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Strategies for the design of biomaterials and bioactive factor delivery systems to control macrophage activation in regenerative medicine Pamela L. Graney, Emily B Lurier, and Kara L. Spiller ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.6b00747 • Publication Date (Web): 15 Feb 2017 Downloaded from http://pubs.acs.org on February 18, 2017

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ACS Biomaterials Science & Engineering

Strategies for the design of biomaterials and bioactive factor delivery systems to control macrophage activation in regenerative medicine Pamela L. Graney, Emily B. Lurier, Kara L. Spiller* School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA *Corresponding author: Kara L. Spiller, PhD Biomaterials and Regenerative Medicine Laboratory Drexel University 3141 Chestnut St. Bossone 718 Philadelphia, PA 19104 [email protected]

Abstract Macrophages play an important role in tissue repair, regeneration, and the ability of biomaterials to mediate these processes. Macrophages are highly plastic cells that exhibit altered behavior in response to changes in the microenvironment. With the growing knowledge of the roles that different macrophage phenotypes play in specific pathologies and/or injuries, researchers are now focusing on designing biomaterials to actively control macrophage behavior and promote healing outcomes. In this review, we highlight a variety of biomaterial strategies for controlling macrophage phenotype in chronic wounds, tissue defects, and inflammatory conditions, although these strategies can be applied to many other applications. In particular, we highlight the different situations in which biomaterials should inhibit or promote M1 or M2 activation, or both, for therapeutic outcomes.

Keywords: macrophage, phenotype, tissue repair, wound healing

ACS Paragon Plus Environment

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Introduction A properly regulated inflammatory response provides the body with a remarkable ability to undergo repair or even regeneration of damaged tissues without scar formation, but when dysregulated, repair cannot be achieved and biomaterial interventions are often required. Macrophages, the primary cells of the inflammatory response, not only respond to changes in the microenvironment to regulate tissue repair processes, but also act as mediators of delayed or impaired tissue repair in critical injuries and autoimmune disease. Macrophages are also known to play a key role in the success or failure of biomaterial-mediated tissue repair. For example, macrophages have been shown to contribute to the formation of fibrous capsules surrounding biomaterials post-implantation, which is detrimental to biomaterial function [1, 2]. The critical role of macrophage-biomaterial interactions in biomaterial function has been reviewed elsewhere [3-5]. This review focuses instead on biomaterial-based strategies that actively target macrophage behavior as a means to promote tissue repair or incorporation of implanted biomaterials. Controlling macrophage phenotype is of particular interest because macrophages exhibit a spectrum of activation states that exert control over all phases of tissue regeneration [6, 7], suggesting that biomaterials that actively control macrophages have the potential to direct this process. Despite the multitude of macrophage phenotypes that undeniably exist in vivo, macrophage classification is commonly oversimplified and denoted as either pro-inflammatory “M1” or pro-healing “M2.” The M2 nomenclature has been recently expanded to encompass several distinct phenotypes, including M2a, M2b, and M2c, which have major roles in tissue repair [7, 8]. However, it is important to note that this nomenclature is not reflective of the full spectrum of phenotypes that exist in vitro and in vivo [9, 10]. For example, M2b macrophages


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(stimulated in vitro using immune complexes) have been shown to exhibit both proinflammatory and anti-inflammatory behavior [11, 12], but their role in tissue repair is not well described. Furthermore, more phenotypes that are critical for tissue repair are expected to be identified in the future. Given their established roles in tissue repair, this review will focus on the M2a and M2c phenotypes. M1 macrophages function in the removal of pathogens and cellular debris in the early stages of the response to injury [13] (Fig. 1a). They can be stimulated in vitro using lipopolysaccharide (LPS) and interferon-γ (IFNγ). An imbalance in the population of M1 macrophages during tissue repair has been implicated in inflammatory disease, chronic wound formation, and delayed healing (Fig. 1b.) [14, 15]. M2 macrophages play diverse, but incompletely understood, roles in tissue repair. M2a macrophages are stimulated in vitro using interleukin-4 (IL4), and M2c macrophages are stimulated in vitro using IL10. M2a macrophages are typically characterized by expression of cluster of differentiation 206 (CD206) and secretion of platelet derived growth factor (PDGF) [8] (Fig. 1a), and have been implicated in fibrosis in a variety of settings, including fibrous capsule formation, and lung and kidney fibrosis [16-18] (Fig. 1c). In contrast, M2c macrophages, characterized by expression of the hemoglobin scavenger CD163, have been shown to have a significantly higher phagocytic capacity for apoptotic cells compared to other known macrophage phenotypes [8, 19]. Additionally, M2c macrophages secrete high levels of matrix metalloproteinases-7, -8, and -9 and have been implicated in vascularization [8, 20, 21]. It remains unclear whether macrophages transition between the different phenotypes directly, or whether new phenotypes are recruited to the injury site during the tissue repair cascade, with some studies showing that repolarization does occur [22-24] and others showing that it does not [25]. Additionally, while it is known that M1


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macrophages accumulate in early stages followed by M2 macrophages at later stages [13, 26], it is not known whether these M2 macrophages resemble M2a or M2c macrophages that have been described in vitro. In fact, recent studies suggest that M2c macrophages may act at early stages of tissue repair, simultaneously with M1 macrophages, while M2a macrophages act at later stages (Fig. 1a) [27-29]. Given that macrophages of different phenotypes heavily contribute to tissue repair in both healthy and chronic injuries, targeting macrophage phenotype holds major potential for therapeutic strategies.

Modulation of the M1 phenotype

Inhibition of M1 activation The resolution of tissue repair requires an initial pro-inflammatory response, mediated by M1 macrophages [30, 31]. However, persistent inflammation can lead to delayed healing because of a build-up of cellular debris and poor vascularization within the wound sites [32], and has been thoroughly described in burns [33], development of chronic ulcers [15, 26, 29, 34] and inflammatory bowel disease [35] among others [36]. Thus, current treatments to restore tissue repair in these ailments include systemic administration of anti-inflammatory therapeutics, including inhibitors of pro-inflammatory factors like tumor necrosis factor-α (TNFα) [14, 37, 38]. However, these treatments are not entirely successful, and also lead to systemic immunosuppression. Therefore, there is a need to precisely control the mediators of this inflammatory state, M1 macrophages. Indeed, numerous biomaterials have been designed to inhibit M1 macrophage activation with beneficial effects on various pathologies (Table 1).


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In rheumatoid arthritis, an autoimmune disease characterized by chronic inflammation of joint tissue, disease severity has been directly linked to the number of macrophages present in the synovium [39]. Not surprisingly, depletion of macrophages both systemically and locally using clodronate liposomes has been shown to reduce inflammation and joint damage in rat antigeninduced arthritis [40]. Because widespread depletion of macrophages is not clinically translatable, researchers have explored biomaterial-based approaches that inhibit proinflammatory M1 behavior to promote healing outcomes. For example, since M1 macrophages are the primary producers of TNFα, Lee et al. designed nanoparticles to deliver small interfering RNA (siRNA) against TNFα following their uptake by macrophages in arthritic joints in mice [41]. Given that siRNA is relatively unstable in physiological fluids, thiol groups on each side of the siRNA were modified to generate self-polymerized poly-siRNA against TNFα, which was subsequently encapsulated into thiolated glycol chitosan (psi-tGC) nanoparticles via chargecharge interactions and crosslinking via disulfide bonds. The authors hypothesized that nanoparticles would localize in arthritic joints and undergo rapid uptake by macrophages, which are known professional phagocytes, causing release of poly-siRNA and subsequent degradation into free siRNA that would inhibit TNFa expression specifically in macrophages. Systemic injection into the tail vein of mice with collagen-induced arthritis (CIA) further demonstrated that psi-tGC nanoparticles accumulated within arthritic joints 1 h post-administration and persisted for up to 24 h, though accumulation in the kidneys was also observed. Unlike free polysiRNA against TNFα, psi-tGC nanoparticles significantly prevented bone loss after 7 weeks and reduced expression of TNFα, which subsequently reduced the expression of tissue degrading enzymes. These findings demonstrate the ability to overcome inflammatory-induced damage in arthritic tissues by inhibiting pro-inflammatory cytokine production by M1 macrophages [41].


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Table 1. Biomaterial control of M1 macrophage activation Wound Model

Method of Control

In vitro / In vivo

Effects on macrophages

Arthritis

Chitosan nanoparticles with anti-TNFα siRNA

In vitro Raw 264.7/ in vivo CIA murine model

Arthritis

Thiolated glycol chitosan nanoparticles loaded with poly-siRNA targeting Notch1

In vitro Raw 264.7/ in vivo CIA murine model

Reduction of TNFα both in Prevented bone vitro and in vivo loss in vivo after 7 weeks post nanoparticle treatment Macrophage-specific Nanoparticles uptake and Notch1 targeted arthritic inhibition in vitro joints in vivo, reducing inflammation, bone erosion and cartilage damage

Arthritis

Tuftsin-modified alginate nanoparticles containing IL10 plasmid DNA

In vitro J774A.1/ in vivo rat adjuvantarthritis model

Enhanced CD163 expression by M1 in vitro and in vivo. NPs localized to inflamed tissue, reduced TNFα, IL6 and IL1β tissue levels

Prevented [43] progression of joint inflammation and damage

Bone Repair

MSC-laden fibrin composites

In vivo rat femoral bone defect

Increased infiltration of CCR7+/CD68+ cells compared to CD163+/CD68+ cells

[44]

Burn

Hyaluronic gel conjugated with anti-TNFα or anti-IL6

In vivo deep partialthickness burn model

Anti-TNFα+HA gel decreased number of local macrophages, decrease in concentration of inflammatory cytokines

Promoted maturation of bone and improved wound healing Decreased area of necrotic tissue

Diabetic Ulcers

Electrospun bovine gelatin/polyglyc olic acid scaffolds releasing MCP-1

In vivo STZinduced diabetic murine model

Recruited large population of macrophages 3 days post-injury

Fully developed epithelial layer 10 days posttreatment, overall improved rate of healing

[46]

Diabetic Ulcers

BMSC-laden hydrogel

In vivo type II diabetic mice

Decreased expression of CD86 while expression of CD206 remained unchanged

Enhanced formation of granulation tissue and angiogenesis, overall improved tissue repair outcomes

[47]


Downstream effects

Ref.

[41]

[42]

[45]

6

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Diabetic ulcers

Human amnion

In vivo db/db mice excisional wound

Increased infiltration of CD68+ cells; after 10 days post-treatment increase in CCR7low/CD206hi cells was observed, with increased production of IGF1, TGFβ1, VEGF

Increased rate of tissue repair, achieving total wound closure after 35 days postimplantation

[48]

Inflammatory bowel disease (IBD)

Gellan gumbased biomaterial coated with antiTNFα mannose moeities

In vivo DSSinduced colitis murine model

Reduction of TNFα specifically in colonic macrophages, suppressed secretion of proinflammatory cytokines IL1β and IL6

Inhibited onset of colitis

[49]

IBD

TNFα siRNA/PEI loaded into polylactide covered with PVA

In vitro Raw 264.7/ in vivo LPS-induced colitis murine model

Nanoparticles inhibited TNFα production by LPSstimulated macrophages in vitro, decrease in TNFα production in vivo specifically in colon


[50]

IBD

Galactosylated trimethyl chitosan-cystein nanoparticles loaded with Map4k4 siRNA

In vitro Raw 264.7/ in vivo DSS-induced colitis murine model

siRNA loaded NPs significantly decreased Map4k4 and TNFα production by macrophages in vitro, limited infiltration of macrophages


[51]

IBD

ECM hydrogel derived from porcine small intestinal mucosa Lipidoid nanoparticles (LPNs) loaded with anti-TNFα siRNA

In vivo DSSinduced colitis murine model

Reduced production of TNFα that led to decrease in M1 macrophages in local region

[52]

In vitro Raw 264.7 cultured in high glucose conditions

LPNs inhibited TNFα production and MCP-1 expression in LPSstimulated macrophages

Accelerated healing and improved function of colonic epithelial barrier Not reported

In vitro

[53]

Nanoparticles have also been used to specifically target macrophage surface receptors to hinder inflammation in inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease [49, 51], which is associated with a dysregulated immune response [54, 55], abnormally high presence of M1 macrophages [35], and overproduction of TNFα [56]. As in RA, systemic inhibition of TNFα is widely used to treat IBD but has harsh side effects including immunosuppression [57]. Therefore, directly targeting TNFα produced by macrophages in


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inflamed tissue in IBD may be a safer and more effective approach. Based on this precedence, Huang et al. designed a gellan gum-based biomaterial coated conjugated with antisense oligonucleotides against TNFα and decorated with mannose moieties to specifically target the mannose receptor found on macrophages [49]. Following intragastric administration in a dextran sulfate sodium (DSS)-induced murine model of colitis, the gels specifically accumulated in CD68+ colonic macrophages within 24 h, and reduced TNFα expression to levels comparable to healthy mice, which was not observed by control gels containing scrambled oligonucleotides. Most notably, these changes were associated with restored body weight, inhibition of myeloperoxidase activity (a marker of mucosal inflammation), decreased production of inflammatory cytokines, and increased survival rate compared to no treatment. Taken together, local targeting of colonic macrophages to inhibit TNFα expression in colitis was an effective treatment, providing evidence that inhibiting M1 macrophages may be beneficial in chronic illness [49]. Studies have also explored the potential of delivering IL10, a known inhibitor of proinflammatory macrophage behavior [58], to minimize inflammation and promote healing following biomaterial implantation. To this end, Gower et al. used a lentiviral gene therapybased approach to achieve localized and sustained expression of IL10 at the tissue-implant interface

of

poly(lactide-co-glycolide)

(PLG)

microsphere

scaffolds

implanted

into

intraperitoneal tissue of mice [59]. Compared to a luciferase virus control, IL10 lentivirus delivery caused a reduction in the number of F4/80+ macrophages, and caused increased production of IL10 by F4/80+ macrophages and reduced leukocyte IFNγ production. Although macrophage phenotype was not thoroughly characterized in this work, these findings provide


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evidence that IL10 gene therapy can be used to modulate cytokine synthesis by macrophages, and other leukocytes, to decrease inflammation.

Promotion of M1 activation Paradoxically, despite higher levels of baseline inflammatory activity in chronic inflammatory disorders, mounting evidence suggests that M1 macrophages may actually enter a state of low-grade chronic inflammation in which they become hypo-responsive to inflammatory stimuli such as an injury, and are unable to mount appropriate response to resolve tissue repair [55, 60, 61]. In diabetic wounds, chronically inflamed M1 macrophages become unable to respond to both pro- and anti-inflammatory stimuli, causing delayed tissue repair [26, 62-64]. Therefore, actively attracting fresh macrophages to the wound site to overcome the chronic lowgrade inflammatory state of local M1 macrophages in the wound environment may be beneficial for re-activating tissue repair resolution [65] (Table 1).

For example, Maruyama et al.

demonstrated that injection of IL1β-stimulated M1 macrophages into subdermal wounds in a diabetic mouse model increased granulation tissue formation 7 days post-treatment compared to wounds treated with unstimulated macrophages or saline [61]. Interestingly, M1-treated wounds also exhibited an increase in lymphatic vessel development. Similarly, Novak et al. [66] showed that injection with exogenously polarized M1 macrophages into a critical muscle laceration in mice led to a reduction in fibrosis 14 days post-injury and decreased time to heal. Recently, researchers have also begun to design biomaterials for local and controlled delivery of macrophage-recruiting agents to attract a fresh population of M1 macrophages to the inflamed tissue for successful inflammation resolution. Yin et al. used electrospun bovine gelatin/polygylcolic acid scaffolds conjugated with monocyte chemoattractant protein-1 (MCP1)


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to recruit macrophages for the treatment of excisional cutaneous wounds in streptozotocin (STZ)-induced diabetic mice [46]. The MCP1-releasing scaffold enhanced the presence of F4/80+ macrophages 3 days post-injury, and led to a significantly faster tissue repair rate compared to control scaffolds without MCP1 alone or to untreated wounds. Wounds treated with the MCP1-releasing scaffolds had a fully developed epithelial layer by day 10 post-injury compared to controls, which had incomplete epithelial development. These data overall suggest that recruitment of fresh macrophages accelerated healing of diabetic ulcers in vivo. Collectively, these studies suggest that modulating abnormal M1 activation via biomaterial design can promote healing in chronically inflamed tissues.

Modulation of M2 Activation In addition to simply inhibiting inflammation by controlling M1 activation, biomaterialinduced stimulation of M2 activation has been explored as an alternative approach to shift macrophage behavior, thereby promoting tissue repair and tissue regeneration in a variety of applications (Table 2). However, it should be noted that just as prolonged M1 activation can lead to impaired healing [29, 67], aberrant M2 activation may also have undesirable outcomes. For example, inhibition of IL4 – a potent stimulator of M2 activation in vitro – has been shown to reduce foreign body giant cell formation around poly(etherurethane urea) cages implanted subcutaneously in mice [17], suggesting that M2 macrophages contribute to the fibrous capsule formation surrounding implanted biomaterials. Actually, several recent studies have found that fibrous capsule formation around subcutaneously implanted scaffolds is associated with high numbers of macrophages expressing the M2 markers Arg1 [8, 68] and CD206 [69], further implicating M2 activation in fibrosis. Consistent with these findings, addition of exogenous


10

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murine bone marrow-derived M1 macrophages has been shown to reduce fibrosis in terms of collagen accumulation following muscle laceration in mice [66]. Despite these findings, the role of M2 macrophages in the foreign body response remains controversial, as several others have found that promotion of the M2 phenotype was associated with reduced fibrosis in kidney injury [70, 71] and inhibition of fibrous encapsulation of biomaterials [72, 73]. The ability to control M2 activation via IL4 release in order to mitigate the foreign body response was recently demonstrated by Hachim et al. [72]; the authors used a layer-by-layer technique with chitosan and dermatan sulfate to create a nanometer thickness multi-layered coating releasing IL4 from the surface of non-degradable polypropylene mesh implants. The number of bilayers enabled tailored release of IL4 in vitro, which was subsequently shown to enhance Arg1 (M2 marker) staining of murine bone marrow-derived macrophages, comparable to an IL4-stimulated positive control. Moreover, subcutaneous implantation of IL4-coated mesh in healthy mice revealed decreased presence of iNOS+ (M1 marker) macrophages and an increased presence of Arg1+ macrophages 7 days post-implantation compared to controls without IL4. Importantly, M2 polarization appeared to be transient as the number of Arg1+ macrophages declined by day 14, though the proportion of Arg+F4/80+ macrophages was still greater than control meshes. After 90 days, the IL4-releasing implants reduced fibrous capsule formation that was associated with the presence of thinner collagen fibers, compared to dense capsules surrounding control implants. Together, these results suggest that promoting transient shifts in macrophage phenotype may improve tissue repair while avoiding the adverse effects of excessive activation. Delivery of IL-4 for control over M2 activation has also been explored to enhance nerve repair. While it has long been known that activated macrophages promote axonal regeneration in


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rats [74], the importance of M2 macrophages in this process has only recently been appreciated, since deficits in M2 activation have been correlated with delayed regeneration [75]. For example, Mokarram et al. investigated the potential for biomaterial control over macrophage phenotype to enhance peripheral nerve repair in a critical-size, non-healing rat sciatic nerve gap [76]. Polysulfone tubes loaded with IFNγ or IL4 in agarose gel were prepared to serve as guidance channels between disconnected nerve stumps. Three weeks post-implantation, a marked increase in macrophage presence was observed for both IFNγ and IL4-treated groups relative to controls without cytokines; however, IL4-treatment increased the presence of CD206+ and CD163+ macrophages (markers of M2 activation) and significantly enhanced migration of Schwann cells, which support neuronal viability, toward the center of the scaffold. Moreover, immunostaining for neurofilament-160 to visualize axons revealed axonal growth from the proximal to distal end of the nerve gap was 20 times greater in IL4-releasing scaffolds compared to the control. These findings emphasize the importance of macrophage phenotype, rather than the extent of macrophage presence at the injury site, in regulating nerve regeneration. Other studies have also used delivery of IL4 and IL10 to treat rheumatoid arthritis, given that inflamed synovial macrophages are known to become unable to respond to the suppressive effects of IL10 [77], which would normally be beneficial for arthritis [78]. Therefore, both inhibiting M1 production of pro-inflammatory signals and promoting proper M2 responses would be expected to reduce the severity of joint destruction resulting from arthritis. Indeed, Tran et al. [79] recently demonstrated the potential for IL4- and IL10-driven macrophage reprograming to provide a synergistic effect against inflammation. Plasmid DNA for IL4 or IL10 was encapsulated in hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles; HA was chosen based on its ability to target CD44-overexpressing macrophages, while PEI was selected


12

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based on its ability to promote endosomal escape, as well as its positive charge that enables electrostatic interactions with negatively charged nucleic acids. Murine J774A.1 M1-polarized macrophages treated with the particles for 1-3 days demonstrated a significant increase in the Arg1/iNOS gene expression ratio compared to untreated M1 macrophages, as well as increased CD206 and CD163 expression, suggesting a shift toward M2 activation. Finally, the ability of the particles to reprogram macrophage behavior was demonstrated by IP-injection of LPS and IFNγ in mice, followed by IL4 and IL10 plasmid DNA HA-PEI administration, causing significant down-regulation of iNOS expression and a 2-fold increase in CD163 fluorescence, but relatively little change in CD206. Overall, these results suggest that HA-PEI particles containing IL4 and IL10 effectively suppress synovial inflammation. Macrophages are also known to play a vital role in bone healing and repair of critical size defects, as depletion of macrophages in a murine femoral fracture model abolished callus formation [80], and have been implicated in several stages of the bone repair cascade. For instance, macrophages have been shown to mediate in vivo woven bone deposition and mineralization [81] and enhance osteogenic differentiation of mesenchymal progenitors [82]. Unfortunately, the role of macrophage phenotype in bone homeostasis is not well understood, but the importance of controlling macrophage responses to bone substitutes is becoming widely appreciated. For example, while titanium (Ti) is commonly used for bone-related applications, Ti implants are often associated with inflammatory-induced fibrous capsule formation that limits osseointegration and can lead to implant failure. In order to mitigate these effects and promote integration of titanium implants, researchers have explored a multitude of surface modification approaches that target macrophage modulation [80, 83, 84]. For example, Lee et al. [83] investigated the synergistic effects of nano-patterning and bioactive ions on M2 activation by


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further modifying the surface of nanofeatured Ti implants with calcium and strontium ions, which have been shown to exhibit anti-inflammatory effects on macrophages [85]. Murine J774.A1 macrophages cultured on calcium- and strontium-doped nanofeatured surfaces significantly up-regulated the M2 markers Arg1, CD206, and CD163, after 1 and 3 days in vitro. These effects were sustained on day 5 by strontium-doped surfaces, which also promoted upregulation of several growth factors important for osteogenesis (BMP2, PDGF-B, VEGF, TGFβ1). In contrast, pure nanofeatured Ti surfaces without ions induced CD86 and iNOS upregulation,

indicative

of

M1

activation.

These

results

were

corroborated

using

immunocytochemistry on day 3, which showed more intense staining of CD206 (an M2 marker) by macrophages on calcium- and strontium-modified surfaces relative to nanofeatured Ti without ions, suggesting that a combination of surface modification approaches can be used to differentially regulate macrophage phenotype. Similarly, Ma et al. found that nanostructured Ti surfaces caused an upregulation in expression of CD163 and CD206, markers of M2 activation, compared to polished surfaces, which resulted in improved implant osseointegration in a rat femoral defect model [80]. In related work, McWhorter et al. demonstrated the ability to control the phenotype of murine bone marrow-derived macrophages in the absence of exogenous stimuli by controlling the geometry of cell adhesion [86]. The authors found that while M1 macrophages display a rounded morphology, M2 macrophages exhibit elongation. Based on these findings, the authors prepared substrates with micropatterned surfaces in order to promote macrophage elongation, finding that these macrophages upregulated Arg1, CD206, and Ym-1, markers of M2 activation. Later, Luu et al. later designed Ti substrates via micro- and nano-patterning in order to induce M2 activation, through which changes in groove width induced expression of Arg1 and secretion


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of IL10 (M2 markers) in murine macrophages [84]. It is worth noting that other studies using primary human macrophages have shown the M1 phenotype to be more elongated than M2 [87], suggesting that macrophages may display species-specific behavior. While it is clear that surface topography and mechanical properties affect macrophage polarization, which has been reviewed elsewhere [88, 89], the ability to precisely control macrophage phenotype has not yet been established. Nonetheless, these studies demonstrate the ability to mitigate inflammation and promote regenerative outcomes in a multitude of applications via biomaterial control over M2 activation.

Table 2. Biomaterial control of M2 activation Wound Model Bone Repair

Method of Control

Bone Repair

Strontiumsubstituted submicron bioactive glass (Sr-SBG)

In vitro RAW 264.7/ in vivo rat femoral condyle defect model

Sr-SBG enhanced CD206 and Arg1 expression in vivo, but reduced NOS2 expression

Suppressed osteoclastogenesis in vitro compared to SBG alone, enhanced bone formation

[90]

Chronic Ischemic Wounds

Modified collagen dressing

In vitro THP-1/ in vivo porcine full-thickness excisional wound model

Enhanced macrophage recruitment; promoted expression of MRC1 (CD206), IL10 and βFGF in vitro. CCR2+ macrophages present in wound tissue 7 days postinjury

Improved tissue regeneration and enhanced vascularization

[91]

Foreign Body Response

Anti-IL4 antibodies injected into poly(etherurethane urea) cages

In vivo murine subcutaneous cageimplantation model

Inhibition of IL4 reduced foreign body giant formation around cages

Not reported

[17]

Hydrophilic, nanostructured TiO2 surfaces via anodization at 5 or 20V

In vitro / In vivo In vitro primary human macrophages/ in vivo rat femur model

Effects on Macrophages NT5 induced M2 polarization in vitro and in vivo; NT20 promoted M1 activation. Reduced CD68+ macrophage distribution in vivo


Downstream effects NT5 surface induced greater bone formation

Ref. [80]

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Porous spheretemplated pHEMA hydrogels

In vivo murine subcutaneous pouch model

Porous implants associated with iNOS+, IL1R1+ (M1) macrophages and greater vessel density; non-porous controls associated with MMR+ (CD206), SRBI/II+ (M2) macrophages and dense fibrous capsule

Reduced fibrosis and increased vascularization, improved biomaterial-tissue integration

[69]


Nanometer thickness multilayered chitosan/dermatan sulfate coating releasing IL4 from polypropylene mesh

In vitro murine bone marrowderived macrophages/ in vivo murine subcutaneous implantation model

Enhanced Arg1+ staining, comparative to IL4 control in vitro. Reduced presence of F4/80+ cells; fewer iNOS+ and greater Arg1+ macrophages 7 days postimplantation.

Reduced fibrosis, enhanced tissue remodeling

[72]


Collagen scaffolds functionalized with poly(lactic-coglycolic acid) multi-stage silicon composite microspheres releasing IL4

In vitro rat bone marrow-derived macrophages/ in vivo rat subcutaneous pouch model

Enhanced early expression of IL6 and IL12b; sustained upregulation of IL10, Arg1 and MRC1 (CD206) expression in vitro. Greater presence of CD206+ macrophages 2472 h post-implantation; upregulation of both M1 and M2 genes after 72 h.

Improved biomaterial-tissue integration

[92]


Poly(lactic-coglycolide) microspheres carrying IL10 plasmid DNA

In vitro RAW 264.7/ in vivo IP implantation in mice

Reduced TNFα production and increased IL10 production poststimulation with LPS in vitro. Decreased number of F4/80+ cells 7-days postimplantation; reduced IFNγ and enhanced CD206 production.

Not reported

[59]

Inflammatory Disease

Hyaluronic acidpoly(ethyleneimine ) nanoparticles carrying IL4 or IL10 plasmid DNA

In vitro J774A.1/ in vivo IP injection in murine inflammatory model

Increased Arg1/iNOS levels, upregulation of CD206 and CD163 posttransfection in vitro. In vivo, NPs targeted CD44+ macrophages, suppressed LPS-induced inflammation, promoted IL10 levels.

Not reported

[79]


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Myocardial Infarction

Liposomes presenting phosphatidylserine

In vivo IP or IM injection in mice/ in vivo rat model of acute MI

Enhanced CD206 expression, IL10 and TGFβ secretion 3 days post-injection in mice; reduced CD86 expression. Liposomes accumulated in cardiac macrophages.

Enhanced angiogenesis at infarct site, inhibited left ventricle remodeling postinfarction

[93]

In vitro

Delivery of IL4 via osmotic pump

In vitro murine bone marrowderived macrophages

Activity of IL4 retained over 4 weeks; exposure of M0 and M1 to conditioned media collected from IL4delivering pumps induced M2 activation at the gene expression and protein levels.

N/A

[94]

In vitro

Titanium implants featuring nanotopography and surface bioactive ions Ca and Sr

In vitro J774A.1

Ca and Sr surfaces elicited less cell spreading than control; and upregulated VEGF, PDGF, TGFB, BMP2, CD206, CD163.

N/A

[83]

In vitro

Titanium surfaces containing microand nano-patterned grooves

In vitro C57BL/6 bone marrowderived macrophages

Grooves influenced macrophage elongation; Grooves stimulated Arg1 expression and IL10 secretion; did not alter iNOS or TNFα levels.

N/A

[84]

Nerve Repair

Release of IL4 from agarose-filled polysulfone guidance channels

In vitro alveolar rat macrophages/ in vivo criticalsize rat sciatic nerve gap

Enhanced ratio of CD206+/CD68+ and CD163+/CD68+ cells 3 weeks post-implantation;

[76]

Pancreatic Islet Engraftment

Delivery of dexamethsone from macroporous polydimethylsiloxa ne scaffolds

In vivo STZinduced diabetic mouse model

Increased dosages reduced macrophage recruitment 57 days posttransplantation; activation of F4/80+ cells skewed towards M2 and delayed engraftment, which was overcome with lower Dex loading.

Enhanced Schwann cell integration into material, enhanced axonal growth from the proximal to distal end of the material Improved islet cell engraftment


[95]

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Biphasic Modulation of M1 and M2 Activation The strategies previously described primarily target control over either M1 or M2 activation for enhanced tissue repair. However, recent evidence suggests that both M1 and M2 macrophages are required for biomaterial integration with host tissue, possibly due to coordinated activities in promoting tissue vascularization [8] and extracellular matrix (ECM) deposition and remodeling [96]. For example, consistent with the M1-to-M2 sequence that is observed in healthy tissue repair, M1 macrophages have been shown to initiate angiogenesis by endothelial cells [8, 97] and the M1-associated cytokine IL6 has been shown to prime fibroblasts for ECM deposition [98], while M2 macrophages have been shown to stabilize angiogenesis [8] and to stimulate fibroblast proliferation and collagen deposition [96]. Based on this precedence, researchers have begun to design strategies that actively promote sequential activation of M1 and M2 macrophages for enhanced biomaterial-mediated tissue repair. A common biomaterial-based approached to achieve temporal modulation over macrophage activation involves an initial release of either MCP1 (to recruit M1 macrophages to the injury site) or IFNγ (to induce M1 activation of surrounding macrophages); subsequently, IL4 or IL10 can be released from the biomaterial to induce M2 activation (by either shifting M1 macrophages toward an M2 state, or inducing M2 activation in freshly recruited, uncommitted macrophages) (Figure 2). To this end, Spiller et al. investigated the ability to temporally regulate macrophage activation via sequential delivery of IFNγ and IL4 from decellularized bone scaffolds implanted subcutaneously in mice [22]. The scaffolds were prepared by conjugation of IL4 via biotinstreptavidin binding to the surface of the scaffolds, followed by physical adsorption of IFNγ. After 3 days in culture with primary human macrophages, rapid release of IFNγ or sustained release of IL4 alone was able to promote gene expression of M1 and M2 markers, respectively,


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compared to a negative control without cytokines. However, simultaneous upregulation of both M1 and M2-specific markers was observed following sequential release of IFNγ and IL4 in vitro, which may be attributed to their overlapping release profiles achieved in vitro, and failed to achieve improved vascularization in vivo. This study further highlights the importance of temporal control over macrophage activation. Similarly, Kumar et al. [99] hypothesized that temporally controlled delivery of monocyte chemoattractant protein-1 (MCP-1) and IL4 can be used to actively recruit macrophages and subsequently drive M2 activation. The authors prepared self-assembling multidomain peptides (MDP) that formed entangled fibrous meshes, which ultimately generated nanofibrous hydrogels, and subsequently loaded the gels with MCP1 and IL4. Due to differential interactions with the MDP hydrogel, the authors were able to demonstrate biphasic release of the cytokines, achieving 80% release of MCP1 within 48 h and prolonged release of IL4 over 16 days. Moreover, MCP1-eluting scaffolds induced migration of THP1 cells, a human monocytic cell line, in a dose-dependent manner, while IL4-eluting scaffolds successfully induced M2 reprogramming in committed M1 macrophages. Most notably, scaffolds eluting both MCP1 and IL4 significantly enhanced cell infiltration 3 days post-subcutaneous injection in rats, compared to empty scaffolds or those eluting only IL4, and by day 7, these scaffolds enhanced M2 activation in terms of both CD206+ and CD163+ macrophages compared to empty scaffolds or those eluting only MCP1. These immunomodulatory gels also displayed distinct blood vessel formation after 7 days, and were fully resorbed within 14 days, demonstrating that proper temporal control over M1 and M2 activation can be used to promote biomaterial-mediated tissue repair.


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In other efforts to actively recruit and modulate macrophage behavior, Kim et al. developed gelatin hydrogels containing the macrophage recruitment agent SEW2871, as well as platelet-rich plasma (PRP), to enhance angiogenesis and osteogenesis via the actions of host macrophages [100]. After 3 days post-implantation in a rat ulna critical-size bone defect model, gelatin hydrogels incorporating both SEW2871 and PRP not only induced a greater amount of collagen, but also significantly increased the number of CD68+ macrophages compared to gelatin hydrogels with PRP alone or PBS in a concentration-dependent manner. Most notably, gelatin hydrogels with SEW2871 and/or PRP elicited early (day 3) up-regulation of TNF-α, IL10 and TGFβ1. TNF-α expression subsided by day 10, though expression was still greater than sham and gelatin-PBS controls, while elevated IL10 and TGFβ1 expression persisted, suggesting an M1-to-M2 transition in macrophage behavior. In vivo bone formation was most pronounced for gelatin hydrogels containing both SEW2871 and PRP. Although the distinct roles of M1 and M2 macrophages in biomaterial-mediated tissue repair are not fully understood, these results provide support that an early and transient inflammatory response with a subsequent shift toward M2 activation may be beneficial for tissue repair.

Conclusions and Future Directions In conclusion, macrophages play a crucial role in regulating inflammation and the response to implanted biomaterials; as result, regenerative medicine strategies should at least consider, if not actively control, macrophage phenotype. It should be appreciated that the roles of macrophage phenotype are controversial, and simply inhibiting the M1 activation and promoting M2 activation may not always lead to healing outcomes. For example, while an impaired M1-to-


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M2 transition has been implicated in disrupted tissue repair of diabetic wounds [14, 26, 29], Jetten et al. showed that wound administration of M2 macrophages actually impaired diabetic wound healing in mice [20]. In addition, administration of M1 macrophages has been shown in some studies to promote tissue repair and inhibit fibrosis [61, 66] and to have the opposite effects in others [101]. It is likely that proper temporal control over macrophage phenotype holds the key to these apparently conflicting reports. For example, suppressed M1 activation immediately after injury has been implicated in the impairment of tissue repair in diabetic wound models [60], but inhibition of M1 activity at 3 days after injury can promote diabetic tissue repair in mice [15, 34]. Despite the increasing appreciation of the importance of macrophage biology in biomaterials outcomes, there is still a need to distinguish between the many different phenotypes, such as the differences between M2a and M2c behavior, in order to advance the design of macrophage-modulating biomaterials. While characterization of macrophage phenotype is typically limited to staining for a handful of phenotype markers, it may be more appropriate to employ a panel of markers, such as by gene expression or protein secretion analysis, since staining positivity has been shown to be a poor marker of specific macrophage phenotype [8] and since macrophages shift hundreds to thousands of genes during polarization to different phenotypes [102]. For example, Xue et al. demonstrated the use of gene expression profiles to characterize macrophages isolated from the in vivo environment via comparison to reference phenotypes prepared in vitro [102]. Functional assays may also shed light on the differences between phenotypic behaviors. For example, researchers have used angiogenesis assays to differentiate between macrophage phenotypes both in vitro and in vivo [8, 20, 103]. This strategy would also allow comparison between macrophages cultivated in vitro and in vivo, which is


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Page 22 of 32

currently challenging. Correlation between human and murine macrophages will also be very important, given that polarized macrophages have been shown to exhibit different morphologies [86, 87] and gene expression profiles [104]. There is also a need to develop a diverse array of biomaterial strategies that specifically target macrophages, because release of macrophage-modulating molecules would be expected to affect many other cells in the local microenvironment. For example, it may be possible to deliver siRNA or other therapeutics using nanoparticles since macrophages are more likely to participate in nanoparticle uptake than other cells. However, in this case the bioactive factor would likely need to act intracellularly. In addition, more translational animal models are needed to investigate the potential of immunomodulatory biomaterials, since macrophage behavior is very different in healthy and diseased animals. Finally, computational models to predict the multitude of potential macrophage phenotypes and macrophage-biomaterial interactions may also be employed to enhance the correlation between in vitro and in vivo results as well as reduce the use of animal models [105, 106]. Mounting evidence for the importance of macrophages in tissue healing and biomaterial success suggests that overcoming these challenges will be critical for the future of biomaterial-mediated regenerative medicine.

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Table of Contents Graphic

Strategies for the design of biomaterials and bioactive factor delivery systems to control macrophage activation in regenerative medicine Pamela L. Graney, Emily B. Lurier, Kara L. Spiller


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Figure 1. Contributions of macrophage phenotypes to tissue repair. (a) In healthy injury, M1 macrophages act at early stages to remove pathogens and apoptotic cells and stimulate angiogenesis. It is believed that M2c macrophages also act at early stages to promote matrix remodeling and angiogenesis, although their roles in tissue repair are not well defined. At later stages, the macrophage population transitions to the M2a phenotype, although it is not known if this transition results from repolarization of macrophages in the injury site or recruitment of new macrophages. In contrast, diseased tissue and chronic injuries are characterized by sustained M1 activation, which fail to transition to the M2a phenotype to resolve inflammation. (b) An imbalance in M1 macrophage behavior leads to impaired tissue repair, with excessive M1 activation leading to chronic inflammation, and insufficient M1 activation failing to initiate the repair process. (c) An imbalance in M2a activation also leads to impaired healing, with excessive M2a activation causing fibrosis and insufficient M2a activation causing chronic wound formation. Figure 1 669x537mm (150 x 150 DPI)



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Figure 2. The ideal biomaterial achieves temporal modulation over macrophage activation, which can be achieved by an initial release of factors that recruit or promote M1 activation, such as MCP1 or IFNγ, followed by release of factors that induce M2 activation, such as IL4 or IL10. Figure 2 203x279mm (150 x 150 DPI)


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Biomaterials and Bioactive Factor Delivery ... - ACS Publications

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