Host response to biomaterials - pathophysiological mechanisms and therapeutic inhibition in biomaterials science

Our goal was to understand the acute reactions in blood when human tissue comes in contact with biomaterials. We aimed to aid biomaterials treatment in applications ranging from the implantation of vascular devices to the administration of nanoparticles. The ability to replace an organ, tissue, or function with a "spare part" is central in today's healthcare. The spare part is a biomaterial and is introduced as a treatment to improve the quality of life, for example, a hip prosthesis, mechanical heart pump, or dialysis filter. A biomaterial is foreign to the body, and its exposure to living tissue is rarely uncomplicated. Contact can cause inflammation and the risk of blood clotting when in contact with blood. These reactions are not desirable and can lead to severe complications. Our focus was mainly on the components of inflammation and blood coagulation and its cross-interactions in biomaterials treatment. Complications related to these host reactions may put the patient in danger or reduce treatment efficiency. Therefore, we studied aspects of host reactions to biomaterials in three parts. Below, we shortly describe the goal and the outcome of the project. 1. The aim was to study the biological mechanisms of how a thrombotic response can influence inflammation. We focused on a protein called thrombin and its interactions with an inflammatory system called the complement system, and a general aspect on activation of cells in the blood and its release of inflammatory mediators. We could show under which pathophysiological conditions thrombin activated C5, thus generating an inflammatory response. We showed that thrombin could modulate the acute inflammatory response in whole blood, but only if other stimuli simultaneously trigger the innate immune system. We identified that platelets specifically potentiated the inflammatory response by releasing soluble mediators which acted on leukocytes. Our data are presented in three separate manuscripts and presented at international conferences, showing modes of interaction between thrombosis and inflammation. 2. The second part aimed to study how biomaterials, flat surfaces, and nanoparticles, could trigger an inflammatory reponse in blood that afterward could affect endothelial cells, which are the cells lining blood vessels. This is an essential aspect of biomaterial treatment and nanoparticle administration; thus, it may cause adverse effects related to systemic inflammation. We thoroughly characterized the interaction between surfaces and blood. We specifically looked at protein binding, activation of coagulation, and the complement system in blood. We could show how endothelial cells are affected by nanoparticles and how phagocytes eliminate these particles in the blood. Our data are presented in three separate manuscripts, two on nanoparticles and one on flat surfaces, showing biomaterials recognition by innate immunity and subsequent inflammatory and thrombotic response. 3. In the third project, we focused on acute complications related to the implantation of a mechanical heart pump, a so-called LVAD. These pumps are implanted into patients suffering from severe heart failure. This treatment saves lives, but complications related to thrombotic reactions and excessive bleeding are associated with implantation. We sampled blood consecutively from patients reviving pump implants and analyzed plasma for biomarkers. We found increased levels of inflammatory and thrombotic markers early after implantation. The increase was especially pronounced immediately after implantation and declined a few days after implantation. Data from this study are presented in one manuscript. Taken together, we could show that device implantation and nanoparticle administration to human blood elicits acute inflammatory and thrombotic responses from activation of innate immunity and hemostatic systems. Moreover, these reactions are highly intertwined, where coagulatory protein thrombin could modulate the inflammatory response by activation of platelets.

The project has made possible development of thromboinflammation in biomaterials treatment in three specific projects. We have generated new data which have been published, or are to be published in scientific journals. This has a direct impact for the scientific community, especially for the understanding of biomaterial-induced thrombin-formation and the subsequent inflammatory response. All project have also led to new hypothesizes and they are now formulated in new grant proposals. Another outcome is the development of new experimental models. We have had several models to study thromboinflammation in human whole blood but all have been further developed. All participants have increased their scientific and methodological knowledge, which also had an impact on other projects. All parts of the project have involved national and international collaborators. Most collaborations have been intensified, some new have been initiated.

Implantation of a medical device, i.e. a biomaterial, into human tissue is inevitably associated with adverse reaction against the non-self biomaterial. Whether the device will be accepted by the host is determined by the biocompatibility, defined as the ability of the material to perform with an appropriate host response in a specific application. Central components in the acute reaction, and of focus in this project proposal, are the acute inflammatory and thrombotic processes which follow immediately after biomaterial implantation. These reaction are highly interconnected and referred to as "thromboinflammation". Thromboinflammation is also present in non-implantable biomaterials applications, e.g. in extracorporeal circulation and in nanoparticle drug delivery systems. A main challenge of experimental medicine is to employ an experimental system which resembles the complexity of the human in vivo pathophysiological mechanisms. By employing a novel model of human whole blood in combination with endothelial cells, a comprehensive panel of read-outs and therapeutic inhibitors, we have developed a system to investigate thromboinflammation in response to biomaterials exposure with high translational value. Our goal is to dissect mechanisms of thromboinflammation in the context of human whole blood to biomaterial response. This will aid in solving critical issues in biomaterials treatment, such as morbidity and mortality related to systemic inflammation in hemodialysis patients and thrombosis in patients on mechanical heart support. This work will increase our understanding on basic concepts of inflammation and thrombosis and generate new scientific knowledge with large impact for the scientific community. It will gain the individual patient by dissecting issues directly related to complications in biomaterial applications in the clinic. Further on, gain the society and biomaterials industry by promoting development of safer and better biomaterials.