissues. Hence, ideally, to enhance the long-term success of medical implants, biomaterials should reduce bacterial levels without compromising the physiological functions of host cells. Yet, the majority of current approaches only focus on either improving cell adhesion or preventing bacterial infection, rarely exploring a combined goal.
Bio-TUNE focuses on multifunctional coatings to simultaneously address implant biointegration while mitigating bacterial infections. Bio-TUNE introduces new paradigms to respond to this unmet clinical need.
For this purpose, Bio-TUNE ambitions to:
1) Study and understand the interaction of host cells and bacteria at the biophysical and molecular level
2) To develop cell instructive and antibacterial surfaces via biochemical and topographical approaches
3) Assess market and industrial regulatory requirements to transfer this technology to medical implants
We seek to decipher the mechanisms of eukaryotic and bacterial cell competition, generate new multi-potential materials, and drive their transfer to clinical applications by establishing direct contact with technology developers and industrial end-users, leading to a generation of advanced biomimetic materials for tissue regeneration.
Bio-TUNE brings together emerging and leading scientists from EU, Asia and America with sound multi-disciplinary expertise in chemistry, materials engineering and biology. The consortium is further strengthen by the collaboration with industrial players, which provide unique training in technological transfer and the know-how related to the specifications for the potential use of the biomaterials, first in clinical trials and then in a commercial setting. It represents an Integrated Innovation approach targeting advances in science and socioeconomic impact.
Bio-TUNE focuses on multifunctional coatings to simultaneously address implant biointegration while mitigating bacterial infections. Bio-TUNE introduces new paradigms to respond to this unmet clinical need.
For this purpose, Bio-TUNE ambitions to:
1) Study and understand the interaction of host cells and bacteria at the biophysical and molecular level
2) To develop cell instructive and antibacterial surfaces via biochemical and topographical approaches
3) Assess market and industrial regulatory requirements to transfer this technology to medical implants
We seek to decipher the mechanisms of eukaryotic and bacterial cell competition, generate new multi-potential materials, and drive their transfer to clinical applications by establishing direct contact with technology developers and industrial end-users, leading to a generation of advanced biomimetic materials for tissue regeneration.
Bio-TUNE brings together emerging and leading scientists from EU, Asia and America with sound multi-disciplinary expertise in chemistry, materials engineering and biology. The consortium is further strengthen by the collaboration with industrial players, which provide unique training in technological transfer and the know-how related to the specifications for the potential use of the biomaterials, first in clinical trials and then in a commercial setting. It represents an Integrated Innovation approach targeting advances in science and socioeconomic impact.
The most representative results achieved during the first reporting period (M1-M36) are:
WP1: Chemically modified and topographically patterned microelectrodes have been produced with the capacity of monitoring cell and bacterial adhesion dynamics in real-time. These sensors represent excellent tools to gain an understanding of the biochemical and biophysical cues that govern human and bacterial cell-surface adhesive interactions.
WP2: Cell instructive materials that fine-tune stem cell responses have been designed and fabricated. In detail, nanostructured materials that control stem cell differentiation, and biofunctional coatings exploiting integrin and growth factor signaling have been developed.
WP3: A collection of cultivable microorganisms able to inhibit S. aureus growth is now available. A set of aptamers against assembly factors from S. aureus have also been produced, with one promising hit. Both strategies will be used to develop anti-infective surfaces that do not promote bacterial resistance.
WP4: Novel peptide-based multifunctional coatings combining cell adhesive, osteogenic and/or antibacterial properties have been synthesized. These molecules have been used to functionalize biomaterials of different nature thus improving their biological potential both in vitro and in vivo.
WP5: The response of macrophages towards different types of micropatterned surfaces have been studied. Significant differences between M1 and M2 macrophages in terms of nuclear deformation, adhesion and cluster formation, were found.
WP1: Chemically modified and topographically patterned microelectrodes have been produced with the capacity of monitoring cell and bacterial adhesion dynamics in real-time. These sensors represent excellent tools to gain an understanding of the biochemical and biophysical cues that govern human and bacterial cell-surface adhesive interactions.
WP2: Cell instructive materials that fine-tune stem cell responses have been designed and fabricated. In detail, nanostructured materials that control stem cell differentiation, and biofunctional coatings exploiting integrin and growth factor signaling have been developed.
WP3: A collection of cultivable microorganisms able to inhibit S. aureus growth is now available. A set of aptamers against assembly factors from S. aureus have also been produced, with one promising hit. Both strategies will be used to develop anti-infective surfaces that do not promote bacterial resistance.
WP4: Novel peptide-based multifunctional coatings combining cell adhesive, osteogenic and/or antibacterial properties have been synthesized. These molecules have been used to functionalize biomaterials of different nature thus improving their biological potential both in vitro and in vivo.
WP5: The response of macrophages towards different types of micropatterned surfaces have been studied. Significant differences between M1 and M2 macrophages in terms of nuclear deformation, adhesion and cluster formation, were found.
1. Socio-economic impact of the project:
Regeneration and healing of non-functional tissues has become a serious challenge worldwide, due to the increase in life expectancy and the prevalence of age-related diseases. In the case of osteoarticular conditions, there is an urgent need to develop new bone graft substitutes that overcome the limitations of autologous bone grafting; the current gold standard. Such disadvantages include the need for a second surgery, patient morbidity and limited availability. The fact that bone is the second tissue most transplanted after blood, with 2.2 million bone grafts procedures performed annually worldwide, highlights the relevance of developing new biomaterials in this area. Orthopedic implants illustrate the extent of this problem as well. Currently approx. 1 million knee and hip replacement surgeries are done every year in the EU and the US, but the rate of implant failure within the first 10-20 years is as high as 10%.
These negative outcomes arise from the fact that bone growth is impaired in elderly patients or with clinically compromised scenarios (infections, osteoporosis, diabetes, cancer, etc.).
For example, osteoporosis, associated with low bone mass density and fragility, accounted for 3.5 million osteoporotic fractures in the EU in 2010 (4.5 million expected in 2025), with an estimated cost of €37 billion. In addition, osteoporotic patients (mostly women) suffer from metabolic imbalance, which hampers optimal bone regeneration. Type 2 diabetes is another major contraindication for the clinical success of bone grafts and implants, as it also significantly delays biomaterial integration and healing. Diabetes is becoming a global pandemic (projected to afflict >300 million individuals worldwide by 2025). Bacterial infections are one of the biggest challenges to ensure successful biomaterial performance and tissue regeneration. Infections on medical implants are initiated by planktonic bacteria, which act as primary colonizers, followed by a second phase, in which late colonizers irreversibly bind to the material substrate creating a bacterial biofilm. Once biofilms are formed they are very difficult to eradicate, as they are highly resistant to the immune system and conventional drugs. Moreover, the emergence of antibiotic resistance, e.g methicillin-resistant S. aureus (MRSA), poses a serious threat.
In summary, the two main reasons of implant failure are: 1) the lack of osteogenic and tissue-integrative potential; and 2) the onset of bacterial infections and biofilm formation. Bio-TUNE aims to address both.
2. Progress beyond the state of the art:
- Production of highly osteogenic materials using topographical cues or biofunctional coatings that either replace the use of BMPs or allow their spatial control and synergy with integrin ligands at very low doses.
- Effective inhibition of bacterial colonization on biomaterials without promoting anti-microbial resistance.
- Combination of new osteogenic and antibacterial strategies (based on both topographical and biochemical cues) to design biomaterials that promote cell adhesion and differentiation while inhibiting bacterial colonization.
- Monitoring the dynamics of bacterial and eukaryotic cell adhesion and their interactions. This would represent the first step towards implants with built-in sensing capabilities, which could provide quantitative information in real-time during the integration process. This could be of high value to predict low integration rates or infections, allowing taking actions to mitigate or revert the process.
Regeneration and healing of non-functional tissues has become a serious challenge worldwide, due to the increase in life expectancy and the prevalence of age-related diseases. In the case of osteoarticular conditions, there is an urgent need to develop new bone graft substitutes that overcome the limitations of autologous bone grafting; the current gold standard. Such disadvantages include the need for a second surgery, patient morbidity and limited availability. The fact that bone is the second tissue most transplanted after blood, with 2.2 million bone grafts procedures performed annually worldwide, highlights the relevance of developing new biomaterials in this area. Orthopedic implants illustrate the extent of this problem as well. Currently approx. 1 million knee and hip replacement surgeries are done every year in the EU and the US, but the rate of implant failure within the first 10-20 years is as high as 10%.
These negative outcomes arise from the fact that bone growth is impaired in elderly patients or with clinically compromised scenarios (infections, osteoporosis, diabetes, cancer, etc.).
For example, osteoporosis, associated with low bone mass density and fragility, accounted for 3.5 million osteoporotic fractures in the EU in 2010 (4.5 million expected in 2025), with an estimated cost of €37 billion. In addition, osteoporotic patients (mostly women) suffer from metabolic imbalance, which hampers optimal bone regeneration. Type 2 diabetes is another major contraindication for the clinical success of bone grafts and implants, as it also significantly delays biomaterial integration and healing. Diabetes is becoming a global pandemic (projected to afflict >300 million individuals worldwide by 2025). Bacterial infections are one of the biggest challenges to ensure successful biomaterial performance and tissue regeneration. Infections on medical implants are initiated by planktonic bacteria, which act as primary colonizers, followed by a second phase, in which late colonizers irreversibly bind to the material substrate creating a bacterial biofilm. Once biofilms are formed they are very difficult to eradicate, as they are highly resistant to the immune system and conventional drugs. Moreover, the emergence of antibiotic resistance, e.g methicillin-resistant S. aureus (MRSA), poses a serious threat.
In summary, the two main reasons of implant failure are: 1) the lack of osteogenic and tissue-integrative potential; and 2) the onset of bacterial infections and biofilm formation. Bio-TUNE aims to address both.
2. Progress beyond the state of the art:
- Production of highly osteogenic materials using topographical cues or biofunctional coatings that either replace the use of BMPs or allow their spatial control and synergy with integrin ligands at very low doses.
- Effective inhibition of bacterial colonization on biomaterials without promoting anti-microbial resistance.
- Combination of new osteogenic and antibacterial strategies (based on both topographical and biochemical cues) to design biomaterials that promote cell adhesion and differentiation while inhibiting bacterial colonization.
- Monitoring the dynamics of bacterial and eukaryotic cell adhesion and their interactions. This would represent the first step towards implants with built-in sensing capabilities, which could provide quantitative information in real-time during the integration process. This could be of high value to predict low integration rates or infections, allowing taking actions to mitigate or revert the process.