{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T23:49:40Z","timestamp":1793576980816,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T00:00:00Z","timestamp":1697241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for post-traumatic cartilage injury and osteoarthritis of the knee; however, efforts for application have been limited due to issues with variable dosing and rapid clearance in vivo. Scaffolds laden with MSC-based exosomes have recently been investigated as a solution to these issues. Here, we review in vivo studies and highlight key strengths and potential clinical uses of exosome\u2013scaffold therapeutics for treatment of post-traumatic cartilage injury and osteoarthritis. In vivo animal studies were gathered using keywords related to the topic, revealing 466 studies after removal of duplicate papers. Inclusion and exclusion criteria were applied for abstract screening and full-text review. Thirteen relevant studies were identified for analysis and extraction. Three predominant scaffold subtypes were identified: hydrogels, acellular extracellular matrices, and hyaluronic acid. Each scaffold\u2013exosome design showcased unique properties with relation to gross findings, tissue histology, biomechanics, and gene expression. All designs demonstrated a reduction in inflammation and induction of tissue regeneration. The results of our review show that current exosome\u2013scaffold therapeutics demonstrate the capability to halt and even reverse the course of post-traumatic cartilage injury and osteoarthritis. While this treatment modality shows incredible promise, future research should aim to characterize long-term biocompatibility and optimize scaffold designs for human treatment.<\/jats:p>","DOI":"10.3390\/ijms242015178","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T14:38:42Z","timestamp":1697294322000},"page":"15178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Exosome-Laden Scaffolds for Treatment of Post-Traumatic Cartilage Injury and Osteoarthritis of the Knee: A Systematic Review"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5770-0292","authenticated-orcid":false,"given":"Jorden","family":"Xavier","sequence":"first","affiliation":[{"name":"Albert Einstein College of Medicine, New York, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jerome","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine, New York, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Zaslav","sequence":"additional","affiliation":[{"name":"Feinstein Institute for Medical Research, New York, NY 11030, USA"},{"name":"Department of Orthopedic Surgery, Lenox Hill Hospital, New York, NY 10075, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Grande","sequence":"additional","affiliation":[{"name":"Feinstein Institute for Medical Research, New York, NY 11030, USA"},{"name":"Department of Orthopedic Surgery, Long Island Jewish Medical Center, New York, NY 11040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1001\/jama.2020.22171","article-title":"Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review","volume":"325","author":"Katz","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"973870","DOI":"10.3389\/fmed.2022.973870","article-title":"Post-traumatic knee osteoarthritis; the role of inflammation and hemarthrosis on disease progression","volume":"9","author":"Evers","year":"2022","journal-title":"Front. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Maglio, M., Brogini, S., Pagani, S., Giavaresi, G., and Tschon, M. (2019). Current Trends in the Evaluation of Osteochondral Lesion Treatments: Histology, Histomorphometry, and Biomechanics in Preclinical Models. BioMed Res. Int., 2019.","DOI":"10.1155\/2019\/4040236"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s43019-020-00080-1","article-title":"Is there an optimal age for total knee arthroplasty?: A systematic review","volume":"32","author":"Lee","year":"2020","journal-title":"Knee Surg. Relat. Res."},{"key":"ref_5","first-page":"73","article-title":"Post-traumatic knee osteoarthritis in the young patient: Therapeutic dilemmas and emerging technologies","volume":"5","author":"Stiebel","year":"2014","journal-title":"Open Access J. Sports Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"D\u2019arrigo, D., Roffi, A., Cucchiarini, M., Moretti, M., Candrian, C., and Filardo, G. (2019). Secretome and Extracellular Vesicles as New Biological Therapies for Knee Osteoarthritis: A Systematic Review. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111867"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s10735-021-10017-x","article-title":"Extracellular vesicles as novel approaches for the treatment of osteoarthritis: A narrative review on potential mechanisms","volume":"52","author":"Jousheghan","year":"2021","journal-title":"Histochem. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13287-018-0791-7","article-title":"Mesenchymal stem cell-derived extracellular vesicles: Novel frontiers in regenerative medicine","volume":"9","author":"Keshtkar","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1186\/s12967-020-02622-3","article-title":"Mesenchymal stem cell derived-exosomes: A modern approach in translational medicine","volume":"18","author":"Nikfarjam","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s13287-020-01781-w","article-title":"Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis","volume":"11","author":"He","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"180","DOI":"10.7150\/thno.17133","article-title":"Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model","volume":"7","author":"Tao","year":"2017","journal-title":"Theranostics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.7150\/thno.31017","article-title":"Desktop-stereolithography 3D printing of a radially oriented extracellular matrix\/mesenchymal stem cell exosome bioink for osteochondral defect regeneration","volume":"9","author":"Chen","year":"2019","journal-title":"Theranostics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1778883","DOI":"10.1080\/20013078.2020.1778883","article-title":"miR-23a-3p-abundant small extracellular vesicles released from Gelma\/nanoclay hydrogel for cartilage regeneration","volume":"9","author":"Hu","year":"2020","journal-title":"J. Extracell. Vesicles"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1016\/j.bioactmat.2021.01.031","article-title":"Enhancement of acellular cartilage matrix scaffold by Wharton\u2019s jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration","volume":"6","author":"Jiang","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4430","DOI":"10.1039\/C7NR00352H","article-title":"Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration","volume":"9","author":"Liu","year":"2017","journal-title":"Nanoscale"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2217\/nnm-2019-0208","article-title":"Kartogenin enhances the therapeutic effect of bone marrow mesenchymal stem cells derived exosomes in cartilage repair","volume":"15","author":"Liu","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2300315","DOI":"10.1002\/adhm.202300315","article-title":"Treatment with Mesenchymal Stem Cell-Derived Nanovesicle-Containing Gelatin Methacryloyl Hydrogels Alleviates Osteoarthritis by Modulating Chondrogenesis and Macrophage Polarization","volume":"12","author":"Pang","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.actbio.2022.02.026","article-title":"Exosomes derived from hypoxia preconditioned mesenchymal stem cells laden in a silk hydrogel promote cartilage regeneration via the miR-205\u20135p\/PTEN\/AKT pathway","volume":"143","author":"Shen","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.1016\/j.bioactmat.2021.04.031","article-title":"Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis","volume":"6","author":"Tao","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/j.arthro.2020.03.031","article-title":"Intra-Articular Injections of Mesenchymal Stem Cell Exosomes and Hyaluronic Acid Improve Structural and Mechanical Properties of Repaired Cartilage in a Rabbit Model","volume":"36","author":"WWong","year":"2020","journal-title":"Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yan, Z., Yin, H., Wu, J., Tian, G., Li, M., Liao, Z., He, S., Deng, H., Ning, C., and Ding, Z. (2023). Engineering exosomes by three-dimensional porous scaffold culture of human umbilical cord mesenchymal stem cells promote osteochondral repair. Mater. Today Bio, 19.","DOI":"10.1016\/j.mtbio.2023.100549"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, F.-X., Liu, P., Ding, W., Meng, Q.-B., Su, D.-H., Zhang, Q.-C., Lian, R.-X., Yu, B.-Q., Zhao, M.-D., and Dong, J. (2021). Injectable Mussel-Inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials, 278.","DOI":"10.1016\/j.biomaterials.2021.121169"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1177\/03635465211068129","article-title":"Mesenchymal Stem Cell Exosomes Promote Functional Osteochondral Repair in a Clinically Relevant Porcine Model","volume":"50","author":"Zhang","year":"2022","journal-title":"Am. J. Sports Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.3389\/fphar.2019.01368","article-title":"Sustained Delivery System for Stem Cell-Derived Exosomes","volume":"10","author":"Riau","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Li, X., Corbett, A.L., Taatizadeh, E., Tasnim, N., Little, J.P., Garnis, C., Daugaard, M., Guns, E., Hoorfar, M., and Li, I.T.S. (2019). Challenges and opportunities in exosome research\u2014Perspectives from biology, engineering, and cancer therapy. APL Bioeng., 3.","DOI":"10.1063\/1.5087122"},{"key":"ref_27","first-page":"13","article-title":"Osteoarthritis and articular cartilage use, disuse, and abuse: Experimental studies","volume":"43","author":"Buckwalter","year":"1995","journal-title":"J. Rheumatol. Suppl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1177\/036354659702500624","article-title":"Athletics and Osteoarthritis","volume":"25","author":"Buckwalter","year":"1997","journal-title":"Am. J. Sports Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1002\/art.11088","article-title":"Impact of type of meniscal tear on radiographic and symptomatic knee osteoarthritis: A sixteen-year followup of meniscectomy with matched controls","volume":"48","author":"Englund","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.7326\/0003-4819-133-5-200009050-00007","article-title":"Joint injury in young adults and risk for subsequent knee and hip osteoarthritis","volume":"133","author":"Gelber","year":"2000","journal-title":"Ann. Intern. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1097\/01.TA.0000020394.32496.52","article-title":"Traumatic Dislocation and fracture-dislocation of the hip: A long-term follow-up study","volume":"54","author":"Sahin","year":"2003","journal-title":"J. Trauma: Inj. Infect. Crit. Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1177\/03635465221073991","article-title":"Exosomes Derived from Human Urine\u2013Derived Stem Cells Overexpressing miR-140-5p Alleviate Knee Osteoarthritis through Downregulation of VEGFA in a Rat Model","volume":"50","author":"Liu","year":"2022","journal-title":"Am. J. Sports Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.biomaterials.2019.03.022","article-title":"miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis","volume":"206","author":"Wu","year":"2019","journal-title":"Biomaterials"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s13287-018-1004-0","article-title":"Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A","volume":"9","author":"Mao","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fan, W.-J., Liu, D., Pan, L.-Y., Wang, W.-Y., Ding, Y.-L., Zhang, Y.-Y., Ye, R.-X., Zhou, Y., An, S.-B., and Xiao, W.-F. (2022). Exosomes in osteoarthritis: Updated insights on pathogenesis, diagnosis, and treatment. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.949690"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/j.knee.2019.07.017","article-title":"Cartilage regeneration in osteoarthritic knees treated with distal femoral osteotomy and intra-lesional implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells: A report of two cases","volume":"26","author":"Song","year":"2019","journal-title":"Knee"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10584","DOI":"10.1073\/pnas.1709210114","article-title":"Isolation of exosomes from whole blood by integrating acoustics and microfluidics","volume":"114","author":"Wu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23262","DOI":"10.3402\/jev.v3.23262","article-title":"Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation","volume":"3","author":"Yuana","year":"2014","journal-title":"J. Extracell. Vesicles"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e0145686","DOI":"10.1371\/journal.pone.0145686","article-title":"Isolation of Exo-somes from Blood Plasma: Qualitative and Quantitative Comparison of Ultracentrifugation and Size Exclusion Chromatog-raphy Methods","volume":"10","author":"Baranyai","year":"2015","journal-title":"PLoS ONE"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"738","DOI":"10.3389\/fimmu.2018.00738","article-title":"Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression","volume":"9","author":"Willms","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tkach, M., Kowal, J., and Th\u00e9ry, C. (2017). Why the need and how to approach the functional diversity of extracellular vesicles. Philos. Trans. R. Soc. B: Biol. Sci., 373.","DOI":"10.1098\/rstb.2016.0479"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jbiotec.2013.03.013","article-title":"Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection","volume":"165","author":"Takahashi","year":"2013","journal-title":"J. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jconrel.2014.12.013","article-title":"Biodistribution and delivery efficiency of unmodified tumor-derived exosomes","volume":"199","author":"Smyth","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"26316","DOI":"10.3402\/jev.v4.26316","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"4","author":"Wiklander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_45","first-page":"316","article-title":"Cell type-specific and common characteristics of exosomes derived from mouse cell lines: Yield, physicochemical properties, and pharmacokinetics","volume":"96","author":"Charoenviriyakul","year":"2017","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1800948","DOI":"10.1002\/advs.201800948","article-title":"3D Cellular Architecture Affects MicroRNA and Protein Cargo of Extracellular Vesicles","volume":"6","author":"Rocha","year":"2018","journal-title":"Adv. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/s41417-022-00427-8","article-title":"Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy","volume":"29","author":"Sohrabi","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7411","DOI":"10.1016\/j.biomaterials.2011.06.037","article-title":"The knee meniscus: Structure\u2013function, pathophysiology, current repair techniques, and prospects for regeneration","volume":"32","author":"Makris","year":"2011","journal-title":"Biomaterials"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"34924","DOI":"10.1021\/acsami.8b11436","article-title":"Combinatorial Screening of Nanoclay-Reinforced Hydrogels: A Glimpse of the \u201cHoly Grail\u201d in Orthopedic Stem Cell Therapy?","volume":"10","author":"Hasany","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.bioactmat.2022.10.010","article-title":"Enhancing cartilage repair with optimized supramolecular hydrogel-based scaffold and pulsed electromagnetic field","volume":"22","author":"Li","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Song, X., Zhu, C., Fan, D., Mi, Y., Li, X., Fu, R.Z., Duan, Z., Wang, Y., and Feng, R.R. (2017). A Novel Human-Like Collagen Hydrogel Scaffold with Porous Structure and Sponge-Like Properties. Polymers, 9.","DOI":"10.3390\/polym9120638"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1016\/j.jbiomech.2015.08.011","article-title":"Loading-induced changes on topographical distributions of the zonal properties of osteoarthritic tibial cartilage\u2014A study by magnetic resonance imaging at microscopic resolution","volume":"48","author":"Lee","year":"2015","journal-title":"J. Biomech."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.mri.2021.01.002","article-title":"Topographical and zonal patterns of T2 relaxation in osteoarthritic tibial cartilage by low- and high-resolution MRI","volume":"78","author":"Badar","year":"2021","journal-title":"Magn. Reson. Imaging"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.addr.2018.12.015","article-title":"Articular fibrocartilage\u2014Why does hyaline cartilage fail to repair?","volume":"146","author":"Armiento","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:06:57Z","timestamp":1760130417000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,14]]},"references-count":55,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015178"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015178","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,14]]}}}