Preclinical to clinical translation for intervertebral disc repair: Effects of species‐specific scale, metabolism, and matrix synthesis rates on cell‐based regeneration

Abstract

BackgroundA significant hurdle for potential cell‐based therapies is the subsequent survival and regenerative capacity of implanted cells. While many exciting developments have demonstrated promise preclinically, cell‐based therapies for intervertebral disc (IVD) degeneration fail to translate equivalent clinical efficacy.AimsThis work aims to ascertain the clinical relevance of both a small and large animal model by experimentally investigating and comparing these animal models to human from the perspective of anatomical scale and their cellular metabolic and regenerative potential.Materials and MethodsFirst, this work experimentally investigated species‐specific geometrical scale, native cell density, nutrient metabolism, and matrix synthesis rates for rat, goat, and human disc cells in a 3D microspheroid configuration. Second, these parameters were employed in silico to elucidate species‐specific nutrient microenvironments and predict differences in temporal regeneration between animal models.ResultsThis work presents in silico models which correlate favorably to preclinical literature in terms of the capabilities of animal regeneration and predict that compromised nutrition is not a significant challenge in small animal discs. On the contrary, it highlights a very fine clinical balance between an adequate cell dose for sufficient repair, through de novo matrix deposition, without exacerbating the human microenvironmental niche.DiscussionOverall, this work aims to provide a path towards understanding the effect of cell injection number on the nutrient microenvironment and the “time to regeneration” between preclinical animal models and the large human IVD. While these findings help to explain failed translation of promising preclinical data and the limited results emerging from clinical trials at present, they also enable the research field and clinicians to manage expectations on cell‐based regeneration.ConclusionUltimately, this work provides a platform to inform the design of clinical trials, and as computing power and software capabilities increase in the future, it is conceivable that generation of patient‐specific models could be used for patient assessment, as well as pre‐ and intraoperative planning.

Intradiscal administration of autologous platelet‐rich plasma in patients with Modic type 1 associated low back pain: A prospective pilot study

“…In this study, we speculated that the PRP injected into the IVDs passed through the endplate defect and reached and acted on the bone marrow, which is the target of treatment. We believe that disc degeneration‐related reduction in cells and nutrient availability may affect the action of PRP 56 , 57 ; however, assessing this in this study was difficult because of the lack of sufficient cases. Therefore, further research is required from the view point of both basic science and clinical medicine in the future.…”

A comprehensive review of cell transplantation and platelet‐rich plasma therapy for the treatment of disc degeneration‐related back and neck pain: A systematic evidence‐based analysis

“… 75 For instance, maintenance of disc height, endplate integrity, and an intact AF are speculated to enhance the potential of regenerative products by enhancing the support and retention of the transplanted products. 17 , 76 , 77 , 78 Another critical restriction is the inability to link objective radiographic findings to subjective pain and disability. 79 , 80 This likely hinders both optimal patient stratification and outcome assessment during the trials.…”

“… 15 In part, the avascular nature results in limited gas, nutrient, and cell replenishment, and the overall cell density in the IVD is low compared to other tissue structures. 16 , 17 , 18 Moreover, the quality of cells shows a rapid decline, with a loss of progenitor cell types and a switch from active proteoglycan‐producing cells to fibrotic and senescent cell types. 19 , 20 , 21 This complex and progressive pathway of structural destruction is complemented by the secretion of inflammatory factors that may promote the influx of immunogenic cells, worsening the pathology.…”

Getting to the Core: Exploring the Embryonic Development from Notochord to Nucleus Pulposus

“…This is achieved through a complex regulatory network that involves intricate positive and negative feedback loops, as well as their interconnected regulation with bone morphogenetic protein (BMP) and transforming growth factor (TGF)-β pathways. Finally, as the NP constitutes the largest avascular tissue in the human body [ 9 ], resident cells are subjected to oxygen and nutrient paucity, demanding metabolic alterations to support NPC survival [ 45 , 46 ]. A key transcription factor regulator to support this adaptation is HIF-1α, a regulator of glycolytic metabolism and suppressor of hypoxia-induced apoptosis [ 47 ].…”