簡易檢索 / 詳目顯示

回結果列表
研究生： 劉原輔
LIU, YUAN FU
論文名稱： 手術感染預防與椎間盤分子退化的橋樑：血小板反應蛋白-1在痤瘡丙酸桿菌誘發椎間盤病變中的介導機制
Bridging Surgical Infection Prevention and Molecular Disc Degeneration: Thrombospondin-1 as a Mediator of Cutibacterium acnes-Induced Intervertebral Disc Pathology
指導教授： 涂庭源
Tu, Ting-Yuan
學位類別： 博士
Doctor
系所名稱： 工學院 - 生物醫學工程學系
Department of BioMedical Engineering
論文出版年： 2026
畢業學年度： 114
語文別： 英文
論文頁數： 112
中文關鍵詞： 術後脊椎感染 、痤瘡丙酸桿菌 、血小板反應蛋白-1 、椎間盤退化 、葡萄糖酸氯己定 、髓核細胞 、氧化壓力
外文關鍵詞： Postoperative spinal infection, Cutibacterium acnes, Thrombospondin-1, Intervertebral disc degeneration, Chlorhexidine gluconate, Nucleus pulposus cells, Oxidative stress
相關次數： 點閱：5  下載：0 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 研究背景：術後脊椎感染是脊椎手術的嚴重併發症，發生率介於0.6%至18%之間。痤瘡丙酸桿菌（Cutibacterium acnes）作為主要低毒性致病菌，不僅可導致慢性手術部位感染，且因其能在低氧環境中存活、抵抗吞噬及分泌促炎性與基質降解因子，日益被認為與椎間盤退化密切相關。血小板反應蛋白-1（TSP-1）是一種參與組織重塑、氧化壓力調控及炎症信號傳遞的基質細胞蛋白，被認為可能作為連結細菌污染與椎間盤病變的關鍵分子介質，然而其在感染相關椎間盤退化中的具體作用機制尚未被闡明。目前，有效的術中抗菌灌洗策略仍未被充分確立，手術污染通過何種分子途徑導致長期椎間盤退化亦未能清楚界定。
    研究方法：本研究採用臨床試驗結合基礎實驗的雙部分設計。第一部分為前瞻性、單盲隨機對照臨床試驗（臨床試驗登錄號：NCT06284174），納入105例接受腰椎側/後路椎間融合術之患者，以1:1:1比例隨機分配至術中灌洗三組：生理鹽水組（NS，n=35）、3.5%聚維酮碘組（PVP-I，n=35）及0.05%葡萄糖酸氯己定組（CHG，n=35）。術中分別於淺表組織、深部組織及植入物表面採集細菌拭子樣本，灌洗前後各一次，以培養及16S rRNA基因定序進行菌種鑑定。第二部分採用原代人類髓核細胞探討C. acnes誘發椎間盤退化的分子機制，以不同濃度（10%、15%、20%）之C. acnes培養基處理細胞，並施用抗TSP-1中和抗體進行干預，透過Western blot、免疫組織化學染色、ROS偵測及蛋白質組學分析，系統評估TSP-1/CD47信號軸的激活、氧化壓力標誌物、纖維化重塑標誌物、炎症細胞因子及細胞衰老標誌物之變化。
    研究結果：第一部分結果顯示，灌洗前淺表、深部及植入物部位的細菌培養陽性率分別為49.5%、31.4%及32.4%。NS灌洗對各部位細菌污染無顯著改善效果。PVP-I僅在淺表部位達到顯著細菌減少效果（減少55.0%；p = 0.015），對深部組織及植入物表面則未見顯著效果。CHG展現最優越的去污染效能，使淺表部位細菌污染減少94.1%（p < 0.0001）、植入物表面細菌污染減少88.9%（p = 0.02），且上述差異在調整基線污染狀態後（ANCOVA分析）仍持續存在。術後手術部位感染率各組之間無顯著差異（NS：1例，PVP-I：0例，CHG：1例；p = 0.72）。所有患者於六個月隨訪時ODI功能評分均顯著改善，無神經功能惡化或再手術病例。第二部分結果顯示，TSP-1及CD47蛋白表達在退化性椎間盤組織中較非退化性對照組顯著上調（均p < 0.01）。痤瘡丙酸桿菌培養液（CACM）以濃度依賴方式誘導TSP-1上調（10%：p < 0.01；15%：p < 0.01；20%：p < 0.001），並同步激活CD47（p < 0.001）及NOX1（p < 0.001），確認TSP-1–CD47–NOX1信號軸的協同激活。抗TSP-1中和抗體顯著減弱CACM誘導的NOX1上調（p < 0.01）、胞內超氧化物生成（p < 0.01）、H₂O₂（p < 0.01）及MDA水平（p < 0.05），並顯著恢復GPX、GSH及SOD抗氧化酶活性（均p < 0.05）。抗TSP-1治療亦顯著抑制CACM誘導的Collagen-I（p < 0.05）、Collagen-III（p < 0.01）及TGF-β（p < 0.01）上調，並降低NF-κB p65磷酸化（p < 0.05）。CACM蛋白質組學分析共鑑定出182種源自痤瘡丙酸桿菌的蛋白質，包含代謝酶、CAMP因子、透明質酸裂解酶及表面黏附素，為CACM驅動TSP-1介導退化信號的機制提供了重要線索。
    結論：CHG灌洗在腰椎後路融合術中展現優於PVP-I及NS的術中去污染效能，支持其作為可行的術中抗菌灌洗策略。本研究證實TSP-1是痤瘡丙酸桿菌誘發椎間盤退化的核心分子介質，通過TSP-1–CD47–NOX1信號軸驅動髓核細胞的氧化壓力、纖維化重塑及炎症反應。上述發現為手術細菌污染導致長期椎間盤病變提供了完整的分子機制框架，並確立TSP-1為預防感染相關椎間盤退化的潛在治療靶點。

    Background: Postoperative spinal infections (PSIs) are serious complications of spine surgery, with reported incidence rates ranging from 0.6% to 18%. Cutibacterium acnes, a prevalent low-virulence pathogen, is increasingly implicated not only in chronic surgical site infections but also in accelerating intervertebral disc (IVD) degeneration through persistent colonization and secretion of proinflammatory and matrix-degrading factors. Thrombospondin-1 (TSP-1), a matricellular protein involved in tissue remodeling, oxidative stress regulation, and inflammatory signaling, has been proposed as a potential molecular mediator linking bacterial contamination to disc pathology; however, its mechanistic role in infection-associated disc degeneration has not been established. Effective intraoperative antiseptic strategies to minimize bacterial contamination remain incompletely defined, and the molecular pathways connecting surgical contamination to long-term disc degeneration are poorly understood.
    Methods: This study employed a two-part design integrating clinical investigation with in vitro mechanistic research. Part I was a prospective, single-blinded, randomized controlled trial ( ClinicalTrials.gov: NCT06284174) enrolling 105 patients undergoing posterior lumbar interbody fusion surgery, randomized 1:1:1 to intraoperative irrigation with normal saline (NS, n = 35), 3.5% povidone-iodine (PVP-I, n = 35), or 0.05% chlorhexidine gluconate (CHG, n = 35). Bacterial swab samples were collected intraoperatively from three anatomical zones — superficial tissue, deep tissue, and implant surfaces — before and after irrigation, with species identification by culture and 16S rRNA gene sequencing. Part II investigated the molecular mechanisms of C. acnes-induced disc degeneration using primary human nucleus pulposus (NP) cells. Cells were treated with C. acnes conditioned medium (CACM) at concentrations of 10%, 15%, and 20%, with or without anti-TSP-1 neutralizing antibody. Outcomes assessed included TSP-1 and CD47 protein expression (Western blot, immunohistochemistry), oxidative stress markers (NOX1, ROS, DHE fluorescence, H₂O₂, MDA, antioxidant enzyme activities), fibrotic remodeling markers (Collagen-I, Collagen-III, TGF-β), inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB p65 phosphorylation), and cellular senescence markers (SA-β-gal, Lamin B1, p21). Proteomic characterization of CACM was performed by mass spectrometry.
    Results: In Part I, prior to irrigation, overall bacterial culture-positive rates were 49.5%, 31.4%, and 32.4% at the superficial, deep, and implant sites, respectively. NS irrigation produced no significant reduction in bacterial contamination across all sites. PVP-I achieved a significant reduction only at the superficial site (55.0% reduction; p = 0.015) but failed to significantly reduce contamination in the deep tissue or on implant surfaces. CHG demonstrated the most robust decontamination efficacy, achieving a 94.1% reduction in superficial bacterial contamination (p < 0.0001) and an 88.9% reduction on implant surfaces (p = 0.02). These differences persisted after ANCOVA adjustment for baseline contamination. Clinical postoperative SSI rates were low and did not differ significantly between groups (NS: 1 case, PVP-I: 0 cases, CHG: 1 case; p = 0.72). All patients demonstrated significant functional improvement by ODI scores at six-month follow-up, with no neurological complications or reoperations. In Part II, TSP-1 and CD47 protein expression were significantly elevated in human degenerative IVD tissue compared to non-degenerative controls (both p < 0.01). In the aged NP cell model (serial passaging), TSP-1 and CD47 were upregulated (p < 0.05) while Collagen-II expression declined (p < 0.05), confirming activation of the TSP-1/CD47 signaling axis under senescent conditions. CACM treatment induced dose-dependent TSP-1 upregulation at 10% (p < 0.01), 15% (p < 0.01), and 20% (p < 0.001) concentrations, with concurrent significant elevation of CD47 (p < 0.001) and NOX1 (p < 0.001), demonstrating coordinated activation of the TSP-1–CD47–NOX1 signaling axis. TSP-1 neutralization by anti-TSP-1 antibody significantly attenuated CACM-induced NOX1 upregulation (p < 0.01), reduced intracellular superoxide generation (p < 0.01), decreased H₂O₂ (p < 0.01) and MDA levels (p < 0.05), and restored GPX, GSH, and SOD antioxidant activities (all p < 0.05). Anti-TSP-1 treatment also significantly suppressed CACM-induced upregulation of Collagen-I (p < 0.05), Collagen-III (p < 0.01), and TGF-β (p < 0.01), indicating attenuation of fibrotic remodeling. CACM significantly elevated IL-1β (p < 0.05), IL-6 (p < 0.01), and TNF-α (p < 0.01), and anti-TSP-1 treatment significantly reduced NF-κB p65 phosphorylation (p < 0.05), partially attenuating the inflammatory response. Proteomic analysis of 20% CACM identified 182 C. acnes-derived proteins, including glycolytic moonlighting enzymes, CAMP factors, hyaluronate lyase HylA, and surface adhesins, providing mechanistic insight into the bacterial factors driving TSP-1-mediated degenerative signaling.
    Conclusions: CHG irrigation demonstrates superior intraoperative decontamination efficacy compared to PVP-I and NS in posterior lumbar fusion surgery, supporting its adoption as a preferred antiseptic irrigation strategy. This study establishes TSP-1 as an important molecular mediator of C. acnes-induced IVD degeneration, acting through the TSP-1–CD47–NOX1 signaling axis to drive oxidative stress, fibrotic remodeling, and inflammatory cascades in nucleus pulposus cells. These findings provide a mechanistic framework linking surgical bacterial contamination to long-term disc pathology and identify TSP-1 as a potential therapeutic target for preventing infection-associated IVD degeneration.

    ABSTRACT (CHINESE) I ABSTRACT (ENGLISH) IV LIST OF FIGURES XIV LIST OF TABLES XV LIST OF ABBREVIATIONS XVI CHAPTER 1. INTRODUCTION 1 1.1 Background 1 1.1.1 Postoperative Spinal Infection 1 1.1.2 Epidemiology 2 1.1.3 Diagnosis 3 1.1.4 Treatment 4 1.1.5 Prevention Strategies 6 1.1.6 Consequences of Bacterial Inoculation Following Spine Surgery 10 1.1.7 Pathogenic Mechanisms of Cutibacterium acnes in Intervertebral Disc Degeneration 10 1.2 Objectives and Scope 14 CHAPTER 2. MATERIALS AND METHODS 16 Part I: Clinical Study — Intraoperative Antiseptic Irrigation in Spinal Fusion Surgery 16 2.1.1 Study Design 16 2.1.2 Patient Selection 16 2.1.3 Inclusion and Exclusion Criteria 17 2.1.4 Randomization and Blinding 17 2.1.5 Sample Size Estimation 18 2.1.6 Surgical Protocol and Interventions 19 2.1.7 Sample Collection and Microbiological Assessment 20 2.1.8 Postoperative Care and Surveillance 22 2.1.9 Microbiological Culture Procedures 22 2.1.10 16S rRNA Gene Sequencing 23 2.1.11 Statistical Analysis 24 Part II: Investigating C. acnes-Induced TSP1 Expression and Downstream Degenerative Signaling 25 2.2.1 Bacterial Strains and Culture Conditions 25 2.2.2 Cutibacterium acnes Conditioned Medium (CACM) 25 2.2.3 Human Tissue Collection and Processing 26 2.2.4 Primary Human NP Cell Isolation and Culture 27 2.2.5 Establishment of NP Cell Aging Model 27 2.2.6 Experimental Treatment Design 28 2.2.7 Molecular and Cellular Analysis 28 2.2.8 ROS Assay 29 2.2.9 Histological Analysis 30 2.2.10 Proteomic Analysis of Cutibacterium acnes Conditioned Medium 31 2.2.11 Statistical Analysis 32 CHAPTER 3. RESULTS 33 3.1 Part I Result 33 3.1.1 Identified Microbial Organisms 34 3.1.2 Effectiveness of Different Rinsing Agents 35 3.1.3 Clinical Results and Complications 38 3.2 Part II Result 38 3.2.1 Elevated TSP-1 and CD47 Expression in Degenerative Intervertebral Disc Tissue 38 3.2.2 Establishment of an NP Cell Degenerative Model Through Serial Passaging 41 3.2.3 C. acnes Conditioned Medium Induces TSP1 Expression via the TSP1–CD47 Signaling Axis in NP Cells 44 3.2.4 TSP-1 Mediates C. acnes-Induced Oxidative Stress in Nucleus Pulposus Cells 47 3.2.5 Anti-TSP-1 Treatment Attenuates C. acnes-Induced Degenerative and Fibrotic Signaling 51 3.2.6 Anti-TSP-1 Treatment Reduces C. acnes-Induced Inflammatory Response 54 3.2.7 Proteomic and Transcriptomic Characterization of C. acnes Conditioned Medium 57 CHAPTER 4. DISCUSSION 61 4.1.1 Intraoperative Bacterial Contamination in Lumbar Fusion Surgery 61 4.1.2 Limited Antimicrobial Effect of Povidone-Iodine Irrigation 61 4.1.3 Efficacy and Safety of Chlorhexidine Irrigation in Spine Surgery 62 4.1.4 Microbial Profile of Intraoperative Contamination 63 4.1.5 TSP1 as a Molecular Link Between Bacterial Exposure and Disc Degeneration 63 4.1.6 TSP1-CD47 Signaling Pathway as a Central Mediator of Disc Degeneration 64 4.1.7 Oxidative Stress as a Key Mechanistic Link 65 4.1.8 Inflammatory Cascade Amplification Through TSP1 66 4.1.9 Matrix Degradation and Fibrotic Remodeling 67 4.1.10 Dose-Dependent Response and Clinical Translation 68 4.1.11 Comparison with Existing Therapeutic Strategies 71 4.2 Limitations 72 4.3 Translational Impact and Clinical Applications 74 4.3.1 Improved Surgical Protocols 74 4.3.2 Risk Stratification 75 4.3.3 Therapeutic Target Development 75 4.3.4 Adjacent Segment Disease Prevention 75 4.4 Future Directions and Research Perspectives 75 4.4.1 Translation to Clinical Practice 76 4.4.2 Mechanistic Validation in Preclinical Models 76 4.4.3 Biomarker Development and Risk Stratification 76 4.4.4 Therapeutic Target Development 77 4.4.5 Expanded Microbiological Investigations 77 4.4.6 Cellular Senescence Interventions 78 4.4.7 Longitudinal Natural History Studies 78 CHAPTER 5. CONCLUSION 79 CHAPTER 6. REFERENCES 80

    1. Yao R, Zhou H, Choma TJ, Kwon BK, Street J. Surgical Site Infection in Spine Surgery: Who Is at Risk? Global Spine J. 2018;8(4 Suppl):5S-30S.
    2. Blam OG, Vaccaro AR, Vanichkachorn JS, et al. Risk factors for surgical site infection in the patient with spinal injury. Spine (Phila Pa 1976). 2003;28(13):1475-80.
    3. Cahill PJ, Warnick DE, Lee MJ, et al. Infection after spinal fusion for pediatric spinal deformity: thirty years of experience at a single institution. Spine (Phila Pa 1976). 2010;35(12):1211-7.
    4. Sasso RC, Garrido BJ. Postoperative spinal wound infections. J Am Acad Orthop Surg. 2008;16(6):330-7.
    5. Guarch-Perez C, Riool M, de Boer L, Kloen P, Zaat SAJ. Bacterial reservoir in deeper skin is a potential source for surgical site and biomaterial-associated infections. J Hosp Infect. 2023;140:62-71.
    6. Baroudi M, Daher M, Parks RD, et al. Cutibacterium acnes in spine surgery: pathophysiology, diagnosis, and treatment. Spine J. 2024;24(9):1545-52.
    7. Rajasekaran S, Tangavel C, Aiyer SN, et al. ISSLS PRIZE IN CLINICAL SCIENCE 2017: Is infection the possible initiator of disc disease? An insight from proteomic analysis. Eur Spine J. 2017;26(5):1384-400.
    8. Atesok K, Papavassiliou E, Heffernan MJ, et al. Current Strategies in Prevention of Postoperative Infections in Spine Surgery. Global Spine J. 2020;10(2):183-94.
    9. Dowdell J, Brochin R, Kim J, et al. Postoperative Spine Infection: Diagnosis and Management. Global Spine J. 2018;8(4 Suppl):37S-43S.
    10. Weinstein MA, McCabe JP, Cammisa FP, Jr. Postoperative spinal wound infection: a review of 2,391 consecutive index procedures. J Spinal Disord. 2000;13(5):422-6.
    11. Pull ter Gunne AF, Cohen DB. Incidence, prevalence, and analysis of risk factors for surgical site infection following adult spinal surgery. Spine (Phila Pa 1976). 2009;34(13):1422-8.
    12. Fang A, Hu SS, Endres N, Bradford DS. Risk factors for infection after spinal surgery. Spine (Phila Pa 1976). 2005;30(12):1460-5.
    13. Veeravagu A, Patil CG, Lad SP, Boakye M. Risk factors for postoperative spinal wound infections after spinal decompression and fusion surgeries. Spine (Phila Pa 1976). 2009;34(17):1869-72.
    14. Smith JS, Shaffrey CI, Sansur CA, et al. Rates of infection after spine surgery based on 108,419 procedures: a report from the Scoliosis Research Society Morbidity and Mortality Committee. Spine (Phila Pa 1976). 2011;36(7):556-63.
    15. Kreitz TM, Mangan J, Schroeder GD, et al. Do Preoperative Epidural Steroid Injections Increase the Risk of Infection After Lumbar Spine Surgery? Spine (Phila Pa 1976). 2021;46(3):E197-E202.
    16. Long DR, Bryson-Cahn C, Pergamit R, et al. 2021 Young Investigator Award Winner: Anatomic Gradients in the Microbiology of Spinal Fusion Surgical Site Infection and Resistance to Surgical Antimicrobial Prophylaxis. Spine (Phila Pa 1976). 2021;46(3):143-51.
    17. Laratta JL, Shillingford JN, Hardy N, et al. Intrawound Tobramycin Powder Eradicates Surgical Wound Contamination: An In Vivo Rabbit Study. Spine (Phila Pa 1976). 2017;42(24):E1393-E7.
    18. Ostermann PA, Seligson D, Henry SL. Local antibiotic therapy for severe open fractures. A review of 1085 consecutive cases. J Bone Joint Surg Br. 1995;77(1):93-7.
    19. Mok JM, Pekmezci M, Piper SL, et al. Use of C-reactive protein after spinal surgery: comparison with erythrocyte sedimentation rate as predictor of early postoperative infectious complications. Spine (Phila Pa 1976). 2008;33(4):415-21.
    20. Herrera Herrera I, Moreno de la Presa R, Gonzalez Gutierrez R, Barcena Ruiz E, Garcia Benassi JM. Evaluation of the postoperative lumbar spine. Radiologia. 2013;55(1):12-23.
    21. Hedequist D, Haugen A, Hresko T, Emans J. Failure of attempted implant retention in spinal deformity delayed surgical site infections. Spine (Phila Pa 1976). 2009;34(1):60-4.
    22. Lall RR, Wong AP, Lall RR, Lawton CD, Smith ZA, Dahdaleh NS. Evidence-based management of deep wound infection after spinal instrumentation. J Clin Neurosci. 2015;22(2):238-42.
    23. Canavese F, Gupta S, Krajbich JI, Emara KM. Vacuum-assisted closure for deep infection after spinal instrumentation for scoliosis. J Bone Joint Surg Br. 2008;90(3):377-81.
    24. Kowalski TJ, Berbari EF, Huddleston PM, Steckelberg JM, Mandrekar JN, Osmon DR. The management and outcome of spinal implant infections: contemporary retrospective cohort study. Clin Infect Dis. 2007;44(7):913-20.
    25. Nunez-Pereira S, Pellise F, Rodriguez-Pardo D, et al. Implant survival after deep infection of an instrumented spinal fusion. Bone Joint J. 2013;95-B(8):1121-6.
    26. Agarwal A, Kelkar A, Agarwal AG, et al. Implant Retention or Removal for Management of Surgical Site Infection After Spinal Surgery. Global Spine J. 2020;10(5):640-6.
    27. Di Silvestre M, Bakaloudis G, Lolli F, Giacomini S. Late-developing infection following posterior fusion for adolescent idiopathic scoliosis. Eur Spine J. 2011;20 Suppl 1(Suppl 1):S121-7.
    28. Ha KY, Kim YH. Postoperative spondylitis after posterior lumbar interbody fusion using cages. Eur Spine J. 2004;13(5):419-24.
    29. Ahmed R, Greenlee JD, Traynelis VC. Preservation of spinal instrumentation after development of postoperative bacterial infections in patients undergoing spinal arthrodesis. J Spinal Disord Tech. 2012;25(6):299-302.
    30. Takizawa T, Tsutsumimoto T, Yui M, Misawa H. Surgical Site Infections Caused by Methicillin-resistant Staphylococcus epidermidis After Spinal Instrumentation Surgery. Spine (Phila Pa 1976). 2017;42(7):525-30.
    31. Vitale MG, Riedel MD, Glotzbecker MP, et al. Building consensus: development of a Best Practice Guideline (BPG) for surgical site infection (SSI) prevention in high-risk pediatric spine surgery. J Pediatr Orthop. 2013;33(5):471-8.
    32. Pull ter Gunne AF, van Laarhoven CJ, Cohen DB. Incidence of surgical site infection following adult spinal deformity surgery: an analysis of patient risk. Eur Spine J. 2010;19(6):982-8.
    33. Cancienne JM, Werner BC, Chen DQ, Hassanzadeh H, Shimer AL. Perioperative hemoglobin A1c as a predictor of deep infection following single-level lumbar decompression in patients with diabetes. Spine J. 2017;17(8):1100-5.
    34. Webster J, Osborne S. Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. Cochrane Database Syst Rev. 2015;2015(2):CD004985.
    35. Ning J, Wang J, Zhang S, Sha X. Nasal colonization of Staphylococcus aureus and the risk of surgical site infection after spine surgery: a meta-analysis. Spine J. 2020;20(3):448-56.
    36. Bible JE, Biswas D, Whang PG, Simpson AK, Grauer JN. Which regions of the operating gown should be considered most sterile? Clin Orthop Relat Res. 2009;467(3):825-30.
    37. Bible JE, O'Neill KR, Crosby CG, Schoenecker JG, McGirt MJ, Devin CJ. Microscope sterility during spine surgery. Spine (Phila Pa 1976). 2012;37(7):623-7.
    38. Ilibman Arzi Y, Assous MV, Livnat K, Yinnon AM, Wiener-Well Y. Bacterial contamination of surgical scrubs in the operating theater. Am J Infect Control. 2020;48(1):56-60.
    39. Rozzelle CJ, Leonardo J, Li V. Antimicrobial suture wound closure for cerebrospinal fluid shunt surgery: a prospective, double-blinded, randomized controlled trial. J Neurosurg Pediatr. 2008;2(2):111-7.
    40. Sweet FA, Roh M, Sliva C. Intrawound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: efficacy, drug levels, and patient outcomes. Spine (Phila Pa 1976). 2011;36(24):2084-8.
    41. Pahys JM, Pahys JR, Cho SK, et al. Methods to decrease postoperative infections following posterior cervical spine surgery. J Bone Joint Surg Am. 2013;95(6):549-54.
    42. Zebala LP, Chuntarapas T, Kelly MP, Talcott M, Greco S, Riew KD. Intrawound vancomycin powder eradicates surgical wound contamination: an in vivo rabbit study. J Bone Joint Surg Am. 2014;96(1):46-51.
    43. Theologis AA, Demirkiran G, Callahan M, Pekmezci M, Ames C, Deviren V. Local intrawound vancomycin powder decreases the risk of surgical site infections in complex adult deformity reconstruction: a cost analysis. Spine (Phila Pa 1976). 2014;39(22):1875-80.
    44. Tubaki VR, Rajasekaran S, Shetty AP. Effects of using intravenous antibiotic only versus local intrawound vancomycin antibiotic powder application in addition to intravenous antibiotics on postoperative infection in spine surgery in 907 patients. Spine (Phila Pa 1976). 2013;38(25):2149-55.
    45. Naylor RM, Gilder HE, Gupta N, et al. Effects of Negative Pressure Wound Therapy on Wound Dehiscence and Surgical Site Infection Following Instrumented Spinal Fusion Surgery-A Single Surgeon's Experience. World Neurosurg. 2020;137:e257-e62.
    46. Mueller KB, D'Antuono M, Patel N, et al. Effect of Incisional Negative Pressure Wound Therapy vs Standard Wound Dressing on the Development of Surgical Site Infection after Spinal Surgery: A Prospective Observational Study. Neurosurgery. 2021;88(5):E445-E51.
    47. Torres KA, Konrade E, White J, et al. Irrigation techniques used in spine surgery for surgical site infection prophylaxis: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2022;23(1):813.
    48. Edmiston CE, Jr., Spencer M, Leaper D. Antiseptic Irrigation as an Effective Interventional Strategy for Reducing the Risk of Surgical Site Infections. Surg Infect (Larchmt). 2018;19(8):774-80.
    49. Cheng MT, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Efficacy of dilute betadine solution irrigation in the prevention of postoperative infection of spinal surgery. Spine (Phila Pa 1976). 2005;30(15):1689-93.
    50. Chang FY, Chang MC, Wang ST, Yu WK, Liu CL, Chen TH. Can povidone-iodine solution be used safely in a spinal surgery? Eur Spine J. 2006;15(6):1005-14.
    51. Edmiston CE, Jr., Bruden B, Rucinski MC, Henen C, Graham MB, Lewis BL. Reducing the risk of surgical site infections: does chlorhexidine gluconate provide a risk reduction benefit? Am J Infect Control. 2013;41(5 Suppl):S49-55.
    52. Frisch NB, Kadri OM, Tenbrunsel T, Abdul-Hak A, Qatu M, Davis JJ. Intraoperative chlorhexidine irrigation to prevent infection in total hip and knee arthroplasty. Arthroplast Today. 2017;3(4):294-7.
    53. Mueller TC, Loos M, Haller B, et al. Intra-operative wound irrigation to reduce surgical site infections after abdominal surgery: a systematic review and meta-analysis. Langenbecks Arch Surg. 2015;400(2):167-81.
    54. Parchi PD, Evangelisti G, Andreani L, et al. Postoperative Spine Infections. Orthop Rev (Pavia). 2015;7(3):5900.
    55. Rajasekaran S, Tangavel C, Vasudevan G, et al. Bacteria in human lumbar discs - subclinical infection or contamination? Metabolomic evidence for colonization, multiplication, and cell-cell cross-talk of bacteria. Spine J. 2023;23(1):163-77.
    56. Aldahamsheh O, Burger LD, Evaniew N, et al. Unexpected intraoperative positive culture (UIPC) in presumed aseptic revision spine surgery: a systematic review and meta-analysis. Spine J. 2023;23(4):492-503.
    57. He D, Zhou M, Bai Z, Wen Y, Shen J, Hu Z. Propionibacterium acnes induces intervertebral disc degeneration by promoting nucleus pulposus cell pyroptosis via NLRP3-dependent pathway. Biochem Biophys Res Commun. 2020;526(3):772-9.
    58. Chen ZH, Jin SH, Wang MY, et al. Enhanced NLRP3, caspase-1, and IL- 1beta levels in degenerate human intervertebral disc and their association with the grades of disc degeneration. Anat Rec (Hoboken). 2015;298(4):720-6.
    59. Lin Y, Tang G, Jiao Y, et al. Propionibacterium acnes Induces Intervertebral Disc Degeneration by Promoting iNOS/NO and COX-2/PGE(2) Activation via the ROS-Dependent NF-kappaB Pathway. Oxid Med Cell Longev. 2018;2018:3692752.
    60. Choi JY, Piao MS, Lee JB, Oh JS, Kim IG, Lee SC. Propionibacterium acnes stimulates pro-matrix metalloproteinase-2 expression through tumor necrosis factor-alpha in human dermal fibroblasts. J Invest Dermatol. 2008;128(4):846-54.
    61. Xiong C, Huang B, Cun Y, Aghdasi BG, Zhou Y. Migration inhibitory factor enhances inflammation via CD74 in cartilage end plates with Modic type 1 changes on MRI. Clin Orthop Relat Res. 2014;472(6):1943-54.
    62. Yang W, Xu Y, Tan Y, et al. Molecular Mechanisms of Intervertebral Disc Degeneration Induced by Propionibacterium acnes. Biomed Res Int. 2025;2025:5513856.
    63. Gutierrez LS, Gutierrez J. Thrombospondin 1 in Metabolic Diseases. Front Endocrinol (Lausanne). 2021;12:638536.
    64. Taraboletti G, Roberts DD, Liotta LA. Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains. J Cell Biol. 1987;105(5):2409-15.
    65. Csanyi G, Yao M, Rodriguez AI, et al. Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1. Arterioscler Thromb Vasc Biol. 2012;32(12):2966-73.
    66. Adams JC, Lawler J. The thrombospondins. Cold Spring Harb Perspect Biol. 2011;3(10):a009712.
    67. Chistiakov DA, Melnichenko AA, Myasoedova VA, Grechko AV, Orekhov AN. Thrombospondins: A Role in Cardiovascular Disease. Int J Mol Sci. 2017;18(7).
    68. Bai D, Zhou F, Wu L. Comparing the efficacy of chlorhexidine and povidone-iodine in preventing surgical site infections: A systematic review and meta-analysis. Int Wound J. 2023;21(2).
    69. Mangold T, Hamilton EK, Johnson HB, Perez R. Standardising intraoperative irrigation with 0.05% chlorhexidine gluconate in caesarean delivery to reduce surgical site infections: A single institution experience. J Perioper Pract. 2020;30(1-2):24-33.
    70. Kaliaperumal C, Kuechler D, Kaar G, Marks C, O'Sullivan M. Does surgical technique affect the incidence of spondylodiscitis post-lumbar microdiscectomy? A retrospective analysis of 3063 patients. Spine (Phila Pa 1976). 2013;38(4):364-7.
    71. Coscia MF, Denys GA, Wack MF. Propionibacterium acnes, Coagulase-Negative Staphylococcus, and the "Biofilm-like" Intervertebral Disc. Spine (Phila Pa 1976). 2016;41(24):1860-5.
    72. Sviggum HP, Jacob AK, Arendt KW, Mauermann ML, Horlocker TT, Hebl JR. Neurologic complications after chlorhexidine antisepsis for spinal anesthesia. Reg Anesth Pain Med. 2012;37(2):139-44.
    73. Hong CK, Hsu KL, Kuan FC, et al. Extended skin cleaning on the shoulder with chlorhexidine reduces the cutaneous bacterial load but fails to decrease suture contamination in patients undergoing arthroscopy rotator cuff repair. J Shoulder Elbow Surg. 2023;32(4):744-50.
    74. Silwal P, Nguyen-Thai AM, Mohammad HA, et al. Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities. Biomolecules. 2023;13(4).
    75. Yuan B, Ji W, Fan B, Zhang B, Zhao Y, Li J. Association analysis between thrombospondin-2 gene polymorphisms and intervertebral disc degeneration in a Chinese Han population. Medicine (Baltimore). 2018;97(2):e9586.
    76. Kalb S, Martirosyan NL, Kalani MY, Broc GG, Theodore N. Genetics of the degenerated intervertebral disc. World Neurosurg. 2012;77(3-4):491-501.
    77. Collin EC, Carroll O, Kilcoyne M, et al. Ageing affects chondroitin sulfates and their synthetic enzymes in the intervertebral disc. Signal Transduct Target Ther. 2017;2:17049.
    78. Illien-Junger S, Gantenbein-Ritter B, Grad S, et al. The combined effects of limited nutrition and high-frequency loading on intervertebral discs with endplates. Spine (Phila Pa 1976). 2010;35(19):1744-52.
    79. Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech. 2011;4(1):31-41.
    80. Isenberg JS, Roberts DD. Thrombospondin-1 in maladaptive aging responses: a concept whose time has come. Am J Physiol Cell Physiol. 2020;319(1):C45-C63.
    81. Gao Q, Chen K, Gao L, Zheng Y, Yang YG. Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells. Cell Death Dis. 2016;7(9):e2368.
    82. Vanhoutte D, Schips TG, Minerath RA, et al. Thbs1 regulates skeletal muscle mass in a TGFbeta-Smad2/3-ATF4-dependent manner. Cell Rep. 2024;43(5):114149.
    83. Isenberg JS, Ridnour LA, Perruccio EM, Espey MG, Wink DA, Roberts DD. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A. 2005;102(37):13141-6.
    84. Zhao W, Shen B, Cheng Q, Zhou Y, Chen K. Roles of TSP1-CD47 signaling pathway in senescence of endothelial cells: cell cycle, inflammation and metabolism. Mol Biol Rep. 2023;50(5):4579-85.
    85. Soto-Pantoja DR, Kaur S, Roberts DD. CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol. 2015;50(3):212-30.
    86. Rogers NM, Sharifi-Sanjani M, Csanyi G, Pagano PJ, Isenberg JS. Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease. Matrix Biol. 2014;37:92-101.
    87. Wang F, Cai F, Shi R, Wang XH, Wu XT. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage. 2016;24(3):398-408.
    88. Clouet J, Fusellier M, Camus A, Le Visage C, Guicheux J. Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Adv Drug Deliv Rev. 2019;146:306-24.
    89. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44-56.
    90. Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther. 2005;7(4):R732-45.
    91. Saito Y, Yamamoto S, Chikenji TS. Role of cellular senescence in inflammation and regeneration. Inflamm Regen. 2024;44(1):28.
    92. Murphy-Ullrich JE, Suto MJ. Thrombospondin-1 regulation of latent TGF-beta activation: A therapeutic target for fibrotic disease. Matrix Biol. 2018;68-69:28-43.
    93. Kaur S, Soto-Pantoja DR, Stein EV, et al. Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci Rep. 2013;3:1673.
    94. Inoue N, Espinoza Orias AA. Biomechanics of intervertebral disk degeneration. Orthop Clin North Am. 2011;42(4):487-99, vii.
    95. Huang X, Cai Y, Chen K, et al. Risk factors and treatment strategies for adjacent segment disease following spinal fusion (Review). Mol Med Rep. 2025;31(2).
    96. Lotz JC, Ulrich JA. Innervation, inflammation, and hypermobility may characterize pathologic disc degeneration: review of animal model data. J Bone Joint Surg Am. 2006;88 Suppl 2:76-82.
    97. Crawford SE, Stellmach V, Murphy-Ullrich JE, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998;93(7):1159-70.
    98. Vo NV, Hartman RA, Yurube T, Jacobs LJ, Sowa GA, Kang JD. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. Spine J. 2013;13(3):331-41.
    99. Liu D, Bhunia AK. Anchorless Bacterial Moonlighting Metabolic Enzymes Modulate the Immune System and Contribute to Pathogenesis. ACS Infect Dis. 2024;10(8):2551-66.
    100. Nakatsuji T, Tang DC, Zhang L, Gallo RL, Huang CM. Propionibacterium acnes CAMP factor and host acid sphingomyelinase contribute to bacterial virulence: potential targets for inflammatory acne treatment. PLoS One. 2011;6(4):e14797.
    101. Chen Q, Liu C, Tao J, et al. Insights into microbial dysbiosis and Cutibacterium acnes CAMP factor interactions in acne vulgaris. Microb Genom. 2025;11(7).
    102. Hajam IA, Katiki M, McNally R, et al. Functional divergence of a bacterial enzyme promotes healthy or acneic skin. Nat Commun. 2023;14(1):8061.
    103. Kaneda G, Zila L, Wechsler JT, et al. What a pain in the back: etiology, diagnosis and future treatment directions for discogenic low back pain. Bone Res. 2025;13(1):89.
    104. Ogaili RH, Alassal A, Za'aba NF, Zulkiflee I, Mohd Isa IL. Regenerative strategies for intervertebral disc degeneration. J Orthop Translat. 2025;53:286-308.
    105. Mai Y, Wu S, Zhang P, Chen N, Wu J, Wei F. The anti-oxidation related bioactive materials for intervertebral disc degeneration regeneration and repair. Bioact Mater. 2025;45:19-40.
    106. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-36.
    107. Shao Z, Wang B, Shi Y, et al. Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-kappaB axis. Osteoarthritis Cartilage. 2021;29(3):413-22.
    108. Meijles DN, Sahoo S, Al Ghouleh I, et al. The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal. 2017;10(501).
    109. Park P, Garton HJ, Gala VC, Hoff JT, McGillicuddy JE. Adjacent segment disease after lumbar or lumbosacral fusion: review of the literature. Spine (Phila Pa 1976). 2004;29(17):1938-44.

    QR CODE