Leaping the hurdles in developing regenerative treatments for the intervertebral disc from preclinical to clinical

Abstract

Chronic back and neck pain is a prevalent disability, often caused by degeneration of the intervertebral disc. Because current treatments for this condition are less than satisfactory, a great deal of effort is being applied to develop new solutions, including regenerative strategies. However, the path from initial promising idea to clinical use is fraught with many hurdles to overcome. Many of the keys to success are not necessarily linked to science or innovation. Successful translation to clinic will also rely on planning and awareness of the hurdles. It will be essential to plan your entire path to clinic from the outset and to do this with a multidisciplinary team. Take advice early on regulatory aspects and focus on generating the proof required to satisfy regulatory approval. Scientific demonstration and societal benefits are important, but translation cannot occur without involving commercial parties, which are instrumental to support expensive clinical trials. This will only be possible when intellectual property can be protected sufficiently to support a business model. In this manner, commercial, societal, medical, and scientific partners can work together to ultimately improve patient health. Based on literature surveys and experiences of the co‐authors, this opinion paper presents this pathway, highlights the most prominent issues and hopefully will aid in your own translational endeavors.

Annulus fibrosus cell sheets limit disc degeneration in a rat annulus fibrosus injury model

“…Cell sheets are easy to handle as the cells are not dispersed, and a scaffold‐free cell sheet can easily be obtained by simply subjected the culture‐ware to a different temperature. This offers promising translational and commercialization potential, as no (commonly) expensive enzymes or complex cell manipulation procedures are required …”

Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section

“…The rationale for and benefits of delivery of cells to the NP are 2‐fold: firstly, transplanted cells may stimulate endogenous NP cells to produce neo‐matrix through paracrine effects; and secondly transplanted cells may adopt an NP cell‐like phenotype and directly reconstitute native tissue . A central challenge, however, that limits the potential of cell‐based regeneration is the harsh local cellular microenvironment within the degenerate disc, which is characterized by low oxygen and nutrient supply, increased acidity, altered osmolarity, as well as elevated levels of pro‐inflammatory cytokines . Therefore, there is a clear need to identify robust cell populations to enhance the likelihood of survival post‐injection, and characterize how such cells will function in the typical degenerate microenvironment to determine if they can contribute effectively to functional disc repair.…”

“…One way to achieve this could be to condition stem cells prior to implantation by acclimatizing them to patient specific in vivo microenvironmental milieu, which may include inflammatory cytokines, acidity, oxygen or nutrient deprivation . These treatments must be assessed using appropriate in vitro and ex vivo culture conditions which mimic those of the degenerate niche to assess the likely behavior and survival of transplanted cells prior to progressing to in vivo testing …”

“…47,48 A central challenge, however, that limits the potential of cell-based regeneration is the harsh local cellular microenvironment within the degenerate disc, which is characterized by low oxygen and nutrient supply, increased acidity, altered osmolarity, as well as elevated levels of pro-inflammatory cytokines. [49][50][51][52][53][54] Therefore, there is a clear need to identify robust cell populations to enhance the likelihood of survival post-injection, and characterize how such cells will function in the typical degenerate microenvironment to determine if they can contribute effectively to functional disc repair. The precise cell number for intradiscal delivery needs to be carefully considered, and to-date the exact number of cells required for functional regeneration is unclear.…”

A novel magnetic resonance imaging postprocessing technique for the assessment of intervertebral disc degeneration—Correlation with histological grading in a rabbit disc degeneration model

“…Many authors in the field of intervertebral disc degeneration have also acknowledged the need for improved nondestructive imaging techniques for the assessment of animal and preclinical models of disc degeneration …”