The clinical efficacy comparison of tibial cortex transverse transport and platelet-rich plasma treatment of severe diabetic foot ulcers

The clinical efficacy comparison of tibial cortex transverse transport and platelet-rich plasma treatment of severe diabetic foot ulcers | 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 Research Article The clinical efficacy comparison of tibial cortex transverse transport and platelet-rich plasma treatment of severe diabetic foot ulcers Puxiang Zhen, Hongjie Su, Sijie Yang, Xiang Chen, Shunan Dong, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4076795/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 Objective The comparison analysis uses the clinical efficacy of the tibial cortex transverse transport and the enrichment of platelet plasma to treat severe diabetic foot ulcers and the effects of vascular endothelial cell vitality. Methods Retrospective analysis was performed on two groups of patients treated at our hospital from July 2019 to June 2022. One group received tibial cortex transverse transport (TTT) and the other received platelet-rich plasma (PRP). Both groups had Wagner level 3 or greater. We compared clinical efficacy, wound healing, arterial and posterior tibial arterial blood flow rates, and horizontal SDF-1 levels in peripheral blood between the groups. Results TTT group had higher healing rates at 1.5-year follow-up than the PRP group (96.67% [29/30] versus 80% [24/30], p < 0.05). The healing time of the TTT group was shorter than the control group (3.02 ± 0.84 versus 6.04 ± 0.85 months, p = 0.000). The amputation rate (3.33% [1/30] versus 20% [6/30], p < 0.05) and recurrence rate (6.67% [2/30] versus 26.67% [8/30], p < 0.05) of the TTT group were lower than the control group. One month after surgery and last follow-up, the SDF-1 concentration in the perimeter of the TTT group was significantly higher than the PRP group (375.36 ± 13.52 versus 251.93 ± 9.82 pg/ml, p = 0.000; 256.62 ± 13.19 versus 239.95 ± 10.78 pg/ml, p = 0.000). The average blood flow speed in the arterial artery of the TTT group was faster than the PRP group (68.93 ± 2.69 versus 58.14 ± 2.48 cm/s, p = 0.000) 4 weeks postoperatively and (55.68 ± 3.43 versus 46.07 ± 3.02 cm/s, p = 0.000) last follow-up. Conclusion The findings showed that TTT had better efficacy than PRP in treating severe diabetic foot ulcers. It could effectively stimulate SDF-1 expression, promote vascular hyperplasia, and accelerate wound healing. Tibial cortex transverse transport Platelet-rich plasma Diabetic foot ulcers Stromal cell derived factor-1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Presently, the global diabetic population stands at approximately 425 million individuals [ 1 ], of whom approximately one-third are susceptible to developing diabetic foot ulcers (DFUs). Among this subgroup, one-fifth ultimately face the risk of amputation [ 2 ]. Clinical practice employs diverse approaches to address diabetic foot complications, primarily encompassing conservative drug replacement [ 3 , 4 ], debridement [ 5 ], vascular reconstruction [ 6 ], tendon transposition [ 7 , 8 ], and skin coverage [ 9 – 11 ]. Nevertheless, these interventions yield unsatisfactory outcomes, particularly in severe cases of diabetic foot, where secondary infections frequently arise, exacerbating the condition and resulting in amputation for a significant number of patients [ 2 ]. Hence, limb preservation is a primary objective for both patients and healthcare practitioners. To date, the utilization of tibial cortex transverse transport, a pioneering surgical technique, has demonstrated favorable outcomes in the management of severe diabetes [ 12 ]. The underlying principle involves providing structural support to the bone, thereby generating a reciprocal force during weight-bearing. This mechanical phenomenon stimulates angiogenesis within the bone and adjacent tissues [ 13 ]. In comparison to traditional surgical approaches, this innovative technology enhances wound healing and limb preservation in patients with persistent diabetic foot ulcers, while exhibiting minimal and mild postoperative complications [ 12 , 14 ]. In recent years, some studies have also found that Platelet-rich Plasma (PRP) can promote collagen synthesis, new blood vessel formation, fibrous tissue, and granulation tissue generation by releasing related biological activity substances, thereby stimulating wound tissue epithelialization and tissue regeneration and repair [ 15 ]. At present, PRP's clinical application scope is getting wider and wider, involving bone and soft tissue repair, chronic wound healing difficulties, medical beauty, and other aspects. Many clinical studies at home and abroad have confirmed the positive role of PRP in the treatment of chronic wounds [ 16 , 17 ]. To date, no literature exists reporting comparisons of TTT and PRP treatment of diabetic foot. We observed 60 patients with diabetic foot receiving TTT and PRP treatment, conducting a retrospective comparative study evaluating efficacy. Patients and methods Patient selection The study retrospectively analyzed 60 patients (ulcerated tendon, joint capsule, or bone [ 18 ]) treated at our institution from July 2019 to June 2022. One group received tibial cortex transverse transport (TTT) and the other received platelet-rich plasma (PRP) treatment. The study was approved by the hospital's Ethics Committee, and patients and families signed informed consent forms (Table 1 ). Table 1 Patient descriptive characteristics TTT(n = 30) PRP(n = 30) P-value Age (years) 64.03 ± 7.42 66.83 ± 6.51 0.73 Male sex, % (n) 60(18) 63.33(19) 0.79 BMI (kg/m 2 ) 23.2 ± 3.2 23.1 ± 3.4 0.72 Duration of diabetes mellitus (years) 21.23 ± 9.61 20.56 ± 8.36 0.83 Duration of ulcers (years) 1.2 ± 0.7 1.1 ± 0.6 0.14 Ulcer area (cm2) 43.23 ± 9.8 40.56 ± 8.6 0.26 Wagner grading 3 43.33(13) 53.33(16) 0.44 4 40.0(12) 33.33(10) 0.59 5 16.67(5) 13.33(4) 0.72 HbA1c (%) 9.6 ± 3.7 9.5 ± 3.5 0.67 Current smoker, % (n) 20(6) 16.67(5) 0.74 Data are presented as the mean ± SD or % (n); TTT = tibial cortex transverse transport; PRP = platelet-rich plasma. Patient inclusion and exclusion criteria Inclusion criteria included patients aged > 18 years; diagnosed with diabetes per American Diabetes Association criteria [ 19 ]; ulcers classified as severe (grade 3 or greater) diabetic foot ulcer per Wagner [ 20 ] grading. Exclusion criteria included patients with lower extremity arterial ultrasound or lower extremity CTA suggesting popliteal artery outflow tract stenosis > 85% or occlusion; patients with psychiatric disorders unable to cooperate with surgery completion; patients with recent cardiovascular or cerebrovascular accidents or high risk thereof, unable to tolerate surgery. Clinical and imaging evaluation We maintained a detailed record of ulcer location, duration, and complications. Preoperatively, we collected wound secretions for culture to determine pathogenic bacteria and their antibiotic susceptibility, enabling selection of appropriate antibiotics. If the ulcer was open, we performed a bone probe test and a flatfoot x-ray to ascertain if diabetic foot osteomyelitis was present [ 21 ]. We defined peripheral arterial hypoperfusion as nonpalpable dorsalis pedis and posterior tibial arteries and/or ankle index 50% diameter reduction) [ 23 ] or arterial occlusion from atherosclerosis, further evaluation by a vascular surgeon and, if necessary, revascularization was required. Surgical techniques The control group received PRP topical wound dressing following debridement, while the observation group underwent tibial cortex transverse transport (Fig. 1 ). Both groups received comprehensive internal medicine treatment to control diabetes mellitus, with prophylactic antibiotics administered intraoperatively and for 1 day postoperatively. Patients in the treatment group underwent minimally invasive osteotomy in the operating room to create bone windows, and a special external fixator was placed under fluoroscopy. On postoperative day 3, bone transfer began according to the "accordion technique" [ 24 ], performed 3 times daily at regular intervals, totaling 1mm of outward transfer over 2 weeks. X-rays were reviewed, and after 3 days of maintenance, reverse bone transfer began for 2 weeks. The tibial bone window was repositioned after 4 weeks, and the external fixation frame removed, with 75% alcohol drops applied to the postoperative pin tract to prevent infection. In the control group, one-stage debridement was performed according to the condition of the affected foot, and 30-60 mL of peripheral venous blood was withdrawn from each patient during the operation. The blood was injected into an anticoagulation tube and then centrifuged at a radius of 15 cm at 3600 r/min for 5 minutes. Most of the lower layer of erythrocytes and leukocytes were removed, and the layer of plasma and platelets was retained. This was then centrifuged at the same time for 5 minutes, and 5-10 mL of PRP was obtained. The prepared autologous PRP was directly applied externally to the wound, on which a sterile dressing was placed. The wound was observed to heal after 3 days of aseptic bandaging, with regular dressing changes for 7 days (this is one treatment cycle of PRP). The above process was repeated until the wound healed. Follow up All patients were followed up in the outpatient clinic at 4 and 12 weeks postoperatively for evaluation and dressing change. Patients were instructed to change dressings at home if the ulcers had not healed. Patients were instructed to avoid weight-bearing on the affected limb until the ulcer was completely healed, after which they were allowed to walk with crutches. Follow-up visits were scheduled once a month for 1.5 years. Outcomes The primary outcomes were the time to ulcer healing, healing rate, recurrence frequency, and amputation rate. Secondary outcomes encompassed blood flow velocities in the popliteal and dorsalis pedis arteries, measured pre- and postoperatively in affected limbs. Concentrations of the pro-angiogenesis factor SDF-1, both pre- and postoperative, were quantified using ELISA. Ulcer healing was defined by the maintenance of complete epithelialization for two weeks, without any exudate [ 25 ]. Recurrent ulcers were identified as any new ulcers in patients with a history of foot ulcers, irrespective of their location or timing. Statistical methods Data were meticulously compared between different groups using a t-test for variables demonstrating normal distribution, a Mann–Whitney U-test for nonparametric variables, and the chi-square or Fisher's exact test (if the expected count was less than 5 for any unanticipated cells) for categorical data, as appropriate. Continuous variables were expressed as mean ± SD, and categorical variables as numbers and percentages. Where data did not obey a normal distribution, the median (P50) was utilized. All statistical analyses were performed using SPSS 26.0 software, developed by SPSS Inc., Chicago, IL, USA. The significance level was set at P < 0.05, a conventionally accepted threshold in many research studies. Result Clinical efficacy Cases in the observation and control groups were followed up for 1.5 year. TTT group had higher healing rates at 1.5-year follow-up than the PRP group (96.67% [29/30] versus 80% [24/30], p < 0.05). The healing time of the TTT group was shorter than the control group (3.02 ± 0.84 versus 6.04 ± 0.85 months, p = 0.000). The amputation rate (3.33% [1/30] versus 20% [6/30], p < 0.05) and recurrence rate (6.67% [2/30] versus 26.67% [8/30], p < 0.05) of the TTT group were lower than the control group (Fig. 2 , Fig. 3 , Fig. 4 ). There was no statistically significant difference in peripheral blood SDF-1 levels between the two groups before treatment (P > 0.05). The peripheral blood SDF-1 levels of the two groups increased significantly at 1 month after treatment, and the observation group was significantly higher than the control group (375.36 ± 13.52 versus 251.93 ± 9.82 pg/ml, p = 0.000). The observation group was significantly higher than the control group at the final follow-up (256.62 ± 13.19 versus 239.95 ± 10.78 pg/ml, p = 0.000) (Fig. 5 ). Before treatment, there was no statistically significant difference between the popliteal artery and dorsalis pedis artery blood flow velocities of the two groups (P > 0.05). At one month after treatment, the popliteal and dorsalis pedis arteries blood flow velocities increased significantly in both groups, and the popliteal and dorsalis pedis arteries blood flow velocities in the observation group were significantly higher than those in the control group (68.93 ± 2.69 versus 58.14 ± 2.48 cm/s, p = 0.000). The popliteal and dorsalis pedis artery blood flow velocities in the observation group were also significantly higher than those in the control group at the last follow-up (55.68 ± 3.43 versus 46.07 ± 3.02 cm/s, p = 0.000) (Fig. 6 , Fig. 7). Discussion The exact mechanism of tibial cortex transverse transport for diabetic foot treatment remains inconclusive, but the most accepted principle is activation and strengthening by tissue regeneration under the tension-stress law [ 26 ], stimulating simultaneous growth of muscle, fascia, vessels, and nerves via bony distraction. In 1989, Ilizarov proposed the "law of tension-stress" as theoretical basis for orthopedic external fixation [ 27 ], finding in animal experiments that microvascular network regeneration in the pulling region between upper and lower fractures precedes osteogenesis. Subsequent angiography suggested reconstruction of "neovascularization and microcirculation" in the limb's pulling region [ 13 ]. Therefore, in the early stage of bone transfer to promote lower limb ulcer wound repair, it is mostly believed that tibial bone transfer promotes regeneration of the local microvascular network and improves blood supply, an important basic guarantee for ulcer wound repair. It is the bone transfer that exerts an important local repair effect. The external fixator bone transfer system was first used for treating large bone defects in osteomyelitis [ 28 ], and its technical core involves fixation, bone lengthening, and bone transfer. This system has achieved good results in treating intractable orthopedic diseases, including bone defects, nonunion, chronic osteomyelitis, limb deformity, and severe joint contracture. Bone transfer shows better efficacy than local tissue repair. Further studies added the "accordion" technique to bone transfer [ 29 ]. This involves opening the tibia into a window for osteotomy, moving the bone piece parallel to the tibia's long axis with continuous lateral distraction, then reversing the transfer to reset the tibia. This active bone transfer stimulation has good local tissue repair efficacy for lower limb ischemic diseases like thromboembolic vasculitis and atherosclerotic thromboembolism, which can cause tissue defects and ulcers. Some related research scholars, in an in-depth study, further discovered [ 30 ] that the regeneration of the microvascular network was most active during the initial 1 to 3 weeks of bone relocation. This period marked the commencement of a crucial phase in the healing process. Remarkably, this slow, continuous pulling force not only stimulated the proliferation of cells but also enhanced their biosynthetic function. Consequently, on this foundation, the local blood vessels, bones, muscles, nerves, and other tissues regenerated, collectively promoting the regenerative healing of the damaged tissues [ 31 ]. Although Ilizarov, a pioneering surgeon, identified the phenomenon of neovascularization of the vascular network during the process of distraction osteogenesis, he didn't apply this innovative technique to the field of microcirculation reconstruction. This represented a missed opportunity to advance the treatment of vascular lesions. However, post-2000, Chinese orthopaedic surgeons emerged as trailblazers, being the first globally to harness the TTT technique for the treatment of vascular lesions in the lower extremity, specifically targeting diabetic foot conditions [ 32 ]. Currently, Chinese orthopaedic surgeons have reached a preliminary consensus: the TTT technique catalyzes the regeneration of the microvasculature in the lower extremity of diabetic foot patients, promoting the healing of foot ulcers and averting the need for amputation. It also lessens the overall risk associated with diabetic foot conditions [ 33 ]. Effectiveness of this treatment was judged microscopically by monitoring stromal cell-derived factor-1 (SDF-1) expression in peripheral blood for this cohort. SDF-1 is the sole ligand for heme receptor CXCR4. The SDF-1/CXCR4 axis provides normal signaling for cells and controls proliferation, differentiation, and survival of many cell types, including human and murine hematopoietic stem and progenitor cells [ 34 , 35 ]. SDF-1 is a major chemokine mediating hematopoietic stem cell (HSC) and endothelial progenitor cell migration [ 36 – 38 ]. In various damaged tissues, SDF-1 upregulation is thought to control repair by recruiting stem/progenitor cells to injury sites [ 39 ]. However, exact mechanisms of SDF-1's proangiogenic effects remain elusive. As an angiogenic growth factor, it's a candidate for antiangiogenic and antiangiogenic therapy. Butler and his group showed that patients with proliferative diabetic retinopathy have increased levels of SDF-1, which may play an important role in the migration of HSC-derived endothelial progenitor cells to sites of vascular wounds through regulatory molecules [ 40 ]. Practical studies have demonstrated that SDF-1 stimulates recruitment of stem cells to ischemic tissues [ 41 ], and related scholars have experimentally demonstrated increased SDF-1 protein levels on the first day after induced myocardial infarction [ 42 ]. Furthermore, overexpression of SDF-1 enhanced stem cell homing and incorporation into ischemic tissue [ 43 ]. In conclusion, SDF-1 is an important angiogenic factor expressed in various cells, particularly endothelial cells, epithelial cells, smooth muscle cells, and cancer cells [ 44 ]. Therefore, elevated SDF-1 is an important indicator of effective diabetic foot treatment [ 45 ]. Previously, we compared tibial cortex transverse transport versus simple wound debridement and dressing, finding significantly better healing, recurrence, and amputation rates with transport, and shorter ulcer healing time. As debridement and postoperative dressing occur simultaneously with transport, does healing improve due to transport or dressing? Moreover, tibial transport doesn't directly affect the ulcer wound, but indirectly stimulates systemic chemokines and growth factors to promote healing. How can this be proven during lateral tibial transfer? To address these questions, we conducted a comparative study using the PRP method with simultaneous monitoring of SDF-1 expression concentration in blood. PRP is rich in chemokines and growth factors, and is applied directly to ulcers. Theoretically, PRP provides more direct raw material for wound healing than tibial cortex transverse transport, but in practice, the present comparative study found tibial cortex transverse transport significantly superior to PRP in healing time, amputation rate, and recurrence rate. SDF-1 concentration in peripheral blood was significantly higher during tibial cortex transverse transport, indicating this therapy can stimulate increase of endogenous factors, mobilize systemic endogenous reserves, improve body's growth and repair function, and promote traumatic site vascular regeneration to accelerate diabetic foot healing. Conclusion In conclusion, tibial cortex transverse transport, a promising new treatment for diabetic foot, can significantly shorten disease duration, reduce amputation rates, and minimize recurrence. Through continuous stimulation of local "tension-stress", endogenous chemokines and growth factors are elevated to achieve total body mobilization, improve repair functions, and promote rapid healing of local ulcers. Currently, no complications have been caused by this treatment, but more cases need follow-up to prove its long-term safety. Declarations Acknowledgements We acknowledge all the participants in this study. Author contributions PXZ wrote the article. HJS and XC were responsible for data collection and analysis. SND and LW was responsible for reviewing the data. PXZ and SNL were responsible for reviewing and revising the article. Funding This study was not funded by any foundation. Availability of data and materials The datasets analyzed during the current study are available from the corresponding author on reasonable request. 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Mayorga ME, Kiedrowski M, McCallinhart P, Forudi F, Ockunzzi J, Weber K, et al. Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes. Stem Cells Transl Med. 2018;7:115–24. Yuan T, Guo S-C, Han P, Zhang C-Q, Zeng B-F. Applications of leukocyte- and platelet-rich plasma (L-PRP) in trauma surgery. Curr Pharm Biotechnol. 2012;13:1173–84. Yuan T, Zhang C, Zeng B. Treatment of chronic femoral osteomyelitis with platelet-rich plasma (PRP): a case report. Transfus Apher Sci Off J World Apher Assoc Off J Eur Soc Haemapheresis. 2008;38:167–73. Pietramaggiori G, Scherer SS, Mathews JC, Alperovich M, Yang H-J, Neuwalder J, et al. Healing modulation induced by freeze-dried platelet-rich plasma and micronized allogenic dermis in a diabetic wound model. Wound Repair Regen Off Publ Wound Heal Soc Eur Tissue Repair Soc. 2008;16:218–25. Additional Declarations No competing interests reported. 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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-4076795","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":279391548,"identity":"156e1941-9c46-44bb-a6b7-7c1bb33df060","order_by":0,"name":"Puxiang Zhen","email":"","orcid":"","institution":"National Demonstration Center for Experimental (General Practice) Education, Hubei University of Science and Technology, Xianning 437100, People’s Republic of China","correspondingAuthor":false,"prefix":"","firstName":"Puxiang","middleName":"","lastName":"Zhen","suffix":""},{"id":279391549,"identity":"bcf518eb-e107-47cc-9878-336597d7d19f","order_by":1,"name":"Hongjie Su","email":"","orcid":"","institution":"Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center), The First Affiliated Hospital of Guangxi Medical University, Nanning 530021","correspondingAuthor":false,"prefix":"","firstName":"Hongjie","middleName":"","lastName":"Su","suffix":""},{"id":279391550,"identity":"460cf2e0-31cf-492b-b5fc-4117cb092cc5","order_by":2,"name":"Sijie Yang","email":"","orcid":"","institution":"Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center), The First Affiliated Hospital of Guangxi Medical University, Nanning 530021","correspondingAuthor":false,"prefix":"","firstName":"Sijie","middleName":"","lastName":"Yang","suffix":""},{"id":279391551,"identity":"5052ee67-2a80-4dc6-895f-165bcfa2e3e1","order_by":3,"name":"Xiang Chen","email":"","orcid":"","institution":"Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center), The First Affiliated Hospital of Guangxi Medical University, Nanning 530021","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Chen","suffix":""},{"id":279391552,"identity":"97792d40-6834-4321-8a87-91e4ab176c65","order_by":4,"name":"Shunan Dong","email":"","orcid":"","institution":"Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center), The First Affiliated Hospital of Guangxi Medical University, Nanning 530021","correspondingAuthor":false,"prefix":"","firstName":"Shunan","middleName":"","lastName":"Dong","suffix":""},{"id":279391553,"identity":"de58d48c-1693-4161-89da-ebda4b2b8bff","order_by":5,"name":"Zhanming Lin","email":"","orcid":"","institution":"Department of Bone and Joint Surgery, (Guangxi Diabetic Foot Salvage Engineering Research Center), The First Affiliated Hospital of Guangxi Medical University, Nanning 530021","correspondingAuthor":false,"prefix":"","firstName":"Zhanming","middleName":"","lastName":"Lin","suffix":""},{"id":279391554,"identity":"13b49a67-204e-4475-9054-bcc7ef2074f3","order_by":6,"name":"Sainan Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACfvmDjQ8SKmp4GNsbiNQiOYP5sMGHM8dkmHsOEKnF4AZbmuTMNmYb9hkJxLrsdo+BNM8ZNh7emY833mCosYkmqINxzhkDY54KGR7J2WnFFgzH0nIbCGlhZsgxSAbZYjg7x0yCseEwYS1sQC2HeduYeexvniFSC49EWmIj0Ps8jDN4iNQiwXP4MAMwkHkYe4B+SSDGL/bHG9t/AKPSnrH98MYbH2psCGtBBgYSCaQoh2ghVccoGAWjYBSMDAAAkmlAWjHm398AAAAASUVORK5CYII=","orcid":"","institution":"The Second Hospital Affiliated to Hubei University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Sainan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-03-11 16:53:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4076795/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4076795/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52792484,"identity":"7314db8d-d3c4-4440-af5b-3889a7eb5201","added_by":"auto","created_at":"2024-03-15 20:20:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1940356,"visible":true,"origin":"","legend":"\u003cp\u003eA-F This figure shows the tibial cortex transverse transport procedure. (A) The positions of incision, corticotomy, and nailing are shown with markings as part of preoperative planning. (B) The soft tissue was retracted with sharp separation and the periosteum was exposed, which was not removed from the cortex. Corticotomy was performed by drilling multiple holes in a rectangle (1.5cm*5.0cm) in the cortex. (C-D) After osteotomy, two 4-mm drill holes were made in the osteotomized cortex (not extending to the contralateral cortex) followed by the insertion of two pins for distraction. Then, two 5-mm nailing holes extending to the contralateral cortex were made, followed by the insertion of two pins to stabilize the external frame. (E-F) The pins were attached to the fixator frame, which had two screws for distraction.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/e11ad853293936856e6db092.png"},{"id":52792483,"identity":"77b84776-0b2f-4eb9-acb7-9ccfceda49b8","added_by":"auto","created_at":"2024-03-15 20:20:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45678,"visible":true,"origin":"","legend":"\u003cp\u003eThis figure shows a comparison of healing times for diabetic foot treatment with TTT and PRP.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/093932ed08b06de39bd47685.png"},{"id":52792020,"identity":"dd46704a-d82d-4424-a6b0-63906db22d6b","added_by":"auto","created_at":"2024-03-15 20:12:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1545134,"visible":true,"origin":"","legend":"\u003cp\u003eA-F This figure shows the effects of tibial cortex transverse distraction in a 68-year-old woman with severe and resistant plantar diabetic foot ulcer. (A-B) These images show ulcers before surgery. The necrosis of the second and third toes of the right foot is obvious. (C) The necrotic second and third toes were removed intraoperatively, and the wound was deep to the cartilage surface. (D) Install the tibial cortex transverse transport stent. (E-F) Four weeks after surgery, the ulcers were completely healed, demonstrating the effectiveness of TTT in promoting ulcer healing.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/e6717edcef30b0874b0f1c27.png"},{"id":52792486,"identity":"6971c3ae-a7bf-4475-8f64-b4d533843d03","added_by":"auto","created_at":"2024-03-15 20:20:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1446665,"visible":true,"origin":"","legend":"\u003cp\u003eA-D This figure shows the effects of tibial cortex transverse distraction in a 75-year-old man with severe and resistant plantar diabetic foot ulcer. (A-B) These images show ulcers before surgery. Gangrene of the fifth toe of the right foot, and large tissue necrosis of the right plantar of the foot. (C) Four weeks after surgery, plantar granulation tissue grows well. (D) Eight weeks after surgery, the ulcers were completely healed, demonstrating the effectiveness of TTT in promoting ulcer healing.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/8d685599a4b9a25b72899619.png"},{"id":52792022,"identity":"19c9ac1c-d1ac-4ed4-b47f-cb2f8b48e899","added_by":"auto","created_at":"2024-03-15 20:12:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":101552,"visible":true,"origin":"","legend":"\u003cp\u003eThis figure shows a comparison of horizontal SDF-1 levels in peripheral blood between TTT and PRP group before surgery, 1 month after surgery and last follow-up.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/efaa1e5e1bcd9726b165f624.png"},{"id":52792017,"identity":"e17aa794-fdd4-4110-95f7-18344b69d4e8","added_by":"auto","created_at":"2024-03-15 20:12:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":77239,"visible":true,"origin":"","legend":"\u003cp\u003eThis figure shows a comparison of the average blood flow speed in the popliteal artery between TTT and PRP group before surgery, 1 month after surgery and last follow-up.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/15725e0e15a28ec9a324130a.png"},{"id":52792019,"identity":"23bf2cfa-edea-461a-8439-c53eda57c85c","added_by":"auto","created_at":"2024-03-15 20:12:25","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":71915,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/56c495143b36f2a612c86f60.png"},{"id":52793775,"identity":"c7083a00-7ee8-44a8-9534-22259ab67d22","added_by":"auto","created_at":"2024-03-15 20:36:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4901958,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/ad121fef-bd36-427f-893e-c1fe8de86a07.pdf"},{"id":52792485,"identity":"ba6823a6-a6a0-4bf4-afde-aaf80c3e8a62","added_by":"auto","created_at":"2024-03-15 20:20:26","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16467,"visible":true,"origin":"","legend":"","description":"","filename":"file.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4076795/v1/b9ed8becceab43bd71e697e7.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The clinical efficacy comparison of tibial cortex transverse transport and platelet-rich plasma treatment of severe diabetic foot ulcers","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePresently, the global diabetic population stands at approximately 425\u0026nbsp;million individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], of whom approximately one-third are susceptible to developing diabetic foot ulcers (DFUs). Among this subgroup, one-fifth ultimately face the risk of amputation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Clinical practice employs diverse approaches to address diabetic foot complications, primarily encompassing conservative drug replacement [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], debridement [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], vascular reconstruction [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], tendon transposition [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and skin coverage [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Nevertheless, these interventions yield unsatisfactory outcomes, particularly in severe cases of diabetic foot, where secondary infections frequently arise, exacerbating the condition and resulting in amputation for a significant number of patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hence, limb preservation is a primary objective for both patients and healthcare practitioners. To date, the utilization of tibial cortex transverse transport, a pioneering surgical technique, has demonstrated favorable outcomes in the management of severe diabetes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The underlying principle involves providing structural support to the bone, thereby generating a reciprocal force during weight-bearing. This mechanical phenomenon stimulates angiogenesis within the bone and adjacent tissues [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In comparison to traditional surgical approaches, this innovative technology enhances wound healing and limb preservation in patients with persistent diabetic foot ulcers, while exhibiting minimal and mild postoperative complications [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, some studies have also found that Platelet-rich Plasma (PRP) can promote collagen synthesis, new blood vessel formation, fibrous tissue, and granulation tissue generation by releasing related biological activity substances, thereby stimulating wound tissue epithelialization and tissue regeneration and repair [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. At present, PRP's clinical application scope is getting wider and wider, involving bone and soft tissue repair, chronic wound healing difficulties, medical beauty, and other aspects. Many clinical studies at home and abroad have confirmed the positive role of PRP in the treatment of chronic wounds [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, no literature exists reporting comparisons of TTT and PRP treatment of diabetic foot. We observed 60 patients with diabetic foot receiving TTT and PRP treatment, conducting a retrospective comparative study evaluating efficacy.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eThe study retrospectively analyzed 60 patients (ulcerated tendon, joint capsule, or bone [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]) treated at our institution from July 2019 to June 2022. One group received tibial cortex transverse transport (TTT) and the other received platelet-rich plasma (PRP) treatment. The study was approved by the hospital's Ethics Committee, and patients and families signed informed consent forms (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient descriptive characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTTT(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRP(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.03\u0026thinsp;\u0026plusmn;\u0026thinsp;7.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.83\u0026thinsp;\u0026plusmn;\u0026thinsp;6.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.33(19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of diabetes mellitus (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.23\u0026thinsp;\u0026plusmn;\u0026thinsp;9.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.56\u0026thinsp;\u0026plusmn;\u0026thinsp;8.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of ulcers (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUlcer area (cm2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.23\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.56\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWagner grading\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.33(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.33(16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.0(12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.33(10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.67(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.33(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoker, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.67(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or % (n); TTT\u0026thinsp;=\u0026thinsp;tibial cortex transverse transport; PRP\u0026thinsp;=\u0026thinsp;platelet-rich plasma.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eInclusion criteria included patients aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years; diagnosed with diabetes per American Diabetes Association criteria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; ulcers classified as severe (grade 3 or greater) diabetic foot ulcer per Wagner [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] grading. Exclusion criteria included patients with lower extremity arterial ultrasound or lower extremity CTA suggesting popliteal artery outflow tract stenosis\u0026thinsp;\u0026gt;\u0026thinsp;85% or occlusion; patients with psychiatric disorders unable to cooperate with surgery completion; patients with recent cardiovascular or cerebrovascular accidents or high risk thereof, unable to tolerate surgery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical and imaging evaluation\u003c/h2\u003e \u003cp\u003eWe maintained a detailed record of ulcer location, duration, and complications. Preoperatively, we collected wound secretions for culture to determine pathogenic bacteria and their antibiotic susceptibility, enabling selection of appropriate antibiotics. If the ulcer was open, we performed a bone probe test and a flatfoot x-ray to ascertain if diabetic foot osteomyelitis was present [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We defined peripheral arterial hypoperfusion as nonpalpable dorsalis pedis and posterior tibial arteries and/or ankle index\u0026thinsp;\u0026lt;\u0026thinsp;0.9 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We assessed lower extremity vascular status preoperatively using computed tomography angiography (CTA). If CTA indicated severe arterial stenosis (\u0026gt;\u0026thinsp;50% diameter reduction) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] or arterial occlusion from atherosclerosis, further evaluation by a vascular surgeon and, if necessary, revascularization was required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSurgical techniques\u003c/h2\u003e \u003cp\u003eThe control group received PRP topical wound dressing following debridement, while the observation group underwent tibial cortex transverse transport (Fig.\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Both groups received comprehensive internal medicine treatment to control diabetes mellitus, with prophylactic antibiotics administered intraoperatively and for 1 day postoperatively. Patients in the treatment group underwent minimally invasive osteotomy in the operating room to create bone windows, and a special external fixator was placed under fluoroscopy. On postoperative day 3, bone transfer began according to the \"accordion technique\" [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], performed 3 times daily at regular intervals, totaling 1mm of outward transfer over 2 weeks. X-rays were reviewed, and after 3 days of maintenance, reverse bone transfer began for 2 weeks. The tibial bone window was repositioned after 4 weeks, and the external fixation frame removed, with 75% alcohol drops applied to the postoperative pin tract to prevent infection. In the control group, one-stage debridement was performed according to the condition of the affected foot, and 30-60 mL of peripheral venous blood was withdrawn from each patient during the operation. The blood was injected into an anticoagulation tube and then centrifuged at a radius of 15 cm at 3600 r/min for 5 minutes. Most of the lower layer of erythrocytes and leukocytes were removed, and the layer of plasma and platelets was retained. This was then centrifuged at the same time for 5 minutes, and 5-10 mL of PRP was obtained. The prepared autologous PRP was directly applied externally to the wound, on which a sterile dressing was placed. The wound was observed to heal after 3 days of aseptic bandaging, with regular dressing changes for 7 days (this is one treatment cycle of PRP). The above process was repeated until the wound healed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eFollow up\u003c/h2\u003e \u003cp\u003eAll patients were followed up in the outpatient clinic at 4 and 12 weeks postoperatively for evaluation and dressing change. Patients were instructed to change dressings at home if the ulcers had not healed. Patients were instructed to avoid weight-bearing on the affected limb until the ulcer was completely healed, after which they were allowed to walk with crutches. Follow-up visits were scheduled once a month for 1.5 years.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcomes were the time to ulcer healing, healing rate, recurrence frequency, and amputation rate. Secondary outcomes encompassed blood flow velocities in the popliteal and dorsalis pedis arteries, measured pre- and postoperatively in affected limbs. Concentrations of the pro-angiogenesis factor SDF-1, both pre- and postoperative, were quantified using ELISA. Ulcer healing was defined by the maintenance of complete epithelialization for two weeks, without any exudate [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Recurrent ulcers were identified as any new ulcers in patients with a history of foot ulcers, irrespective of their location or timing.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eData were meticulously compared between different groups using a t-test for variables demonstrating normal distribution, a Mann\u0026ndash;Whitney U-test for nonparametric variables, and the chi-square or Fisher's exact test (if the expected count was less than 5 for any unanticipated cells) for categorical data, as appropriate. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and categorical variables as numbers and percentages. Where data did not obey a normal distribution, the median (P50) was utilized. All statistical analyses were performed using SPSS 26.0 software, developed by SPSS Inc., Chicago, IL, USA. The significance level was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, a conventionally accepted threshold in many research studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical efficacy\u003c/h2\u003e \u003cp\u003e Cases in the observation and control groups were followed up for 1.5 year. TTT group had higher healing rates at 1.5-year follow-up than the PRP group (96.67% [29/30] versus 80% [24/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The healing time of the TTT group was shorter than the control group (3.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84 versus 6.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85 months, p\u0026thinsp;=\u0026thinsp;0.000). The amputation rate (3.33% [1/30] versus 20% [6/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and recurrence rate (6.67% [2/30] versus 26.67% [8/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) of the TTT group were lower than the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference in peripheral blood SDF-1 levels between the two groups before treatment (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The peripheral blood SDF-1 levels of the two groups increased significantly at 1 month after treatment, and the observation group was significantly higher than the control group (375.36\u0026thinsp;\u0026plusmn;\u0026thinsp;13.52 versus 251.93\u0026thinsp;\u0026plusmn;\u0026thinsp;9.82 pg/ml, p\u0026thinsp;=\u0026thinsp;0.000). The observation group was significantly higher than the control group at the final follow-up (256.62\u0026thinsp;\u0026plusmn;\u0026thinsp;13.19 versus 239.95\u0026thinsp;\u0026plusmn;\u0026thinsp;10.78 pg/ml, p\u0026thinsp;=\u0026thinsp;0.000) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBefore treatment, there was no statistically significant difference between the popliteal artery and dorsalis pedis artery blood flow velocities of the two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At one month after treatment, the popliteal and dorsalis pedis arteries blood flow velocities increased significantly in both groups, and the popliteal and dorsalis pedis arteries blood flow velocities in the observation group were significantly higher than those in the control group (68.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.69 versus 58.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 cm/s, p\u0026thinsp;=\u0026thinsp;0.000). The popliteal and dorsalis pedis artery blood flow velocities in the observation group were also significantly higher than those in the control group at the last follow-up (55.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43 versus 46.07\u0026thinsp;\u0026plusmn;\u0026thinsp;3.02 cm/s, p\u0026thinsp;=\u0026thinsp;0.000) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, Fig.\u0026nbsp;7).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe exact mechanism of tibial cortex transverse transport for diabetic foot treatment remains inconclusive, but the most accepted principle is activation and strengthening by tissue regeneration under the tension-stress law [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], stimulating simultaneous growth of muscle, fascia, vessels, and nerves via bony distraction. In 1989, Ilizarov proposed the \"law of tension-stress\" as theoretical basis for orthopedic external fixation [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], finding in animal experiments that microvascular network regeneration in the pulling region between upper and lower fractures precedes osteogenesis. Subsequent angiography suggested reconstruction of \"neovascularization and microcirculation\" in the limb's pulling region [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, in the early stage of bone transfer to promote lower limb ulcer wound repair, it is mostly believed that tibial bone transfer promotes regeneration of the local microvascular network and improves blood supply, an important basic guarantee for ulcer wound repair. It is the bone transfer that exerts an important local repair effect.\u003c/p\u003e \u003cp\u003eThe external fixator bone transfer system was first used for treating large bone defects in osteomyelitis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and its technical core involves fixation, bone lengthening, and bone transfer. This system has achieved good results in treating intractable orthopedic diseases, including bone defects, nonunion, chronic osteomyelitis, limb deformity, and severe joint contracture. Bone transfer shows better efficacy than local tissue repair. Further studies added the \"accordion\" technique to bone transfer [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This involves opening the tibia into a window for osteotomy, moving the bone piece parallel to the tibia's long axis with continuous lateral distraction, then reversing the transfer to reset the tibia. This active bone transfer stimulation has good local tissue repair efficacy for lower limb ischemic diseases like thromboembolic vasculitis and atherosclerotic thromboembolism, which can cause tissue defects and ulcers.\u003c/p\u003e \u003cp\u003eSome related research scholars, in an in-depth study, further discovered [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] that the regeneration of the microvascular network was most active during the initial 1 to 3 weeks of bone relocation. This period marked the commencement of a crucial phase in the healing process. Remarkably, this slow, continuous pulling force not only stimulated the proliferation of cells but also enhanced their biosynthetic function. Consequently, on this foundation, the local blood vessels, bones, muscles, nerves, and other tissues regenerated, collectively promoting the regenerative healing of the damaged tissues [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Although Ilizarov, a pioneering surgeon, identified the phenomenon of neovascularization of the vascular network during the process of distraction osteogenesis, he didn't apply this innovative technique to the field of microcirculation reconstruction. This represented a missed opportunity to advance the treatment of vascular lesions. However, post-2000, Chinese orthopaedic surgeons emerged as trailblazers, being the first globally to harness the TTT technique for the treatment of vascular lesions in the lower extremity, specifically targeting diabetic foot conditions [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Currently, Chinese orthopaedic surgeons have reached a preliminary consensus: the TTT technique catalyzes the regeneration of the microvasculature in the lower extremity of diabetic foot patients, promoting the healing of foot ulcers and averting the need for amputation. It also lessens the overall risk associated with diabetic foot conditions [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEffectiveness of this treatment was judged microscopically by monitoring stromal cell-derived factor-1 (SDF-1) expression in peripheral blood for this cohort. SDF-1 is the sole ligand for heme receptor CXCR4. The SDF-1/CXCR4 axis provides normal signaling for cells and controls proliferation, differentiation, and survival of many cell types, including human and murine hematopoietic stem and progenitor cells [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. SDF-1 is a major chemokine mediating hematopoietic stem cell (HSC) and endothelial progenitor cell migration [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In various damaged tissues, SDF-1 upregulation is thought to control repair by recruiting stem/progenitor cells to injury sites [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, exact mechanisms of SDF-1's proangiogenic effects remain elusive. As an angiogenic growth factor, it's a candidate for antiangiogenic and antiangiogenic therapy. Butler and his group showed that patients with proliferative diabetic retinopathy have increased levels of SDF-1, which may play an important role in the migration of HSC-derived endothelial progenitor cells to sites of vascular wounds through regulatory molecules [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Practical studies have demonstrated that SDF-1 stimulates recruitment of stem cells to ischemic tissues [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and related scholars have experimentally demonstrated increased SDF-1 protein levels on the first day after induced myocardial infarction [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Furthermore, overexpression of SDF-1 enhanced stem cell homing and incorporation into ischemic tissue [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In conclusion, SDF-1 is an important angiogenic factor expressed in various cells, particularly endothelial cells, epithelial cells, smooth muscle cells, and cancer cells [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Therefore, elevated SDF-1 is an important indicator of effective diabetic foot treatment [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreviously, we compared tibial cortex transverse transport versus simple wound debridement and dressing, finding significantly better healing, recurrence, and amputation rates with transport, and shorter ulcer healing time. As debridement and postoperative dressing occur simultaneously with transport, does healing improve due to transport or dressing? Moreover, tibial transport doesn't directly affect the ulcer wound, but indirectly stimulates systemic chemokines and growth factors to promote healing. How can this be proven during lateral tibial transfer? To address these questions, we conducted a comparative study using the PRP method with simultaneous monitoring of SDF-1 expression concentration in blood.\u003c/p\u003e \u003cp\u003ePRP is rich in chemokines and growth factors, and is applied directly to ulcers. Theoretically, PRP provides more direct raw material for wound healing than tibial cortex transverse transport, but in practice, the present comparative study found tibial cortex transverse transport significantly superior to PRP in healing time, amputation rate, and recurrence rate. SDF-1 concentration in peripheral blood was significantly higher during tibial cortex transverse transport, indicating this therapy can stimulate increase of endogenous factors, mobilize systemic endogenous reserves, improve body's growth and repair function, and promote traumatic site vascular regeneration to accelerate diabetic foot healing.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, tibial cortex transverse transport, a promising new treatment for diabetic foot, can significantly shorten disease duration, reduce amputation rates, and minimize recurrence. Through continuous stimulation of local \"tension-stress\", endogenous chemokines and growth factors are elevated to achieve total body mobilization, improve repair functions, and promote rapid healing of local ulcers. Currently, no complications have been caused by this treatment, but more cases need follow-up to prove its long-term safety.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge all the participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePXZ wrote the article. HJS and XC were responsible for data collection and analysis. SND and LW was responsible for reviewing the data. PXZ and SNL were responsible for reviewing and revising the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not funded by any foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and was approved by the Ethics Committee of The First Hospital Affiliated to Hubei University of Science and Technology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStandl E, Khunti K, Hansen TB, Schnell O. 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Wound Repair Regen Off Publ Wound Heal Soc Eur Tissue Repair Soc. 2008;16:218\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Tibial cortex transverse transport, Platelet-rich plasma, Diabetic foot ulcers, Stromal cell derived factor-1","lastPublishedDoi":"10.21203/rs.3.rs-4076795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4076795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe comparison analysis uses the clinical efficacy of the tibial cortex transverse transport and the enrichment of platelet plasma to treat severe diabetic foot ulcers and the effects of vascular endothelial cell vitality.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eRetrospective analysis was performed on two groups of patients treated at our hospital from July 2019 to June 2022. One group received tibial cortex transverse transport (TTT) and the other received platelet-rich plasma (PRP). Both groups had Wagner level 3 or greater. We compared clinical efficacy, wound healing, arterial and posterior tibial arterial blood flow rates, and horizontal SDF-1 levels in peripheral blood between the groups.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTTT group had higher healing rates at 1.5-year follow-up than the PRP group (96.67% [29/30] versus 80% [24/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The healing time of the TTT group was shorter than the control group (3.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84 versus 6.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85 months, p\u0026thinsp;=\u0026thinsp;0.000). The amputation rate (3.33% [1/30] versus 20% [6/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and recurrence rate (6.67% [2/30] versus 26.67% [8/30], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) of the TTT group were lower than the control group. One month after surgery and last follow-up, the SDF-1 concentration in the perimeter of the TTT group was significantly higher than the PRP group (375.36\u0026thinsp;\u0026plusmn;\u0026thinsp;13.52 versus 251.93\u0026thinsp;\u0026plusmn;\u0026thinsp;9.82 pg/ml, p\u0026thinsp;=\u0026thinsp;0.000; 256.62\u0026thinsp;\u0026plusmn;\u0026thinsp;13.19 versus 239.95\u0026thinsp;\u0026plusmn;\u0026thinsp;10.78 pg/ml, p\u0026thinsp;=\u0026thinsp;0.000). The average blood flow speed in the arterial artery of the TTT group was faster than the PRP group (68.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.69 versus 58.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 cm/s, p\u0026thinsp;=\u0026thinsp;0.000) 4 weeks postoperatively and (55.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43 versus 46.07\u0026thinsp;\u0026plusmn;\u0026thinsp;3.02 cm/s, p\u0026thinsp;=\u0026thinsp;0.000) last follow-up.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe findings showed that TTT had better efficacy than PRP in treating severe diabetic foot ulcers. It could effectively stimulate SDF-1 expression, promote vascular hyperplasia, and accelerate wound healing.\u003c/p\u003e","manuscriptTitle":"The clinical efficacy comparison of tibial cortex transverse transport and platelet-rich plasma treatment of severe diabetic foot ulcers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-15 20:12:20","doi":"10.21203/rs.3.rs-4076795/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":"59c11c4e-ebd5-4d08-bc28-ae7eb1fd9546","owner":[],"postedDate":"March 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-15T20:12:23+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-15 20:12:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4076795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4076795","identity":"rs-4076795","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}