Abstract
Peripheral arterial disease (PAD) is one of the most common underlying causes of major lower extremity amputations (LEAs). Often revascularization is not adequate to save the leg. Tibial Transverse Transport (TTT) represents a revolutionary approach to increase angiogenesis in people with critical limb threatening ischemia (CLTI). A systematic review and meta-analysis was conducted across six databases. Inclusion criteria required studies to evaluate TTT combined with revascularization versus revascularization or TTT alone as a monotherapy. Outcomes analyzed included tarsal-metatarsal amputation (TMA), wound healing, and change in visual analogue scale (VAS) for pain. A total of five studies were identified across four databases that met inclusion criteria. TTT + Revascularization was shown to have a protective effect in reducing follow up TMA, O.R = 0.44 [0.23, 0.81], p = 0.009. TTT + Revascularization was also found to have an association with wound healing, OR = 3.25 [1.84,5.73], p = 0.0001. Four studies observed the change in Visual Analogue Scale (VAS), and the cumulative effect showed no association between either TTT + Revascularization or monotherapy with change in VAS pain pre and post procedure, standard mean difference = −0.05 [-0.16, 0.05], p = 0.33. TTT in combination with peripheral endovascular revascularization offers a promising addition for patients with CLTI with lower incidence of TMA increase rates of wound healing. However, considering the limited studies available and overall small sample size, further trials are necessary to understand the relationship between this novel therapy and CLTI management.
Keywords
Major lower extremity amputations (LEA) are usually the result of a combination of several component factors including peripheral arterial disease (PAD), poor wound healing, smoking, dialysis, and infection.1,2 However, PAD alone may be a sufficient cause of LEA. Despite advances in vascular surgery, revascularization is often inadequate to heal a foot wound.3,4
TTT offers a radical approach to treat people with CLTI. Illizarov popularized the surgical technique for distraction osteogenesis or osteosynthesis to lengthen and reconstruct complex fractures.5,6 In addition to osteogenesis, Illizarov reported increased soft tissue angiogenesis. 7 Fokin and colleagues used Ilizarov's method to treat PAD. 8 However, it was not until 2001 that this approach started to be widely used to treat PAD in the People's Republic of China. 9 The literature from China refers to the procedures as tibial transverse transport (TTT), often referred to as TTT. 9
The procedure creates a unicortical bone window or rectangular section of bone that is gradually distracted for 7- 10 days. The bone segment is then gradually reduced back to its original position (Figure 1). Research over the last 24 years from Chinese investigators has reported systemic release of stem cells and angiographic cytokines, improve perfusion, enhance wound healing, reduction of major LEA, reduced mortality, and even improve perfusion to the contralateral extremity. However, most of the studies are retrospective cohort studies and the procedure is usually done without traditional revascularization. The objective of this analysis is to summarize studies that compare the TTT procedure plus traditional revascularization procedures versus traditional revascularization surgical procedures alone in people with CLTI.
Schematic of the TODA Surgery. Figure 1A-G: Anterior view of the proximal tibia and cross Section of the tibia to demonstrate location of the osteotomies and distraction of the bone. Figure A shows the anatomic placement of the rectangular osteotomy over the anterior and medial aspect of the proximal tibia. Figure B is an enlarged view showing placement of the pins of the external fixation frame and bone traction needles through the block of bone. Figure C is a cross section of the tibia that shows placement of the bone traction needles. Figure D demonstrates distraction of the block of the cortex. The blue arrow shows the direction of bone movement. The bone segment is moved 1 mm a day for 7–14 days. Figure E is a cross section of the bone that shows distraction of the cortex. Figure F and G show the movement of the block of bone back to its original position in the tibia.
Methods
A literature search was performed on February 10, 2025 across PubMed, Embase, CNKI (China National Knowledge Infrastructure) and Wanfang Data using the term “transverse tibial transport” AND “revascularization” OR “intervention” OR “vascular reconstruction”. Papers and abstracts were reviewed in English and Chinese to determine if they met inclusion criteria (CX and DCL). Figure 2 shows the study flow chart of the retrieval process. This systematic review and meta-analysis was registered through research registry, review number 1755.
Flow chart of study retrieval.
All citations were imported to Endnote 20. Duplicates were removed and the remaining citations were screened by their titles and abstracts in accordance with inclusion and exclusion criteria. The inclusion criteria required subjects diagnosed with non-healing ulcers from peripheral artery disease, or non-healing wounds (eg: wounds secondary to thrombophlebitis) and treated surgically with TTT. Studies that were included report outcomes of TTT with mention of amputation, healing, mortality, recurrence, and complication rate, in the English language or have a manuscript in complete translation to the English language, and be of retrospective, prospective, or randomized controlled trial in design. Manuscripts that did not examine the TTT modality, case-controlled, case series, and other systematic reviews/ meta-analyses were excluded. The literature was independently reviewed by two investigators (LAL and AT). Disagreements resolved by a third independent reviewer (DCL).
After title and abstract screening, the remaining citations were examined in their full length and matched against the inclusion and exclusion criteria. The data from articles determined eligible for this review were then extracted. We evaluated age, gender, comorbidities, wound classification, CLI classification, pre- and post-treatment Arterial Doppler Studies, Computer tomography angiography (CTA), pain, and temperature. The primary outcomes of this study included the qualitative outcomes following TTT + revascularization versus monotherapy alone (TTT or revascularization) in addition to the quantitative findings that compare TTT + revascularization versus monotherapy alone. Collectively, among the included studies, only articles that were deemed to have extractable data points where chi-squared analysis and odds-ratio could be calculated were included in the meta-analysis portion of this study. The primary quantitative outcomes assessed included tarsal-metatarsal amputation, ulcer healing, and visual analogue scale (VAS) pain reduction.
We used STATA BE17 for statistical analyses and Forest plots generated using R-Studio. A p-value < 0.05 was considered statistically significant. All categorical variables were reported as n (%), while continuous variables were reported as average ± standard deviation. Eggers test and funnel plots were produced to assess publication bias. Heterogeneity was calculated using a I2 and a random effects model was used in all analytics.
Results
After initial query, there were 381 results, including 279 academic journal articles. Of these, 236 were related to diabetic foot ulcers (DFUs). Applying additional filters for “intervention” or “revascularization” narrowed the results to 10 articles. A second search on Wanfang Data returned 486 results. After applying the same filters, 8 articles remained, all of which overlapped with the CNKI data search. After duplicate removal, 10 articles remained, of which 8 met eligibility for full systematic review. Among these studies, only five had outcomes reported with findings that could be extracted and used in the final meta-analysis. All studies were conducted in China, between 2018 and 2024. A flow chart illustrating the study selection process is detailed in Figure 2. Follow-up time periods ranged from 3 months to 24 months. A summary of study characteristics is presented in table 1.
Study Characteristics.
The average age of subjects ranged from 45 to 74 years old. A total of 583 subjects were included across the 8 studies. TTT and revascularization was performed in 207 subjects, TTT alone was performed in 137 subjects, and revascularization alone was performed in 235 subjects. There was a total n = 384 males and n = 199 females across all studies. The cumulative sum from the data available showed the number of subjects with diabetes (n = 152), coronary artery disease (n = 74), active smoking (n = 216), CKD (n = 3), and peripheral artery disease (n = 508)
Wounds were classified according to the Wagner, UT, or Rutherford grading system. Wagner was used in 5 studies and included the following number of subjects in each grade: II = 21, III = 11, IV = 74, V = 46, III-IV = 41. UT scoring was used in three studies, with the following subjects per score: UT2-3/B-D = 41, and UT 3B = 107. Rutherford was discussed in two studies, with the following findings: V = 41 and VI = 90.
The interventions within each study included TTT + revascularization, TTT alone, or revascularization alone. Two studies compared TTT + revascularization with TTT alone; four studied compared TTT + revascularization with Revascularization alone; and two studied compared TTT alone with Revascularization alone. Across all studies, an improvement in ABI and increase in skin temperature was observed regardless of intervention. In addition, for the studies the reported before and after pain ratings, there was a decreased in overall pain regardless of intervention as well.
Three findings reported the outcome of tarsal-metatarsal amputation (TMA). The cumulative effect size for the three studies showed a protective association between TTT + Revascularization and TMA, O.R = 0.44 [0.23, 0.81], p = 0.009 (Figure 3). The same three studies also examined wound healing. The cumulative effect size shows an associated between TTT + Revascularization with ulcer healing by the end of the study period, OR = 3.25 [1.84,5.73], p = 0.0001 (Figure 4). Four studies observed the change in VAS, and a cumulative effect size shows no association between either intervention with change in VAS pain pre and post procedure, Mean difference = −0.05 [-0.16, 0.05], p = 0.33 (Figure 5).
TMA. Three studies evaluated TMA, with TTT + Revascularization exhibiting a protective effective from TMA, O.R = 0.44 [0.23, 0.81]. A random-effects model was used and there was no heterogeneity, p=0.23.
Ulcer healing. Three studies evaluated Ulcer Healing Likelihood, with TTT + Revascularization exhibiting a greater association with ulcer healing, O.R = 3.25 [1.84, 5.73]. A random-effects model was used and there was no heterogeneity, p=0.60.
VAS pain reduction. Three studies evaluated VAS pain Reduction, with TTT + Revascularization exhibiting a larger mean difference in pain reduction, standard mean difference = −0.05 [-0.16, −0.05]. A random-effects model was used. No heterogeneity was present (p=0.70).
Outcomes.
Values are presented as mean ± standard deviation or n (%), unless otherwise specified.
Risk of Bias/ Publication Bias
A risk of bias assessment was conducted to evaluate the quality of studies, and the Cochrane Risk of Bias 2 (RoB 2) tool was used, assessing domains such as randomization, blinding, missing data, and selective reporting. Overall, there were low to some concern of bias across the studies (Supplementary 2). In addition, this study demonstrates no evidence of publication bias, as indicated by a non-significant Egger's test (p > 0.05) and a symmetrical funnel plot (Supplementary 3)
Discussion:
The results of this meta-analysis suggest that TTT combined with traditional revascularization performed better than traditional revascularization procedures alone in patients that have wounds and PAD. There were fewer TMAs and more ulcer healing with TTT combination with traditional revascularization. There was no significant difference in change of VAS pain score between interventions.
Gavriil Ilizarov developed the techniques used for distraction osteogenesis and angiogenesis. 10 This technique harnesses the intrinsic regenerative capacity of bone by creating an osteotomy and gradually separating the segments. This controlled separation stimulates the production of new bone tissue, and it increases angiogenesis at sites distal to the procedure.11,12 This mechanical distraction seems to initiate an amazing cascade of biochemical signals that promote tissue regeneration, including angiogenesis, modulation of the inflammatory response, and immunomodulatory effects.13–15 The studies included in this review demonstrated an increase in perfusion to the foot based on serial arterial Dopplers, CTA, and arterial Doppler Ultrasound.
The challenges in treating PAD and healing complex wounds in people with diabetes are compounded by the severity and extent of PAD. In people with diabetes and PAD, vascular disease is characterized by infrapopliteal disease with multi-segmental occlusions and the involvement of the medium and small vessel. The microvascular component of the disease process cannot be repaired with traditional open or endovascular procedures. The success of traditional revascularization procedures for wound healing depends on restoring direct revascularization, so there is increased perfusion to the affected wound's angiosomes.4,16–18 If there is successful revascularization to an artery, but the artery does not supply blood to the wound's angiosomes (indirect revascularization), the risk of not healing and amputation is 1.8 to 2.6 times higher. 4 The success of TTT is in its ability to increase small unnamed arteries on the dorsum and plantar aspect of the foot.
The benefits of TTT are three-fold. First TTT seems to work synergistically with traditional revascularization procedures to create better outcomes than the outcomes that would result from traditional revascularization procedures alone. Second, TTT generates a systemic increase in angiogenic cytokines and increases angiogenesis on the dorsum and sole of the foot resulting in a significant increase in microcirculation and improved healing of DFUs. Third, TTT significantly increases perfusion and wound healing to both extremities, not just to the limb that receives the TTT procedure. Furthermore, there is anecdotal evidence the TTT provides a system wide palliative effect of other circulatory problems related to diabetes mellitus, such as heart disease, and neuropathy.
There are important limitations to current publications on this topic. First, most of the studies are short and do not report the rate of amputation or death. Amputation free survival, one year mortality and one-year incidence of major amputation are common outcomes reported in most of the vascular surgery literature. These outcome measures were not consistently reported in the Chinese studies we included in this analysis. Another outcome was ulcer healing, which was not uniformly defined across the studies and the knowledge of whether a surrogate marker was used versus true full reepithelialization of the lesion was unknown. On the contrary, outcomes including visual analog pain, foot temperatures and arterial Doppler studies were reported in almost every study. While these provide some consistent insights, they are often not reported in the vascular surgery literature. Monkenberg sclerosis is very common in this population In a third of cases, ABIs cannot be calculated because of arterial calcification. 19 In addition, only one ABI is reported (usually the artery with the best result) rather than reporting changes in both the dorsalis pedis and posterior tibial arteries. Second, there is considerable heterogeneity among the studies in the level of detail reported in the methods, as well as details of the severity of PAD, co-morbidities, and outcome measures. Most of the studies were retrospective, there is only one prospective, randomized clinical trial that compares TTT and traditional treatment methods. None of the studies provided any angiographic classification of PAD before or after surgery. All studies reviewed were conducted in People's Republic of China, with possible differences in wound management and vascular surgery compared to the US and Europe, and therefore should be viewed with caution when generalizing the findings to western populations.
While there is a growing body of work, with promising outcomes, the endpoint measures that can be extracted from the systematic review of the medical literature. This literature is surprisingly homogenous in its reporting of Pain, foot temperature and ABIs. The overall quality of the studies that were included in this meta-analysis was variable. Most studies were conducted in single centers with small sample sizes, potentially limiting the generalizability of the findings to other populations. Publication bias may also be present, as studies with positive results are more likely to be published. This could lead to an overestimation of the true effect of TTT. Lastly, the number of studies was relatively small, and the follow-up periods were generally short. Larger, long-term studies are needed to confirm these findings and assess the durability of TTT's effects.
Conclusion
The novel approach of TTT offers an option for individuals with limb ischemia who may not be suitable candidates for traditional revascularization procedures, in cases where traditional revascularization fails or in addition to traditional revascularization. While this study found promise in the ability of TTT to heal wounds and reduce TMAs, there are significant limitations in the published studies. To better understand the scientific efficacy of the TTT process, research should be conducted using larger, randomized, controlled trials to confirm or refute the extremely beneficial effects of TTT of circulatory related disease reported in Chinese medical journals.
Footnotes
Ethics Approval and Consent to Participate:
This study is a systematic review and meta-analysis of previously published studies. No new human or animal subjects were involved; therefore, institutional review board approval and informed consent were not required.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.