Molecular Detection and Assessment of Intervertebral Disc Degeneration via a Collagen Hybridizing Peptide

Xiao, Li; Majumdar, Rahul; Dai, Jun; Li, Yang; Xie, Lin; Shen, Francis H.; Jin, Li; Li, Xudong

doi:10.1021/acsbiomaterials.9b00070

Cited by 24 publications

(32 citation statements)

References 43 publications

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“…However, the SHG intensity within the AF was generally decreased in 12 months old WT and Phlpp1 KO mice. A recent study by Xiao et al 49 demonstrated a strong correlation between AF collagen damage and age by using a collagen-hybridizing peptide (which integrates into damaged collagen) and observed a significant increase in damaged collagen between 6–8 months and 10–12 months old mice. Given that the damage to the secondary and tertiary protein structure of collagen is also detectable by decreased SHG intensity 50 , their findings supported the lower SHG intensity detected in the AF tissues of 12 months old mice relative to 6 months group.…”

Section: Discussionmentioning

confidence: 99%

“…Besides Akt, Phlpp1 also directly controls other cell survival signaling pathways, including PKC and p70 S6 kinase 15,52,53 and the pro-apoptotic kinase Mst1 54,55 , which likely explains the protective effect of Phlpp1 depletion on cell proliferation but less pronounced effects on Akt phosphorylation. Phlpp1 deficiency also activates the negative feedback regulation of the Akt pathway, where PTEN, a lipid phosphatase, participates in the feedback loop by dephosphorylating PI3K to balance the level of phosphorylated Akt 29,49 . PTEN is an another phosphatase that has several off-target effects.…”

Section: Discussionmentioning

confidence: 99%

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Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

et al. 2019

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Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

et al. 2019

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“…Since the number of defects increases with degeneration, we note severely degenerated IVDs would have an increase in structural disruptions in addition to the collagen network changes described in this SHG study. The fibrosis hypothesis presented suggests that the original collagenous structure within the AF degenerates and is replaced with new collagen, and future studies can assess degenerated collagen using collagen hybridizing peptide as a probe 54‐56 . Lastly, future SHG analysis concurrent with biomechanical experiments may further elucidate structure‐function relationships since structural changes in collagen are expected upon load application 49,57‐59 …”

Section: Discussionmentioning

confidence: 98%

“…The fibrosis hypothesis presented suggests that the original collagenous structure within the AF degenerates and is replaced with new collagen, and future studies can assess degenerated collagen using collagen hybridizing peptide as a probe. [54][55][56] Lastly, future SHG analysis concurrent with biomechanical experiments may further elucidate structurefunction relationships since structural changes in collagen are expected upon load application. 49,[57][58][59] In conclusion, this study applied SHG imaging and multiple image processing algorithms to quantify the spatial changes in collagen structure with IVD degeneration.…”

Section: Discussionmentioning

confidence: 99%

Spatial mapping of collagen content and structure in human intervertebral disk degeneration

et al. 2020

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Collagen plays a key structural role in both the annulus fibrosus (AF) and nucleus pulposus (NP) of intervertebral disks (IVDs). Changes in collagen content with degeneration suggest a shift from collagen type II to type I within the NP, and the activation of pro-inflammatory factors is indicative of fibrosis throughout. While IVD degeneration is considered a fibrotic process, an increase in collagen content with degeneration, reflective of fibrosis, has not been demonstrated. Additionally, changes in collagen content and structure in human IVDs with degeneration have not been characterized with high spatial resolution. The collagen content of 23 human lumbar L2/3 or L3/4 IVDs was quantified using second harmonic generation imaging (SHG) and multiple image processing algorithms, and these parameters were correlated with the Rutges histological degeneration grade. In the NP, SHG intensity increased with degeneration grade, suggesting fibrotic collagen deposition. In the AF, the entropy of SHG intensity was reduced with degeneration indicating increased collagen uniformity and suggesting less-organized lamellar structure. Collagen orientation entropy decreased throughout most IVD regions with increasing degeneration grade, further supporting a loss in collagen structural complexity. Overall, SHG imaging enabled visualization and quantification of IVD collagen content and organization with degeneration. There was an observed shift from an initially complex structure to more uniform structure with loss of microstructural elements and increased NP collagen polarity, suggesting fibrotic remodeling.

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“…Fluorescence microscopy of rat skin tissue slide (without mounting) was performed using a Nikon DS‐Ri2 digital microscope camera mounted on a Nikon Eclipse E‐600 microscope with a TRITC channel. Images were captured with the exact same exposure time and analog gain at 200× magnification using the NIS Elements Software (Nikon Corp.) following the published protocols …”

Section: Methodsmentioning

confidence: 99%

3D Printed Microheater Sensor‐Integrated, Drug‐Encapsulated Microneedle Patch System for Pain Management

Yin

Xiao

Liu

et al. 2019

Adv Healthcare Materials

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Microneedle patch devices have been widely utilized for transdermal drug delivery in pain management, but is challenged by accurate control of drug release and subsequent diffusion to human body. The recent emerging wearable electronics that could be integrated with microneedle devices offer a facile approach to address such a challenge. Here a 3D‐printed microheater integrated drug‐encapsulated microneedle patch system for drug delivery is presented. The ink solution comprised polydimethylsiloxane (PDMS) and multiwalled carbon nanotubes (MWCNTs) with a mass concentration of up to 45% (≈10 times higher of existing ones) is prepared and used to print crack‐free stretchable microheaters on substrates with a broad range of materials and geometric curves. The adhesion strength of the printed microheater on the microneedle patch in elevated temperatures is measured to evaluate their integration performance. Assessments of encapsulated drug release into rat's skin are confirmed by examining degradation of microneedles, skin morphologies, and released fluorescent signals. Results and demonstrations established here creates a new opportunity for developing sensor controlled smart microneedle patch systems by integrating with wearable electronics, potentially useful in clinical and biomedical research.

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Molecular Detection and Assessment of Intervertebral Disc Degeneration via a Collagen Hybridizing Peptide

Cited by 24 publications

References 43 publications

Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

Spatial mapping of collagen content and structure in human intervertebral disk degeneration

3D Printed Microheater Sensor‐Integrated, Drug‐Encapsulated Microneedle Patch System for Pain Management

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