Periodic Reporting for period 1 - MiNeMI (Microneedle-assisted nanovector skin patch for immunomodulation of the inflammatory response upon occurrence of myocardial infarction injury (MiNeMi))
Período documentado: 2020-11-01 hasta 2022-10-31
ISSUE BEING ADDRESSED
Cardiovascular diseases (CVD) are the leading global cause of death, causing 17.9 million deaths (31%) in 2016. In Europe, CVD cause more than 3.8 million deaths every year, being ischemic heart disease alone responsible for 1.7 million deaths. Furthermore, 36% of myocardial infarction (MI) survivors will have an increased risk of developing heart failure. Despite the state-of-the-art application of emergency coronary revascularization (reperfusion) to patients with acute MI, mortality and morbidity have remained substantial. To date, the conventional therapeutics only ameliorate the state of care of MI patients, and no approved therapy has been developed for heart scars. Promising approaches might come based on the latest knowledge on new pathophysiological concepts, e.g. on the inflammation and immune responses upon MI. The inflammatory phase on MI presents itself as a therapeutic opportunity, with immunomodulation for heart regeneration showing great promise for MI treatment.
IMPORTANCE FOR SOCIETY
The development of a therapeutic capable of not only ameliorate the state of care of MI patients but also to induce restoration of functional cardiac tissue, would improve the quality of life of MI patients and diminish mortality and morbidity associated to MI. Additionally, it would reduce the economic burden associated to the healthcare strategies applied to MI patients.
OVERALL OBJECTIVES
The main aim of the project was to answer the question if it is possible to modulate the immune system to regulate inflammation and promote heart regeneration through a non-invasive approach. To this end, in this project, it was developed a novel and unique biodegradable non-invasive microneedle (MN)-assisted nanovector skin patch, loaded with nanoparticles and immunomodulatory (cytokines) cargos. The MN-patch approach would deliver the cargos into the dermal layer of the skin, a reservoir of immune cells, and revolutionize the way to regulate the inflammatory systemic immune response upon cardiac ischemia.
Cardiovascular diseases (CVD) are the leading global cause of death, causing 17.9 million deaths (31%) in 2016. In Europe, CVD cause more than 3.8 million deaths every year, being ischemic heart disease alone responsible for 1.7 million deaths. Furthermore, 36% of myocardial infarction (MI) survivors will have an increased risk of developing heart failure. Despite the state-of-the-art application of emergency coronary revascularization (reperfusion) to patients with acute MI, mortality and morbidity have remained substantial. To date, the conventional therapeutics only ameliorate the state of care of MI patients, and no approved therapy has been developed for heart scars. Promising approaches might come based on the latest knowledge on new pathophysiological concepts, e.g. on the inflammation and immune responses upon MI. The inflammatory phase on MI presents itself as a therapeutic opportunity, with immunomodulation for heart regeneration showing great promise for MI treatment.
IMPORTANCE FOR SOCIETY
The development of a therapeutic capable of not only ameliorate the state of care of MI patients but also to induce restoration of functional cardiac tissue, would improve the quality of life of MI patients and diminish mortality and morbidity associated to MI. Additionally, it would reduce the economic burden associated to the healthcare strategies applied to MI patients.
OVERALL OBJECTIVES
The main aim of the project was to answer the question if it is possible to modulate the immune system to regulate inflammation and promote heart regeneration through a non-invasive approach. To this end, in this project, it was developed a novel and unique biodegradable non-invasive microneedle (MN)-assisted nanovector skin patch, loaded with nanoparticles and immunomodulatory (cytokines) cargos. The MN-patch approach would deliver the cargos into the dermal layer of the skin, a reservoir of immune cells, and revolutionize the way to regulate the inflammatory systemic immune response upon cardiac ischemia.
In this project we produced MNs skin patches capable of modulating the immune system towards a regenerative and reparative response for post-MI application to and this way to enhance the restoration of functional cardiac tissue. For this purpose, during the reporting period, several materials have been tested to develop MNs and conjugated nanoparticles (NPs) to achieve the desired properties. Moreover, to enhance the mechanical properties of the produced MNs and form a fast-dissolving layer, polyvinylpyrrolidone was applied in different concentrations. The backing layer was also optimized and was composed of polyvinylpyrrolidone, polyvinyl alcohol and glycerol. To assess the mechanical properties of the MNs several techniques were applied such as, insertion into Parafilm membrane (to mimic the skin), insertion into porcine skin and compression studies using a texture analyzer.
To enhance the targeting to macrophages and modulate their polarization, the used NPs were conjugated with D-mannose. Furthermore, an immunomodulator was loaded into these NPs to further modulate the macrophages. The produced NPs were loaded into the MNs, and the loading and mechanical properties were assessed and compared to empty MNs. It was found that the loading was controllable by adjusting the concentration of NPs within the polymeric solution to prepare the MNs. Moreover, the NPs did not have a significant effect on the MNs physicochemical properties.
To study the effects of the MNs and NPs in vitro, different cell models were used. Firstly, immortal cell lines were used for cytotoxic studies. Afterwards, bone marrow derived macrophages were differentiated from monocytes isolated from mice bone marrow and used to assess the polarization potential of the developed systems. In these studies, it was found that the system was biocompatible and had the intrinsic ability to polarize the macrophages towards the M2 type.
Although additional studies are needed, the results derived from this project suggest the potential use of this MN patch loaded with NPs to modulate the immune system post-MI.
EXPLOITATION & DISSEMINATION
The results of the project were disseminated through a series of conferences (Controlled Release Society Annual Meeting and Expo 2022, Controlled Release Society Virtual Annual Meeting 2021) and publications (DOI: 10.1002/smll.202200291)
Moreover, a short video was created and is uploaded in Youtube (https://www.youtube.com/watch?v=mRi5yqtdrBE&list=PLSnFjP87sO23rxB9-XA7dQu9sbzE7RJPq&index=2(se abrirá en una nueva ventana))
To enhance the targeting to macrophages and modulate their polarization, the used NPs were conjugated with D-mannose. Furthermore, an immunomodulator was loaded into these NPs to further modulate the macrophages. The produced NPs were loaded into the MNs, and the loading and mechanical properties were assessed and compared to empty MNs. It was found that the loading was controllable by adjusting the concentration of NPs within the polymeric solution to prepare the MNs. Moreover, the NPs did not have a significant effect on the MNs physicochemical properties.
To study the effects of the MNs and NPs in vitro, different cell models were used. Firstly, immortal cell lines were used for cytotoxic studies. Afterwards, bone marrow derived macrophages were differentiated from monocytes isolated from mice bone marrow and used to assess the polarization potential of the developed systems. In these studies, it was found that the system was biocompatible and had the intrinsic ability to polarize the macrophages towards the M2 type.
Although additional studies are needed, the results derived from this project suggest the potential use of this MN patch loaded with NPs to modulate the immune system post-MI.
EXPLOITATION & DISSEMINATION
The results of the project were disseminated through a series of conferences (Controlled Release Society Annual Meeting and Expo 2022, Controlled Release Society Virtual Annual Meeting 2021) and publications (DOI: 10.1002/smll.202200291)
Moreover, a short video was created and is uploaded in Youtube (https://www.youtube.com/watch?v=mRi5yqtdrBE&list=PLSnFjP87sO23rxB9-XA7dQu9sbzE7RJPq&index=2(se abrirá en una nueva ventana))
In the MiNeMI project we were able to develop a MN patch loaded with NPs and immunomodulators capable of inducing polarization of macrophages towards the anti-inflammatory state. Moreover, we were also able to conjugate targeting groups into the NPs to enhance their targeting and uptake by macrophages. Overall, the MiNeMI project has shown that the developed system is biocompatible, and it has immunomodulatory properties capable of polarizing macrophages from a pro-inflammatory state to an anti-inflammatory state. Thereby, it is a promising approach for application post-MI.
Two of the main aspects of the project were to achieve socio-economic impact and societal implications. However, so far, the generated data doesn’t allow to make conclusions regarding these points. Nonetheless, the produced data is encouraging to promote further research on the developed system and expected to lead to socio-economic impact and societal implications if pursued and preclinical and clinal studies are carried out.
Two of the main aspects of the project were to achieve socio-economic impact and societal implications. However, so far, the generated data doesn’t allow to make conclusions regarding these points. Nonetheless, the produced data is encouraging to promote further research on the developed system and expected to lead to socio-economic impact and societal implications if pursued and preclinical and clinal studies are carried out.