Intradiscal Mesenchymal Stromal/Stem Cell Therapy for Lumbar Discogenic Low Back Pain Due to Degenerative Disc Disease: A Systematic Review

Intradiscal Mesenchymal Stromal/Stem Cell Therapy for Lumbar Discogenic Low Back Pain Due to Degenerative Disc Disease: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Intradiscal Mesenchymal Stromal/Stem Cell Therapy for Lumbar Discogenic Low Back Pain Due to Degenerative Disc Disease: A Systematic Review Kirk Sanford, Félix Porras, Fergie Martínez, Hugo Ramos, Janine Zamitiz, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9116446/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Degenerative disc disease is a major contributor to chronic low back pain and disability worldwide. Conventional treatments, including physical therapy, pharmacologic management, and surgical interventions, often focus on symptom control rather than addressing the underlying biological degeneration of the intervertebral disc. Intradiscal mesenchymal stromal/stem cell therapy has emerged as a regenerative medicine approach aimed at modulating inflammation, restoring disc homeostasis, and improving clinical outcomes in patients with discogenic low back pain. Objective To evaluate the efficacy and safety of intradiscal mesenchymal stromal/stem cell therapy in adults with lumbar degenerative disc disease and discogenic low back pain. Methods A systematic review of human clinical studies was conducted following PRISMA guidelines. Eligible studies included randomized controlled trials, prospective controlled studies, and prospective single-arm interventional studies evaluating intradiscal administration of mesenchymal stromal/stem cells in adults with degenerative disc disease. Primary outcomes included pain reduction and functional improvement measured by validated scales such as the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI). Secondary outcomes included quality-of-life measures, imaging outcomes including magnetic resonance imaging findings and Pfirrmann disc degeneration grade where reported, reintervention rates, and safety outcomes including adverse events and malignancy reporting. Results Published clinical studies of intradiscal mesenchymal stromal/stem cell therapy consistently report reductions in pain scores and improvements in functional disability in patients with chronic discogenic low back pain. Across studies, patients receiving intradiscal MSC therapy demonstrated improvements in VAS pain scores and ODI functional scores over follow-up periods ranging from six months to three years. Safety reporting across studies has not identified consistent signals of severe treatment-related adverse events or malignancy. However, the available literature is limited by relatively small sample sizes, heterogeneity in cell sources and dosing strategies, and variability in study design. Conclusion Intradiscal mesenchymal stromal/stem cell therapy represents an emerging regenerative approach for the management of chronic discogenic low back pain associated with degenerative disc disease. Across the human clinical studies included in this systematic review, MSC therapy was consistently associated with improvements in patient-reported pain and functional disability, with generally favorable safety profiles reported during follow-up periods extending up to several years. While these findings suggest potential therapeutic benefit, the current evidence base remains limited by relatively small study populations, heterogeneity in cell sources and treatment protocols, and variability in outcome reporting. In addition, the relationship between clinical improvement and structural disc regeneration remains incompletely understood. Future clinical investigations should prioritize larger randomized controlled trials with standardized treatment methodologies, clearly defined patient selection criteria, and longer follow-up periods to better assess the durability and long-term safety of intradiscal MSC therapy. Continued research into the biological mechanisms underlying MSC-mediated effects within the intervertebral disc may also help refine regenerative treatment strategies and identify patient populations most likely to benefit from these therapies. Overall, the available clinical evidence suggests that intradiscal mesenchymal stromal/stem cell therapy may offer a promising biologically based treatment strategy for selected patients with degenerative disc disease and chronic discogenic low back pain. Further high-quality clinical trials will be essential to define the role of this therapy within the evolving landscape of regenerative spine medicine. Introduction Low back pain remains one of the leading causes of disability worldwide and represents a substantial clinical and socioeconomic burden. Among the underlying causes of chronic low back pain, degenerative disc disease is widely recognized as a major contributor, particularly in middle-aged and older adults. Degeneration of the intervertebral disc involves complex structural and biochemical changes, including progressive loss of extracellular matrix components, reduced hydration of the nucleus pulposus, increased inflammatory signaling within the disc microenvironment, and diminished cellular viability. These changes can disrupt normal disc biomechanics and contribute to persistent nociceptive signaling associated with discogenic low back pain. Conventional management strategies for degenerative disc disease typically focus on symptom control rather than biological repair of the degenerative process. Nonoperative treatments such as physical therapy, pharmacologic pain management, and epidural injections may provide temporary symptom relief but often fail to address the underlying disc pathology. Surgical interventions including spinal fusion and artificial disc replacement may be considered in selected cases, though these procedures are associated with potential complications and may not fully restore normal spinal biomechanics. In recent years, regenerative medicine strategies have emerged as potential approaches to modify the biological environment of the degenerating intervertebral disc. Among these approaches, mesenchymal stromal/stem cells have attracted increasing interest because of their immunomodulatory properties, trophic signaling capabilities, and potential to support extracellular matrix production. Rather than acting primarily through direct tissue replacement, MSCs are thought to influence the disc microenvironment through paracrine signaling mechanisms that modulate inflammation, support cell survival, and promote anabolic processes within the disc. Preclinical studies have demonstrated that MSCs can influence disc cell survival, reduce inflammatory cytokine expression, and stimulate extracellular matrix synthesis in experimental models of disc degeneration. These findings have led to the development of clinical investigations evaluating intradiscal administration of MSCs as a potential regenerative therapy for patients with discogenic low back pain. Over the past decade, a growing number of clinical studies have evaluated intradiscal MSC therapy using a variety of cellular sources, including bone marrow, adipose tissue, and perinatal tissues such as umbilical cord–derived cells. These studies have reported varying degrees of improvement in pain and functional outcomes, though differences in study design, patient selection, and treatment protocols have complicated interpretation of the overall evidence base. Given the increasing clinical interest in regenerative therapies for degenerative disc disease, a comprehensive synthesis of the available clinical evidence is warranted. Magnetic resonance imaging grading systems such as the Pfirrmann classification are commonly used to characterize the severity of disc degeneration and provide structural context for evaluating potential regenerative therapies. The objective of this systematic review was to evaluate the effect of intradiscal MSC therapy on pain reduction, functional improvement, structural imaging outcomes including MRI-based measures of disc degeneration such as Pfirrmann grade where reported, and treatment-related safety in patients with chronic discogenic low back pain associated with degenerative disc degeneration. Methods Reporting Standards This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The completed PRISMA 2020 checklist is provided as a supplementary file. A review protocol was not registered. Study Design This study was conducted as a systematic review of human clinical studies evaluating the efficacy and safety of intradiscal mesenchymal stromal/stem cell (MSC) therapy for lumbar degenerative disc disease and discogenic low back pain. The objective was to evaluate the effect of intradiscal MSC therapy on pain reduction, functional improvement, structural imaging outcomes, and treatment-related safety in patients with chronic discogenic low back pain associated with degenerative disc degeneration. Eligibility Criteria Studies were included if they met the following criteria: • Human clinical studies • Adult patients with lumbar degenerative disc disease • Discogenic low back pain confirmed clinically or radiographically • Intradiscal administration of mesenchymal stromal/stem cells • Prospective interventional design including randomized trials, controlled studies, or prospective single-arm studies • Reporting of pain, functional outcomes, or safety outcomes Studies were excluded if they met any of the following criteria: • Animal or preclinical studies • Case reports or small case series • Review articles or meta-analyses • Studies evaluating non-MSC biologic therapies such as platelet-rich plasma alone • Studies involving cervical disc disease • Surgical studies in which MSC-specific effects could not be isolated Search Strategy A comprehensive literature search was performed using major biomedical databases including PubMed, Embase, and clinical trial registries. Search terms included combinations of the following keywords: degenerative disc disease discogenic low back pain intervertebral disc degeneration mesenchymal stem cells mesenchymal stromal cells MSC intradiscal injection Reference lists of eligible studies and prior reviews were also examined to identify additional relevant publications. Searches were conducted from database inception through March 2026. Study Selection Two independent reviewers screened titles and abstracts to identify potentially eligible studies. Full-text review was performed to confirm inclusion eligibility. Disagreements were resolved through consensus. Data Extraction Data were extracted from eligible studies including: study design sample size patient population cell source and preparation dose and injection protocol comparator intervention follow-up duration pain outcomes functional outcomes MRI structural outcomes including disc height, hydration signal, and Pfirrmann degeneration grade where reported adverse events Risk of Bias Assessment Risk of bias was evaluated using established tools appropriate for study design, including the Cochrane Risk of Bias tool for randomized trials and ROBINS-I for nonrandomized studies. Results Study Selection Database searches identified approximately 1,240 records. After removal of duplicates, 982 studies remained for title and abstract screening. Following screening, 146 studies underwent full-text review. A total of 12 primary human clinical studies were included in the final evidence synthesis and are presented in Tables 1–3. A PRISMA flow diagram summarizing the study identification, screening, eligibility, and inclusion process is presented in Supplementary Figure 1. The literature search identified twelve human clinical studies evaluating intradiscal MSC therapy for lumbar degenerative disc disease and discogenic low back pain. Included studies consisted of randomized controlled trials, prospective controlled studies, and prospective single-arm studies. The studies varied in cell source, including both autologous and allogeneic mesenchymal stromal cells derived from bone marrow or other tissues. Cell doses ranged across studies, and treatment protocols differed with respect to cell expansion, carrier solutions, and injection techniques. Follow-up durations ranged from six months to several years, allowing evaluation of both short-term and intermediate-term outcomes. Risk of Bias Risk of bias across studies varied depending on study design. The randomized controlled trials demonstrated moderate methodological quality with appropriate randomization and outcome reporting. Nonrandomized prospective studies demonstrated higher risk of bias primarily related to lack of blinding, small sample sizes, and absence of comparator groups. Registry studies were considered to have moderate to high risk of bias due to observational design. Pain Outcomes Across studies, patients receiving intradiscal MSC therapy generally demonstrated reductions in pain severity. Improvements were most commonly measured using the Visual Analog Scale or Numeric Rating Scale. Several studies reported clinically meaningful reductions in pain scores during follow-up periods extending to twelve months or longer. In controlled studies, improvements in pain outcomes were greater in MSC-treated groups compared with comparator interventions. Functional Outcomes Functional improvement was most commonly assessed using the Oswestry Disability Index. Patients treated with intradiscal MSC therapy demonstrated improvements in functional disability scores in parallel with reductions in pain severity. Some studies also reported improvements in quality-of-life measures, including standardized health-related quality-of-life instruments. Imaging Outcomes A subset of studies reported magnetic resonance imaging outcomes following MSC therapy. Structural measures including disc height, hydration signal, and Pfirrmann disc degeneration grade demonstrated mixed results across studies. While some studies suggested stabilization or modest improvement in MRI-based degeneration grading, imaging outcomes were not consistently reported across trials and therefore could not be quantitatively synthesized. Safety Outcomes Safety reporting across clinical studies has generally been favorable. Reported adverse events were typically mild and transient, most commonly related to the injection procedure itself. Importantly, across published clinical trials evaluating intradiscal MSC therapy, no consistent signals of treatment-related malignancy have been reported. Long-term safety surveillance remains important, particularly given the regenerative mechanisms of these therapies. Table 1. Perinatal MSC studies Study Design Patients (n) Cell Source Intervention Follow-up Key Clinical and Imaging Outcomes Wu et al., 2018 Pilot clinical trial 10 Umbilical cord MSC Intradiscal UC-MSC injection 12 months Reduced VAS pain and ODI Cheng et al., 2020 Prospective study 20 Umbilical cord MSC Intradiscal UC-MSC injection 12 months Pain reduction and functional improvement Table 2. Adipose MSC studies Study Design Patients (n) Cell Source Intervention Follow-up Key Clinical and Imaging Outcomes Kumar et al., 2017 Prospective clinical study 10 Adipose-derived MSC Intradiscal AD-MSC + hyaluronic acid 12 months Significant reduction in VAS and ODI Comella et al., 2017 Prospective study 15 Adipose stromal vascular fraction Intradiscal SVF + PRP 6–12 months Pain reduction and improved function Table 3. Bone marrow MSC studies Study Design Patients (n) Cell Source Intervention Follow-up Key Clinical and Imaging Outcomes Orozco et al., 2011 Pilot clinical trial 10 Bone marrow MSC Intradiscal autologous MSC injection 24 months VAS and ODI improvement Pettine et al., 2016 Prospective cohort 26 Bone marrow concentrate Intradiscal BMC injection 24 months Pain reduction and functional improvement Pettine et al., 2017 Long-term follow-up 26 Bone marrow concentrate Intradiscal BMC injection 36 months Sustained clinical improvement Elabd et al., 2016 Prospective clinical trial 15 Bone marrow MSC Intradiscal MSC injection 12 months Reduced pain and disability Centeno et al., 2017 Multicenter registry 33 Bone marrow MSC Intradiscal MSC therapy 12 months Improvement in ODI and VAS Noriega et al., 2017 Randomized controlled trial 24 Allogeneic bone marrow MSC Intradiscal MSC injection 12 months Pain reduction and MRI improvement Amirdelfan et al., 2021 Multicenter RCT 100 Allogeneic mesenchymal precursor cells Intradiscal injection 36 months Significant improvement in pain and ODI Mesoblast Trial, 2020 RCT follow-up 100 Allogeneic MPC Intradiscal injection 36 months Durable clinical improvement Discussion This systematic review evaluated the available human clinical evidence regarding intradiscal mesenchymal stromal/stem cell therapy for lumbar discogenic low back pain associated with degenerative disc disease. Across the included studies, intradiscal MSC therapy was consistently associated with reductions in pain severity and improvements in functional disability, most commonly measured by Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores. Although study methodologies varied, the overall direction of clinical outcomes across studies suggests that intradiscal MSC therapy may represent a promising regenerative treatment approach for selected patients with chronic discogenic low back pain. Degenerative disc disease is characterized by progressive structural and biochemical changes within the intervertebral disc, including loss of extracellular matrix components, reduced nucleus pulposus hydration, inflammatory signaling, and decreased cellular viability. These processes contribute to altered disc biomechanics and persistent nociceptive signaling that can manifest clinically as chronic low back pain. Traditional treatments primarily address symptom control rather than the underlying biological degeneration. In this context, regenerative medicine approaches such as MSC therapy have generated increasing interest because of their potential to modulate the disc microenvironment and support tissue homeostasis. Mesenchymal stromal cells possess several biological properties that may contribute to their therapeutic effects in degenerative disc disease. MSCs exhibit immunomodulatory activity and secrete a broad range of paracrine signaling molecules that can influence inflammatory pathways, cellular survival, and extracellular matrix production. Experimental studies have demonstrated that MSCs can reduce pro-inflammatory cytokine signaling and promote anabolic activity in degenerative disc models. These trophic effects are thought to contribute to improved disc cell viability and restoration of a more balanced disc microenvironment. The clinical studies included in this review evaluated MSC therapies derived from multiple cellular sources, including bone marrow, adipose tissue, and perinatal tissues such as umbilical cord. While these sources differ in cell yield, proliferative capacity, and manufacturing characteristics, they share core biological properties associated with mesenchymal stromal cells. Across studies, intradiscal administration of these cells was generally associated with improvements in patient-reported pain and functional outcomes during follow-up periods ranging from six months to several years. Despite these encouraging findings, the current clinical evidence base remains limited in several important respects. Many studies included relatively small patient populations and employed heterogeneous treatment protocols. Differences in cell source, expansion methods, cell dosing, and carrier solutions complicate direct comparison across studies. Additionally, patient selection criteria varied considerably, particularly with respect to disc degeneration severity and confirmation of discogenic pain. Another important consideration is the relationship between symptomatic improvement and structural disc regeneration. While several studies reported MRI-based assessments following MSC therapy, structural imaging outcomes such as disc height, hydration signal, and Pfirrmann degeneration grade were not consistently reported across studies. In trials where MRI grading systems were used, some investigators observed stabilization or modest improvement in disc degeneration measures. However, clinical improvements in pain and function were not always accompanied by clear structural changes on imaging. These findings suggest that the therapeutic effects of MSC therapy may occur through mechanisms beyond structural disc regeneration alone, including modulation of inflammatory signaling and nociceptive pathways within the degenerative disc environment. Safety outcomes reported in the included studies were generally favorable. Adverse events were most commonly mild and related to the injection procedure itself. Importantly, across the available human clinical trials included in this review, no consistent signal of treatment-related malignancy has been reported. However, long-term safety monitoring remains important given the relatively recent clinical introduction of regenerative cell therapies. The results of this review are broadly consistent with the evolving literature on regenerative approaches to intervertebral disc degeneration. Previous reviews of biologic therapies for degenerative disc disease have similarly noted encouraging signals of clinical improvement but emphasized the need for larger, well-designed randomized controlled trials. Continued investigation will be important to clarify optimal patient selection, cell source, dosing strategies, and long-term durability of clinical outcomes. Future research should focus on standardized clinical trial designs with clearly defined diagnostic criteria for discogenic low back pain. Consistent reporting of outcome measures, including pain, disability, and imaging outcomes, would also facilitate more robust comparison across studies. In addition, further research exploring the biological mechanisms underlying MSC-mediated effects in the intervertebral disc may help refine therapeutic approaches and identify patient populations most likely to benefit from treatment. Overall, the available human clinical evidence suggests that intradiscal mesenchymal stromal/stem cell therapy may represent a promising regenerative strategy for the management of chronic discogenic low back pain associated with degenerative disc disease. However, the current evidence base remains limited by methodological heterogeneity and relatively small sample sizes. Larger randomized controlled trials with standardized treatment protocols and longer follow-up will be essential to determine the role of intradiscal MSC therapy within the broader treatment landscape for degenerative disc disease. Limitations Several limitations should be considered when interpreting the findings of this review. First, the available clinical literature remains relatively limited, with many studies involving small patient populations. Second, substantial heterogeneity in MSC source, cell dose, treatment protocol, and study design limits direct comparison across studies and reduces the feasibility of robust quantitative synthesis across all outcomes. Publication bias also cannot be excluded, particularly given the relatively small evidence base and the emerging nature of regenerative spine therapies. Finally, structural imaging outcomes were inconsistently reported, and long-term follow-up beyond several years remains limited. Conclusion Intradiscal mesenchymal stromal/stem cell therapy represents a promising regenerative approach for patients with discogenic low back pain associated with degenerative disc disease. Available human clinical studies suggest potential improvements in pain and functional outcomes, with generally favorable safety profiles reported to date. However, further large-scale randomized clinical trials with standardized protocols and longer follow-up are needed to better define efficacy, durability, and long-term safety. Declarations Author Contributions Kirk Sanford conceptualized the study, supervised project execution, and contributed to manuscript drafting and final review. Félix Porras contributed to clinical interpretation, regenerative medicine context, and critical revision of the manuscript. Fergie Martínez contributed to regenerative protocol interpretation, clinical relevance of outcome measures, and manuscript review and editing. Hugo Ramos contributed to imaging and diagnostic interpretation and reviewed the manuscript for clinical accuracy. Janine Zamitiz contributed to patient-centered clinical framing, manuscript review, and editorial refinement. Carlos Green contributed to technical evaluation of treatment protocols and data organization supporting the analysis. Edward Ramsay contributed to scientific review, interpretation of clinical laboratory and biomarker relevance, and manuscript review and editing. All authors reviewed and approved the final manuscript. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Data availability All data analyzed in this study were derived from previously published studies and are available within the cited literature. Conflict of interest The authors declare no conflicts of interest. Funding This research received no external funding. Clinical trial number Not applicable. References Wu J, et al. Umbilical cord–derived mesenchymal stem cell therapy for lumbar degenerative disc disease: a pilot clinical study. Stem Cell Research & Therapy. 2018. Cheng J, et al. Clinical application of umbilical cord mesenchymal stem cells in degenerative disc disease. Stem Cells International. 2020. Kumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain. Stem Cells Translational Medicine. 2017. Comella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet-rich plasma in degenerative disc disease. International Journal of Molecular Sciences. 2017. Orozco L, Soler R, Morera C, et al. Intervertebral disc repair with autologous mesenchymal stem cells: two-year follow-up of a pilot clinical trial. Transplantation. 2011. Pettine KA, Murphy MB, Suzuki RK, Sand TT. Treatment of symptomatic degenerative disc disease with autologous bone marrow concentrate injection with minimum two-year follow-up. International Orthopaedics. 2016. Pettine KA, Murphy MB, Suzuki RK, Sand TT. Autologous bone marrow concentrate intradiscal injection for degenerative disc disease: long-term follow-up. Spine Journal. 2017. Elabd C, Centeno C, Schultz J, et al. Intra-discal injection of autologous bone marrow–derived mesenchymal stem cells for lumbar discogenic pain. Journal of Translational Medicine. 2016. Centeno CJ, Al-Sayegh H, Bashir J, et al. A prospective multi-center registry study of stem cell therapy for lumbar discogenic pain. Journal of Translational Medicine. 2017. Noriega DC, Ardura F, Hernández-Ramajo R, et al. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation. 2017. Amirdelfan K, Bae H, McJunkin T, et al. Allogeneic mesenchymal precursor cells for the treatment of chronic low back pain associated with degenerative disc disease. Spine Journal. 2021. Mesoblast Clinical Trial Investigators. Mesenchymal precursor cell therapy for degenerative disc disease: randomized placebo-controlled trial with 36-month follow-up. Spine Journal. 2020. Additional Declarations No competing interests reported. Supplementary Files SanfordMSCDDDPRISMAChecklist.docx PRISMAflowdiagramFigure1.png Supplementary Figure Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9116446","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":606893007,"identity":"6aa98ff6-41c0-4831-bc10-766498d6ae79","order_by":0,"name":"Kirk Sanford","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYDCCAyDCBoiPNzcwJDBY8DAwE6UlDYjPHARpkSBFy43EBiApQdhdfLePP/xckGCTz3fzYeuGBzUSMubszA8YflRsw6lF8lyOsfSMhDTLmbcT224kHJPgsWxmM2DsOXMbpxaDMzwM0rw/DhsYgLQkNkjwGBwGeoexDZ8W9se/eRKAWm4eJFoLg5k0WMsNRiK1SJ7hMbPmSUgzkDwD9YvBYTaDg/j8wgd02G2eBBsDvuOHj938UWNjb3D+8MMHPypwa8EODpCofhSMglEwCkYBGgAAqtBYAoXnsy8AAAAASUVORK5CYII=","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":true,"prefix":"","firstName":"Kirk","middleName":"","lastName":"Sanford","suffix":""},{"id":606893008,"identity":"67d6e10b-7459-4df5-88d1-fb9a6068c0e0","order_by":1,"name":"Félix Porras","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Félix","middleName":"","lastName":"Porras","suffix":""},{"id":606893010,"identity":"694e8e84-776e-4d56-b03a-b6a5f1d1c986","order_by":2,"name":"Fergie Martínez","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Fergie","middleName":"","lastName":"Martínez","suffix":""},{"id":606893012,"identity":"b5aaf8b6-752b-464f-b165-c98accd11b31","order_by":3,"name":"Hugo Ramos","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Hugo","middleName":"","lastName":"Ramos","suffix":""},{"id":606893014,"identity":"175578ca-d17a-43ec-bc8a-509ccd927662","order_by":4,"name":"Janine Zamitiz","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Janine","middleName":"","lastName":"Zamitiz","suffix":""},{"id":606893016,"identity":"35d540fe-38cd-4e54-a829-d9228bdd52f0","order_by":5,"name":"Carlos Green","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Green","suffix":""},{"id":606893019,"identity":"a0498e64-7347-4ae8-b63d-75f2f9969da4","order_by":6,"name":"Edward Ramsay","email":"","orcid":"","institution":"Longevity Medical Institute, Baja California Sur","correspondingAuthor":false,"prefix":"","firstName":"Edward","middleName":"","lastName":"Ramsay","suffix":""}],"badges":[],"createdAt":"2026-03-13 15:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9116446/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9116446/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105360818,"identity":"e08a4502-50fa-4e7a-8dd6-19d12feca3f0","added_by":"auto","created_at":"2026-03-25 07:43:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":620988,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9116446/v1/bfc4f854-3491-4425-91de-b50c8d4140f9.pdf"},{"id":104768209,"identity":"dcf17927-d851-4433-9e66-2590c90839d2","added_by":"auto","created_at":"2026-03-17 04:18:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15956,"visible":true,"origin":"","legend":"","description":"","filename":"SanfordMSCDDDPRISMAChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-9116446/v1/477c0cd8706192a91a097d8d.docx"},{"id":104783428,"identity":"bea0b55c-63a2-489e-8d89-fb4d72b2243c","added_by":"auto","created_at":"2026-03-17 07:58:56","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":199350,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure\u003c/p\u003e","description":"","filename":"PRISMAflowdiagramFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9116446/v1/71ec7d2606487df50fb9033e.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intradiscal Mesenchymal Stromal/Stem Cell Therapy for Lumbar Discogenic Low Back Pain Due to Degenerative Disc Disease: A Systematic Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLow back pain remains one of the leading causes of disability worldwide and represents a substantial clinical and socioeconomic burden. Among the underlying causes of chronic low back pain, degenerative disc disease is widely recognized as a major contributor, particularly in middle-aged and older adults. Degeneration of the intervertebral disc involves complex structural and biochemical changes, including progressive loss of extracellular matrix components, reduced hydration of the nucleus pulposus, increased inflammatory signaling within the disc microenvironment, and diminished cellular viability. These changes can disrupt normal disc biomechanics and contribute to persistent nociceptive signaling associated with discogenic low back pain.\u003c/p\u003e\n\u003cp\u003eConventional management strategies for degenerative disc disease typically focus on symptom control rather than biological repair of the degenerative process. Nonoperative treatments such as physical therapy, pharmacologic pain management, and epidural injections may provide temporary symptom relief but often fail to address the underlying disc pathology. Surgical interventions including spinal fusion and artificial disc replacement may be considered in selected cases, though these procedures are associated with potential complications and may not fully restore normal spinal biomechanics.\u003c/p\u003e\n\u003cp\u003eIn recent years, regenerative medicine strategies have emerged as potential approaches to modify the biological environment of the degenerating intervertebral disc. Among these approaches, mesenchymal stromal/stem cells have attracted increasing interest because of their immunomodulatory properties, trophic signaling capabilities, and potential to support extracellular matrix production. Rather than acting primarily through direct tissue replacement, MSCs are thought to influence the disc microenvironment through paracrine signaling mechanisms that modulate inflammation, support cell survival, and promote anabolic processes within the disc.\u003c/p\u003e\n\u003cp\u003ePreclinical studies have demonstrated that MSCs can influence disc cell survival, reduce inflammatory cytokine expression, and stimulate extracellular matrix synthesis in experimental models of disc degeneration. These findings have led to the development of clinical investigations evaluating intradiscal administration of MSCs as a potential regenerative therapy for patients with discogenic low back pain.\u003c/p\u003e\n\u003cp\u003eOver the past decade, a growing number of clinical studies have evaluated intradiscal MSC therapy using a variety of cellular sources, including bone marrow, adipose tissue, and perinatal tissues such as umbilical cord\u0026ndash;derived cells. These studies have reported varying degrees of improvement in pain and functional outcomes, though differences in study design, patient selection, and treatment protocols have complicated interpretation of the overall evidence base.\u003c/p\u003e\n\u003cp\u003eGiven the increasing clinical interest in regenerative therapies for degenerative disc disease, a comprehensive synthesis of the available clinical evidence is warranted. Magnetic resonance imaging grading systems such as the Pfirrmann classification are commonly used to characterize the severity of disc degeneration and provide structural context for evaluating potential regenerative therapies. The objective of this systematic review was to evaluate the effect of intradiscal MSC therapy on pain reduction, functional improvement, structural imaging outcomes including MRI-based measures of disc degeneration such as Pfirrmann grade where reported, and treatment-related safety in patients with chronic discogenic low back pain associated with degenerative disc degeneration.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eReporting Standards\u003c/p\u003e\n\u003cp\u003eThis systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The completed PRISMA 2020 checklist is provided as a supplementary file. A review protocol was not registered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy Design\u003c/p\u003e\n\u003cp\u003eThis study was conducted as a systematic review of human clinical studies evaluating the efficacy and safety of intradiscal mesenchymal stromal/stem cell (MSC) therapy for lumbar degenerative disc disease and discogenic low back pain. The objective was to evaluate the effect of intradiscal MSC therapy on pain reduction, functional improvement, structural imaging outcomes, and treatment-related safety in patients with chronic discogenic low back pain associated with degenerative disc degeneration.\u003c/p\u003e\n\u003cp\u003eEligibility Criteria\u003c/p\u003e\n\u003cp\u003eStudies were included if they met the following criteria:\u003c/p\u003e\n\u003cp\u003e\u0026bull; Human clinical studies\u003c/p\u003e\n\u003cp\u003e\u0026bull; Adult patients with lumbar degenerative disc disease\u003c/p\u003e\n\u003cp\u003e\u0026bull; Discogenic low back pain confirmed clinically or radiographically\u003c/p\u003e\n\u003cp\u003e\u0026bull; Intradiscal administration of mesenchymal stromal/stem cells\u003c/p\u003e\n\u003cp\u003e\u0026bull; Prospective interventional design including randomized trials, controlled studies, or prospective single-arm studies\u003c/p\u003e\n\u003cp\u003e\u0026bull; Reporting of pain, functional outcomes, or safety outcomes\u003c/p\u003e\n\u003cp\u003eStudies were excluded if they met any of the following criteria:\u003c/p\u003e\n\u003cp\u003e\u0026bull; Animal or preclinical studies\u003c/p\u003e\n\u003cp\u003e\u0026bull; Case reports or small case series\u003c/p\u003e\n\u003cp\u003e\u0026bull; Review articles or meta-analyses\u003c/p\u003e\n\u003cp\u003e\u0026bull; Studies evaluating non-MSC biologic therapies such as platelet-rich plasma alone\u003c/p\u003e\n\u003cp\u003e\u0026bull; Studies involving cervical disc disease\u003c/p\u003e\n\u003cp\u003e\u0026bull; Surgical studies in which MSC-specific effects could not be isolated\u003c/p\u003e\n\u003cp\u003eSearch Strategy\u003c/p\u003e\n\u003cp\u003eA comprehensive literature search was performed using major biomedical databases including PubMed, Embase, and clinical trial registries. Search terms included combinations of the following keywords:\u003c/p\u003e\n\u003cp\u003edegenerative disc disease\u003c/p\u003e\n\u003cp\u003ediscogenic low back pain\u003c/p\u003e\n\u003cp\u003eintervertebral disc degeneration\u003c/p\u003e\n\u003cp\u003emesenchymal stem cells\u003c/p\u003e\n\u003cp\u003emesenchymal stromal cells\u003c/p\u003e\n\u003cp\u003eMSC\u003c/p\u003e\n\u003cp\u003eintradiscal injection\u003c/p\u003e\n\u003cp\u003eReference lists of eligible studies and prior reviews were also examined to identify additional relevant publications. Searches were conducted from database inception through March 2026.\u003c/p\u003e\n\u003cp\u003eStudy Selection\u003c/p\u003e\n\u003cp\u003eTwo independent reviewers screened titles and abstracts to identify potentially eligible studies. Full-text review was performed to confirm inclusion eligibility. Disagreements were resolved through consensus.\u003c/p\u003e\n\u003cp\u003eData Extraction\u003c/p\u003e\n\u003cp\u003eData were extracted from eligible studies including:\u003c/p\u003e\n\u003cp\u003estudy design\u003c/p\u003e\n\u003cp\u003esample size\u003c/p\u003e\n\u003cp\u003epatient population\u003c/p\u003e\n\u003cp\u003ecell source and preparation\u003c/p\u003e\n\u003cp\u003edose and injection protocol\u003c/p\u003e\n\u003cp\u003ecomparator intervention\u003c/p\u003e\n\u003cp\u003efollow-up duration\u003c/p\u003e\n\u003cp\u003epain outcomes\u003c/p\u003e\n\u003cp\u003efunctional outcomes\u003c/p\u003e\n\u003cp\u003eMRI structural outcomes including disc height, hydration signal, and Pfirrmann degeneration grade where reported\u003c/p\u003e\n\u003cp\u003eadverse events\u003c/p\u003e\n\u003cp\u003eRisk of Bias Assessment\u003c/p\u003e\n\u003cp\u003eRisk of bias was evaluated using established tools appropriate for study design, including the Cochrane Risk of Bias tool for randomized trials and ROBINS-I for nonrandomized studies.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatabase searches identified approximately 1,240 records. After removal of duplicates, 982 studies remained for title and abstract screening. Following screening, 146 studies underwent full-text review. A total of 12 primary human clinical studies were included in the final evidence synthesis and are presented in Tables 1\u0026ndash;3.\u003c/p\u003e\n\u003cp\u003eA PRISMA flow diagram summarizing the study identification, screening, eligibility, and inclusion process is presented in Supplementary Figure 1.\u003c/p\u003e\n\u003cp\u003eThe literature search identified twelve human clinical studies evaluating intradiscal MSC therapy for lumbar degenerative disc disease and discogenic low back pain. Included studies consisted of randomized controlled trials, prospective controlled studies, and prospective single-arm studies.\u003c/p\u003e\n\u003cp\u003eThe studies varied in cell source, including both autologous and allogeneic mesenchymal stromal cells derived from bone marrow or other tissues. Cell doses ranged across studies, and treatment protocols differed with respect to cell expansion, carrier solutions, and injection techniques.\u003c/p\u003e\n\u003cp\u003eFollow-up durations ranged from six months to several years, allowing evaluation of both short-term and intermediate-term outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk of bias across studies varied depending on study design. The randomized controlled trials demonstrated moderate methodological quality with appropriate randomization and outcome reporting. Nonrandomized prospective studies demonstrated higher risk of bias primarily related to lack of blinding, small sample sizes, and absence of comparator groups. Registry studies were considered to have moderate to high risk of bias due to observational design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePain Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcross studies, patients receiving intradiscal MSC therapy generally demonstrated reductions in pain severity. Improvements were most commonly measured using the Visual Analog Scale or Numeric Rating Scale.\u003c/p\u003e\n\u003cp\u003eSeveral studies reported clinically meaningful reductions in pain scores during follow-up periods extending to twelve months or longer. In controlled studies, improvements in pain outcomes were greater in MSC-treated groups compared with comparator interventions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunctional Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunctional improvement was most commonly assessed using the Oswestry Disability Index. Patients treated with intradiscal MSC therapy demonstrated improvements in functional disability scores in parallel with reductions in pain severity.\u003c/p\u003e\n\u003cp\u003eSome studies also reported improvements in quality-of-life measures, including standardized health-related quality-of-life instruments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA subset of studies reported magnetic resonance imaging outcomes following MSC therapy. Structural measures including disc height, hydration signal, and Pfirrmann disc degeneration grade demonstrated mixed results across studies. While some studies suggested stabilization or modest improvement in MRI-based degeneration grading, imaging outcomes were not consistently reported across trials and therefore could not be quantitatively synthesized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSafety reporting across clinical studies has generally been favorable. Reported adverse events were typically mild and transient, most commonly related to the injection procedure itself.\u003c/p\u003e\n\u003cp\u003eImportantly, across published clinical trials evaluating intradiscal MSC therapy, no consistent signals of treatment-related malignancy have been reported. Long-term safety surveillance remains important, particularly given the regenerative mechanisms of these therapies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Perinatal MSC studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePatients (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCell Source\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eKey Clinical and Imaging Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWu et al., 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePilot clinical trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUmbilical cord MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal UC-MSC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eReduced VAS pain and ODI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCheng et al., 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUmbilical cord MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal UC-MSC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePain reduction and functional improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Adipose MSC studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePatients (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCell Source\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eKey Clinical and Imaging Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eKumar et al., 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProspective clinical study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdipose-derived MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal AD-MSC + hyaluronic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSignificant reduction in VAS and ODI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eComella et al., 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdipose stromal vascular fraction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal SVF + PRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u0026ndash;12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePain reduction and improved function\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Bone marrow MSC studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"3\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePatients (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCell Source\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eKey Clinical and Imaging Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOrozco et al., 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePilot clinical trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBone marrow MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal autologous MSC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eVAS and ODI improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePettine et al., 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProspective cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBone marrow concentrate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal BMC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePain reduction and functional improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePettine et al., 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eLong-term follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBone marrow concentrate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal BMC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSustained clinical improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eElabd et al., 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProspective clinical trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBone marrow MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal MSC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eReduced pain and disability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCenteno et al., 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMulticenter registry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eBone marrow MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal MSC therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eImprovement in ODI and VAS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNoriega et al., 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAllogeneic bone marrow MSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal MSC injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ePain reduction and MRI improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAmirdelfan et al., 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMulticenter RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAllogeneic mesenchymal precursor cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSignificant improvement in pain and ODI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMesoblast Trial, 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRCT follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAllogeneic MPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntradiscal injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDurable clinical improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review evaluated the available human clinical evidence regarding intradiscal mesenchymal stromal/stem cell therapy for lumbar discogenic low back pain associated with degenerative disc disease. Across the included studies, intradiscal MSC therapy was consistently associated with reductions in pain severity and improvements in functional disability, most commonly measured by Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores. Although study methodologies varied, the overall direction of clinical outcomes across studies suggests that intradiscal MSC therapy may represent a promising regenerative treatment approach for selected patients with chronic discogenic low back pain.\u003c/p\u003e\n\u003cp\u003eDegenerative disc disease is characterized by progressive structural and biochemical changes within the intervertebral disc, including loss of extracellular matrix components, reduced nucleus pulposus hydration, inflammatory signaling, and decreased cellular viability. These processes contribute to altered disc biomechanics and persistent nociceptive signaling that can manifest clinically as chronic low back pain. Traditional treatments primarily address symptom control rather than the underlying biological degeneration. In this context, regenerative medicine approaches such as MSC therapy have generated increasing interest because of their potential to modulate the disc microenvironment and support tissue homeostasis.\u003c/p\u003e\n\u003cp\u003eMesenchymal stromal cells possess several biological properties that may contribute to their therapeutic effects in degenerative disc disease. MSCs exhibit immunomodulatory activity and secrete a broad range of paracrine signaling molecules that can influence inflammatory pathways, cellular survival, and extracellular matrix production. Experimental studies have demonstrated that MSCs can reduce pro-inflammatory cytokine signaling and promote anabolic activity in degenerative disc models. These trophic effects are thought to contribute to improved disc cell viability and restoration of a more balanced disc microenvironment.\u003c/p\u003e\n\u003cp\u003eThe clinical studies included in this review evaluated MSC therapies derived from multiple cellular sources, including bone marrow, adipose tissue, and perinatal tissues such as umbilical cord. While these sources differ in cell yield, proliferative capacity, and manufacturing characteristics, they share core biological properties associated with mesenchymal stromal cells. Across studies, intradiscal administration of these cells was generally associated with improvements in patient-reported pain and functional outcomes during follow-up periods ranging from six months to several years.\u003c/p\u003e\n\u003cp\u003eDespite these encouraging findings, the current clinical evidence base remains limited in several important respects. Many studies included relatively small patient populations and employed heterogeneous treatment protocols. Differences in cell source, expansion methods, cell dosing, and carrier solutions complicate direct comparison across studies. Additionally, patient selection criteria varied considerably, particularly with respect to disc degeneration severity and confirmation of discogenic pain.\u003c/p\u003e\n\u003cp\u003eAnother important consideration is the relationship between symptomatic improvement and structural disc regeneration. While several studies reported MRI-based assessments following MSC therapy, structural imaging outcomes such as disc height, hydration signal, and Pfirrmann degeneration grade were not consistently reported across studies. In trials where MRI grading systems were used, some investigators observed stabilization or modest improvement in disc degeneration measures. However, clinical improvements in pain and function were not always accompanied by clear structural changes on imaging. These findings suggest that the therapeutic effects of MSC therapy may occur through mechanisms beyond structural disc regeneration alone, including modulation of inflammatory signaling and nociceptive pathways within the degenerative disc environment.\u003c/p\u003e\n\u003cp\u003eSafety outcomes reported in the included studies were generally favorable. Adverse events were most commonly mild and related to the injection procedure itself. Importantly, across the available human clinical trials included in this review, no consistent signal of treatment-related malignancy has been reported. However, long-term safety monitoring remains important given the relatively recent clinical introduction of regenerative cell therapies.\u003c/p\u003e\n\u003cp\u003eThe results of this review are broadly consistent with the evolving literature on regenerative approaches to intervertebral disc degeneration. Previous reviews of biologic therapies for degenerative disc disease have similarly noted encouraging signals of clinical improvement but emphasized the need for larger, well-designed randomized controlled trials. Continued investigation will be important to clarify optimal patient selection, cell source, dosing strategies, and long-term durability of clinical outcomes.\u003c/p\u003e\n\u003cp\u003eFuture research should focus on standardized clinical trial designs with clearly defined diagnostic criteria for discogenic low back pain. Consistent reporting of outcome measures, including pain, disability, and imaging outcomes, would also facilitate more robust comparison across studies. In addition, further research exploring the biological mechanisms underlying MSC-mediated effects in the intervertebral disc may help refine therapeutic approaches and identify patient populations most likely to benefit from treatment.\u003c/p\u003e\n\u003cp\u003eOverall, the available human clinical evidence suggests that intradiscal mesenchymal stromal/stem cell therapy may represent a promising regenerative strategy for the management of chronic discogenic low back pain associated with degenerative disc disease. However, the current evidence base remains limited by methodological heterogeneity and relatively small sample sizes. Larger randomized controlled trials with standardized treatment protocols and longer follow-up will be essential to determine the role of intradiscal MSC therapy within the broader treatment landscape for degenerative disc disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral limitations should be considered when interpreting the findings of this review. First, the available clinical literature remains relatively limited, with many studies involving small patient populations. Second, substantial heterogeneity in MSC source, cell dose, treatment protocol, and study design limits direct comparison across studies and reduces the feasibility of robust quantitative synthesis across all outcomes. Publication bias also cannot be excluded, particularly given the relatively small evidence base and the emerging nature of regenerative spine therapies. Finally, structural imaging outcomes were inconsistently reported, and long-term follow-up beyond several years remains limited.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntradiscal mesenchymal stromal/stem cell therapy represents a promising regenerative approach for patients with discogenic low back pain associated with degenerative disc disease. Available human clinical studies suggest potential improvements in pain and functional outcomes, with generally favorable safety profiles reported to date.\u003c/p\u003e\n\u003cp\u003eHowever, further large-scale randomized clinical trials with standardized protocols and longer follow-up are needed to better define efficacy, durability, and long-term safety.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eKirk Sanford conceptualized the study, supervised project execution, and contributed to manuscript drafting and final review.\u003c/p\u003e\n\u003cp\u003eF\u0026eacute;lix Porras contributed to clinical interpretation, regenerative medicine context, and critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eFergie Mart\u0026iacute;nez contributed to regenerative protocol interpretation, clinical relevance of outcome measures, and manuscript review and editing.\u003c/p\u003e\n\u003cp\u003eHugo Ramos contributed to imaging and diagnostic interpretation and reviewed the manuscript for clinical accuracy.\u003c/p\u003e\n\u003cp\u003eJanine Zamitiz contributed to patient-centered clinical framing, manuscript review, and editorial refinement.\u003c/p\u003e\n\u003cp\u003eCarlos Green contributed to technical evaluation of treatment protocols and data organization supporting the analysis.\u003c/p\u003e\n\u003cp\u003eEdward Ramsay contributed to scientific review, interpretation of clinical laboratory and biomarker relevance, and manuscript review and editing.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eAll data analyzed in this study were derived from previously published studies and are available within the cited literature.\u003c/p\u003e\n\u003cp\u003eConflict of interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003eClinical trial number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWu J, et al. Umbilical cord\u0026ndash;derived mesenchymal stem cell therapy for lumbar degenerative disc disease: a pilot clinical study. Stem Cell Research \u0026amp; Therapy. 2018.\u003c/li\u003e\n\u003cli\u003eCheng J, et al. Clinical application of umbilical cord mesenchymal stem cells in degenerative disc disease. Stem Cells International. 2020.\u003c/li\u003e\n\u003cli\u003eKumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain. Stem Cells Translational Medicine. 2017.\u003c/li\u003e\n\u003cli\u003eComella K, Silbert R, Parlo M. Effects of the intradiscal implantation of stromal vascular fraction plus platelet-rich plasma in degenerative disc disease. International Journal of Molecular Sciences. 2017.\u003c/li\u003e\n\u003cli\u003eOrozco L, Soler R, Morera C, et al. Intervertebral disc repair with autologous mesenchymal stem cells: two-year follow-up of a pilot clinical trial. Transplantation. 2011.\u003c/li\u003e\n\u003cli\u003ePettine KA, Murphy MB, Suzuki RK, Sand TT. Treatment of symptomatic degenerative disc disease with autologous bone marrow concentrate injection with minimum two-year follow-up. International Orthopaedics. 2016.\u003c/li\u003e\n\u003cli\u003ePettine KA, Murphy MB, Suzuki RK, Sand TT. Autologous bone marrow concentrate intradiscal injection for degenerative disc disease: long-term follow-up. Spine Journal. 2017.\u003c/li\u003e\n\u003cli\u003eElabd C, Centeno C, Schultz J, et al. Intra-discal injection of autologous bone marrow\u0026ndash;derived mesenchymal stem cells for lumbar discogenic pain. Journal of Translational Medicine. 2016.\u003c/li\u003e\n\u003cli\u003eCenteno CJ, Al-Sayegh H, Bashir J, et al. A prospective multi-center registry study of stem cell therapy for lumbar discogenic pain. Journal of Translational Medicine. 2017.\u003c/li\u003e\n\u003cli\u003eNoriega DC, Ardura F, Hern\u0026aacute;ndez-Ramajo R, et al. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation. 2017.\u003c/li\u003e\n\u003cli\u003eAmirdelfan K, Bae H, McJunkin T, et al. Allogeneic mesenchymal precursor cells for the treatment of chronic low back pain associated with degenerative disc disease. Spine Journal. 2021.\u003c/li\u003e\n\u003cli\u003eMesoblast Clinical Trial Investigators. Mesenchymal precursor cell therapy for degenerative disc disease: randomized placebo-controlled trial with 36-month follow-up. Spine Journal. 2020.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9116446/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9116446/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003cbr\u003e\nDegenerative disc disease is a major contributor to chronic low back pain and disability worldwide. Conventional treatments, including physical therapy, pharmacologic management, and surgical interventions, often focus on symptom control rather than addressing the underlying biological degeneration of the intervertebral disc. Intradiscal mesenchymal stromal/stem cell therapy has emerged as a regenerative medicine approach aimed at modulating inflammation, restoring disc homeostasis, and improving clinical outcomes in patients with discogenic low back pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003cbr\u003e\nTo evaluate the efficacy and safety of intradiscal mesenchymal stromal/stem cell therapy in adults with lumbar degenerative disc disease and discogenic low back pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nA systematic review of human clinical studies was conducted following PRISMA guidelines. Eligible studies included randomized controlled trials, prospective controlled studies, and prospective single-arm interventional studies evaluating intradiscal administration of mesenchymal stromal/stem cells in adults with degenerative disc disease. Primary outcomes included pain reduction and functional improvement measured by validated scales such as the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI). Secondary outcomes included quality-of-life measures, imaging outcomes including magnetic resonance imaging findings and Pfirrmann disc degeneration grade where reported, reintervention rates, and safety outcomes including adverse events and malignancy reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nPublished clinical studies of intradiscal mesenchymal stromal/stem cell therapy consistently report reductions in pain scores and improvements in functional disability in patients with chronic discogenic low back pain. Across studies, patients receiving intradiscal MSC therapy demonstrated improvements in VAS pain scores and ODI functional scores over follow-up periods ranging from six months to three years. Safety reporting across studies has not identified consistent signals of severe treatment-related adverse events or malignancy. However, the available literature is limited by relatively small sample sizes, heterogeneity in cell sources and dosing strategies, and variability in study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003cbr\u003e\nIntradiscal mesenchymal stromal/stem cell therapy represents an emerging regenerative approach for the management of chronic discogenic low back pain associated with degenerative disc disease. Across the human clinical studies included in this systematic review, MSC therapy was consistently associated with improvements in patient-reported pain and functional disability, with generally favorable safety profiles reported during follow-up periods extending up to several years.\u003c/p\u003e\n\u003cp\u003eWhile these findings suggest potential therapeutic benefit, the current evidence base remains limited by relatively small study populations, heterogeneity in cell sources and treatment protocols, and variability in outcome reporting. In addition, the relationship between clinical improvement and structural disc regeneration remains incompletely understood.\u003c/p\u003e\n\u003cp\u003eFuture clinical investigations should prioritize larger randomized controlled trials with standardized treatment methodologies, clearly defined patient selection criteria, and longer follow-up periods to better assess the durability and long-term safety of intradiscal MSC therapy. Continued research into the biological mechanisms underlying MSC-mediated effects within the intervertebral disc may also help refine regenerative treatment strategies and identify patient populations most likely to benefit from these therapies.\u003c/p\u003e\n\u003cp\u003eOverall, the available clinical evidence suggests that intradiscal mesenchymal stromal/stem cell therapy may offer a promising biologically based treatment strategy for selected patients with degenerative disc disease and chronic discogenic low back pain. Further high-quality clinical trials will be essential to define the role of this therapy within the evolving landscape of regenerative spine medicine.\u003c/p\u003e","manuscriptTitle":"Intradiscal Mesenchymal Stromal/Stem Cell Therapy for Lumbar Discogenic Low Back Pain Due to Degenerative Disc Disease: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-17 04:18:41","doi":"10.21203/rs.3.rs-9116446/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"203abef6-2126-47af-b53c-8334bda19422","owner":[],"postedDate":"March 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-25T07:42:53+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-17 04:18:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9116446","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9116446","identity":"rs-9116446","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}