Interleukin‐4‐loaded hydrogel scaffold regulates macrophages polarization to promote bone mesenchymal stem cells osteogenic differentiation via TGF‐β1/Smad pathway for repair of bone defect

Zhang, Jiankang; Shi, Haitao; Zhang, Nian; Hu, Liru; Wei, Jing; Pan, Jian

doi:10.1111/cpr.12907

Cited by 44 publications

(38 citation statements)

References 43 publications

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“…Therefore, great efforts are currently being addressed to design immunomodulatory and, at the same time, pro-osteogenic scaffolds capable of regulating and boosting the switch of M1 macrophages to M2 phenotype. The use of pro-osteogenic scaffolds carrying immunomodulatory molecules such as ILs or micro ribonucleic acids (microRNAs) [ 129 , 130 ] or the modulation of surface topographical cues of the scaffolds [ 131 ] are among the strategies currently being used to improve the bone healing facilitated by endogenous macrophages.…”

Section: Strategies Promoting Bone Healing Through An Endogenous Responsementioning

confidence: 99%

“…The combined use of a wide range of pro-osteogenic scaffolds such as decellularized bone matrix, bi-layer hydrogel-porous scaffolds, and calcium-enriched hydrogels [ 129 , 132 , 133 ] loaded with IL-4, a key anti-inflammatory cytokine secreted by M2 macrophages, is now being explored as a promising strategy for repair of bone defects [ 129 , 133 ]. Interestingly, calcium-enriched hydrogels loaded with IL-4 showed superior in vitro and in vivo abilities in inducing both M2 macrophages polarization and MSCs osteogenesis by enhancing TGF-β1/Smad pathway.…”

Section: Strategies Promoting Bone Healing Through An Endogenous Responsementioning

confidence: 99%

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Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration

Macías

Alcorta-Sevillano

Infante

et al. 2021

IJMS

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Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or extrinsic ones coming from external insults such as trauma or surgery. Although bone tissue has an intrinsic capacity of self-repair, large bone defects often require anabolic treatments targeting bone formation process and/or bone grafts, aiming to restore bone loss. The current bone surrogates used for clinical purposes are autologous, allogeneic, or xenogeneic bone grafts, which although effective imply a number of limitations: the need to remove bone from another location in the case of autologous transplants and the possibility of an immune rejection when using allogeneic or xenogeneic grafts. To overcome these limitations, cutting edge therapies for skeletal regeneration of bone defects are currently under extensive research with promising results; such as those boosting endogenous bone regeneration, by the stimulation of host cells, or the ones driven exogenously with scaffolds, biomolecules, and mesenchymal stem cells as key players of bone healing process.

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Section: Strategies Promoting Bone Healing Through An Endogenous Responsementioning

confidence: 99%

Section: Strategies Promoting Bone Healing Through An Endogenous Responsementioning

confidence: 99%

Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration

Macías

Alcorta-Sevillano

Infante

et al. 2021

IJMS

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“…Among these cytokines, IL-4 is widely studied, as it polarizes macrophages into an anti-inflammatory phenotype and inhibits LPS-induced pro-inflammatory cytokine synthesis [ 6 , 7 , 8 , 9 ]. Several prominent studies incorporated IL-4 into the scaffold and relied on its controlled release to modulate inflammation [ 10 , 11 , 12 , 13 , 14 ]. Yet, these studies and many others in the literature largely ignored the inflammatory environment at the injury site and its deleterious effects on immunomodulatory scaffolds, including the scaffold degradation rate and cytokine release profile.…”

Section: Introductionmentioning

confidence: 99%

Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold

Shortridge

Fakhrabadi

Wuescher

et al. 2021

IJMS

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The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation and providing a sustained release of anti-inflammatory cytokine from the scaffold in the digestive inflammatory environment are predicated upon a comprehensive understanding of three fundamental questions. (1) How does the release rate of cytokine from the scaffold change in the digestive inflammatory environment? (2) Can we prevent the premature scaffold degradation and burst release of the loaded cytokine in the digestive inflammatory environment? (3) How does the scaffold degradation prevention technique affect the immunomodulatory capacity of the scaffold? This study investigated the impacts of the digestive inflammatory environment on scaffold degradation and how pre-mature degradation can be prevented using genipin crosslinking and how genipin crosslinking affects the interleukin-4 (IL-4) release from the scaffold and differentiation of naïve macrophages (M0). Our results demonstrated that the digestive inflammatory environment (DIE) attenuates protein retention within the scaffold. Over 14 days, the encapsulated protein released 46% more in DIE than in phosphate buffer saline (PBS), which was improved through genipin crosslinking. We have identified the 0.5 (w/v) genipin concentration as an optimal concentration for improved IL-4 released from the scaffold, cell viability, mechanical strength, and scaffold porosity, and immunomodulation studies. The IL-4 released from the injectable scaffold could differentiate naïve macrophages to an anti-inflammatory (M2) lineage; however, upon genipin crosslinking, the immunomodulatory capacity of the scaffold diminished significantly, and pro-inflammatory markers were expressed dominantly.

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“…Moreover, upregulation of M2 macrophages in fracture calluses by in situ application of IL-4 and IL-13 results in enhanced fracture healing (Schlundt et al, 2018). Correspondingly, a study by Zhang et al (2018) on human patients has determined a positive correlation between the percentage of M2 macrophages in clavicle fracture calluses and the rate of bone healing.…”

Section: M2 Macrophage Upregulation Is Essential During Bone Regeneration and Precedes Osteoinduction By Calcium Phosphate In Vivomentioning

confidence: 97%

“…In the context of biomaterials, augmenting the number of M2 macrophages during bone repair with various implants has been consistently linked to enhanced bone formation. For example, loading of different implant materials with IL-4, leading to M2 macrophage upregulation, results in enhanced bone defect regeneration or implant osseointegration (Hachim et al, 2017;Zhang et al, 2020;Zhao et al, 2021;. Moreover, Mahon et al (2020) and Yang et al (2021) also showed that M2 macrophage activation by materials in vitro corresponds to enhanced bone formation in vivo.…”

Section: M2 Macrophage Upregulation Is Essential During Bone Regeneration and Precedes Osteoinduction By Calcium Phosphate In Vivomentioning

confidence: 99%

From benchtop to clinic: a translational analysis of the immune response to submicron topography and its relevance to bone healing

Dijk¹,

Groot²,

Yuan³

et al. 2021

eCM

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Proper regulation of the innate immune response to bone biomaterials after implantation is pivotal for successful bone healing. Pro-inflammatory M1 and anti-inflammatory M2 macrophages are known to have an important role in regulating the healing response to biomaterials. Materials with defined structural and topographical features have recently been found to favourably modulate the innate immune response, leading to improved healing outcomes. Calcium phosphate bone grafts with submicron-sized needle-shaped surface features have been shown to trigger a pro-healing response through upregulation of M2 polarised macrophages, leading to accelerated and enhanced bone regeneration. The present review describes the recent research on these and other materials, all the way from benchtop to the clinic, including in vitro and in vivo fundamental studies, evaluation in clinically relevant spinal fusion models and clinical validation in a case series of 77 patients with posterolateral and/or interbody fusion in the lumbar and cervical spine. This research demonstrates the feasibility of enhancing biomaterial-directed bone formation by modulating the innate immune response through topographic surface features.

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Interleukin‐4‐loaded hydrogel scaffold regulates macrophages polarization to promote bone mesenchymal stem cells osteogenic differentiation via TGF‐β1/Smad pathway for repair of bone defect

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 44 publications

References 43 publications

Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration

Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration

Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold

From benchtop to clinic: a translational analysis of the immune response to submicron topography and its relevance to bone healing

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