03191nas a2200241   4500000000100000008004100001260001500042653001700057653001400074653002100088653002600109653002300135100002100158700002300179700002800202700002400230245011200254856007200366300000900438490000800447520248000455022001402935       2023                            d  c2023-01-0110abiomaterials10aEndotoxin10aImmunomodulatory10aRegenerative Medicine10aTissue engineering1 aDaniel Salthouse1 aKatarina Novakovic1 aCatharien M. U. Hilkens1 aAna Marina Ferreira00aInterplay between biomaterials and the immune system: Challenges and opportunities in regenerative medicine  uhttps://www.sciencedirect.com/science/article/pii/S1742706122007255  a1-180 v1553 aThe use of biomaterials for tissue engineering and regenerative medicine applications has increased dramatically over recent years. However, the clinical uptake of a wide variety of biomaterials remains limited due to adverse effects commonly exhibited by patients, which are caused by the host immune response. Despite this, current in vitro evaluation standards (ISO-10993) for assessing the host response to biomaterials have limitations in predicting the likelihood of in vivo biomaterial acceptance. Furthermore, endotoxin contamination of biomaterials is rarely considered, despite its ability to significantly affect the performance of biomaterials and engineered tissues. This review highlights the importance of the immune response to biomaterials and discusses existing challenges and opportunities in the development and standardised assessment of the immune response to biomaterials, including the importance of endotoxin levels. In addition, the properties of biomaterials that impact the host immune response and the exploitation of immunomodulatory biomaterials in regenerative medicine are explored. Finally, a standardised in vitro pathway of evaluating the immune response to biomaterials (hydrogels) and their regenerative potential is proposed, aiming to ensure safety and consistency, while reducing costs and the use of animals in the biomaterials research for tissue engineering and regenerative medicine.
Statement of significance
This review presents a critical analysis of the role of the interactions between the immune system and biomaterials in determining the therapeutic success of biomaterial-based approaches. No such review addressing the lack of understanding of biomaterial-immune system interactions during the developmental and pre-clinical stages of biomaterials, including the impact of the endotoxin levels of biomaterials on the immune response, is published. As there is a lack of in vitro regulations to evaluate the immune response to biomaterials, a standardised in vitro pathway to evaluate the immune response to biomaterials (hydrogels) and their immunomodulatory and regenerative potential for use in tissue engineering/regenerative medicine applications is presented. The aim of the proposed pathway of biomaterial evaluation is to ensure safety and consistency in the biomaterials research community, while reducing costs and animal use (through the concept of the 3R's - reduction, refinement, and replacement of animals).  a1742-7061