Synergistic Effect of NELL-1 and an Ultra-Low Dose of BMP-2 on Spinal Fusion

Liu, Ling; Lam, Wing Moon Raymond; Naidu, Mathanapriya; Yang, Zheng; Wang, Ming; Ren, Xingjie; Hu, Tao; Kumarsing, Ramruttun Amit; Ting, Kang; Goh, James Cho‐Hong; Wong, Hee‐Kit

doi:10.1089/ten.tea.2019.0124

Cited by 10 publications

(13 citation statements)

References 48 publications

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“…These genes tested in the present study have been widely adopted in many researches to detect the osteoblastic induction of BMP-2. , The NH-GS + BMP group presented upregulated osteogenic bioactivity for at least 21 days compared with NF + BMP and NF, whereas upregulated expression was only detected at days 3 and 7 days for GS + BMP compared with GS. It is generally accepted that the bioactivity of BMP-2 has dose-dependent effect with concentration. , And the biological effect of BMP-2 depends on its loading system which determines the release kinetics. , In the present study, when we loaded the same amount of BMP-2, the lower burst release and sustainer release kinetics was shown in NH-GS + BMP group. Therefore, at the same time points, NH-GS stabilized BMP-2 with a relative high concentration.…”

Section: Discussionsupporting

confidence: 49%

Shape-Memory ECM-Mimicking Heparin-Modified Nanofibrous Gelatin Scaffold for Enhanced Bone Regeneration in Sinus Augmentation

Ying

Liu

et al. 2021

ACS Biomater. Sci. Eng.

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Biomaterials with clinical maneuverability and predictable bone regeneration are needed in the field of maxillary sinus augmentation. Herein, gelatin was chemically modified with heparin that specifically interacted with and stabilized bone morphogenetic protein-2 (BMP-2). We then introduced thermally induced phase separation to form the injectable, shape-memory, highly porous scaffold for bone regeneration in sinus augmentation. The hydrated heparin-modified nanofibrous gelatin scaffolds (NH-GS) were demonstrated with high resilience and shapememory property, both macroscopically and microscopically, making them injectable scaffolds and expected to be applied in sinus augmentation. This novel scaffold was verified to be biocompatible and an excellent matrix to support cell attachment, proliferation, and infiltration. Further, the growth factor-loaded NH-GS showed sustained release kinetics of BMP-2 through affinity-based scaffold-growth factor interaction, compared with BMP-2 loaded gelatin sponge (GS) and nanofibrous gelatin scaffold (NF). Both in vitro and in vivo experiments demonstrated that the BMP-2-loaded NH-GS exhibited the highest osteogenesis among the other groups. Taken together, this study introduces a new regenerative strategy in maxillary sinus augmentation, which is injectable with a predefined shape and structure and promotes bone regeneration through a more sustained BMP-2 release.

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Section: Discussionsupporting

confidence: 49%

Shape-Memory ECM-Mimicking Heparin-Modified Nanofibrous Gelatin Scaffold for Enhanced Bone Regeneration in Sinus Augmentation

Ying

Liu

et al. 2021

ACS Biomater. Sci. Eng.

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“…NELL-1 was applied in four dosages of 1, 10, 50, and 100 ng/mL for stem cells derived from adipose tissue [30]. High concentrations of 5 and 10 µg/mL were used for bone marrow stem cells from pigs [31]. Similarly, high concentrations ranging from 0.5 µg/mL to 50 µg/mL were used for various cells including ST2, MC3T3, C3H10T1/2, M2-10B4, and ATDC5 cells [32].…”

Section: Discussionmentioning

confidence: 99%

NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells

et al. 2021

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Background and objectives: NELL-1 is a competent growth factor and it reported to target cells committed to the osteochondral lineage. The secreted, osteoinductive glycoproteins are reported to rheostatically control skeletal ossification. This study was performed to determine the effects of NELL-1 on spheroid morphology and cell viability and the promotion of osteogenic differentiation of stem cell spheroids. Materials and Methods: Cultures of stem cell spheroids of gingiva-derived stem cells were grown in the presence of NELL-1 at concentrations of 1, 10, 100, and 500 ng/mL. Evaluations of cell morphology were performed using a microscope, and cell viability was assessed using a two-color assay and Cell Counting Kit-8. Evaluation of the activity of alkaline phosphatase and calcium deposition assays involved anthraquinone dye assay to determine the level of osteogenic differentiation of cell spheroids treated with NELL-1. Real-time quantitative polymerase chain reaction (qPCR) was used to evaluate the expressions of RUNX2, BSP, OCN, COL1A1, and β-actin mRNAs. Results: The applied stem cells produced well-formed spheroids, and the addition of NELL-1 at tested concentrations did not show any apparent changes in spheroid shape. There were no significant changes in diameter with addition of NELL-1 at 0, 1, 10, 100, and 500 ng/mL concentrations. The quantitative cell viability results derived on Days 1, 3, and 7 did not show significant disparities among groups (p > 0.05). There was statistically higher alkaline phosphatase activity in the 10 ng/mL group compared with the unloaded control on Day 7 (p < 0.05). A significant increase in anthraquinone dye staining was observed with the addition of NELL-1, and the highest value was noted at 10 ng/mL (p < 0.05). qPCR results demonstrated that the mRNA expression levels of RUNX2 and BSP were significantly increased when NELL-1 was added to the culture. Conclusions: Based on these findings, we conclude that NELL-1 can be applied for increased osteogenic differentiation of stem cell spheroids.

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“…In future research, the combinatory release of growth factors and other biologic agents from Reb should be considered, as previously evaluated using ACS and other scaffolds with similar applications and desired outcomes in addition to single application of BMP-2. 11,36,37…”

Section: Discussionmentioning

confidence: 99%

Electrospun, synthetic bone void filler promotes human MSC function and BMP-2 mediated spinal fusion

et al. 2020

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Introduction Synthetic bone grafts are often used to achieve a well-consolidated fusion mass in spinal fusion procedures. These bone grafts function as scaffolds, and ideally support cell function and facilitate protein binding. Objective The aim was to characterize an electrospun, synthetic bone void filler (Reb) for its bone morphogenetic protein (BMP)-2 release properties and support of human mesenchymal stem cell (hMSC) function in vitro, and its efficacy in promoting BMP-2-/bone marrow aspirate-(BMA)-mediated posterolateral spinal fusion (PLF) in vivo. Methods BMP-2 release kinetics from Reb versus standard absorbable collagen sponge (ACS) was determined. hMSC adhesion and proliferation on Reb was tested using cell counting, fluorescence microscopy and MTS. Cell osteogenic differentiation was quantified via cellular alkaline phosphatase (ALP) activity. For in vivo analysis, 18 Lewis rats were treated during PLF surgery with the following groups: (I) Reb + BMA, (II) Reb + BMA + BMP-2 and (III) BMA. A safe, minimally effective dose of BMP-2 was used. Fusion consolidation was followed for 3 months using radiography and micro-CT. After sacrifice, fusion rate and biomechanical stiffness was determined using manual palpation, biomechanical tests and histology. Results In vitro, BMP-2 release kinetics were similar between Reb versus ACS. MSC proliferation and differentiation were increased in the presence of Reb. At 3 months post-surgery, fusion rates were 29% (group I), 100% (group II), and 0% (group III). Biomechanical stiffness was higher in group II versus I. Micro-CT showed an increased bone volume and connectivity density in group II. Trabecular thickness was increased in group I versus II. H&E staining showed newly formed bone in group II only. Conclusions Reb possesses a high protein binding affinity and promotes hMSC function. Combination with BMA and minimal dose BMP-2 allowed for 100% bone fusion in vivo. This data suggests that a minimally effective dose of BMP-2 can be used when combined with Reb.

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Synergistic Effect of NELL-1 and an Ultra-Low Dose of BMP-2 on Spinal Fusion

Cited by 10 publications

References 48 publications

Shape-Memory ECM-Mimicking Heparin-Modified Nanofibrous Gelatin Scaffold for Enhanced Bone Regeneration in Sinus Augmentation

Shape-Memory ECM-Mimicking Heparin-Modified Nanofibrous Gelatin Scaffold for Enhanced Bone Regeneration in Sinus Augmentation

NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells

Electrospun, synthetic bone void filler promotes human MSC function and BMP-2 mediated spinal fusion

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