Sequential drug delivery to modulate macrophage behavior and enhance implant integration

O’Brien, Erin M.; Risser, Gregory E.; Spiller, Kara L.

doi:10.1016/j.addr.2019.05.005

Cited by 100 publications

(93 citation statements)

References 112 publications

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“…They play a protective role in pathogen immunity, tissue development, homeostasis and regeneration after injury [ 2 ], responding to signal fluctuation of microenvironment by changing their function rapidly. Drug treatment is one of the most important approaches to achieve macrophage functionalization [ 3 ], and in addition to the widely used chemical drugs, nanomedicines are attractive due to their controlled drug release, prolonged half-life and lower side effects [ 4 ]. Indeed, nanoparticles have been used in therapeutic applications of anti-inflammation and macrophage-related disorders [ 5 ] and to inhibit tumor growth by inducing pro-inflammatory macrophage polarization [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Spatially Resolved Correlation between Stiffness Increase and Actin Aggregation around Nanofibers Internalized in Living Macrophages

et al. 2020

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Plasticity and functional diversity of macrophages play an important role in resisting pathogens invasion, tumor progression and tissue repair. At present, nanodrug formulations are becoming increasingly important to induce and control the functional diversity of macrophages. In this framework, the internalization process of nanodrugs is co-regulated by a complex interplay of biochemistry, cell physiology and cell mechanics. From a biophysical perspective, little is known about cellular mechanics’ modulation induced by the nanodrug carrier’s internalization. In this study, we used the polylactic-co-glycolic acid (PLGA)–polyethylene glycol (PEG) nanofibers as a model drug carrier, and we investigated their influence on macrophage mechanics. Interestingly, the nanofibers internalized in macrophages induced a local increase of stiffness detected by atomic force microscopy (AFM) nanomechanical investigation. Confocal laser scanning microscopy revealed a thickening of actin filaments around nanofibers during the internalization process. Following geometry and mechanical properties by AFM, indentation experiments are virtualized in a finite element model simulation. It turned out that it is necessary to include an additional actin wrapping layer around nanofiber in order to achieve similar reaction force of AFM experiments, consistent with confocal observation. The quantitative investigation of actin reconfiguration around internalized nanofibers can be exploited to develop novel strategies for drug delivery.

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Section: Introductionmentioning

confidence: 99%

Spatially Resolved Correlation between Stiffness Increase and Actin Aggregation around Nanofibers Internalized in Living Macrophages

et al. 2020

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“…In this light, the biomaterial systems capable of modulating macrophage phenotype sequentially are deemed particularly rewarding for implant integration. The strategies and examples of sequential delivery systems for macrophage modulation have been reviewed recently [24]. This clearly demonstrates that materials which seek to avoid the host immune response may elicit poorer than desired remodeling outcomes due to poor vascularization.…”

Section: Biomaterials That Harness Macrophages To Drive Angiogenesismentioning

confidence: 99%

“…Thus, while the success of tissue engineering and regenerative medicine strategies depends critically upon the ability to orchestrate the highly complex and temporal process of angiogenesis, it also depends upon the ability to influence a similarly complex host immune response. Macrophages of multiple phenotypes have now been shown to be potent modulators of the angiogenic process [23][24][25][26], demonstrating that the host response and angiogenic response are inextricable from one another and must be considered in tandem to achieve improved outcomes.…”

Section: Introductionmentioning

confidence: 99%

Beyond Growth Factors: Macrophage-Centric Strategies for Angiogenesis

et al. 2020

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Functional angiogenesis is a critical therapeutic goal in many pathological conditions. Logically, the use of pro-angiogenic growth factors has been the mainstay approach despite obvious limitations and modest success. Recently, macrophages have been identified as key regulators of the host response to implanted materials. Particularly, our understanding of dynamically plastic macrophage phenotypes, their interactions with biomaterials, and varied roles in different stages of angiogenic processes is evolving rapidly. In this review, we discuss changing perspectives on therapeutic angiogenesis, in relation to implantable materials and macrophage-centric strategies therein. Harnessing the different mechanisms through which the macrophage-driven host response is involved in angiogenesis has great potential for improving clinical outcome.

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“…However, the extent of the diversity of the M2 population is not known, and numerous M2 subtypes have been described [6]. While the field continues to evolve, the current state of knowledge is that M1 macrophages initiate healing while M2 macrophages promote healing resolution (for review, see [7,8]). In addition, recent studies employing single cell transcriptomic profiling have shown that macrophages often exist as hybrid phenotypes in vivo, simultaneously expressing markers of both archetypal M1 and M2 phenotypes [9].…”

Section: Introductionmentioning

confidence: 99%

Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages

Witherel

Sao

Brisson

et al. 2020

Preprint

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Aberrant extracellular matrix (ECM) assembly surrounding implanted biomaterials is the hallmark of the foreign body response, in which implants become encapsulated in thick fibrous tissue that prevents their proper function. While macrophages are known regulators of fibroblast behavior, how their phenotype influences ECM assembly and the progression of the foreign body response is poorly understood. In this study, we used in vitro models with physiologically relevant macrophage phenotypes, as well as controlled release of macrophage-modulating cytokines from gelatin hydrogels implanted subcutaneously in vivo to investigate the role of macrophages in ECM assembly. Primary human macrophages were polarized to four distinct phenotypes, which have each been associated with fibrosis, including pro-inflammatory M1, pro-healing M2, and a hybrid M1/M2, generated by exposing macrophages to M1- and M2-promoting stimuli simultaneously. Additionally, macrophages were first polarized to M1 and then to M2 (M1->M2) to generate a phenotype typically observed during normal wound healing. Human dermal fibroblasts that were cultured in macrophage-conditioned media upregulated numerous genes involved in regulation of ECM assembly, especially in M2-conditioned media. Hybrid M1/M2 macrophage-conditioned media caused fibroblasts to produce a matrix with thicker and less aligned fibers, while M2 macrophage-conditioned media caused the formation of a more aligned matrix with thinner fibers. Gelatin methacrylate hydrogels containing interleukin-4 (IL4) and IL13-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were designed to promote the M2 phenotype in a murine subcutaneous in vivo model. NanoString multiplex gene expression analysis of hydrogel explants showed that hydrogels with and without drug caused markers of both M1 and M2 phenotypes to be highly expressed, but the release of IL4+IL13 promoted upregulation of M2 markers and genes associated with regulation of ECM assembly, such as Col5a1 and Col6a1. Biochemical analysis and second harmonic generation microscopy showed that the release of IL4+IL13 increased total sulfated glycosaminoglycan content and decreased fibril alignment, which is typically associated with less fibrotic tissue. Together, these results show that hybrid M1/M2 macrophages regulate ECM assembly, and that shifting the balance towards M2 may promote architectural and compositional changes in ECM with enhanced potential for downstream remodeling.

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Sequential drug delivery to modulate macrophage behavior and enhance implant integration

Cited by 100 publications

References 112 publications

Spatially Resolved Correlation between Stiffness Increase and Actin Aggregation around Nanofibers Internalized in Living Macrophages

Spatially Resolved Correlation between Stiffness Increase and Actin Aggregation around Nanofibers Internalized in Living Macrophages

Beyond Growth Factors: Macrophage-Centric Strategies for Angiogenesis

Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages

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