Organ Culture Bioreactors – Platforms to Study Human Intervertebral Disc Degeneration and Regenerative Therapy

Abstract

In recent decades the application of bioreactors has revolutionized the concept of culturing tissues and organs that require mechanical loading. In intervertebral disc (IVD) research, collaborative efforts of biomedical engineering, biology and mechatronics have led to the innovation of new loading devices that can maintain viable IVD organ explants from large animals and human cadavers in precisely defined nutritional and mechanical environments over extended culture periods. Particularly in spine and IVD research, these organ culture models offer appealing alternatives, as large bipedal animal models with naturally occurring IVD degeneration and a genetic background similar to the human condition do not exist. Latest research has demonstrated important concepts including the potential of homing of mesenchymal stem cells to nutritionally or mechanically stressed IVDs, and the regenerative potential of “smart” biomaterials for nucleus pulposus or annulus fibrosus repair. In this review, we summarize the current knowledge about cell therapy, injection of cytokines and short peptides to rescue the degenerating IVD. We further stress that most bioreactor systems simplify the real in vivo conditions providing a useful proof of concept. Limitations are that certain aspects of the immune host response and pain assessments cannot be addressed with ex vivo systems. Coccygeal animal disc models are commonly used because of their availability and similarity to human IVDs. Although in vitro loading environments are not identical to the human in vivo situation, 3D ex vivo organ culture models of large animal coccygeal and human lumbar IVDs should be seen as valid alternatives for screening and feasibility testing to augment existing small animal, large animal, and human clinical trial experiments.

An Inflammatory Nucleus Pulposus Tissue Culture Model to Test Molecular Regenerative Therapies: Validation with Epigallocatechin 3-Gallate

“…Organ cultures can bridge basic science with translational medicine and allow in vitro experiments while maintaining cells in their native tissue [39]. NP cultures confined in Dyneema jackets exhibit rather stable characteristics over sustained periods of time.…”

“…Unlike cell cultures, organ culture models retain the native ECM and allow for mechanical loading [39]. Induction of degeneration in these models can be achieved by injection of ECM degrading enzymes such as trypsin [40,41] and papain [42,43].…”

Duration-dependent influence of dynamic torsion on the intervertebral disc: an intact disc organ culture study

“…Organ culture models provide a unique platform to bridge from simple cell culture models to in vivo models to study cell behaviour under the native cell microenvironment [12], but one of the limitations of organ culture studies is that the load distribution and the forces that are experienced by the disc cells are unknown. Usually, only the reaction force from the overall loading is recorded.…”

“…In short, dynamic and static compression influence disc cell viability, matrix turnover and water content in a magnitude-and duration-dependent manner [5,33]. It has also been demonstrated both in vitro and in vivo that static and dynamic loading affect the homeostasis of the disc matrix by the changes in matrix gene expression over different loading durations [8,12,21]. For instance, Lotz et al found a magnitude-and duration-dependent cell death caused by static compression over 1-7 days in an in vivo rat tail model [19].…”

A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement

“…To test the performance of the composite hydrogel as a potential NP replacement, we used a bovine ex vivo IVD organ culture model (age of the animals: between 10 and 14 month old), which have been proven to be a adequate option [41,42]. Bovine caudal discs showed to be similar to human IVDs in terms of size, biomechanical behavior and biology [43,44].…”