Therapy For Intervertebral Disc Regeneration Research Articles

Cell Therapy for Intervertebral Disc Regeneration: Progress and Hurdles in Clinical Translation

Abstract Low back pain (LBP) is a pervasive global issue causing substantial disability and significant economic burden. The primary etiological factor behind LBP is intervertebral disc (IVD) degeneration, initiated in early adolescence and potentially leading to multiple spinal pathologies. However, current treatments for discogenic LBP are mainly palliative or involve invasive surgery, lacking disease-modifying therapies. Regenerative strategies, including cell therapy, may offer promising avenues to address the underlying pathology of IVD degeneration. Preclinical studies and clinical trials have demonstrated the potential of intradiscal cell transplantation to alleviate disc degeneration and associated pain with an overall favorable safety profile. Nonetheless, clinical trials present challenges, such as varying patient inclusion criteria, lack of adequate control groups, and short follow-up periods, necessitating cautious interpretation of results. This narrative review aims to provide an overview of clinical trials published to date and discuss the progress and translational hurdles of cell-based therapies for IVD degeneration and discogenic pain.

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

Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long‐term efficacy of most approaches is poor. Cell‐based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low‐risk, low‐cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell‐based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials.

Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair.

Stem cells and tissue-derived stromal cells stimulate the repair of degenerated and injured tissues, motivating a growing number of cell-based interventions in the musculoskeletal field. Recent investigations have indicated that these cells are critical for their trophic and immunomodulatory role in controlling endogenous cells. This Review presents recent clinical advances where stem cells and stromal cells have been used to stimulate musculoskeletal tissue repair, including delivery strategies to improve cell viability and retention. Emerging bioengineering strategies are highlighted, particularly toward the development of biomaterials for capturing aspects of the native tissue environment, altering the healing niche, and recruiting endogenous cells.

Stem cell therapy for intervertebral disc regeneration: obstacles and solutions.

Intervertebral disc (IVD) degeneration is frequently associated with low back and neck pain, which accounts for disability worldwide. Despite the known outcomes of the IVD degeneration cascade, the treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of IVD cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal conditions. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on IVD cells and their niche indicates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused research, both in the laboratory and in the clinic.

Adipose-derived stromal cells protect intervertebral disc cells in compression: implications for stem cell regenerative disc therapy.

Introduction: Abnormal biomechanics plays a role in intervertebral disc degeneration. Adipose-derived stromal cells (ADSCs) have been implicated in disc integrity; however, their role in the setting of mechanical stimuli upon the disc's nucleus pulposus (NP) remains unknown. As such, the present study aimed to evaluate the influence of ADSCs upon NP cells in compressive load culture.Methods: Human NP cells were cultured in compressive load at 3.0MPa for 48 hours with or without ADSCs co-culture (the ratio was 50:50). We used flow cytometry, live/dead staining and scanning electron microscopy (SEM) to evaluate cell death, and determined the expression of specific apoptotic pathways by characterizing the expression of activated caspases-3, -8 and -9. We further used real-time (RT-) PCR and immunostaining to determine the expression of the extracellular matrix (ECM), mediators of matrix degradation (e.g. MMPs, TIMPs and ADAMTSs), pro-inflammatory factors and NP cell phenotype markers.Results: ADSCs inhibited human NP cell apoptosis via suppression of activated caspase-9 and caspase-3. Furthermore, ADSCs protected NP cells from the degradative effects of compressive load by significantly up-regulating the expression of ECM genes (SOX9, COL2A1 and ACAN), tissue inhibitors of metalloproteinases (TIMPs) genes (TIMP-1 and TIMP-2) and cytokeratin 8 (CK8) protein expression. Alternatively, ADSCs showed protective effect by inhibiting compressive load mediated increase of matrix metalloproteinases (MMPs; MMP-3 and MMP-13), disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs; ADAMTS-1 and 5), and pro-inflammatory factors (IL-1beta, IL-6, TGF-beta1 and TNF-alpha).Conclusions: Our study is the first in vitro study assessing the impact of ADSCs on NP cells in an un-physiological mechanical stimulation culture environment. Our study noted that ADSCs protect compressive load induced NP cell death and degradation by inhibition of activated caspase-9 and -3 activity; regulating ECM and modulator genes, suppressing pro-inflammatory factors and preserving CK8. Consequently, the protective impact of ADSCs found in this study provides an essential understanding and expands our knowledge as to the utility of ADSCs therapy for intervertebral disc regeneration.

Effect of cartilage endplate on cell based disc regeneration: a finite element analysis.

This study examines the effects of cartilage endplate (CEP) calcification and the injection of intervertebral disc (IVD) cells on the nutrition distributions inside the human IVD under physiological loading conditions using multiphasic finite element modeling. The human disc was modeled as an inhomogeneous mixture consisting of a charged elastic solid, water, ions (Na+ and Cl-), and nutrient solute (oxygen, glucose and lactate) phases. The effect of the endplate calcification was simulated by a reduction of the tissue porosity (i.e., water volume faction) from 0.60 to 0.48. The effect of cell injection was simulated by increasing the cell density in the nucleus pulposus (NP) region by 50%, 100%, and 150%. Strain-dependent transport properties (e.g., hydraulic permeability and solute diffusivities) were considered to couple the solute transport and the mechanical loading. The simulation results showed that nutrient solute distribution inside the disc is maintained at a stable state during the day and night. The physiological diurnal cyclic loading does not change the nutrient environment in the human IVD. The cartilage endplate plays a significant role in the nutrient supply to human IVD. Calcification of the cartilage endplate significantly reduces the nutrient levels in human IVD. Therefore, in cell based therapy for IVD regeneration, the increased nutrient demand as a result of cell injection needs to be addressed. Excessive numbers of injected cells may cause further deterioration of the nutrient environment in the degenerated disc. This study is important for understanding the pathology of IVD degeneration and providing new insights into cell based therapies for low back pain.

Structured Bilaminar Coculture Outperforms Stem Cells and Disc Cells in a Simulated Degenerate Disc Environment

This study explores the use of bilaminar coculture pellets of mesenchymal stem cells (MSCs) and nucleus pulposus cells (NPCs) as a cell-based therapy for intervertebral disc regeneration. The pellets were tested under conditions that mimic the degenerative disc. Our goal was to optimize our cell-based therapy in vitro under conditions representative of the eventual diseased tissue. Harnessing the potential of stem cells is an important strategy for regenerative medicine. Our approach directed the behavior of stem cells by mimicking embryonic processes underlying cartilage and intervertebral disc development. Prior experiments have shown that bilaminar coculture can help differentiate MSC and substantially improve new matrix deposition. We have designed a novel spherical bilaminar cell pellet (BCP) where MSCs are enclosed in a shell of NPC. There were 3 groups: MSC, NPC, and BCP. The pellets were tested under 3 different culture conditions: 1) in a bioreactor that provides pressure and hypoxia (mimicking normal disc conditions): 2) with inflammatory cytokines (IL-1b and TNF-a); and 3) a bioreactor with inflammation (mimicking painful disc conditions). When cultured in the bioreactor, the NPC pellets produced significantly more glycosaminoglycans (GAGs) per cell than the other groups: 70% to 80% more than the BCP and the MSC alone. When cultured in an inflammatory environment, the MSC and BCP groups produced 30% to 34% more GAGs per cell than NPC (P < 0.05). When the pellets were cultured in a bioreactor with inflammation, the BCP made 25% more GAGs per cell than the MSC and 57% more than the NPC (P < 0.05). This study shows that BCPs outperform controls in a simulated degenerated disc environment. Adapting inductive mechanisms from development to trigger differentiation and restore diseased tissue has many advantages. As opposed to strategies that require growth factor supplements or genetic manipulations, our method is self-sustaining, targeted, and minimally invasive injection.

Structured coculture of stem cells and disc cells prevent disc degeneration in a rat model

Background context Harnessing the potential of stem cells is an important strategy for regenerative medicine. This study explores the use of bilaminar coculture pellets (BCPs) of mesenchymal stem cells (MSCs) and nucleus pulposus cells (NPCs) as a cell-based therapy for intervertebral disc regeneration. Prior in vitro experiments have shown that BCP can help differentiate MSCs and substantially improve new matrix deposition. Purpose To evaluate the clinical relevance of BCPs by testing the system in vivo. Study design/setting We have designed a novel spherical BCP where MSCs are enclosed in a shell of NPCs. The pellets were tested in vivo in a rat tail model of disc degeneration. Methods Rat caudal intervertebral discs were denucleated and treated with BCP in a fibrin sealant (FS) carrier (controls were MSCs suspended in FS; NPCs suspended in FS; MSCs and NPCs suspended in FS; FS only; and surgery only). At 14 and 35 days after implantation, the animals were euthanized and discs were evaluated for proteoglycan content, enzyme-linked immunosorbent assay for inflammatory cytokines, cell retention using polymerase chain reaction, disc height, histology, and disc grade based on a blinded scoring system. Results The proteoglycan and cytokine levels were not significantly different among groups. The BCP group had higher cell retention than controls. Disc height and disc grade increased over time only in the BCP group. Bilaminar coculture pellets were the only treatment to show proteoglycan staining in the nucleus space at 35 days. Conclusions This study shows that BCPs may prevent postnucleotomy disc degeneration in vivo. Larger animals and longer time points will be necessary to further judge potential clinical impact. As opposed to strategies that require growth factor supplements, predifferentiation, or genetic manipulations, BCPs are a self-sustaining and targeted method for tissue regeneration in situ.

Adipose-Derived Stem Cell Therapy for Intervertebral Disc Regeneration: AnIn VitroReconstructed Tissue in Alginate Capsules

The degenerative pathologies of the intervertebral disc have a remarkable social impact in the industrialized countries and can provide serious disabilities in the population. The current treatment consists of conservative treatments (such as symptomatic pharmacological therapies and physiokinetic therapy) and surgical treatments (intervertebral fusion, total disc replacement, nucleus pulposus (NP) replacement, or surgical exeresis). Recent advances in cell therapy foresee the possibility of regenerating the damaged disc; the autologous disc tissue can be withdrawn, in vitro regenerated, and re-implanted. The aim of this work was to verify whether autologous adipose-derived adult stem cells can improve the quality of an in vitro reconstructed nucleus pulposus tissue. A three-dimensional (3D) co-culture of NP cells and adipose tissue non-adipocyte fraction cells (nAFs) was assessed in a previously developed alginate 3D culture system following the good manufacturing practice guidelines to ensure patient safety for clinical studies. Morphological investigation of cultured and co-cultured cells was performed using transmission electron microscopy and immunofluorescence for collagen type I, aggrecan, CD90, CD34, and vimentin. Results indicate that co-culture of NP and nAFs improves the quality of the in vitro reconstructed tissue in term of extracellular matrix production and 3D cell organization. Technological resources are available for NP cell encapsulation intended for regenerating the intervertebral disc.