Biological Responses to Materials PDF

Volume 49 Number 15 7 August 2020 Pages 5103–5640 Chem Soc Rev Chemical Society Reviews rsc.li/chem-soc-rev ISSN 0306-0012 REVIEW ARTICLE Håvard J. Haugen et al. Biological responses to physicochemical properties of biomaterial surface Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue Biological responses to physicochemical This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. properties of biomaterial surface Cite this: Chem. Soc. Rev., 2020, Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. 49, 5178 Maryam Rahmati,a Eduardo A. Silva, b Janne E. Reseland,a Catherine A. Heywardc and Håvard J. Haugen *a Biomedical scientists use chemistry-driven processes found in nature as an inspiration to design biomaterials as promising diagnostic tools, therapeutic solutions, or tissue substitutes. While substantial consideration is devoted to the design and validation of biomaterials, the nature of their interactions with the surrounding biological microenvironment is commonly neglected. This gap of knowledge could be owing to our poor understanding of biochemical signaling pathways, lack of reliable techniques for designing biomaterials with optimal physicochemical properties, and/or poor stability of biomaterial properties after implantation. The success of host responses to biomaterials, known as biocompatibility, depends on chemical principles as the root of both cell signaling pathways in the body and how the biomaterial surface is designed. Most of the current review papers have discussed chemical engineering and biological principles of designing biomaterials as separate topics, which has resulted in neglecting the main role of chemistry in this field. In this review, we discuss biocompatibility in the context of chemistry, what it is and how to assess it, while describing contributions from both biochemical cues and biomaterials as well as the means of harmonizing them. We address both biochemical signal- transduction pathways and engineering principles of designing a biomaterial with an emphasis on its surface physicochemistry. As we aim to show the role of chemistry in the crosstalk between the surface Received 8th February 2020 physicochemical properties and body responses, we concisely highlight the main biochemical signal- DOI: 10.1039/d0cs00103a transduction pathways involved in the biocompatibility complex. Finally, we discuss the progress and challenges associated with the current strategies used for improving the chemical and physical rsc.li/chem-soc-rev interactions between cells and biomaterial surface. 1. Introduction function of the body, to maintain or improve the quality of life of the individual’’.4,5 Biomaterials engineering is a highly In the case of severe tissue injuries, the body is not able to interdisciplinary research field in which scientists (mostly with successfully repair the injured tissues.1 Owing to the emergence of a background in chemistry) introduce biological alternatives for tissue engineering and regenerative medicine fields, many promis- replacing or enhancing tissue and/or organ functions.1,6 Over ing treatment strategies are currently available for repairing and/or the past few decades, chemical scientists and engineers have replacing damaged tissues.2,3 However, there is no doubt that, if achieved substantial progress in designing promising bio- not all, most of these approaches are dependent on using chemical materials as key diagnostic or therapeutic solutions for several principles for designing biomaterials as biological substitutes that disorders.7–9 mimic and/or stimulate tissue functions. The American National Although considerable eﬀort is devoted to developing Institutes of Health defines a biomaterial as ‘‘any substance or biomaterials as successful tissue replacements for clinical combination of substances, other than drugs, synthetic or natural applications, most of the suggested strategies fail to match in origin, which can be used for any period of time, which the functional properties of targeted tissues in vivo, due to their augments or replaces partially or totally any tissue, organ or poor biocompatibility.1 The nature of the interaction of bio- materials with the surrounding biological microenvironment defines their biocompatibility. There is still a critical gap in a Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, successfully matching the biomaterial surface physicochemical 0317 Oslo, Norway. E-mail: h.j.haugen.odont.uio.no b characteristics to biochemical signal-transduction pathways Department of Biomedical Engineering, University of California, One Shields Avenue, Davis, CA 95616, USA in vivo. This gap could be owing to our poor understanding of c Oral Research Laboratory, Institute of Clinical Dentistry, University of Oslo, biochemical signaling pathways, lack of reliable techniques for 0317 Oslo, Norway designing biomaterials with optimal physicochemical properties, 5178 | Chem. Soc. Rev., 2020, 49, 5178--5224 This journal is © The Royal Society of Chemistry 2020 View Article Online Review Article Chem Soc Rev and/or poor stability of biomaterial properties after implan- biochemical signaling pathways of local innate immune cells and tation.10–13 The designed biomaterials for tissue engineering their receptors, the other neighboring tissues or factors around applications should have a strong affinity to targeted cells by the targeted tissue, and the biological systems a material might sending chemical and physical signals to stimulate neo-tissue face are very diverse in diﬀerent tissues.16,17 formation. Establishing strong positive interactions between From the materials engineering point of view, each physico- the biomaterial surface and cells is entirely dependent on both chemical property of the biomaterial surface (such as topo- the materials and targeted biological system chemistry.14 graphical features, stiﬀness, functional groups, and interfacial From the biochemical point of view, the features of cellular free energy) can profoundly aﬀect biochemical mechanisms niche are highly important. The cellular niche is a highly (Fig. 1). In addition, the commonly applied techniques and This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. complex tissue-specific microenvironment within a particular chemical strategies for modifying the surface properties can anatomic location providing physicochemical signals for cell influence biomaterial–cell interactions. Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. communication.15 Diﬀerent mechanotransduction, macro- Despite several reviews in the literature that address molecular adsorption and biochemical signaling pathways, the importance of surface properties in regulating cell which can be dependent on the tissue type, play key roles in responses,10,11,13,18–20 none of the recently published reviews determining the material’s success after implantation. The main have comprehensively discussed the vital roles of chemistry in Maryam Rahmati is a PhD Eduardo Silva is an Associate Research Fellow in Tissue Regene- Professor of Biomedical Engi- ration at University of Oslo. She neering at the University of is currently working on the corre- California, Davis. Dr Silva lation between recently developed obtained his degree in Metal- chemical and biological imaging lurgical and Materials Science techniques for analyzing body Engineering and PhD in Bio- responses to biomaterials. She is engineering from the University doing her PhD in Prof. Haugen’s of Porto. Dr Silva has been research group and her projects studying polymeric biomaterials, are funded by European Training including alginate and chitosan, Network within the framework of for over 15 years. The long-term Maryam Rahmati Horizon2020 Marie Skłodowska- Eduardo A. Silva goal of his current research is Curie Action (MSCA). She was to engineer biomaterials for awarded a master’s degree in biomaterials science from controlled delivery of cells, drugs and/or genes. Dr Silva received Materials and Energy Research Center, Tehran, Iran, 2016. She several honors and awards, including the Hellman Family Fellow worked as a biomaterials and tissue engineer at Iran University of and the Biomaterials Emerging Investigator award. He has 8 Medical Sciences, Tehran, Iran, 2016–2018. patents or patent applications and Novartis recently licensed one of his patents. Dr Janne E. Reseland obtained Catherine A. Heyward completed her PhD in biochemistry from her MBiochem at Oxford Univer- the University of Oslo (UiO) in sity in 2001, and PhD in lipid 1995. She was a postdoc fellow signalling under the supervision and research scientist at the of Prof. Michael Wakelam at the Faculty of Medicine, UiO, for a University of Birmingham in period of 8 years. In 2003 2006. Since then she has worked Reseland started working on the on live cell confocal imaging for development of stable extra- the study of numerous proteins. cellular matrices as novel thera- She has also trained others in the peutics for biomimetic induction preparation and imaging of of hard tissue growth at the samples at the Institute for Janne E. Reseland Institute for Clinical Dentistry, Catherine A. Heyward Biological Sciences at the Faculty of Dentistry, UiO. University of Oslo. She currently Reseland became an associate professor in 2005 and a professor works at the Institute for Clinical Dentistry at the University of in Biomaterials at the Department of Biomaterials in 2007. She is Oslo, where she is responsible for histology and imaging of a range currently (from 2010) the head of the Oral Research Laboratory. of biomaterial samples. This journal is © The Royal Society of Chemistry 2020 Chem. Soc. Rev., 2020, 49, 5178--5224 | 5179 View Article Online Chem Soc Rev Review Article This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. Fig. 1 An illustration of the key surface physicochemical properties in directing biological responses to biomaterials. Biomaterials can manipulate molecular and cellular signaling pathways through their surface physicochemical properties (e.g. topography, stiﬀness, functional groups, biological moieties, ions, charges, and surface free energy). regulating biological pathways, manipulating biomaterial surface biomaterials, we briefly highlight the main biochemical signal- properties, and directing molecular and cellular responses after ing mechanisms and concepts of biocompatibility. Then, we biomaterial implantation. In addition, it is time to provide an address the current progress and challenges in biological updated state-of-the-art and future perspective for researchers in responses to biomaterial surface physicochemical properties this field based on the recent chemical, physical and biological such as topographical features, functional groups, interfacial research findings. This review aims at emphasizing the key roles free energy, ion enrichment, and biological moieties. Although of chemistry in determining the biocompatibility of biomaterials we use biomaterials in different tissue engineering applications, by presenting an overview of both biochemical and chemical reliable evaluation of biological responses is still a big challenge. engineering principles and challenges in designing biocompatible Altogether, this review provides an overview of the progress systems. As biochemical signaling pathways of the immune and challenges of each part to the readers; however, due to the system are critical factors in determining the success of complex nature of biological responses to biomaterials, not all related issues are possible to discuss here. Professor Haugen is the leader of 2. Using biomaterials for tissue Biomaterials group, Faculty of regeneration applications Dentistry, University of Oslo. He received his master’s degree in The self-renewal potential of tissues decreases or completely chemical engineering from Imperial disappears over time due to several reasons such as increasing College, UK, in 2001, and his PhD age, reducing the amount and capability of host stem cell/ in biomaterials from Technische progenitor populations, naturally poor repair potential of Universität München, Germany, in tissues, or undesirable inflammatory responses in damaged 2004. He worked as a scientist at tissues and/or organs.21,22 Tissue engineering and regenerative the Central Institute for Medical medicine approaches represent a clinically appealing and pro- Engineering, Munich, Helmholtz mising strategy to repair biological processes associated with Institute for Biomedical Engi- injured tissues.22 In the past few decades, scientists have used Håvard J. Haugen neering, Aachen and the Tissue various cell types as key elements in diﬀerent tissue regenera- Engineering Centre of Imperial tion therapies.23–25 However, if cells are transplanted freely into College, London. Haugen has been awarded many research the body, only a small proportion might reach the targeted grants and innovation awards from both the European Research tissue.26 Council and the Research Council of Norway. Haugen was the past Biomedical scientists use naturally occurring chemical President of the Scandinavian Society for Biomaterials. processes as an inspiration to design new biomaterials. Diﬀerent 5180 | Chem. Soc. Rev., 2020, 49, 5178--5224 This journal is © The Royal Society of Chemistry 2020 View Article Online Review Article Chem Soc Rev classes of biomaterials are designed to oﬀer suitable micro- controlled degradation rate, optimal physicochemical properties, environments for enhancing cell engraftment, including both and stimulating ideal biochemical signaling pathways.42,43 Thus, naturally occurring and synthetic polymers, ceramics, metals composite biomaterials designed by combining the chemistries of and composites (Fig. 2).26,27 Implanted biomaterials in tissue diﬀerent materials tend to exhibit greater success in stimulating engineering are categorized generally into two main groups: tissue regeneration after implantation.44,45 Manipulating the (i) auto-, allo- or xeno-based cellularized or decellularized biomaterial surface physico-chemistry based on the targeted scaﬀolds known as natural/physiological polymers (e.g. proteins, site is essential for achieving optimal biological performance. polysaccharides and decellularized tissue matrices) and (ii) other Indeed, selecting biomaterials for tissue engineering applications materials such as synthetic polymers, implants, ceramics and is reliant on their physicochemical surface properties such This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. composites.5 Chemical strategies can be employed for designing a as surface roughness,46 architecture,47 charge,48 energy,49 and wide range of naturally occurring and synthetic biomaterials while functional groups.50 Hence, the eﬀects of each physicochemical Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. stimulating cells to secrete and deposit the native extracellular surface property on the biological performance of biomaterials matrix (ECM) locally.28–30 The substantial progress in chemical should be precisely investigated in vitro and in vivo.37 and tissue engineering fields has led to the existence of smart biomaterials as promising therapeutic solutions for several devastating disorders. Nowadays, we clinically use biomaterials 3. The evolution of the definition of as valid therapeutic candidates for various tissue regeneration host responses applications such as musculoskeletal system,31 cardiovascular system,32 neural system,33 and skin.34 In addition, biomaterials In the early 20th century, a prodigious revolution took place in can affect the results of regenerative medicine strategies such as both therapeutic and diagnosis strategies through designing cell-based therapies, and engineered living tissues or organs.35 synthetic biomaterials by manipulating the chemistry of For successfully using biomaterials in the medicine world, materials.51 Since naturally occurring chemistry was used for designed biomaterials should be able to enhance the cell designing biomaterials, modifying and/or proving their biolo- survival and functions after transplantation as well as stimulate gical safety were among the most challenging issues in this autologous tissue growth.36,37 The designed biomaterials for field. Some decades ago, James Anderson defined foreign body tissue regeneration applications should provide provisional reactions to biomaterials by demonstrating short- and long-term mechanical support and mass transport to stimulate biochemical inflammatory responses to biomaterials and the substantial roles signaling pathway functions toward tissue healing.38 Additionally, of macrophages in each step.16,52–54 Owing to Anderson group’s biomaterials could increase the success of tissue regeneration by work, the biomedical scientists’ understanding of molecular and sending physicochemical signals with spatiotemporal precision cellular responses to biomaterials increased so that these days at toward cells.39 With this concept, a biomaterial is dynamically the time of designing each biomaterial its effects on the foreign involved in providing some physicochemical cues to targeted cells body responses determine its biocompatibility. resulting in neo-tissue formation.40 For initiating biochemical Although this definition favors non-degradable inert bio- signaling pathways, considering the presence of soluble signaling materials, it cannot thoroughly define the body responses to molecules such as growth factors and cytokines is also the recently developed biomaterials with bioactive degradable important.41 surfaces suitable for tissue regeneration.10,11,13,55 Owing to the On the other hand, scaﬀolds designed from one material advances in chemistry, the recently developed biomaterials type would not be able to meet the requirements for tissue are designed and formulated to stimulate diﬀerent bio- regeneration applications, which is owing to the absence of a chemical signaling pathways. In these cases, we could not define Fig. 2 An illustration of the role of chemistry in bridging the gap between biomaterials engineering and biology. The chemistry-driven processes in the body have inspired biomedical engineers to fabricate biomaterials using chemical strategies. Chemistry promotes tissue regeneration through designing diﬀerent biomaterials for stimulating cells to deposit the native extracellular matrix (ECM). This journal is © The Royal Society of Chemistry 2020 Chem. Soc. Rev., 2020, 49, 5178--5224 | 5181 View Article Online Chem Soc Rev Review Article biocompatibility as only not having any adverse eﬀects.56 The network of {–NH–CaHR–CO–}, where R describes a specific designed biomaterials should have a strong aﬃnity for targeted side group structure that gives the amino acid its specific cells to stimulate biochemical signaling pathways toward the functional properties. Based on the R structure, the amino neo-tissue formation. This ability is entirely dependent on the acids are divided into three main types: nonpolar, polar, and specific chemical characteristics of both the material system and charged amino acids, in which each class has an affinity to the biological environment of targeted tissue.14 surfaces with unique physicochemical properties.14,62 Furthermore, The biomaterial surface physicochemical properties such the size of proteins affects their adsorption to the biomaterial as charges, functional groups, biological moieties, and ion surface. Small proteins move faster and are responsible for the enrichment play key roles in directing biological responses to primary adsorption on surfaces. However, the larger proteins This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. biomaterials.14,56 From the biochemical perspective, diﬀerent have higher affinity to the surface, which is owing to their greater mechanotransduction, physiological, macromolecular adsorp- surface area.63 Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. tion and biochemical signaling pathways are crucial, which can Moreover, the protein conformation defines its structure, be diﬀerent from tissue to tissue. Because diﬀerent tissues and bioactivity and communication with other biomolecules on the cells have diﬀerent chemical signals and physical characteristics, surface.64 Most proteins have at least one active region to it is hard to say whether a material compatible with one adsorb on the biomaterial surface, ligands, and receptors. tissue will make positive interactions with other cell types and The receptor domain of extracellular molecules accepts a signal tissues.10,13 In addition, although both innate and adaptive from the upstream part and as a result changes its conformation, immune systems respond to biomaterial implantation, their leading to stimulating the formation of a ligand binding biochemical cues are diﬀerent from each other, which requires domain.14 These receptor binding proteins are connected into a evaluating their responses individually.57 chain, which transmit the biochemical signals across the cell membrane.14 Researchers can achieve diﬀerent protein–surface interactions through modifying the physicochemical properties of 4. The classical perspective of proteins.14 biological responses to biomaterials Monocytes released into the area diﬀerentiate into type 1 and type 2 macrophages. Type 1 macrophages are responsible The host responses to biomaterials mainly originate from for the acute inflammatory phase and release pro-inflammatory biochemical signals and cues. As our knowledge in the bio- factors. On the other hand, type 2 macrophages are responsible chemistry field has tremendously grown since the first defini- for the chronic inflammatory phase and release anti- tion of biocompatibility, we should update our definitions inflammatory factors.59,60,65,66 regarding host responses to biomaterials. Here we briefly discuss Monocytes, type 2 macrophages, and lymphocytes control the out-of-date concept of cellular responses and biochemical the chronic inflammatory phase. During this phase, tissue signaling pathways involved in foreign body responses to bio- granulation, fibroblast infiltration, and neovascularization materials. Then, we provide an overview of the recently updated occur, which can subsequently lead to the formation of blood biochemical signaling pathways in the next sections. vessels and connective tissue to allow wound healing to Foreign body responses to implanted biomaterials are proceed.66,67 In the wound healing phase, the proliferation of generally defined as a sequence of body reactions, which start fibroblasts and vascular endothelial cells changes the fibrin instantly after biomaterial implantation.14,56 With this concept, clot into an extremely vascularized granulation tissue. The after biomaterial implantation, the tissue injury stimulates presence of several growth factors is important in this phase several chemical signaling cascades, which result in a sequence including platelet-derived growth factor, fibroblast growth of acute and chronic inflammatory as well as wound healing factor, transforming growth factor-b, transforming growth responses.58,59 Protein adsorption, neutrophils, and type 1 factor-a/epidermal growth factor, interleukin-1 (IL-1), and macrophages direct the acute inflammatory phase. This phase tumor necrosis factor.68–70 Fibroblasts are also active in synthe- is essentially responsible for provisional matrix formation and sizing collagen and proteoglycans, which lead to replacement wound site cleaning, which can take from some hours to days.60 of the granulation tissue with ECM (Fig. 3). Depending on the After the release of some biochemical cues, blood vessels severity of injury at the implanted site, tissue type, and bio- start expanding and consequently more blood flows into the material properties, the acute phase takes less than one week injured area. Some blood and tissue proteins (such as fibro- and the chronic phase about two weeks.71,72 nectin, fibrinogen, vitronectin, complement C3, albumin and Based on this traditional definition of foreign body responses growth factors) as well as leukocytes are released, which adhere to biomaterials, the ability of a biomaterial to stimulate minimal to the blood vessel endothelium.59–61 inflammatory responses defines its success. Hence, the focus in Proteins are made from 20 natural amino acids. A linear designing biomaterials is on reducing foreign body responses chain of amino acid residues is called a polypeptide. A protein through directing macrophage responses. However, because contains at least one long polypeptide. Short polypeptides, allowing natural body responses to occur is more useful for both containing less than 20–30 residues, are rarely considered as biomaterial integration and function, this definition started to proteins and are commonly called peptides, or sometimes be redefined over the past few years.73–75 The synchronization oligopeptides. Each amino acid has a general backbone between inflammation and its resolution is essential for wound 5182 | Chem. Soc. Rev., 2020, 49, 5178--5224 This journal is © The Royal Society of Chemistry 2020 View Article Online Review Article Chem Soc Rev Responsible cells in the innate immune system consist of phagocyte cells (including dendritic cells, monocytes, and macrophages) and lymphocytes (natural killer cells, gamma delta T-cells, and innate lymphoid cells).16,81,82 However, the adaptive immune system is responsible for showing particular antigen responses and making a long-term memory through B and T lymphocytes.16,81,83 A suitable immune system response requires organized crosstalk between these two systems, where chemical cues are This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. intrinsically present and play pivotal roles. After biomaterial implantation, the degradation products and subsequent Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. chemical surface changes of biomaterials can stimulate the immune system.71 The interactions between the surface and the immune system are reliant on the targeted tissue nearby the biomaterial causing tissue-specific biochemical responses.81 After biomaterial implantation, the native vasculature is likely to be disrupted, which could induce interactions between blood and the implanted biomaterial.56 Depending on the biomaterial surface physicochemistry, the plasma constituents including proteins, lipids, sugars, and ions can be adsorbed on it.77 Platelets, which through aggregation and coagulation form a fibrin-rich clot, are also a part of the blood exudate. The formed clot is a temporary provisional matrix for supporting cellular and molecular functions.84 The adsorbed proteins elicit biochemical signaling pathways and make interactions with the innate immune system cells such as neutrophils, monocytes, fibroblasts and endothelial cells Fig. 3 An illustration of the traditional concepts regarding foreign body responses to the biomaterial surface. The foreign body responses are a through their particular recognition sites including C-termini, combination of both acute and chronic phases of inflammation. The N-termini, proline–histidine–serine–arginine–asparagine (PHSRN) mechanism starts with protein adsorption and desorption (Vroman bind- and arginine–glycine–aspartic acid (RGD).85–87 ing) on the surface of the biomaterial after its implantation. It continues Neutrophils are commonly the first responders to foreign with thrombin formation through activating platelets. After that, mono- materials. These cells are stimulated when the adsorbed pro- cytes diﬀerentiate into type ‘‘1’’ macrophages which are responsible for the acute phase of inflammation. After some days, type ‘‘1’’ macrophages teins (RGD, PHSRN), microbes (pathogen associated molecular diﬀerentiate into type ‘‘2’’ macrophages which are responsible for chronic patterns or PAMPs), and/or dead cell residues (damage- inflammation. T cells and mast cells also express cytokines that increase associated molecular patterns or DAMPs) bind to their ligands foreign body giant cell (FBGC) creation. In addition, FBGCs express through biochemical reactions.87–90 The adsorbed proteins fibroblast-recruiting factors and consequently by collagen deposition, a bind to macrophage type 1 antigen, lymphocyte function- capsule starts forming around the biomaterial. associated antigen 1, and integrin alphaXbeta2. However, DAMPs and PAMPs bind to toll-like receptors (TLRs) and some healing, which is dependent on the biochemical signaling path- specific pattern recognition receptors (PRRs), which also exist ways and cues.76 To enhance the healing process, biomaterials are on the surface of macrophages and dendritic cells.87,91 currently designed with a focus on improving their chemical Neutrophils stimulate the expression of cytokines as pro- interactions with immune system components.77–79 inflammatory chemical mediators through sending biochemical signals.92,93 These chemical mediators stimulate directed chemo- taxis of other innate inflammatory cells and dendritic cells, which 5. The role of innate and adaptive leads to the stimulation of adaptive immunity responses through immune systems and biochemical cues B and T lymphocytes.77,94 in biological responses to biomaterials DAMPs are endogenous molecules that under normal phy- siological conditions are sequestered intracellularly and cannot The immune system is the main biological network, which be recognized by the innate immune system.95 Nevertheless, releases biochemical cues responsible for protecting the body under cellular stress or injury conditions, they are released into against foreign materials and keeping homeostasis. It consists the extracellular environment leading to the transmission of two main parts: innate and adaptive immune systems. of biochemical signals to cells for initiating inflammatory Just after the instant recognition of foreign materials, the responses under sterile conditions.95 The DAMP release from innate immune system causes a non-specific inflammatory cells depends on the type of cell injury or death. Chromatin- response through a chain of biochemical reactions.16,77,80,81 associated protein, high-mobility group box 1, heat shock This journal is © The Royal Society of Chemistry 2020 Chem. Soc. Rev., 2020, 49, 5178--5224 | 5183 View Article Online Chem Soc Rev Review Article proteins, and purine metabolites are prototypical DAMPs After the polarization of type 1 macrophages to type 2, they derived from damaged cells.95–98 Furthermore, ECM degrada- locally release several growth factors (such as transforming tion can send biochemical signals for releasing DAMPs. DAMPs growth factor beta and vascular endothelial growth factor) can initiate inflammatory responses, and the lack of DAMPs while stimulating fibroblast and endothelial cell migration in the environment leads to a decrease of inflammatory bio- and proliferation by sending biochemical signals. Fibroblasts chemical cues.99 produce collagen to form the ECM, whereas endothelial cells There are diﬀerent types of PRRs in the innate immune nourish the formation of new blood vessels to oﬀer essential system that stimulate the expression of various types of pro- nutrients for neo-tissue formation as well as for waste inflammatory cytokines and biochemical markers. According to removal.118 In the chronic inflammatory phase, T lymphocytes, This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. the subcellular location of PRRs, they are classified into two mainly helper T cells, play key roles in controlling the expression main groups: (i) TLRs and C-type lectin receptors, which are of pro- and anti-inflammatory mediators.119 In this system, B Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. transmembrane proteins, and (ii) RIG-I-like receptors (retinoic lymphocytes are responsible for making antibodies (Fig. 4).120 acid-inducible gene-I-like receptors, RLRs) and NOD-like Immune-modulatory biomaterials should direct biochemical receptors (NLR), which exist in the intracellular compartments. signaling pathways and cues, which are responsible for the PAMPs and DAMPs activate these receptors and subsequently functions of neutrophils, PAMPs, DAMPs, inflammasomes, inflammasome complexes.100,101 endothelial cells, and mesenchymal stem cells (MSCs).121 The inflammasome complex contains a cytosolic sensor that As describing the details of innate and adaptive immune can be a PRR of the NLR, absent in melanoma 2 (AIM2) receptors, system mechanisms and the responsible biochemical cues is and an eﬀector protein.102 There are various types of PRRs, which out of the scope of this review, we refer the readers to the can form inflammasomes such as NLRP1, NLRP3, NLRC4 (the following seminal review papers.16,73,77,80,95 NLR family of intracellular proteins) and AIM2.103–105 In response to PAMPs and DAMPs, the pentameric or heptameric assembly of PRRs can oligomerize the caspase 6. The roles of ion channels in recruitment domain in filaments. This might cause the inflam- regulating immune system responses masome formation through stimulating caspase-1.106 The NLRP3 inflammasome is the most known inflammasome, Cell surface receptors play key roles in receiving biochemical which contains the NLRP3 scaﬀold, caspase recruitment domain signals (from chemical substances such as hormones, growth adaptor protein, caspase-1, and accessory protein serine/ factors, cell adhesion molecules, nutrients, and neurotransmitters) threonine-protein kinase.107,108 Monocytes, macrophages, and initiating biochemical and/or biophysical signaling in the granulocytes, dendritic cells, epithelial cells and osteoblasts cells.123–126 Ion channels are a class of surface receptors, which mainly express this inflammasome.109 control many cellular signaling events in cells.127–129 Ion exchanges After cellular injury through biomaterial implantation, between the intra and extracellular environments create the DAMPs and PAMPs activate the NLRP3 inflammasome through mechanisms essential for controlling the cell metabolism and sending biochemical signals.110,111 Examples of such stimuli activation state.130 In addition, ion channels are important from the DAMP group are crystalline matter such as asbestos, regulators of cell–cell communication. As a result, genes calcium influx, mitochondrial reactive oxygen species (ROS), encoding proteins responsible for regulating membrane perme- and extracellular neurotransmitter adenosine triphosphate ability to ions are also vital in most of the complex intra and (ATP).112 However, this process is not yet fully understood extracellular signaling events.130 Because of the key roles of and needs further detailed studies.73 The inflammasome immune cells in controlling foreign body responses, we discuss can through subsequent control over the rest of immune some ion channels that regulate innate and adaptive immune response processes either cause the resolution of inflammation system responses here. and tissue regeneration, or lead to chronic inflammation Ion channels direct immune responses mostly by regulating and fibrosis.113 After inflammasome expression, the migrated endosomal pH and intracellular calcium concentrations.131,132 monocytes/macrophages adhere to the temporary provisional Regulating the intracellular calcium amounts is dependent on matrix formed on the biomaterial surface.114 the biophysical properties of the ion channels and their ability After 24 to 48 hours, the activated neutrophils die through to control the calcium passage across the membrane.130 The apoptosis and release some vesicles and lipids through bio- calcium permeability can be changed by activating particular chemical signals (e.g. lipoxins and resolvins), which have anti- ligands, feedforward responses to the calcium release from inflammatory influences.87,115,116 Hence, neutrophils through intracellular stores, changes in cell polarization, and the binding to PAMPs and DAMPs and initiating inflammasome strength of sodium driving force.130 responses are vital for activating type 1 macrophages and the In adaptive immune system cells (B- and T-lymphocytes), acute inflammatory phase. Apoptotic neutrophils are also crucial regulating the intracellular calcium amount is important as for stimulating macrophage polarization from type 1 to type 2 and releasing calcium from intracellular stores activates the the following inflammation resolution. Therefore, if their lifespan immune response pathways.133 In addition, the CAV1 (caveolin 1) is extended and/or if they increase in number at the biomaterial ion channel (as a subfamily of L-type voltage-gated calcium channels) surface, chronic inflammation can occur at the site.117 is vital in activating B- and T-lymphocytes.134,135 5184 | Chem. Soc. Rev., 2020, 49, 5178--5224 This journal is © The Royal Society of Chemistry 2020 View Article Online Review Article Chem Soc Rev to the neurotransmitters adenosine triphosphate (ATP) and glutamate, respectively.139 By regulating the intracellular calcium concentration, these receptors can aﬀect microglial activation. P2X receptors (P2XRs) are trimeric plasma membrane channels, permeable to small inorganic cations (e.g. Na+, K+, and Ca2+).127,140 However, some P2XR channels are permeable to both cationic and anionic organic ions.141 Ferreira et al.142 studied the Ca2+-activated K+ channel (KCa3.1)- dependent responses in microglia under ROS.142 They concluded This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. that increasing the cyclic guanosine monophosphate (cGMP) concentration leads to protein kinase activation and, subsequently, Open Access Article. Published on 09 July 2020. Downloaded on 10/11/2022 2:51:58 AM. ROS formation in mitochondria. The ROS formation causes endo- plasmic reticulum calcium release, which subsequently binds to calmodulin to activate the KCa3.1 channel.142 Connexin and pannexin cell–cell channels, unopposed hemichannels as well as P2 receptors are essential in initiating and regulating the inflammatory responses.143 For instance, the activation of connexin and pannexin channels leads to the release of ATP and other metabolites to the extracellular media. Extracellular ATP can stimulate intracellular signaling pathways by acting on P2 receptors, which leads to inflammation.143 Overall, the activation of ion channels can be ‘‘danger’’ signals propagating the inflammatory responses of immune systems.143 Their biochemical eﬀects on cell homeostasis aﬀect the immune system functions.133 Therefore, the activation of ion channels can be vital in directing the host responses to Fig. 4 Innate and adaptive immune system responses. Recruited and biomaterials. However, more research on understanding resident macrophages start experiencing marked phenotypic and func- the ion channel roles in regulating signaling pathways and tional changes in response to damage-associated molecular patterns directing cell–biomaterial interactions is vital. (DAMPs), pathogen associated molecular patterns (PAMPs), growth factors, cytokines, and other mediators released into the interface area. The main phenotypic changes regulate inflammation, tissue repair, regeneration, and resolution. Macrophages then express diﬀerent types 7. The role of mesenchymal stem cells of factors which can direct diﬀerent functions in fibroblasts, epithelial cells, endothelial cells, and stem and progenitor cells to promote tissue repair. in biological responses to biomaterials During the final stages of the healing process, a regulatory pro-resolving MSCs have many roles in modulating the immune system phenotype, which confirms the suppression of the tissue-damaging inflammatory response, is expected. If the process does not successfully responses to implanted biomaterials, particularly in bio- proceed, persistent inflammation and/or maladaptive repair processes can chemical signaling pathways responsible for stimulating the cause tissue-destructive fibrosis. Sometimes, the recruited monocytes innate immune system.144,145 These cells can have immuno- lead to the formation of a resident macrophage phenotype in tissues.122 suppressive roles by releasing several soluble biochemical Abbreviations: DAMP, damage-associated molecular pattern; PAMP, factors responsible for controlling the functions of lymphoid pathogen-associated molecular pattern; Treg cell, regulatory T cell; IRF5, interferon regulatory factor 5; NOS2, nitric oxide synthase 2; LXR, liver X and myeloid cells.145–147 For example, prostaglandin E2 (PGE2) receptor; AREG, amphiregulin; Arg1, arginase-1; IRF4, interferon regulatory synthesized by MSCs can stimulate macrophages to have an factor 4; PPARg, peroxisome proliferator-activated receptor g; FGF, fibro- adapted directing phenotype by increasing IL-10 and decreasing blast growth factor; GAL-3, galectin-3; TGF, transforming growth factor; tumor necrosis factor-a and IL-12 expression.148 The biochemical GR, glucocorticoid receptor; ATF3, activating transcription factor 3; SOCS, soluble factors released by MSCs (e.g. IL-10, PGE2 and IL-1b) can silencer of cytokine signaling. play vital roles in the crosstalk between MSCs and macrophages, mainly in macrophage type 1 to 2 polarization.149 In addition, Increasing ROS activates transient receptor potential mela- interferon gamma and tumor necrosis factor-alpha cytokines statin (TRPM) 2 ion channels.136 The TRPM2 activation causes the expressed

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