A translational approach integrating developmental biology and tissue engineering towards regeneration of the annulus fibrosus of the intervertebral disc (PrintDisc)


Intervertebral disc (IVD) degeneration can lead to severe and chronic low back pain, which represents the leading cause of disability worldwide. IVD degeneration can be characterized by the dehydration of the central nucleus pulposus (NP) and subsequent structural breakdown of the peripheral annulus fibrosus (AF). Currently, there are no clinically acceptable solutions for sealing the ruptured AF, so biologic based therapies, such as tissue engineering, are being investigated. The current state of AF tissue engineering may be advanced with a strategy that captures the essential building blocks of AF tissue morphogenesis: Biomimetic cell patterning, mechanical forces to induce circumferential cell elongation, and an extracellular matrix (ECM)-based molecular cocktail that supports tissue assembly. 


Herein we aim for three important milestones: 1) The development of a novel, gentle method for preparation of AF decellularized ECM from bovine donors which preserves bioactivity. 2) The development of a free-form reversible embedding technique that supports biomimetic cell patterning, mechanical loading, and long-term culture of patterned cells. 3) The combination of these approaches in a 3D bioprinted construct that supports the spontaneous assembly of AF tissue with biomimetic histoarchitecture. The outcome of this work will be a platform which can be adapted to tissue morphogenesis of the central NP of the IVD, paving the way towards the goal of regenerating a whole tissue.

  • Publication

    Alexeev D, Cui S, Grad S, Li Z, Ferguson S. Mechanical and biological characterisation of a composite annulus fibrosus repair strategy in an endplate delamination model. JOR Spine. 2020 Jul 16;3(4):e1107. doi: 10.1002/jsp2.1107. eCollection 2020 Dec.

    Pfannkuche JJ, Guo W, Cui S, Ma J, Lang G, Peroglio M, Richards RG, Alini M, Grad S, Li Z. Intervertebral disc organ culture for the investigation of disc pathology and regeneration - benefits, limitations, and future directions of bioreactors. Connect Tissue Res. 61(3-4):304-321, 2020. doi: 10.1080/03008207.2019.1665652.

    Vernengo AJ, Grad S, Eglin D, Alin M, Li Z. Bioprinting Tissue Analogues with Decellularized Extracellular Matrix Bioink for Regeneration and Tissue Models of Cartilage and Intervertebral Discs. Adv. Funct. Mater. 2020, 1909044. DOI: 10.1002/adfm.201909044

    Kluser N. 3D Printed Multi-Scale Scaffolds with Topographical Guidance for Annulus Fibrosus Regeneration. 2020 ETH Zürich (A. Vernengo, S. Grad, S. Ferguson) – MSc ETH HST (Thesis)

    Zhang F, Liu X, Li B, Li Z, Grad S, Chen D, Gao M, Liu S.  The effect of hyaluronic acid on nucleus pulposus extracellular matrix production through hypoxia-inducible factor-1alpha transcriptional activation of CD44 under hypoxia.  Eur Cell Mater. 2021;41:142-52 https://www.doi.org/10.22203/eCM.v041a10

    Chen J-X, Li Y-H, Wen J, Li Z, Yu B-S, Huang Y-C. Annular defects impair the mechanical stability of the intervertebral disc. Global Spine J. 2021;epub Mar 30. https://doi.org/10.1177/21925682211006061

    Guo W, Douma L, Hu MH, Eglin D, Alini M, Secerovic A, Grad S, Peng X, Zou X, D'Este M, Peroglio M. Hyaluronic acid-based interpenetrating network hydrogel as a cell carrier for nucleus pulposus repair. Carbohydr Polym. 2021;277:118828. https://doi.org/10.1016/j.carbpol.2021.118828 

    Zhou L, Guo P, D'Este M, Tong W, Xu J, Yao H, Stoddart MJ, van Osch GJVM, Ki-Wai Ho K, Li Z, Qin L. Functionalized hydrogels for articular cartilage tissue engineering. Engineering. 2022;epub April 12, https://doi.org/10.1016/j.eng.2022.03.008

    Zhou J, Ren R, Li Z, Zhu S, Jiang N. Temporomandibular joint osteoarthritis: A review of animal models induced by surgical interventions. Oral Dis. 2022;epub May 25.  https://doi.org/10.1111/odi.14266 

  • Presentation

    Alig G, D'Este M, Grad S, Alini M, Vernengo A. Temperature-responsive engineered matrices for the spatial positioning and long-term culture of bioprinted cells.  2021 BIOFAB online (poster)

    Guo P, Vernengo A, Miklosic G, D'Este M, Grad S, Alini M, Li Z. A natural biomimetic hydrogel for cartilage regeneration. 2021 SSB+RM YSS (oral)

    Guo P, Mini C, Miklosic G, Vernengo A, D'Este M, Grad S, Alini M, Li Z. A hydrogel based on decellularized extracellular matrix particles for cartilage regeneration.
    2021 eCM cancelled (oral)/abstract published. https://www.ecmconferences.org/abstracts/2021/Collection3/oral.pdf 

    Egger S, Alig G, D'Este M, Grad S, Alini M, Vernengo A. Temperature-responsive engineered matrices for spatial positioning and long-term culture of bioprinted cells. 2021 eCM cancelled (poster)/abstract published. https://www.ecmconferences.org/abstracts/2021/Collection3/poster.pdf

    Egger S, Alig G, D'Este M, Wychowaniec JK, Weiser JR, Grad S, Vernengo AJ. Microextrusion-based anisotropic cell patterning within temperature-sensitive hydrogel matrices for annulus fibrosus regeneration. 2022 eCM (oral)