Neutrophils at the BiologicalâMaterial Interface - American Chemical

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Neutrophils at the Biological−Material Interface Siddharth Jhunjhunwala* Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India 560012 ABSTRACT: Integral to the development of new biomaterials is the characterization of immune responses to biomaterial implants, and formulating methods to overcome or utilize these actions for therapeutic benefit. Neutrophils are an essential component of the immune response against biomaterials, but studies on the neutrophil−biomaterial interaction have been largely limited to characterizing their role in establishing an inflammatory microenvironment and antimicrobial activity at implant surfaces. Recent advances in neutrophil biology, especially recognition of their cellular heterogeneity, ability to suppress immune responses, the identification of a new process of cell death, and crosstalk with other immune cell types, have brought about a fundamental change in our perception regarding the activities of neutrophils. Herein, in the context of the progress in our comprehension of neutrophil function, potential avenues for effectively employing neutrophil activity to develop the next generation of regenerative biomaterials are discussed. KEYWORDS: polymorphonuclear cells, fibrosis, foreign body response, tissue engineering

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INTRODUCTION Implantation of materials of biological or synthetic origin results in disruption of the local tissue architecture that triggers the body’s defense system. The principal aim of this system is to degrade the implant and rebuild local tissue, which it may achieve through the concerted effort of a variety of immune cells.1−4 Key cellular players in this process are neutrophils, the first circulating immune cells that respond to tissue-injuries.5 At injury sites, the primary role of neutrophils is to kill potential pathogens through a variety of mechanisms that include but are not limited to phagocytic uptake and neutralization of microbes, release of reactive oxygen species and granule proteins, and the secretion of inflammatory cytokines.6,7 Traditionally, neutrophil responses to biomaterials were presumed to be predominantly a secondary effect of the aforementioned actions, which result in alteration of local tissue environment and facilitate recruitment of other immune cells, such as monocytes. Recent advances in neutrophil biology have revealed that these cells have broader mechanisms of action, resulting in their involvement in a wider range of immune responses at sites of tissue injury.8 For example, neutrophils are now known to undergo a process of cell death that leads to the release of intranuclear DNA into the extracellular space, forming neutrophil extracellular traps (NETs).9,10 Additionally, it has been suggested that various subsets of neutrophils or their progenitors have suppressive functions, which might help with resolution of inflammation and potentially promote tissue growth.11 These new findings have raised questions regarding the exact nature of interactions between neutrophils and biomaterials. Also, they have brought up the possibility of © 2017 American Chemical Society

directly modulating neutrophil function or harnessing suppressive neutrophils to reduce inflammatory reactions against biomaterials. As our understanding of the role of neutrophils in the wound healing response expands, characterizing neutrophil−biomaterial interactions in the context of these advances is essential for designing biomaterials with better compatibility and functionality. The aim of this article is 2-fold: to review recent literature on the interactions between neutrophils and biomaterials; and, to provide broad summary of recent developments in our comprehension of neutrophil biology and associated implications on the development of new regenerative biomaterials.

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NEUTROPHIL−BIOMATERIAL INTERACTION Implantation of any biomaterial (biological and synthetic origin, soft and hard mechanical properties, smooth and rough texture, charged and neutral surface, etc.) elicits an immune reaction involving sequential events that finally result in phagocytosis or degradation or fibrosis of the implant. The immune response begins during the process of biomaterial implantation, as the surgical or injection procedure causes tissue damage resulting in the local generation of endogenous damage associated molecular patterns (DAMPs).12 Along with DAMPs, the injured epithelial/endothelial cells and activated platelets secrete numerous cytokines including two potent neutrophil Special Issue: Regenerative Biomaterials Received: December 1, 2016 Accepted: March 17, 2017 Published: March 17, 2017 1128

DOI: 10.1021/acsbiomaterials.6b00743 ACS Biomater. Sci. Eng. 2018, 4, 1128−1136

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ACS Biomaterials Science & Engineering

Figure 1. Overview of the interactions between neutrophils and biomaterials, highlighting some of the key molecular players.

colleagues21−25 have elegantly demonstrated that upon interaction with biomaterials ex vivo cultured human neutrophils also produce ROS, release granule proteins (myeloperoxidase and matrix metalloprotease-9 (MMP-9)), and secrete the cytokine MIP-1β and human neutrophil peptides. Specifically, they show that PEG containing hydrogels resulted in increased secretion of all the aforementioned molecules (except for ROS) in comparison to PDMS, gelatin scaffolds and tissue culture polystyrene. Further, they show that these increases were a result of neutrophil adhesion to material surfaces and were mediated by signaling through the intracellular Src family kinase and phosphoinositide 3-kinase-γ.25 Human neutrophil interactions with hydroxyapatite particulates and fibers show similar responses with an increase in secretion of MMP-9, the cytokines/chemokines IL-1α, IL-8, macrophage inflammatory protein-1α (CCL3) and macrophage inflammatory protein-1β (CCL4),26 and ROS production.27 Additionally, their interaction with polyester grafts haa been shown to bring about secretion of neutrophil elastase (another granule protein).15 Through multiple investigations Girard and colleagues show that human neutrophil interaction with metal oxide (primarily titanium oxide) nanoparticles results in increased production of IL-8, secretion of myeloperoxidase, MMP-9 and gelatinase, and also results in augmented neutrophil phagocytic activity.28−30 They also show that similar results are observed upon implantation of titanium oxide particles in mice.31 Neutrophil presence and ROS production in vivo (mouse models of study) at biomaterial implantation sites have also been observed through noninvasive or minimally invasive imaging.32−34 Further, in a peritoneal biomaterial implantation model (mouse) we have shown that neutrophils secrete the granule proteins, elastase and myeloperoxidase, and the cytokines/chemokines, IL-6, IL-12, monocyte chemotactic protein-1, CXCL1, CXCL2, and RANTES (CCL5).35 In summary, both human and mouse neutrophils secrete a variety of granule proteins and numerous cytokines and produce ROS following interaction with biomaterials. The exact causes for neutrophil activation and factor secretion following biomaterial interaction remain unclear.

chemoattractants (CXCL8 (also called IL-8) and CXCL4). Neutrophils, with their wide array of cell surface receptors to detect DAMPs and chemokines, sense these signals and initiate migration to injured tissue sites.13,14 Neutrophil recruitment initiates a cascade of events, which are summarized below (Figure 1). Activation. Tissue injury associated inflammatory milieu present at implant sites and the direct interaction of neutrophils with implant surfaces, results in their activation. One of the first signs of activation is a change in expression patterns of cell surface receptors. Indeed, ex vivo cultures of human neutrophils with polyester vascular grafts,15 and cellulose and polyamide containing implantable sensors16 leads to an increase in CD11b (a subunit of the integrin αMβ2), and decrease in CD62L (Lselectin) expression. We have observed a similar increase in CD11b expression and an increase in CD14 expression in mouse neutrophils upon recruitment to alginate implant sites.17 These changes are thought to promote neutrophil adhesion to implant surfaces, but current in vivo observations show correlation and not causation. Simultaneously, alterations in the expression of chemokine receptors−such as decrease in CXCR215,17 and increase in fMLP-R15 − is also observed, which has potential implications in retaining neutrophils at sites of inflammation and preventing their reverse migration. Neutrophils express numerous other cell surface receptors, such as integrins, toll like receptors (TLR), and cytokine/ chemokine receptors, however, their expression patterns in response to interaction with biomaterials remains to be studied. A point of note in this context is that although the expression of TLRs has been suggested to be important for neutrophil activation,18 Rogers and Babansee19 showed that the absence of TLR-4 receptor does not diminish (and might result in an increase in) neutrophil responses to polyethylene terephthalate implants. Reactive Oxygen Species (ROS), Granule Protein, and Cytokine Secretion. Neutrophils produce reactive oxygen species, degranulate to release proteins in the extracellular milieu, and secrete a variety of cytokines following activation. 18,20 Through a series of studies, Kao and 1129


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proaches that have been tested to modulate neutrophil function involve using RNA aptamers to sequester IL-852 or the use of gene therapy for sustained expression of the immunomodulatory (pro-wound healing) cytokine IL-10.53 An interesting alternate approach reported by Hoemann et al. involved the use of chitosan-glycerol phosphate-blood implants, where increased recruitment of neutrophils and alternately activated macrophages (expressing arginase-1) was observed.54 Although this study may not have been designed to directly alter neutrophil activity, the results raise the possibility that a pro-healing or suppressive neutrophil cell phenotype might be involved. Recruiting or activating such suppressive cells could lead to improved biomaterial performance.

Protein adsorption on material surfaces, especially enrichment of specific proteins and their unfolding, has been suggested to influence neutrophil activity.2,25,36 Although numerous ex vivo studies have shown that adsorption of specific proteins on material surfaces is necessary for activation, whether this event alone is sufficient has not yet been tested. In vivo, in addition to protein adsorption on biomaterials, neutrophil activation at implant sites may proceed because of the presence of local inflammatory microenvironment (presence of inflammatory cytokines such as TNF-α, IL-1β, and chemokines5) generated during the implantation procedure. Apoptosis. A unique feature of neutrophils is their short life-spans.5,7 Neutrophils naturally undergo apoptosis at sites of tissue damage and are cleared by monocytes/macrophages. Although questions regarding neutrophil apoptosis on biomaterial surfaces and subsequent uptake by macrophages remain, using ex vivo cultures of human neutrophils, numerous studies have shown that these cells do undergo apoptosis following interaction with biomaterials.22,27,37,38 Additionally, the shape,27 roughness38 and surface coating39 of the biomaterial influences neutrophil apoptosis. But the clearance mechanisms following apoptosis on biomaterial surface is not clearly understood. Consequences of Neutrophil−Biomaterial Interactions. The effects of neutrophil on implanted biomaterials varies considerably based on the material used to make implants and the anatomical site of the implant. Nevertheless a few common features exist. ROS and cytokines/chemokines secreted by neutrophils reinforce the establishment of a local inflammatory microenvironment following implantation of most biomaterials, which leads to recruitment of even more neutrophils, and influences monocyte recruitment, activation, adhesion and function.4,3,22,35 A major drawback of such an inflammatory microenvironment is the nonspecific destruction of adjacent healthy tissue, which might prevent proper integration of biomaterials in the body. Additionally, ROS and granule proteins secreted into the extracellular milieu (on biomaterial surfaces) may directly cause biomaterial degradation. For example, neutrophil recruitment, activation and secretion MMPs results in the degradation of collagen scaffolds.40−42 Also, factors secreted by neutrophils have been shown to be responsible for the degradation of polyurethanes43 as well as carbon nanotubes.44 Alternately, interaction with polymeric biomaterials may directly affect neutrophil potency.45−47 Similar changes in neutrophil activity were also observed in studies involving metallic implants for total hip arthroplasty, where antimicrobial potency was significantly reduced due to the release of cobalt ions from the implants.48 In summary, neutrophil-biomaterial interactions: (i) affect both biomaterial and neutrophil activity; (ii) influence monocyte recruitment and activity; and (iii) alter the structural integrity healthy tissue in the vicinity of the implant site. Modulation of Neutrophil Activity. As neutrophil function has traditionally been considered deleterious in the context of biomaterial integration with native tissues, a few studies have been performed to limit their activity. Sandberg and colleagues show that precoating of polymer substrates with a highly glycosylated protein, mucin, reduces adhesion and activity of neutrophils, suggesting that inflammatory responses against these coated surfaces might be reduced.49,50 Using a similar approach, Finley et al.51 show that covalent attachment of modified versions of the protein, CD47, onto polyvinyl chloride surfaces reduces neutrophil adhesion. Other ap-

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ADVANCES IN NEUTROPHIL BIOLOGY AND IMPLICATIONS FOR BIOMATERIALS To further characterize neutrophil actions in responding to implanted materials and develop means to modulate them, it is important to know about the progress made in our understanding of neutrophil biology. Numerous recent studies have shined new light on phenotypic characteristics of neutrophils and expanded our comprehension of their broad activity. In this section, a summary of some of these advances and their implications on the development of biomaterials is presented. Identifying Neutrophils (nuclear shape and granules). Terminally differentiated neutrophils in the blood are known as polymorphonuclear cells, and as this name suggests, the nucleus has a polymorphous or segmented shape. Polymorphonuclear cells primarily arise from hematopoietic stem cells in the bone marrow through a series of differentiation steps involving numerous intermediate progenitor and differentiated (nonprogenitor) cells.20 Intermediate differentiated cells, such as the band cell, are known to be present in the blood, and form a small percentage of the circulating neutrophil pool. Now it has been demonstrated that certain progenitor cells, such as the myelocyte, are also present in circulation during infection and injury.55 Notably, these intermediate cells (myelocytes, band cells) do not have a nucleus that is entirely segmented.20 Another distinct feature of neutrophils is the presence of numerous granules (hence the alternate name−granulocyte) in the cellular cytoplasm. These granules contain a variety of enzymes including lysozyme, elastase, myeloperoxidase, gelatinase, metalloproteases, and many other proteases, which upon extracellular release are responsible for microbial killing and remodeling of the extracellular matrix.20 Neutrophils that have undergone degranulation were thought to become apoptotic, but recent evidence suggests that these cells may continue to survive in their degranulated states (as neutrophil cellular densities that are comparable to mononuclear cells have been observed56). Given this heterogeneity in circulating neutrophils,11,57 identifying them at biomaterial implant sites using cellular features such as nuclear shape and granularity,38,43 may result in an misrepresentation of their true numbers. Identifying neutrophils based on the expression of specific cell-surface proteins, either through immunofluorescence imaging or flow cytometry, has been suggested to be viable alternative.11 The most common method used to identify neutrophils in research samples today is based on the cell-surface protein Ly6G (identified using antibody clone 1A8 against it) for mouse cells, and the use of the cell-surface protein CD15 (potentially in combination with CD63 and CD66b) for human cells. In addition to these markers, other cell surface proteins may be 1130


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Figure 2. New roles for neutrophils at the biological-material interface. A summary of a few advances in neutrophil biology that broaden the potential functions for neutrophils at the biological−material interface, and suggestions to either circumvent neutrophil action or utilize them to augment biomaterial function.

varies considerably across animal species, which would be used as a model for preclinical trials of new materials, drug delivery systems and tissue engineering scaffolds. The effect of this variation on the translatability of new biomaterials to the clinic is not clearly understood. Crosstalk with Other Immune Cells. Neutrophil contribution to establishing inflammation is not limited to the secretion of chemokines and cytokines. Recent evidence suggests cellular crosstalk between neutrophils and other immune cells.18 The influence of neutrophils on monocyte activity is well documented.1,63 However, the dynamics of this interaction is more complicated than previously believed. It is well-known that neutrophils secrete chemokines that aid in the recruitment of monocytes.7,14,64 Additionally, neutrophils have been shown to actively induce monocyte adherence to damaged tissue through secretion of specific proteins from their granules.65 They also promote monocyte (and macrophage) activation.66,67 The functional interaction between neutrophils and monocytes is not unidirectional. Monocytes (and macrophages) are able to promote recruitment of neutrophils and influence neutrophil activity, as shown in sterile and infectious models of inflammation.68,69 Neutrophils have also been shown to influence dendritic cells, both through secreted cytokines and direct cellular contact.70,71 Interestingly, it has been demonstrated that neutrophils also interact with the cellular components of the adaptive immune system in a bidirectional manner. Neutrophils activate T cells through direct antigen presentation resulting in T cell activation and differentiation both in vitro and in vivo.72,73 In turn, T cells secrete factors that promote neutrophil survival and indirectly induce production of neutrophil growth and chemotactic factors.18,74

used to identify different neutrophil subsets as reviewed by Scapini et al.11 Notably, many of these surface proteins while unique to granulocytes, are not always unique to neutrophils. Eosinophils and basophils can express them, albeit to a lower extent. Also, while these cell surface proteins might be useful for distinguishing phenotypic heterogeneity, they are insufficient for differentiating phenotypically similar but functionally dissimilar neutrophils. New methods to identify neutrophils are necessary to fully characterize their presence at biomaterial implant sites. Recruitment and Numbers. Although it has been clearly demonstrated that neutrophils migrate to sites of tissue damage and sterile inflammation, questions regarding the molecular mechanisms of recruitment remain. Recent studies show that the movement of neutrophils toward damaged tissue is highly coordinated, resembling swarmlike migration patterns.58−60 Although the initial steps of this recruitment process are better understood, a lot remains unknown about the regulation in number of cells recruited and the reverse-migration or clearance following apoptosis of recruited cells. In the context of biomaterials, these studies, coupled with recent observations by others61 and us17,35 showing presence of neutrophils at implant sites for relatively longer times, raise questions about recruitment and clearance of these cells. These questions are pertinent as neutrophil clearance could potentially result in new tissue growth, whereas neutrophil presence may lead to continued inflammation and fibrosis. A further complication with studies on neutrophils is that their presence in the blood (percentage of total white blood cells (WBC)) varies dramatically based on species. For example, between 10 and 25% of the WBC in mice are neutrophils, whereas it is 50−70% for humans.62 This number 1131


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phagosome maturation occurs through fusion with granules,82,83 and not through endocytic pathways of maturation. The effect of these differences on particulate biomaterials that are taken up via phagocytosis by neutrophils vs macrophages, is yet to be explored. Additionally, the eventual fate of neutrophils that have phagocytosed nondegradable particulates has not been studied. That is, it remains to be determined if a neutrophil, which has taken up a particulate, will carry the cargo to sites of inflammation,84 or undergo apoptosis to be cleared by macrophages at the site of particle uptake, or would reverse migrate85 out of the tissue where it has taken up the particulate to travel to the liver or bone marrow for eventual apoptosis. Finally, with respect to biomaterials and drug delivery systems, there is a dearth of studies on phagocytosis by human neutrophils. Although a significant proportion of phagocytosable particulate systems end up in monocytes and macrophages in murine laboratory models, an interesting question is whether these numbers will be lower in humans because of increased neutrophil presence? Crucial differences in number of cells across species, coupled with the aforementioned distinct features of neutrophil phagosomes, make it imperative to further explore the role of neutrophil phagocytosis on biomaterial and drug delivery systems (Figure 2). Neutrophil Heterogeneity and Subsets. Until very recently, neutrophils were thought to be a homogeneous pool of cells that were terminally differentiated. A significant advance in neutrophil biology was the recognition that peripheral (not present in the bone marrow or other niches of generation) neutrophils are a heterogeneous population of cells.11 As mentioned previously, both band cells as well as polymorphonuclear cells are simultaneously present in the blood,55 but it remains unclear if these cells are functionally different. Additionally, a variety of neutrophil subsets with either suppressive or inflammatory function have been identified.11,57 Further, ex vivo studies suggest that neutrophils might also differentiate into N1 or N2 subtype, analogous to the M1 or M2 subtype in macrophages, with inflammatory or wound healing characteristics, respectively.86,87 Neutrophil heterogeneity has been truly appreciated following studies on individuals with various forms of cancer, where diverse neutrophil subsets have been observed in both the tumor microenvironment and general circulation.88 The subsets observed include, but are not limited to, pro-inflammatory polymorphonuclear cells (traditionally defined as neutrophils), low density neutrophils with immunosuppressive functions,56,89 low density neutrophils with pro-inflammatory functions,90 granulocytic-myeloid derived suppressor cells,91 and immature neutrophils. Significantly, these neutrophil subsets are not unique to the tumor microenvironment, as they have been observed at sites of (and in circulation) autoimmunity,92 infection,90 and even in altered immune states induced by artificial means.93 Among the numerous neutrophil subsets, granulocyticmyeloid derived precursor cells (G-MDSC) are one of the better-studied cells. MDSC (which contain both granulocytic and monocytic cells) were identified first in human tumors,91,94 later confirmed to be present in numerous mouse tumor models too,95,96 and have since shown to be present in sepsis, infectious diseases, and autoimmune disorders.97−99 A significant proportion of MDSC are of the granulocytic subset.91 While unique markers for identifying G-MDSC are yet to be found, numerous cell surface proteins have been shown to be expressed at higher levels in G-MDSC.100 Functionally, G-

On the basis of these advances incorporating features that modify neutrophil crosstalk could be considered as a potential methodology for the successful development of regenerative biomaterials (Figure 2). Directly affecting migratory capacity by targeting neutrophil surface receptor might not result in desired outcomes, as no one neutrophil cell surface receptor appears to be absolutely necessary for migration, as demonstrated by individually depleting or deleting any one of the numerous receptors on neutrophils.59 Instead, developing biomaterial scaffolds loaded with molecules that modulate neutrophil cytokine secretion profiles, or its interactions with dendritic cells and T cells, might offer new avenues for limiting the foreign body responses and enhancing biomaterial activity. Neutrophil Extracellular Traps (NETs). A recently identified mechanism of neutrophil action against microbial agents is their ability to release intranuclear chromatin into the extracellular space.9 The released chromatin (containing both DNA and histone proteins) form dense fiber like structures that entrap microbes and potentially neutralize them. Additionally, these structures are associated with (and require) a variety of granule proteins that aid in the microbicidal activity.6,10 A recent study showed that neutrophils potentially sense size of the pathogen, and if unable to phagocytose the pathogen for neutralization, undergo NETosis.75 In the context of these observations, it remained to be seen if NETs form only in response to microbial agents or if they would also be formed on biomaterial surfaces in the absence of pathogenic agents. Bartneck et al.76 showed that in an ex vivo model of study involving gold nanoparticles, human neutrophils are able to secrete NETs in a cell culture system. But questions such as, was the production of NETs directly against the gold nanoparticles or due to activation during isolation and would such activity occur in vivo, remained. Recently, we showed that NET formation does occur on the surface of sterile implants made of different materials35 and Fetz et al.77 demonstrated the same on polydioxanone fibers. However, further studies are required to determine if NETosis occurs at all in vivo implant sites, in other animal models, and if the triggers for it are similar to the ones observed during an infection with pathogenic microbes. Additionally, the consequences of NETs on implant surfaces, such as how they (i) interfere with implant activity, (ii) enable inflammation, and (iii) might be cleared during the foreign-body response, remain to be worked out. Certain microbes circumvent NETs through the secretion of DNases, which enables their pathogenicity.78 Mimicking this strategy, through the controlled release of DNase or presentation of it on the surface of implants, has the potential to degrade NETs deposited on implant surfaces (Figure 2). A point to be noted here is that degradation of NET structures alone might not be sufficient to prevent implant fibrosis in vivo (unpublished observations by the author). Phagocytosis. Neutrophils are one of the few mammalian cell types capable of taking up substances from the extracellular space through phagocytosis. Although a majority of studies on phagocytosis have used macrophages as the model cell-type,6,79 a few studies have been performed using neutrophils, which has led to the identification of key differences in the phagocytic process between them and macrophages. First, phagosomal pH in neutrophils is in the alkaline to neutral range,80 which is thought to be a result of the activity of NADPH oxidase in neutrophil phagosomes that leads to reduced numbers of proton pumps on phagosome surface and increased passive membrane permeability of protons.81 Second, neutrophil 1132


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Figure 3. Granulocytic myeloid derived suppressor cells (G-MDSC) at implant sites. Neutrophils (identified as Ly6G expressing cells) from mice with implants were screened for the presence of G-MDSC subset using the unique cell surface proteins CD115 and CD244.95 G-MDSC (bounded by the red polygon) were observed at implant sites, but not in the blood and bone marrow of animals with implants.

biomaterials; and could certain neutrophil responses, such as the ones mediated by suppressive neutrophils, to biomaterial implants be helpful? To answer both these questions, a reevaluation of neutrophil involvement in the biomaterialspecific immune response is required. Such studies have the potential to not only improve our understanding of the reactions occurring at the biological-material interface, but also provide a framework for the development of new biomaterials with better compatibility and higher efficacy. Specifically, three improvements may be achieved: (i) for the purposes of regenerative tissue engineering, promotion of tissue healing and regrowth through the utilization of suppressive neutrophils; (ii) for the purposes of drug delivery, the development of systems that are either able to effectively evade neutrophils or use neutrophil-specific phagocytic uptake for tissue targeting; and (iii) for the purposes of medical devices, reengineered materials that are able to overcome fibrosis through modulation of neutrophil-mediated inflammatory responses. Finally, it is important to note that new developments in neutrophil biology do not imply that altering neutrophil function in isolation might be sufficient to achieve significant advances in biomaterial functionality. Rather these advances, especially the interplay between neutrophils and other cells of the immune system, emphasize the need to study the immune response as cohesive system involving numerous cellular and molecular players. Any specific interventions must be developed and tested in the context of this “system”.

MDSC have been shown to be able to suppress immune responses.95,96 The primary mode of suppression employed by G-MDSC is thought to be cell contact mediated, through the expression of arginase and production of reactive oxygen species,95,96,101 but secretion of immunosuppressive cytokines for contact-independent suppression cannot be ruled out. The exact means of G-MDSC production and recruitment to inflammatory sites remains an open question, however, several cytokines and growth factors have been shown to be necessary for their increased presence.91,102 Of relevance to regenerative biomaterials is the potential to exploit suppressive neutrophils, such as G-MDSC, for therapeutic purposes (Figure 2). Similar to previous work on regulatory T cells103,104 and alternatively activated macrophages,105,106 modulation of immune responses at implant sites may be achievable through the recruitment and utilization of GMDSC′s suppressive capabilities. In pursuit of this goal, we attempted to ascertain if G-MDSC are present at sites of biomaterial implants. In a mouse model of peritoneal biomaterial implantation,35 a subpopulation of neutrophils expressing both CD115 and CD244 (characterized as GMDSC95) were observed (Figure 3 and unpublished observations by the author). However, the kinetics of their recruitment to implant sites remains to be determined. Further, similar to their availability at sites of autoimmunity, mere presence may be insufficient to effectively modulate immune responses. Development of biomaterial systems that either recruit GMDSC in larger numbers or enable their function, might be required for achieving regenerative and therapeutic benefit. Alternately, it may be possible to build biomaterial systems that are able to reduce the number of G-MDSC in a given tissue. Given the prominent presence of these cells in the tumor microenvironment, implants that are able to reduce or eliminate them could be envisaged as potential therapeutics for cancer, similar to biomaterial systems developed to inactivate other suppressive arms of the immune system.107,108

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +91 80 22932452. ORCID

Siddharth Jhunjhunwala: 0000-0001-8046-2288 Notes

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The author declares no competing financial interest.

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CONCLUDING PERSPECTIVES Numerous recent studies demonstrate an expanded role of neutrophils in the inflammatory process against microbial pathogens and following sterile injury. Two questions arise from these advances: are the newly identified neutrophil functions pertinent to the foreign body response against

ACKNOWLEDGMENTS

S.J. is supported in part by the Ramanujan Fellowship from the Department of Science and Technology, Government of India, and the R.I. Mazumdar Young Investigator Fellowship at the Indian Institute of Science. 1133


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