{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T09:27:30Z","timestamp":1786958850723,"version":"build-2736575974"},"reference-count":90,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T00:00:00Z","timestamp":1786752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Spinal pathologies, including degenerative disc disease, spinal cord injury, and conditions requiring spinal fusion, pose a substantial global health burden. While contemporary interventions provide symptomatic relief, achieving durable tissue repair in biologically compromised environments remains a critical challenge. This narrative review synthesizes the current literature on three major nanotechnology applications in spine care: nanostructured implant surfaces, nanoparticle-enhanced bone grafts, and nano-drug delivery systems (NDDSs). Preclinical evidence indicates that nanoscale surface modifications and nanoparticle-augmented synthetic grafts significantly enhance osseointegration and bone fusion by mimicking the native extracellular matrix. Furthermore, in animal models of intervertebral disc degeneration, NDDSs utilizing polymeric nanoparticles and exosomes facilitate sustained, stimuli-responsive therapeutic delivery into the avascular disc space. Although early clinical data on nanostructured cages demonstrate reduced subsidence and stable long-term fusion, the direct translation of these robust preclinical outcomes to widespread clinical efficacy faces substantial hurdles. Significant translational barriers include stringent Class III regulatory classifications, sparse long-term safety data regarding nanoparticle biodistribution, and scale-up manufacturing challenges such as batch variability. Future progress relies on artificial intelligence-guided design, three-dimensional (3D) bioprinting, and multifunctional \u201csmart\u201d nanomaterials. Ultimately, close collaboration among materials scientists, clinicians, and regulatory bodies is essential to safely bridge the gap between preclinical innovation and predictable clinical therapeutic success.<\/jats:p>","DOI":"10.3390\/biology15161400","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T08:05:41Z","timestamp":1786953941000},"page":"1400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reimagining Spinal Surgery at the Nanoscale: Smart Implants, Targeted Therapies, and Translational Challenges"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3195-5491","authenticated-orcid":false,"given":"Alexander Shao-Rong","family":"Pang","sequence":"first","affiliation":[{"name":"Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley Yun-Lin","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0498-9237","authenticated-orcid":false,"given":"Zi Qiang Glen","family":"Liau","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, National University Hospital, Singapore 119074, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-4500","authenticated-orcid":false,"given":"Arun-Kumar","family":"Kaliya-Perumal","sequence":"additional","affiliation":[{"name":"Rehabilitation Research Institute of Singapore, Nanyang Technological University, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob Yoong-Leong","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-5441","authenticated-orcid":false,"given":"Dinesh Kumar","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1177\/2192568218770769","article-title":"Degenerative Lumbar Spine Disease: Estimating Global Incidence and Worldwide Volume","volume":"8","author":"Ravindra","year":"2018","journal-title":"Glob. Spine J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1177\/21925682251370639","article-title":"An Analysis of the Burden of Spinal Cord Injury Differences Between Global Epidemiology and Trends to America, China and India","volume":"16","author":"Wei","year":"2026","journal-title":"Glob. Spine J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e289815","DOI":"10.1590\/1413-785220253303e289815","article-title":"Risks and Benefits of Spinal Fusion Surgery for Degenerative Spine Diseases: Systematic Review of Literature","volume":"33","author":"Rodrigues","year":"2025","journal-title":"Acta Ortop. Bras."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Michalak, M., Druszcz, A., Mis, M., Mis, M., Paprocka-Borowicz, M., and Rosinczuk, J. (2026). Functional and Neurological Outcomes After Spine Surgery and Neurorehabilitation for Chronic Discogenic Low Back Pain: A Prospective Observational Pre-Post Study. Healthcare, 14.","DOI":"10.3390\/healthcare14020258"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"752","DOI":"10.21037\/jss-20-492","article-title":"Trends in lumbar spinal fusion-a literature review","volume":"6","author":"Reisener","year":"2020","journal-title":"J. Spine Surg."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mensah, E.O., Chalif, J.I., Baker, J.G., Chalif, E., Biundo, J., and Groff, M.W. (2024). Challenges in Contemporary Spine Surgery: A Comprehensive Review of Surgical, Technological, and Patient-Specific Issues. J. Clin. Med., 13.","DOI":"10.3390\/jcm13185460"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.wneu.2018.11.035","article-title":"Nanotechnology in Spine Surgery: A Current Update and Critical Review of the Literature","volume":"123","author":"Viswanathan","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cost\u0103chescu, B., Moldoveanu, E.T., Niculescu, A.G., Grumezescu, A.M., and Teleanu, D.M. (2025). Advancements in Nanotechnology for Spinal Surgery: Innovations in Spinal Fixation Devices for Enhanced Biomechanical Performance and Osteointegration. Nanomaterials, 15.","DOI":"10.3390\/nano15141073"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.2147\/DDDT.S448807","article-title":"The Emerging Roles of Nanocarrier Drug Delivery System in Treatment of Intervertebral Disc Degeneration-Current Knowledge, Hot Spots, Challenges and Future Perspectives","volume":"18","author":"Hu","year":"2024","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121162","DOI":"10.1016\/j.biomaterials.2021.121162","article-title":"A micro\/nano-biomimetic coating on titanium orchestrates osteo\/angio-genesis and osteoimmunomodulation for advanced osseointegration","volume":"278","author":"Bai","year":"2021","journal-title":"Biomaterials"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1016\/j.actbio.2014.03.037","article-title":"Implant osseointegration and the role of microroughness and nanostructures: Lessons for spine implants","volume":"10","author":"Gittens","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_12","first-page":"274","article-title":"Multiple nano-drug delivery systems for intervertebral disc degeneration: Current status and future perspectives","volume":"23","author":"Liu","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liang, W., Zhou, C., Bai, J., Zhang, H., Long, H., Jiang, B., Dai, H., Wang, J., and Zhao, J. (2024). Current developments and future perspectives of nanotechnology in orthopedic implants: An updated review. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1342340"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"dmm033084","DOI":"10.1242\/dmm.033084","article-title":"Animal models for bone tissue engineering and modelling disease","volume":"11","author":"McGovern","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"114409","DOI":"10.1016\/j.jconrel.2025.114409","article-title":"Nanoparticle-mediated bone regeneration: From molecular mechanisms to clinical translation","volume":"389","author":"Wang","year":"2026","journal-title":"J. Control Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.nic.2007.01.002","article-title":"Degenerative disease of the spine","volume":"17","author":"Gallucci","year":"2007","journal-title":"Neuroimaging Clin. N. Am."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1242\/dmm.006403","article-title":"Degeneration and regeneration of the intervertebral disc: Lessons from development","volume":"4","author":"Smith","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E6","DOI":"10.3171\/2020.5.FOCUS20289","article-title":"Association of osteopenia and osteoporosis with higher rates of pseudarthrosis and revision surgery in adult patients undergoing single-level lumbar fusion","volume":"49","author":"Khalid","year":"2020","journal-title":"Neurosurg. Focus"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"206","DOI":"10.2106\/JBJS.23.00272","article-title":"Impact of Teriparatide on Complications and Patient-Reported Outcomes of Patients Undergoing Long Spinal Fusion According to Bone Density","volume":"106","author":"Mohanty","year":"2024","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1093\/neuros\/nyab317","article-title":"Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Perioperative Spine: Preoperative Osteoporosis Assessment","volume":"89","author":"Dimar","year":"2021","journal-title":"Neurosurgery"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1093\/neuros\/nyab318","article-title":"Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Perioperative Spine: Preoperative Nutritional Assessment","volume":"89","author":"Bisson","year":"2021","journal-title":"Neurosurgery"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/jbm.a.37052","article-title":"Influence of nano-hydroxyapatite coating implants on gene expression of osteogenic markers and micro-CT parameters. An in vivo study in diabetic rats","volume":"109","author":"Silveira","year":"2021","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Noh, S.H., Sung, K., Byeon, H.E., Kim, S.E., and Kim, K.N. (2023). Lactoferrin-Anchored Tannylated Mesoporous Silica Nanomaterials-Induced Bone Fusion in a Rat Model of Lumbar Spinal Fusion. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115782"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.biomaterials.2018.04.004","article-title":"PLGA\/\u03b2-TCP composite scaffold incorporating salvianolic acid B promotes bone fusion by angiogenesis and osteogenesis in a rat spinal fusion model","volume":"196","author":"Lin","year":"2019","journal-title":"Biomaterials"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1002\/jor.24073","article-title":"Enhancing the effects of exfoliated carbon nanofibers using bone morphogenetic protein in a rat spinal fusion model","volume":"36","author":"Notani","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Van Eps, J.L., Fernandez-Moure, J.S., Cabrera, F.J., Taraballi, F., Paradiso, F., Minardi, S., Wang, X., Aghdasi, B., Tasciotti, E., and Weiner, B.K. (2021). Improved Posterolateral Lumbar Spinal Fusion Using a Biomimetic, Nanocomposite Scaffold Augmented by Autologous Platelet-Rich Plasma. Front. Bioeng. Biotechnol., 9.","DOI":"10.3389\/fbioe.2021.622099"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1016\/j.spinee.2021.05.017","article-title":"The efficacy of a nanosynthetic bone graft substitute as a bone graft extender in rabbit posterolateral fusion","volume":"21","author":"Conway","year":"2021","journal-title":"Spine J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E625","DOI":"10.1097\/BRS.0000000000002463","article-title":"Effects of Combined Magnetic Fields Treatment and Nano-Hydroxyapatite Coating on Porous Biphasic Calcium Phosphate Bone Graft in Rabbit Spinal Fusion Model","volume":"43","author":"Zhuo","year":"2018","journal-title":"Spine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1080\/17435889.2025.2511465","article-title":"Emerging nanomaterials capable of effectively facilitating osteoblast maturation","volume":"20","author":"Elkhenany","year":"2025","journal-title":"Nanomedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3171\/2023.6.SPINE23382","article-title":"Promotion of higher rates of early fusion using activated titanium versus polyetheretherketone cages in adults undergoing 1- and 2-level transforaminal lumbar interbody fusion procedures: A randomized controlled trial","volume":"39","author":"Toop","year":"2023","journal-title":"J. Neurosurg. Spine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S579","DOI":"10.3928\/0147-7447-20020502-06","article-title":"Adjunctive use of ultraporous beta-tricalcium phosphate bone void filler in spinal arthrodesis","volume":"25","author":"Meadows","year":"2002","journal-title":"Orthopedics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.spinee.2007.11.005","article-title":"An analysis of noninstrumented posterolateral lumbar fusions performed in predominantly geriatric patients using lamina autograft and beta tricalcium phosphate","volume":"8","author":"Epstein","year":"2008","journal-title":"Spine J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, L., Zhou, C., Jiang, C., Huang, X., Liu, Z., Zhang, H., Liang, W., and Zhao, J. (2023). Translation of nanotechnology-based implants for orthopedic applications: Current barriers and future perspective. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1206806"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/jor.24576","article-title":"Orthopaedic osseointegration: Implantology and future directions","volume":"38","author":"Overmann","year":"2020","journal-title":"J. Orthop. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1002\/jbm.a.35401","article-title":"The role of nanostructures and hydrophilicity in osseointegration: In-vitro protein-adsorption and blood-interaction studies","volume":"103","author":"Kopf","year":"2015","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.2147\/IJN.S362720","article-title":"Nanostructured Titanium Implant Surface Facilitating Osseointegration from Protein Adsorption to Osteogenesis: The Example of TiO(2) NTAs","volume":"17","author":"Wu","year":"2022","journal-title":"Int. J. Nanomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"171945","DOI":"10.1155\/2015\/171945","article-title":"Cellular responses evoked by different surface characteristics of intraosseous titanium implants","volume":"2015","author":"Feller","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/jbm.a.37323","article-title":"Nanoscale hybrid implant surfaces and Osterix-mediated osseointegration","volume":"110","author":"Sartori","year":"2022","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.actbio.2023.10.030","article-title":"Evaluation of nanoscale versus hybrid micro\/nano surface topographies for endosseous implants","volume":"173","author":"Shirazi","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1016\/j.biomaterials.2009.04.010","article-title":"The effects of implant surface nanoscale features on osteoblast-specific gene expression","volume":"30","author":"Leite","year":"2009","journal-title":"Biomaterials"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Velasco-Ortega, E., Fos-Parra, I., Cabanillas-Balsera, D., Gil, J., Ortiz-Garc\u00eda, I., Giner, M., Bocio-N\u00fa\u00f1ez, J., Montoya-Garc\u00eda, M.J., and Jim\u00e9nez-Guerra, \u00c1. (2023). Osteoblastic Cell Behavior and Gene Expression Related to Bone Metabolism on Different Titanium Surfaces. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043523"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31966","DOI":"10.1039\/D3RA08185K","article-title":"A novel porous interbody fusion cage modified by microarc oxidation and hydrothermal treatment technology accelerate osseointegration and spinal fusion in sheep","volume":"14","author":"Sun","year":"2024","journal-title":"RSC Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.msec.2016.05.096","article-title":"Improved bioactivity of selective laser melting titanium: Surface modification with micro-\/nano-textured hierarchical topography and bone regeneration performance evaluation","volume":"68","author":"Xu","year":"2016","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.spinee.2022.01.003","article-title":"Subsidence and fusion performance of a 3D-printed porous interbody cage with stress-optimized body lattice and microporous endplates\u2014A comprehensive mechanical and biological analysis","volume":"22","author":"Fogel","year":"2022","journal-title":"Spine J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e626","DOI":"10.1016\/j.wneu.2022.03.087","article-title":"Choice of Spinal Interbody Fusion Cage Material and Design Influences Subsidence and Osseointegration Performance","volume":"162","author":"Fogel","year":"2022","journal-title":"World Neurosurg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1302\/0301-620X.100B1.BJJ-2017-0551.R1","article-title":"Effects of titanium nanotubes on the osseointegration, cell differentiation, mineralisation and antibacterial properties of orthopaedic implant surfaces","volume":"100-b","author":"Su","year":"2018","journal-title":"Bone Jt. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e2006287","DOI":"10.1002\/smll.202006287","article-title":"Targeting Early Healing Phase with Titania Nanotube Arrays on Tunable Diameters to Accelerate Bone Regeneration and Osseointegration","volume":"17","author":"Bai","year":"2021","journal-title":"Small"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.actbio.2018.06.023","article-title":"Differential effect of hydroxyapatite nano-particle versus nano-rod decorated titanium micro-surface on osseointegration","volume":"76","author":"Bai","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.clineuro.2018.11.015","article-title":"A comparison of long-term outcomes of nanohydroxyapatite\/polyamide-66 cage and titanium mesh cage in anterior cervical corpectomy and fusion: A clinical follow-up study of least 8 years","volume":"176","author":"Hu","year":"2019","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/BRS.0000000000005126","article-title":"Comparison of Titanium Mesh Cage, Nano-Hydroxyapatite\/Polyamide Cage, and Three-Dimensional-Printed Vertebral Body for Anterior Cervical Corpectomy and Fusion","volume":"50","author":"Li","year":"2025","journal-title":"Spine"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Almeida, D., Sartoretto, S.C., Calasans-Maia, J.A., Ghiraldini, B., Bezerra, F.J.B., Granjeiro, J.M., and Calasans-Maia, M.D. (2023). In vivo osseointegration evaluation of implants coated with nanostructured hydroxyapatite in low density bone. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0282067"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1016\/j.biomaterials.2007.12.011","article-title":"The response of bone to nanocrystalline hydroxyapatite-coated Ti13Nb11Zr alloy in an animal model","volume":"29","author":"Bigi","year":"2008","journal-title":"Biomaterials"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6605","DOI":"10.2147\/IJN.S268372","article-title":"Electrochemical Deposition of Nanostructured Hydroxyapatite Coating on Titanium with Enhanced Early Stage Osteogenic Activity and Osseointegration","volume":"15","author":"Lu","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_54","first-page":"859","article-title":"Bone integration capability of nanopolymorphic crystalline hydroxyapatite coated on titanium implants","volume":"7","author":"Yamada","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"D\u2019Avenio, G., Daniele, C., and Grigioni, M. (2024). Nanostructured Medical Devices: Regulatory Perspective and Current Applications. Materials, 17.","DOI":"10.3390\/ma17081787"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Wang, W., Yong, J., Marciano, P., O\u2019Hare Doig, R., Mao, G., and Clark, J. (2024). The Translation of Nanomedicines in the Contexts of Spinal Cord Injury and Repair. Cells, 13.","DOI":"10.3390\/cells13070569"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9423","DOI":"10.1016\/j.actbio.2013.08.019","article-title":"Dual release of dexamethasone and TGF-\u03b23 from polymeric microspheres for stem cell matrix accumulation in a rat disc degeneration model","volume":"9","author":"Liang","year":"2013","journal-title":"Acta Biomater."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.actbio.2018.03.032","article-title":"Stromal cell-derived factor-1\u03b1-encapsulated albumin\/heparin nanoparticles for induced stem cell migration and intervertebral disc regeneration in vivo","volume":"72","author":"Zhang","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.actbio.2023.08.029","article-title":"In situ forming macroporous biohybrid hydrogel for nucleus pulposus cell delivery","volume":"170","author":"Brissenden","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.actbio.2016.06.013","article-title":"Anti-inflammatory Chitosan\/Poly-\u03b3-glutamic acid nanoparticles control inflammation while remodeling extracellular matrix in degenerated intervertebral disc","volume":"42","author":"Teixeira","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"122132","DOI":"10.1016\/j.biomaterials.2023.122132","article-title":"Repair of degenerative nucleus pulposus by polyphenol nanosphere-encapsulated hydrogel gene delivery system","volume":"298","author":"Wang","year":"2023","journal-title":"Biomaterials"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e09806","DOI":"10.1002\/smll.202509806","article-title":"Engineering Nanomaterials for the Treatment of Intervertebral Disc Degeneration: From Application to Therapeutic Mechanisms","volume":"21","author":"Song","year":"2025","journal-title":"Small"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e2303021","DOI":"10.1002\/adma.202303021","article-title":"Effective Modulation of Inflammation and Oxidative Stress for Enhanced Regeneration of Intervertebral Discs Using 3D Porous Hybrid Protein Nanoscaffold","volume":"35","author":"Yang","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.actbio.2025.07.033","article-title":"A hydrogel-based drug delivery system reduces inflammation and oxidative stress to alleviate intervertebral disc degeneration","volume":"203","author":"Wang","year":"2025","journal-title":"Acta Biomater."},{"key":"ref_65","first-page":"157","article-title":"An intelligent nanoliposome alleviates disc degeneration and discogenic pain by inhibiting neurovascular ingrowth via a \u201cSoil-conditioning, seed-modulating, and weeds-suppressing\u201d strategy","volume":"58","author":"Li","year":"2026","journal-title":"Bioact. Mater."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1021\/acsnano.2c11441","article-title":"Development of a Nanohybrid Peptide Hydrogel for Enhanced Intervertebral Disc Repair and Regeneration","volume":"17","author":"Conley","year":"2023","journal-title":"ACS Nano"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s10020-024-00777-z","article-title":"Decellularized nucleus pulposus matrix\/chitosan hybrid hydrogel combined with nucleus pulposus stem cells and GDF5-loaded microspheres for intervertebral disc degeneration prevention","volume":"30","author":"Ma","year":"2024","journal-title":"Mol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2019.07.026","article-title":"Mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration via anti-oxidant and anti-inflammatory effects","volume":"143","author":"Xia","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.actbio.2021.11.044","article-title":"Small extracellular vesicles from hypoxic mesenchymal stem cells alleviate intervertebral disc degeneration by delivering miR-17-5p","volume":"140","author":"Zhou","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.actbio.2025.09.027","article-title":"An engineering-reinforced hypoxia-preconditioned exosome-integrated hydrogel delays intervertebral disc degeneration via the PPAR\u03b3-autophagy axis","volume":"206","author":"Sun","year":"2025","journal-title":"Acta Biomater."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"122562","DOI":"10.1016\/j.biomaterials.2024.122562","article-title":"Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain","volume":"308","author":"Tang","year":"2024","journal-title":"Biomaterials"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Wei, Y.P., Shiue, Y.L., Tsai, C.S., and Tarng, Y.W. (2026). Therapeutic effects of stem cell-derived extracellular vesicles in animal models of intervertebral disc degeneration: A systematic review and meta-analysis of species differences and delivery strategies. Front. Bioeng. Biotechnol., 14.","DOI":"10.3389\/fbioe.2026.1749916"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"112343","DOI":"10.1016\/j.msec.2021.112343","article-title":"Injectable nanostructured colloidal gels resembling native nucleus pulposus as carriers of mesenchymal stem cells for the repair of degenerated intervertebral discs","volume":"128","author":"Wang","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Han, L., Wang, Z., Chen, H., Li, J., Zhang, S., Shao, S., Zhang, Y., Shen, C., and Tao, H. (2022). Sa12b-Modified Functional Self-Assembling Peptide Hydrogel Enhances the Biological Activity of Nucleus Pulposus Mesenchymal Stem Cells by Inhibiting Acid-Sensing Ion Channels. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.822501"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.actbio.2016.09.033","article-title":"Self-assembling peptide hydrogel for intervertebral disc tissue engineering","volume":"46","author":"Wan","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"120193","DOI":"10.1016\/j.carbpol.2022.120193","article-title":"Nanofiber reinforced alginate hydrogel for leak-proof delivery and higher stress loading in nucleus pulposus","volume":"299","author":"Li","year":"2023","journal-title":"Carbohydr. Polym."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"58103","DOI":"10.1021\/acsami.3c11710","article-title":"Minimally Invasive Intradiscal Delivery of BM-MSCs via Fibrous Microscaffold Carriers","volume":"15","author":"Nakielski","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e2404963","DOI":"10.1002\/smll.202404963","article-title":"Injectable PLGA Microscaffolds with Laser-Induced Enhanced Microporosity for Nucleus Pulposus Cell Delivery","volume":"21","author":"Nakielski","year":"2025","journal-title":"Small"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Ding, Y., Li, F., Wang, Y., Pan, W., Fu, X., and Tan, S. (2025). Nanomedicine Approaches for Intervertebral Disc Regeneration: From Bench to Bedside. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17030313"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Smith, W.R., Hudson, P.W., Ponce, B.A., and Rajaram Manoharan, S.R. (2018). Nanotechnology in orthopedics: A clinically oriented review. BMC Musculoskelet. Disord., 19.","DOI":"10.1186\/s12891-018-1990-1"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3390\/jnt5040011","article-title":"Nanotechnology-Enhanced Orthopaedic Surgery","volume":"5","author":"Pang","year":"2024","journal-title":"J. Nanotheranostics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9227","DOI":"10.1039\/D0TB01440K","article-title":"Carbon nanotube-based biomaterials for orthopaedic applications","volume":"8","author":"Aoki","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"19992","DOI":"10.1039\/D1RA00861G","article-title":"Design of graphenic nanocomposites containing chitosan and polyethylene glycol for spinal cord injury improvement","volume":"11","author":"Farhoudi","year":"2021","journal-title":"RSC Adv."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"14043","DOI":"10.2147\/IJN.S500364","article-title":"Nanotechnology-Enhanced Pharmacotherapy for Intervertebral Disc Degeneration Treatment","volume":"19","author":"Shi","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Fr\u0105czek, W., Kotela, A., Kotela, I., and Grodzik, M. (2024). Nanostructures in Orthopedics: Advancing Diagnostics, Targeted Therapies, and Tissue Regeneration. Materials, 17.","DOI":"10.3390\/ma17246162"},{"key":"ref_86","first-page":"353","article-title":"Advances in medical devices using nanomaterials and nanotechnology: Innovation and regulatory science","volume":"48","author":"Lin","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"110154","DOI":"10.1016\/j.msec.2019.110154","article-title":"Nanotechnology-based biomaterials for orthopaedic applications: Recent advances and future prospects","volume":"106","author":"Kumar","year":"2020","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1001\/jamainternmed.2021.6626","article-title":"Renewing the Call for Reforms to Medical Device Safety-The Case of Penumbra","volume":"182","author":"Kadakia","year":"2022","journal-title":"JAMA Intern. Med."},{"key":"ref_89","first-page":"173","article-title":"A Suggested Model for Building Robust Biomedical Implants Registries","volume":"238","author":"Aloufi","year":"2017","journal-title":"Stud. Health Technol. Inform."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2106\/JBJS.22.00561","article-title":"International Registries: U.K. National Joint Registry, Nordic Registries, and Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR)","volume":"104","author":"Porter","year":"2022","journal-title":"J. Bone Jt. Surg. 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