IP Library Granted Patent US 12,213,997
Granted Patent B1
US 12,213,997 · App. 17/165,011 · Granted Feb 4, 2025

Compositions and methods for supporting nucleus pulposus (NP) cell phenotype and biosynthesis

Inventors: Lori Setton (St. Louis, MO); Marcos Barcellona (St. Louis, MO); Julie Speer (St. Louis, MO)
Assignee: Washington University
A61K35/32A61K35/545A61K47/60C07K14/78C12N5/0654
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Quick Facts
Patent No.
US 12,213,997
App. No.
17/165,011
Granted
Feb 4, 2025
Kind
B1
Abstract

Among the various aspects of the present disclosure is the provision of compositions and methods for the generation of a supporting matrix for cells, such as stem cells and NP cells (and precursors thereof). For example, an NP cell-specific phenotype precursor cell can be an adult NP cell, such as a cell taken from the adult and degenerated intervertebral disc and/or a progenitor cell, such as stem cells, induced pluripotent cells, pluripotent cells, precursor cells, or stromal cells.

Claims (51)

1. A biocompatible composition comprising:

a PEG maleimide biocompatible polymer component; and

at least one cell-adhesive peptide,

wherein

the cell-adhesive peptide is between about 5 and about 30 amino acids long;

the cell-adhesive peptide comprises at least one syndecan-binding or integrin-binding peptide selected from SEQ ID NO: 1, CGG-terminated SEQ ID NO: 1, SEQ ID NO: 2, and C-terminated SEQ ID NO: 2;

the cell-adhesive peptide is coupled to the biocompatible polymer component to form a cell-adhesive peptide-functionalized monomer;

the cell-adhesive peptide-functionalized monomer is crosslinked to form a cell-adhesive peptide-functionalized polymer, wherein the cell-adhesive peptide-functionalized polymer has a density greater than 10% (w/v);

the biocompatible composition has a stiffness of about 10 kPa; and

the biocompatible composition comprises a cell-adhesive peptide density between about 50 μM and about 100 μM sufficient to support nucleus pulposus (NP) cell-specific morphology, biosynthesis, or phenotype.

2. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide is derived from a sequence found in naturally occurring laminin proteins, a functional portion of the LG domains of full length laminin, isoforms thereof, or a functional fragment or variant thereof.

3. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide is a laminin-mimetic peptide.

4. The biocompatible composition of claim 3 , wherein the laminin-mimetic peptide is a laminin-based integrin-binding peptide or a laminin-based syndecan-binding peptide.

5. The biocompatible composition of claim 1 , comprising a first integrin-binding peptide and a second integrin-binding peptide.

6. The biocompatible composition of claim 1 , wherein the biocompatible polymer component comprises a terminal component capable of conjugating a cell-adhesive peptide.

7. The biocompatible composition of claim 6 , wherein the terminal component comprises maleimide, cysteine, or carboxylate.

8. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide-functionalized monomer is crosslinked via coupling of the biocompatible polymer component via side group coupling, a terminal group on the biocompatible polymer component, a sulfo-, a dithiol crosslinker, a PEG crosslinker, an amine, or EDC/NHS coupling.

9. The biocompatible composition of claim 8 , wherein the dithiol crosslinker is SH-PEG-SH.

10. The biocompatible composition of claim 1 , wherein if the cell-adhesive peptide density is increased, the biocompatible composition stiffness increases.

11. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide comprises a terminal group capable of conjugating to a biocompatible polymer component comprising a bioconjugation component capable of conjugating with the terminal group.

12. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide comprises a thiol terminal group capable of conjugating to a biocompatible polymer component comprising maleimide.

13. The biocompatible composition of claim 1 , wherein the at least one cell-adhesive peptide is a combination of a syndecan-binding peptide and an integrin-binding peptide.

14. The biocompatible composition of claim 1 , wherein the at least one cell-adhesive peptide is at least two of integrin-binding, syndecan-binding, or cadherin-binding peptides.

15. The biocompatible composition of claim 3 , wherein the laminin-mimetic peptide further comprises a sequence selected from the group consisting of PPFLMLLKGSTR (SEQ ID NO: 3), EGYGEGYIGSR (SEQ ID NO: 4), AGQWHRVSRWG (SEQ ID NO: 5), KQNCLSSRASFRGCVRNLRLSR (SEQ ID NO: 6), and combinations thereof.

16. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide-functionalized polymer density is between about 15% (w/v) and about 40% (w/v).

17. The biocompatible composition of claim 1 , further comprising a population of undifferentiated precursor cells, a population of stem cells, a population of nucleus pulposus (NP) cell precursors, a population of adult primary NP cells, or a population of primary intervertebral disc (IVD) cells, or a combination thereof.

18. The biocompatible composition of claim 16 , wherein the NP cell precursors are NP progenitor cells.

19. The biocompatible composition of claim 1 , wherein the biocompatible composition comprises a cell having an NP cell-specific phenotype characterized by the gene expression of COL1A1, ACAN, COL2A1, GLUT1, or CDH2, or combinations thereof.

20. The biocompatible composition of claim 1 , wherein the biocompatible composition comprises a population of NP cell-specific phenotype precursor cells selected from IVD cells, primary adult NP cells, NP precursor cells, adult NP cells, or pathological NP cells, or combinations thereof.

21. The biocompatible composition of claim 16 , wherein the NP cell precursors are undifferentiated precursor cells.

22. The biocompatible composition of claim 1 , further comprising at least one progenitor cell in its undifferentiated state.

23. The biocompatible composition of claim 1 , wherein the biocompatible composition further comprises stem cells selected from adipose stromal/stem cells (ASCs), adipose-derived stem cells (ADSCs), amniotic fluid stem cells, bone marrow-derived mesenchymal stem/stromal cells (BMSCs), bone marrow stem cells, cord blood stem cells, embryonic stem (ES) cells, hematopoietic stem cells, induced pluripotent stem cells (iPSCs), mesenchymal stromal, non-embryonic (adult) stem cells, pluripotent stem cells (PSCs), progenitor cells, induced pluripotent stem (iPS) cells), induced pluripotent stem cells (iPSCs), mesenchymal stromal cells, mesenchymal stem cells (MSCs), cord blood stem cells, umbilical cord-derived progenitor cells, umbilical cord-MSCs, umbilical cord-derived progenitor cells, amniotic fluid stem cells, and other progenitor cells.

24. The biocompatible composition of claim 23 , wherein the stem cells promote cell attachment, promote the secretion of inflammatory mediating factors, or promote the secretion of matrix degrading protease mediating factors.

25. The biocompatible composition of claim 24 , wherein the inflammatory mediating factors are selected from interleukin (IL)-1 receptor agonist (RA), SIL-6R, soluble tumor necrosis factor receptor (sTNFR) I, sTNFRII, tissue inhibitor of metalloproteinases (TIMP) 1, TIMP 2, TIMP 3, TIMP 4, and combinations thereof.

26. The biocompatible composition of claim 1 , wherein the biocompatible composition supports progenitor cell secretions of chemokines that exert an anti-inflammatory effect upon neighboring cells.

27. The biocompatible composition of claim 1 , further comprising progenitor cells cultured in or on the biocompatible composition, wherein the progenitor cells secrete inflammatory-mediating factors that result in inflammatory mediating effects upon neighboring cells.

28. The biocompatible composition of claim 27 , wherein the inflammatory-mediating factors are selected from IL-1RA, sIL-6R, sTNFRI, STNFRII, and combinations thereof.

29. The biocompatible composition of claim 1 , further comprising progenitor cells cultured in or on the biocompatible composition, wherein the progenitor cells secrete protease mediating factors which result in protease mediating effects upon neighboring cells.

30. The biocompatible composition of claim 29 , wherein the protease mediating factors are selected from TIMP_1, TIMP 2, TIMP_3, TIMP_4, and combinations thereof.

31. The biocompatible composition of claim 1 , wherein the biocompatible composition supports progenitor cells capable of secreting extracellular matrix biosynthesis promoting chemokines within neighboring cells.

32. The biocompatible composition of claim 31 , wherein anabolic effects are achieved through secretion of extracellular matrix proteins.

33. The biocompatible composition of claim 1 , wherein the biocompatible composition is suitable for use as an injectable material mixed with cells or cell-free, wherein the biocompatible composition has a viscosity that does not exceed G′ of 100 Pa and G″ of 25 Pa at temperatures between about 4° C. and about 37° C.

34. The biocompatible composition of claim 1 , wherein the biocompatible composition is suitable for delivery to a defect site when injected in its precursor form mixed with cells or cell-free through a 12 G-22 G needle.

35. The biocompatible composition of claim 1 , wherein the biocompatible composition is a 3D cell supporting matrix or coats a tissue culture surface.

36. The biocompatible composition of claim 1 , wherein the biocompatible composition is capable of being used in cell-polymer culture constructs in vitro in volumes between about 10 mL and about 1 mL and between about 0 million cells/mL and up to about 10 million cells/mL.

37. The biocompatible composition of claim 1 , wherein the biocompatible composition delivers cells to an intervertebral disc.

38. The biocompatible composition of claim 1 , wherein the cell-adhesive peptide densities and co-combinations of coupling to peptide-functionalized polymer components modulate a range of cell phenotypic changes.

39. The biocompatible composition of claim 1 , wherein the biocompatible composition supports cell survival, when introduced to a population of cells, in a peptide-functionalized polymer component solution, and crosslinked into a three-dimensional construct.

40. The biocompatible composition of claim 1 , wherein the biocompatible composition is capable of delivering and localizing NP precursor cells or primary human NP cells and peptide-functionalized polymer components to defects in an intervertebral disc in a subject.

41. A method of supporting adult human NP cells towards a healthy nucleus pulposus (NP) cell-specific phenotype or delivering undifferentiated progenitor cells comprising administering to a subject the biocompatible composition of claim 1 .

42. The method of claim 41 , wherein the subject has intervertebral disc degeneration or damage.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 2, 2023
From: WASHINGTON UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065431/0200 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 15, 2021
From: SETTON, LORI; BARCELLONA, MARCOS; SPEER, JULIE
To: WASHINGTON UNIVERSITY
Reel/Frame 055253/0566 →
Continuity (1)
Provisional Application 62969982 · Feb 4, 2020
References Cited (162)
US 9011545B2 · Nakamura et al. · 2015 [cited by applicant]
US 9549962B2 · Berlemann et al. · 2017 [cited by applicant]
US 20080071379A1 · Rydell et al. · 2008 [cited by applicant]
US 20120276008A1 · Walkenhorst et al. · 2012 [cited by applicant]
US 20120282697A1 · Henry et al. · 2012 [cited by applicant]
US 20130052155A1 · Marcolongo et al. · 2013 [cited by applicant]
US 20180346902A1 · Jansen et al. · 2018 [cited by applicant]
Francisco et al. (2014, Acta Biomaterialia 10:1102-1111). [cited by examiner]
Kikkawa et al. (2013, Cell Adhesion & Migration 7(1): 150-159). [cited by examiner]
Gonçalves (2019, Master's Thesis, Faculdade de Engenharia da Universidade do Porto, Instituto de Ciências Biomédicas Abel Salazar). [cited by examiner]
Bridgen et al. (2017, Acta Biomaterialia 55:100-108). [cited by examiner]
“Peptide,” https://www.oxfordlearnersdictionaries.com/us/definition/english/peptide#:˜:text=%2F%CB%88pepta%C9%AAd%2F-,%2F%CB%88pepta%C9%AAd%2F,more%20amino%20acids%20joined%20together (accessed Aug. 14, 2023). [cited by examiner]
Adams, M.A. & Roughley, P.J. (2006) What is Intervertebral Disc Degeneration, and What Causes It? [cited by applicant]
Aker, L. et al. (2017) Molecular Biology and Interactions in Intervertebral Disc Development, Homeostasis, and Degeneration, with Emphasis on Future Therapies : A Systematic Review. Spine Sch. vol. 1, No. 1, pp. 2-20. [cited by applicant]
Ali, S.A. (2014) Hedgehog Signaling Modulates Cholesterol Homeostasis in Chondrocytes and in Osteoarthritis. Dissertation deposited at University of Toronto, retrieved from https://tspace.library.utoronto.ca/bitstream/1… [cited by applicant]
Alonso, R. et al. (2005) Diacylglycerol Kinase a Regulates the Secretion of Lethal Exosomes Bearing Fas Ligand during Activation induced Cell Death of T Lymphocytes. [cited by applicant]
Bai, X.-H. (2014) XB130—A Novel Adaptor Protein: Gene, Function, and Roles in Tumorigenesis. [cited by applicant]
Balaoing, L.R et al. (2015) Laminin Peptide-Immobilized Hydrogels Modulate Valve Endothelial Cell Hemostatic Regulation. [cited by applicant]
Bangasser B.L., et al. (2017) Shifting the optimal stiffness for cell migration. [cited by applicant]
Barcellona, M.N. et al. (2020) Control of adhesive ligand density for modulation of nucleus pulposus cell phenotype. [cited by applicant]
Barik, M., Mishra, P.R, & Mohapatra, A.K. (2018) Missing Links Between Genetically Inherited Molecules in Split Cord Malformation and Other Anomaly: A Bench to Bedside Approach., [cited by applicant]
Bidarra, S.J., Barrias, C.C. & Granja, P.L. (2014) Injectable alginate hydrogels for cell delivery in tissue engineering. [cited by applicant]
Binch, A., Snuggs, J. & Le Maitre, C.L. (2020) Immunohistochemical analysis of protein expression in formalin fixed paraffin embedded human intervertebral disc tissues. [cited by applicant]
Bonnevie, E.D. et al. (2019) Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. [cited by applicant]
Boos, N. et al. (2002) Classification of age-related changes in lumbar intervertebral discs. [cited by applicant]
Borg, D.J. et al. (2016) Macroporous biohybrid cryogels for co-housing pancreatic islets with mesenchymal stromal cells. [cited by applicant]
Bowles, R.D. et al. (2010) Self-Assembly of Aligned Tissue-Engineered Annulus and Intervertebral Disc Composite via Collagen Gel Contraction. [cited by applicant]
Bowles, R.D. & Setton L.A. (2017) Biomaterials for intervertebral disc regeneration and repair. [cited by applicant]
Bridgen, D.T. et al. (2013) Integrin-Mediated Interactions with Extracellular Matrix Proteins for Nucleus Pulposus Cells of the Human Intervertebral Disc. [cited by applicant]
Bridgen, D.T. et al. (2017) Regulation of human nucleus pulposus cells by peptide-coupled substrates. [cited by applicant]
Budd, E. (2016) MicroRNAs in Osteoarthritis and Chondrogenesis. Dissertation deposited at University of Southampton; Institute of Developmental Health, retrieved from https://eprints.soton.ac.uk/407447/1/Emma_Budd_PhD_T… [cited by applicant]
Bult, C.J. et al. (2019) Mouse Genome Database (MGD) 2019. [cited by applicant]
Burdick, J.A. & Anseth, K.S. (2002) Photoencapsulation of osteoblasts in injectable RGD-modified PEG hydrogels for bone tissue engineering. [cited by applicant]
Chan, S.C.W., Ferguson, S.J. & Gantenbein-Ritter, B. (2011) The effects of dynamic loading on the intervertebral disc. [cited by applicant]
Chan, W.C.W. et al. (2011) Structure and Biology of the Intervertebral Disk in Health and Disease. [cited by applicant]
Chen, J. et al. (2009) Expression of Laminin Isoforms, Receptors, and Binding Proteins Unique to Nucleus Pulposus Cells of Immature Intervertebral Disc. [cited by applicant]
Chen, Z., Liu, J., & Zhang, Y. (2017) Role of Epithelial Cell Transforming Sequence 2 (ECT2) in Predicting Prognosis of Osteosarcoma. [cited by applicant]
Choi, H., Johnson, Z.I., & Risbud, M.V. (2015) Understanding Nucleus Pulposus Cell Phenotype: A Prerequisite for Stem Cell Based Therapies to Treat Intervertebral Disc Degeneration. [cited by applicant]
Cloyd, J. M. et al. (2007) Material properties in unconfined compression of human nucleus pulposus, injectable hyaluronic acid-based hydrogels and tissue engineering scaffolds. [cited by applicant]
Colombini, A. et al. (2014) Fibrin in Intervertebral Disc Tissue Engineering. [cited by applicant]
Connelly, J.T., Garcia, A.J., & Levenston M.E. (2008) Interactions between integrin density and cytoskeletal integrity regulate BMSC chondrogenesis, [cited by applicant]
Connelly, J.T. et al. (2010) Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. [cited by applicant]
Couchman, J.R. & Woods, A. (1999) Syndecan-4 and integrins: combinatorial signaling in cell adhesion. [cited by applicant]
Crowder, S.W. et al. (2016) Material Cues as Potent Regulators of Epigenetics and Stem Cell Function. [cited by applicant]
Cui, Y. (2011) Interplay of the osmotic environment and a fibronectin fragment in intervertebral disc cell metabolism. Dissertation deposited at the University of Oxford, retrieved from https://ora.ox.ac.uk/objects/uuid… [cited by applicant]
Darling, N.J. et al. (2016) Controlling the kinetics of thiol-maleimide Michael-type addition gelation kinetics for the generation of homogenous poly(ethylene glycol) hydrogels. [cited by applicant]
Diez-Roux, G. et al. (2011) A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo. PLoS Biol. vol. 9, No. 1, e1000582, 13 pages. [cited by applicant]
Du, L. et al. (2019) Engineering a biomimetic integrated scaffold for intervertebral disc replacement. [cited by applicant]
Eleftherohorinou, H. et al. (2011) Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. [cited by applicant]
Enemchukwu, N.O. et al. (2016) Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. [cited by applicant]
Engler, A.J. et al. (2006) Matrix Elasticity Directs Stem Cell Lineage Specification. [cited by applicant]
Fearing, B.V. et al. (2019) Mechanosensitive transcriptional coactivators MRTF-A and YAP / TAZ regulate nucleus pulposus cell phenotype through cell shape. [cited by applicant]
Fearing, B.V. et al. (2020), Verteporfin treatment controls morphology, phenotype, and global gene expression for cells of the human nucleus pulposus. [cited by applicant]
Fields, A.J., Liebenberg, E.C. & Lotz, J.C. (2014) Innervation of pathologies in the lumbar vertebral end plate and intervertebral disc. [cited by applicant]
Francisco, A.T. et al. (2013) Injectable laminin-functionalized hydrogel for nucleus pulposus regeneration. [cited by applicant]
Francisco, A.T. et al. (2014) Photocrosslinkable laminin-functionalized polyethylene glycol hydrogel for intervertebral disc regeneration. [cited by applicant]
Frauchiger, D.A. et al. (2017) A review of the application of reinforced hydrogels and silk as biomaterials for intervertebral disc repair. [cited by applicant]
Freemont, A.J. et al. (1997) Nerve ingrowth into diseased intervertebral disc in chronic back pain. [cited by applicant]
Fujita, N. et al. (2012) Prolyl hydroxylase 3 (PHD3) modulates catabolic effects of tumor necrosis factor-α (TNF-α) on cells of the nucleus pulposus through co-activation of nuclear factor κB (NF-κB)/p65 signaling. [cited by applicant]
Gao, L., McBeath, R., & Chen, C.S. (2010) Stem Cell Shape Regulates a Chondrogenic Versus Myogenic Fate Through Rac1 and N-Cadherin. [cited by applicant]
Giannattasio, G. et al. (2011) The Purinergic G Protein-Coupled Receptor 6 Inhibits Effector T Cell Activation in Allergic Pulmonary Inflammation. [cited by applicant]
Gilchrist, C.L. et al. (2011) Extracellular matrix ligand and stiffness modulate immature nucleus pulposus cell-cell interactions. [cited by applicant]
Gullbrand, S.E. et al. (2017) Translation of an injectable triple-interpenetrating-network Hydrogel for Intervertebral Disc Regeneration in a Goat Model. [cited by applicant]
Hiyama, A. et al. (2011) Hypoxia Activates the Notch Signaling Pathway in Cells of the Intervertebral Disc. [cited by applicant]
Hong, X. et al. (2018) Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation. [cited by applicant]
Hossain, S., Mineno, K., & Katafuchi, T. (2016) Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling. [cited by applicant]
Hozumi, K. et al. (2010) Syndecan- and integrin-binding peptides synergistically accelerate cell adhesion. [cited by applicant]
Huebsch, N. et al. (2010) Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. [cited by applicant]
Huebsch, N. (2019) Translational mechanobiology: Designing synthetic hydrogel matrices for improved in vitro models and cell-based therapies. [cited by applicant]
Hughes, C.E. & Nibbs, R.J.B. (2018) A guide to chemokines and their receptors. [cited by applicant]
Humphrey, J.D., Dufresne, E.R., & Schwartz, M.A. (2014) Mechanotransduction and extracellular matrix homeostasis. [cited by applicant]
Hwang, P.Y. et al. (2014) N-Cadherin-Mediated Signaling Regulates Cell Phenotype for Nucleus Pulposus Cells of the Intervertebral Disc. [cited by applicant]
Hwang, P.Y. et al. (2016) N-cadherin is Key to Expression of the Nucleus Pulposus Cell Phenotype under Selective Substrate Culture Conditions. [cited by applicant]
Iatridis, J.C. et al. (1996) Is the Nucleus Pulposus a Solid or a Fluid? Mechanical Behaviors of the Nucleus Pulposus of the Human Intervertebral Disc. [cited by applicant]
Iatridis, J.C. et al. (1997) Alterations in the Mechanical Behavior of the Human Lumbar Nucleus Pulposus with Degeneration and Aging. [cited by applicant]
Iatridis, J.C. et al. (1998) Degeneration affects the anisotropic and nonlinear behaviors of human anulus fibrosus in compression. [cited by applicant]
Ishiguro, H. et al. (2019) Intervertebral disc regeneration with an adipose mesenchymal stem cell-derived tissue-engineered construct in a rat nucleotomy model. [cited by applicant]
Iwamoto, T. et al. (2006) Monocyte chemoattractant protein-4 (MCP-4)/CCL 13 is highly expressed in cartilage from patients with rheumatoid arthritis. [cited by applicant]
Jang, J-H et al. (2018) Novel analgesic effects of melanin-concentrating hormone on persistent neuropathic and inflammatory pain in mice. [cited by applicant]
Jeong, C.G. et al. (2014) Screening of hyaluronic acid-poly(ethylene glycol) composite hydrogels to support intervertebral disc cell biosynthesis using artificial neural network analysis. [cited by applicant]
Jing, J. et al. (2015) Annexin V-induced rat Leydig cell proliferation involves Ect2 via RhoA/ROCK signaling pathway. [cited by applicant]
Johnson, Z.I. et al. (2017) TNF-α promotes nuclear enrichment of the transcription factor TonEBP/NFAT5 to selectively control inflammatory but not osmoregulatory responses in nucleus pulposus cells. [cited by applicant]
Karimi, F. et al. (2018) Integrin Clustering Matters: A Review of Biomaterials Functionalized with Multivalent Integrin-Binding Ligands to Improve Cell Adhesion, Migration, Differentiation, Angiogenesis, and Biomedical … [cited by applicant]
Kauppila, L.I. (1995) Ingrowth of Blood Vessels in Disc Degeneration. [cited by applicant]
Kikkawa, Y. et al. (2013) Laminin-111-derived peptides and cancer. [cited by applicant]
Kilian, K.A. et al. (2010) Geometric cues for directing the differentiation of mesenchymal stem cells. [cited by applicant]
Kilian, K.A. & Mrksich, M. (2012) Directing stem cell fate by controlling the affinity and density of ligand receptor interactions at the biomaterials interface. [cited by applicant]
Kim, T. et al. (2009) Identification of LRRc17 as a Negative Regulator of Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation. [cited by applicant]
Korecki, C.L., Costi, J.J. & Iatridis, J.C. (2008) Needle Puncture Injury Affects Intervertebral Disc Mechanics and Biology in an Organ Culture Model. [cited by applicant]
Koyanagi, S. et al. (2016) Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia. [cited by applicant]
Kringel, D. et al. (2018) A machine-learned analysis of human gene polymorphisms modulating persisting pain points to major roles of neuroimmune processes. [cited by applicant]
Kupka, J. et al. (2020) Adrenoceptor Expression during Intervertebral Disc Degeneration. [cited by applicant]
Leblanc, K.T. (2013) Runx Expression in Normal and Osteoarthritic Cartilage: Possible Functions of Runx Proteins in Chondrocytes: A Dissertation. University of Massachusetts Medical School, accessed from https://eschola… [cited by applicant]
Lee, J. (2013) Directing stem cell fate on hydrogel substrates by controlling cell geometry, matrix mechanics and adhesion ligand composition. [cited by applicant]
Leimer, E.M. et al. (2019) Behavioral Compensations and Neuronal Remodeling in a Rodent Model of Chronic Intervertebral Disc Degeneration. [cited by applicant]
Li, J. et al. (2017) Investigation of bioeffects of G protein-coupled receptor 1 on bone turnover in male mice. [cited by applicant]
Liu, Z. et al. (2017) Hypoxia-inducible factor-la mediates aggrecan and collagen π expression via NOTCH1 signaling in nucleus pulposus cells during intervertebral disc degeneration. [cited by applicant]
Lo, C.M. (2000) Cell Movement Is Guided by the Rigidity of the Substrate. Biophys. J. vol. 79, No. 1, pp. 144-152. [cited by applicant]
Luo, J. et al. (2019) The role of GPCRs in bone diseases and dysfunctions. [cited by applicant]
Maheshwari, G. et al. (2000) Cell adhesion and motility depend on nanoscale RGD clustering. [cited by applicant]
Maroudas, A. et al. (1975). Factors involved in the nutrition of the human lumbar intervertebral disc: cellularity and diffusion of glucose in vitro. [cited by applicant]
Martin, J.T. et al. (2013) Needle puncture injury causes acute and long-term mechanical deficiency in a mouse model of intervertebral disc degeneration. [cited by applicant]
Masuda, K. et al. (2005) A Novel Rabbit Model of Mild, Reproducible Disc Degeneration by an Anulus Needle Puncture: Correlation Between the Degree of Disc Injury and Radiological and Histological Appearances of Disc Deg… [cited by applicant]
McBeath, R. et al. (2004) Cell Shape, Cytoskeletal Tension, and RhoA Regulate Stem Cell Lineage Commitment. [cited by applicant]
McLeod, C.M. & Mauck, R.L. (2016) High fidelity visualization of cell-to-cell variation and temporal dynamics in nascent extracellular matrix formation. [cited by applicant]
Mitra, A. et al. (2017) Cell geometry dictates TNFα-induced genome response. [cited by applicant]
Miyagi, M. et al. (2011) Disk Injury in Rats Produces Persistent Increases in Pain-Related Neuropeptides in Dorsal Root Ganglia and Spinal Cord Glia but Only Transient Increases in Inflammatory Mediators. [cited by applicant]
Mizuno, H. et al. (2004) Tissue-Engineered Composites of Anulus Fibrosus and Nucleus Pulposus for Intervertebral Disc Replacement. [cited by applicant]
Mohanty, S. et al. (2019) Chondrocyte—like nested cells in the aged intervertebral disc are late-stage nucleus pulposus cells. [cited by applicant]
Mohd Isa, I. L. et al. (2018) Implantation of hyaluronic acid hydrogel prevents the pain phenotype in a rat model of intervertebral disc injury. [cited by applicant]
Mok, G.F. et al. (2020) Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension. [cited by applicant]
Mroue, R. & Bissell, M. J. (2013) Three-Dimensional Cultures of Mouse Mammary Epithelial Cells. [cited by applicant]
Nagae, M. et al. (2007) Intervertebral Disc Regeneration Using Platelet-Rich Plasma and Biodegradable Gelatin Hydrogel Microspheres. [cited by applicant]
Nerlich, A.G. et al. (2006) Temporo-spatial distribution of blood vessels in human lumbar intervertebral discs. [cited by applicant]
Nguyen, M. et al. (2017), Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl. [cited by applicant]
Nilsson, E., Nakamae, T. & Olmarker, K. (2011) Pain Behavior Changes Following Disc 5 Puncture Relate to Nucleus Pulposus Rather than to the Disc Injury Per Se: An Experimental Study in Rats. [cited by applicant]
O'Brien, L. E., Zegers, M. M. P. & Mostov, K. E. (2002) Building epithelial architecture: insights from three-dimensional culture models. [cited by applicant]
Park, E.J. et al. (2014) Indispensable Platforms for Bioimmobilization: Maleimide-Based Thiol Reactive Hydrogels. [cited by applicant]
Pattappa, G. et al. (2012) Diversity of intervertebral disc cells: phenotype and function. [cited by applicant]
Rajesh, D. & Dahia, C. L. (2018) Role of Sonic Hedgehog Signaling Pathway in Intervertebral Disc Formation and Maintenance. [cited by applicant]
Rattner, A. et al. (2013) Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis. [cited by applicant]
Resutek, L. & Hsieh, A. H. (2019) The vacuolated morphology of chordoma cells is dependent on cytokeratin intermediate filaments. [cited by applicant]
Riquier, S. et al. (2020), Detailed analysis of public RNAseq data and long non-coding RNA: a proposed enhancement to mesenchymal stem cell characterization. [cited by applicant]
Risbud, M.V. et al. (2015) Defining the Phenotype of Young Healthy Nucleus Pulposus Cells: Recommendations of the Spine Research Interest Group at the 2014 Annual ORS Meeting. [cited by applicant]
Rodrigues-Pinto, R. et al. (2018) Human notochordal cell transcriptome unveils potential regulators of cell function in the developing intervertebral disc. [cited by applicant]
Roughley, P.J. (2004) Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix. [cited by applicant]
Rouillard, A.D. et al. (2016) The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. [cited by applicant]
Sasson, A. et al. (2012) Hyperelastic mechanical behavior of chitosan hydrogels for nucleus pulposus replacement-experimental testing and constitutive modeling. [cited by applicant]
Satoh, S. & Lipton, S. (2017) Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like … [cited by applicant]
Setton, L.A. & Chen, J. (2006) Mechanobiology of the Intervertebral Disc and Relevance to Disc Degeneration. [cited by applicant]
Smith, L.J. et al. (2018) Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section. [cited by applicant]
Sohn, P. et al. (2010) Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc. [cited by applicant]
Southern, C. et al. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. [cited by applicant]
Sozzani, S. et al. (2015) Chemokines as effector and target molecules in vascular biology. [cited by applicant]
Speichert, S. et al. (2019) Role of Norepinephrine in IL-1β-Induced Chondrocyte Dedifferentiation under Physioxia. [cited by applicant]
Szklarczyk, D. et al. (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. [cited by applicant]
Tam, V. et al. (2014) A Comparison of Intravenous and Intradiscal Delivery of Multipotential Stem Cells on the Healing of Injured Intervertebral Disk Architecture nor the Disk Height Index. [cited by applicant]
Tang, R. et al. (2018) Differentiation of human-induced pluripotent stem cells into nucleus pulposus-like cells. [cited by applicant]
Tenn, N.A. (2015) Investigating The Mechanism of Ectopic Mineralization in a Mouse Model of Diffuse Idiopathic Skeletal Hyperostosis (DISH). Dissertation deposited at The University of Western Ontario, accessed from htt… [cited by applicant]
Thorpe, A.A. et al. (2017) Thermally triggered hydrogel injection into bovine intervertebral disc tissue explants induces differentiation of mesenchymal stem cells and restores mechanical function. [cited by applicant]
Tondreau, T. et al. (2008) Gene expression pattern of functional neuronal cells derived from human bone marrow mesenchymal stromal cells. [cited by applicant]
Trout, J.J. et al. (1982) Ultrastructure of the human intervertebral disc. I. Changes in notochordal cells with age. [cited by applicant]
Tsujimoto, T. et al. (2018) An acellular bioresorbable ultra-purified alginate gel promotes intervertebral disc repair: A preclinical proof-of-concept study. [cited by applicant]
Uhlen, M. et al. (2015) Tissue based map of the human proteome. [cited by applicant]
Urban, J P.G. & Roberts, S. (2003) Degeneration of the intervertebral disc. [cited by applicant]
US Burden of Disease Collaborators (2013) The State of US Health. 1990-2010. [cited by applicant]
Vadala, G. et al. (2012) Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. [cited by applicant]
Van Den Akker, G.G.H. et al. (2020) A Membranome-Centered Approach Defines Novel Biomarkers for Cellular Subtypes in the Intervertebral Disc. [cited by applicant]
Vincent, K. et al. (2019) Aging of mouse intervertebral disc and association with back pain. [cited by applicant]
Walter, B. A. et al. (2017) MR Elastography-derived Stiffness: A Biomarker for Intervertebral Disc Degeneration. [cited by applicant]
Wang, F. et al. (2017) Formation, function, and exhaustion of notochordal cytoplasmic vacuoles within intervertebral disc: current understanding and speculation. [cited by applicant]
Wang, Y. et al. (2018) Bioinformatics analysis reveals different gene expression patterns in the annulus fibrosis and nucleus pulpous during intervertebral disc degeneration. [cited by applicant]
Williams, S., Alkhatib, B., & Serra, R. (2019) Development of the axial skeleton and intervertebral disc, in: [cited by applicant]
Woiciechowsky, C. et al. (2014) Regeneration of nucleus pulposus tissue in an ovine intervertebral disc degeneration model by cell-free resorbable polymer scaffolds. [cited by applicant]
Wu, Y. et al. (2017) Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases. [cited by applicant]
Yuen, T.J. et al. (2013) Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. [cited by applicant]
Zandi-Nejad, K. et al. (2013) The role of HCA2 (GPR109A) in regulating macrophage function. [cited by applicant]
Zhang, Y. et al. (2020) Directed Differentiation of Notochord-like and Nucleus Pulposus-like Cells Using Human Pluripotent Stem Cells. [cited by applicant]
Zhao, C. et al. (2020) Identification of significant gene biomarkers of low back pain caused by changes in the osmotic pressure of nucleus pulposus cells. [cited by applicant]
Zhou, X. et al. (2018) Injectable decellularized nucleus pulposus-based cell delivery system for differentiation of adipose-derived stem cells and nucleus pulposus regeneration. [cited by applicant]
Zhu, J. (2010) Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. [cited by applicant]
Zorina-Lichtenwalter, K. et al. (2016) Genetic predictors of human chronic pain conditions. [cited by applicant]