Background: The management of severe and recalcitrant diabetic foot ulcers is challenging. Distraction osteogenesis is accompanied by vascularization and regeneration of the surrounding tissues. Longitudinal distraction of the proximal tibia stimulates increased and prolonged blood flow to the distal tibia. However, the effects of transverse distraction of the proximal tibia cortex on severe and recalcitrant diabetic foot ulcers are largely unknown. Questions/purposes: (1) Does tibial cortex transverse distraction increase healing and decrease major amputation and recurrence of severe and recalcitrant diabetic foot ulcers compared with routine management (which generally included débridement, revascularization, negative pressure wound therapy, local or free flaps, or skin grafts as indicated)? (2) Does neovascularization and perfusion increase at the foot after the procedure? (3) What are the complications of tibial cortex transverse distraction in patients with severe and recalcitrant diabetic foot ulcers? Methods: Between July 2014 and March 2017, we treated 136 patients with diabetes mellitus and University of Texas Grade 2B to 3D ulcers (wound penetrating to the tendon, capsule, bone, or joint with infection and/or ischemia). The patients had failed to respond to treatment for at least 6 months, and their ulcers had a mean ± SD area of 44 cm² ± 10 cm². All 136 patients underwent tibial cortex transverse distraction (partial corticotomy of the upper tibia, which was in normal condition, followed by 4 weeks of transverse distraction medially then laterally). We compared these patients with the last 137 consecutive patients we treated with standard surgical treatment, consisting of débridement, revascularization, local or free flap or skin equivalent, or graft reconstruction along with negative-pressure wound therapy between May 2011 and June 2013; there was a 1-year period during which both treatments were in use, and we did not include patients whose procedures were performed during this time in either group. Patients in both groups received standard off-loading and wound care. The patients lost to follow-up by 2 years (0.7% of the treatment group [one of 137] and 1.4% of the control group [two of 139]; p = 0.57) were excluded. The patients in the treatment and control groups had a mean age of 61 years and 60 years, respectively, and they were predominantly men in both groups (70% [95 of 136] versus 64% [88 of 137]; p = 0.32). There were no differences with respect to parameters associated with the likelihood of ulcer healing, such as diabetes and ulcer duration, ulcer grades and area, smoking, and arterial status. We compared the groups with respect to ulcer healing (complete epithelialization without discharge, maintained for at least 2 weeks, which was determined by an assessor not involved with clinical care) in a 2-year follow-up, the proportion of ulcers that healed by 6 months, major amputation, recurrence, and complications in the 2-year follow-up. Foot arterial status and perfusion were assessed in the tibial cortex transverse distraction group using CT angiography and perfusion imaging. Results: The tibial cortex transverse distraction group had a higher proportion of ulcers that healed in the 2-year follow-up than the control group (96% [131 of 136] versus 68% [98 of 137]; odds ratio 10.40 [95% confidence interval 3.96 to 27.43]; p < 0.001). By 6 months, a higher proportion of ulcers healed in the tibia cortex transverse distraction group than the control group (93% [126 of 136] versus 41% [56 of 137]; OR 18.2 [95% CI 8.80 to 37.76]; p < 0.001). Lower proportions of patients in the tibia cortex transverse distraction group underwent major amputation (2.9% [four of 136] versus 23% [31 of 137], OR 0.10 [95% CI 0.04 to 0.30]; p < 0.001) or had recurrences 2.9% (4 of 136) versus 17% (23 of 137), OR 0.20 [95% CI 0.05 to 0.45]; p < 0.001) than the control group in 2-year follow-up. In the feet of the patients in the tibial cortex transverse distraction group, there was a higher density of small vessels (19 ± 2.1/mm² versus 9 ± 1.9/mm²; mean difference 10/mm²; p = 0.010), higher blood flow (24 ± 5 mL/100 g/min versus 8 ± 2.4 mL/100 g/min, mean difference 16 mL/100 g/min; p = 0.004) and blood volume (2.5 ± 0.29 mL/100 g versus 1.3 ± 0.33 mL/100 g, mean difference 1.2 mL/100 g; p = 0.03) 12 weeks postoperatively than preoperatively. Complications included closed fractures at the corticotomy site (in 1.5% of patients; two of 136), which were treated with closed reduction and healed, as well as pin-site infections (in 2.2% of patients; three of 136), which were treated with dressing changes and they resolved without osteomyelitis. Conclusions: Proximal tibial cortex transverse distraction substantially facilitated healing and limb salvage and decreased the recurrence of severe and recalcitrant diabetic foot ulcers. The surgical techniques were relatively straightforward although the treatment was unorthodox, and the complications were few and minor. These findings suggest that tibial cortex transverse distraction is an effective procedure to treat severe and recalcitrant diabetic foot ulcers compared with standard surgical therapy. Randomized controlled trials are required to confirm these findings. Level of Evidence: Level II, therapeutic study.

Management of recalcitrant diabetic foot ulcer (DFU) remains difficult. Distraction osteogenesis mediates new bone formation and angiogenesis in the bone itself and the surrounding tissues. Recently it was reported that tibial cortex transverse transport (TTT) was associated with neovascularization and increased perfusion at the foot in patients with recalcitrant DFUs and facilitated healing and limb salvage. However, the findings were from several single-center studies with relatively small populations, which need to be confirmed in multicenter cohort studies with relatively large populations. Furthermore, the effect of this technique on patient's health-related quality of life is still unclear. We treated patients with recalcitrant (University of Texas wound grading system 2-C to 3-D and not responding to prior routine conservative and surgical treatments for at least 8 weeks) DFUs from seven centers using TTT (a 5 ​cm ​× ​1.5 ​cm corticotomy followed by 4 weeks of medial and lateral distraction) between July 2016 and June 2019. We analyzed ulcer healing, major amputation, recurrence, health-related quality of life (physical and mental component summary scores), and complications in the 2-year follow-up. Foot arterial and perfusion changes were evaluated using computed tomography angiography and perfusion imaging 12 weeks postoperatively. A total of 1175 patients were enrolled. Patients who died (85, 7.2%) or lost to follow-up (18, 1.7%) were excluded, leaving 1072 patients for evaluation. Most of the patients were male (752, 70.1%) and with a mean age of 60.4 ​± ​9.1 years. The mean ulcer size was 41.0 ​± ​8.5 ​cm² and 187 (16.6%) ulcers extended above the ankle. During the follow-up, 1019 (94.9%) patients healed in a mean time of 12.4 ​± ​5.6 weeks, 53 (4.9%) had major amputations, and 33 (3.1%) experienced recurrences. Compared to preoperatively, the patients had higher physical (26.2 ​± ​8.3 versus 41.3 ​± ​10.6, p ​= ​0.008) and mental (33.6 ​± ​10.7 versus 45.4 ​± ​11.3, p ​= ​0.031) component summary scores at the 2-year follow-up. Closed tibial fracture at the corticotomy site was found in 8 (0.7%) patients and was treated using external fixation and healed uneventfully. There were 23 (2.1%) patients who had pin site infections and were treated successfully with dressing changes. Compared to preoperatively, the patients had more small arteries and higher foot blood flow (8.1 ​± ​2.2 versus 28.3 ​± ​3.9 ml/100 ​g/min, p ​= ​0.003) and volume (1.5 ​± ​0.3 versus 2.7 ​± ​0.4 ml/100 ​g, p ​= ​0.037) 12 weeks postoperatively. TTT promotes healing, limb salvage, and health-related quality of life in patients with recalcitrant DFUs as demonstrated in this multicenter cohort study. The surgical procedure was simple and straightforward and the complications were few and minor. The effect of this technique was associated with neovascularization and improved perfusion at the foot mediated by the cortex distraction. The findings are required to confirm in randomized controlled trials. The Translational Potential of this Article: TTT can be used as an effective treatment in patients with recalcitrant DFUs. The mechanism is associated with neovascularization and consequently increased perfusion in the foot after operation.

The treatment of recalcitrant not-diabetic leg ulcers remains challenging. Distraction osteogenesis is accompanying by angiogenesis and neovascularization in the surrounding tissues. We previously applied tibial cortex transverse transport (TTT) to patients with recalcitrant diabetic foot ulcers and found neovascularization and increased perfusion in the foot and consequently enhanced healing and limb salvage and reduced recurrence. However, the effects of TTT on recalcitrant non-diabetic leg ulcer remains largely unknown. Consecutive patients (n ​= ​85) with recalcitrant non-diabetic leg ulcers (University of Texas Grade 2-B to 3-D, ie, wound penetrating to the tendon, capsule, bone, or joint with infection and/or ischemia) were recruited and divided into TTT (n ​= ​42) and control (n ​= ​43) groups based on the treatment they received. There were 36 (85.7%) arterial ulcers, 4 (9.5%) venous ulcers and 2 (4.8%) mixed ulcers in the TTT group and 32 (74.4%) arterial ulcers, 7 (16.7%) venous ulcers and 4 (9.3%) mixed ulcers in the control group (p ​> ​0.05). The two groups were matched on demographic and clinical characteristics. Patients in the TTT group underwent tibial corticotomy followed by 4 weeks of distraction medially then laterally, while those in the control group received conventional surgeries (debridements, revascularization, reconstruction with flaps, or skin grafts or equivalents). Ulcer healing and healing time, limb salvage, recurrence, and patient death were evaluated at a 1-year follow-up. Changes in leg small vessels were assessed in the TTT group using computed tomography angiography (CTA). TTT group had higher healing rates at 1-year follow-up than the control group (78.6% [33/42] vs. 58.1% [25/43], OR 2.64 [95% CI 1.10 to 6.85], p ​= ​0.04). The healing time of the TTT group was shorter than the control group (4.5 vs. 6.1 months, mean difference −1.60 [95% CI -2.93 to −0.26], p ​= ​0.02). There were no significant differences in rates of major amputation, reulceration, or mortality between the groups (p ​> ​0.05). TTT group displayed more small vessels 4 weeks postoperatively at the wound area, the foot, and the calf of the ipsilateral side in CTA. All patients in the TTT group achieved good union at the osteotomy site and had no skin or soft tissue necrosis or infection around the incision area. The findings showed that TTT facilitated the healing of recalcitrant non-diabetic leg ulcers and reduced the healing time compared with conventional surgeries. They suggest that TTT is an effective procedure to treat recalcitrant non-diabetic foot ulcers compared with standard surgical therapy. The procedure of TTT is relatively simple. Randomized controlled trials are required to confirm these findings. TTT can be used as an effective treatment for recalcitrant non-diabetic leg ulcers in patients. The mechanism may be associated with the neovascularization in the ulcerated foot induced by TTT and consequently increased perfusion. Together with previous findings from recalcitrant diabetic leg ulcers, the findings suggest TTT as an effective procedure to treat recalcitrant chronic leg ulcers.

Purpose: Management of severe diabetic foot ulcers (DFUs) remains challenging. Tibial cortex transverse transport (TTT) facilitates healing and limb salvage in patients with recalcitrant DFUs. However, the underlying mechanism is largely unknown, necessitating the establishment of an animal model and mechanism exploration. Methods: Severe DFUs were induced in rats, then assigned to TTT, sham, or control groups (n=16/group). The TTT group underwent a tibial corticotomy, with 6 days each of medial and lateral transport; the sham group had a corticotomy without transport. Ulcer healing was assessed through Laser Doppler, CT angiography, histology, and immunohistochemistry. Serum HIF-1α, PDGF-BB, SDF-1, and VEGF levels were measured by ELISA. Results: The TTT group showed lower percentages of wound area, higher dermis thickness (all p < 0.001 expect for p = 0.001 for TTT vs Sham at day 6) and percentage of collagen content (all p < 0.001) than the other two groups. The TTT group had higher perfusion and vessel volume in the hindlimb (all p < 0.001). The number of CD31⁺ cells (all p < 0.001) and VEGFR2⁺ cells (at day 6, TTT vs Control, p = 0.001, TTT vs Sham, p = 0.006; at day 12, TTT vs Control, p = 0.003, TTT vs Sham, p = 0.01) were higher in the TTT group. The activity of HIF-1α, PDGF-BB, and SDF-1 was increased in the TTT group (all p < 0.001 except for SDF-1 at day 12, TTT vs Sham, p = 0.005). The TTT group had higher levels of HIF-1α, PDGF-BB, SDF-1, and VEGF in serum than the other groups (all p < 0.001). Conclusion: TTT enhanced neovascularization and perfusion at the hindlimb and accelerated healing of the severe DFUs. The underlying mechanism is related to HIF-1α-induced angiogenesis.

The clinical treatment of patients with severe diabetic foot (DF) is difficult. Recently, the First Affiliated Hospital of Guangxi Medical University began to apply tibial transverse transport (TTT) in patients with DF. This treatment has achieved significant effects, but its mechanism of action is unclear. Recently, microcirculation and the pathogenesis of diabetes have become the foci of research in this field. The evaluation of the possible mechanism of microcirculation reconstruction requires relevant indicators. The aim of this study was to investigate the value of computed tomography perfusion in evaluations of the curative effects of TTT and establish corresponding quantitative evaluation indicators. Twelve patients with DF treated with TTT were recruited as the research participants. All diabetic feet were divided into the transport foot (TF) group and nontransport foot (NTF) group according to whether the patients underwent TTT. All patients underwent CT shuttle scanning preoperatively and 8 weeks after surgery. The shuttle scan data were transferred to Siemens VPCT body software and postprocessed with Customized Tumor2. We chose the TF posterior tibial artery from a distance of approximately 15 cm to the bifurcation of the plantar medial artery and the lateral plantar artery as the input artery. We selected the centre of the bilateral medial plantar muscle group on the coronal and axial regions of interest. We applied a deconvolution approach to obtain data from both sides of the plantar tissue perfusion. Skin temperature (ST) detection was performed with an ST gun to measure the average ST values in the dorsal and plantar areas, the first and fifth heads of the phalanges, and the medial and lateral malleolus points of both feet of patients with DF preoperatively and 8 weeks after surgery. The preoperative and postoperative ST values of the patients in the TF group were 30.73 ± 1.86 °C and 32.22 ± 1.51 °C, respectively. The preoperative and postoperative ST values for the patients in the NTF group were 30.93 ± 2.65 °C and 32.07 ± 2.09 °C, respectively. There were significant differences in the preoperative and postoperative data between the TF (P = 0.001) and NTF (P = 0.013) groups. In the patients with DF who underwent TTT, there were both preoperative and postoperative differences inside the medial plantar muscle group in the relative blood volume (rBV) value and relative mean transit time (rMTT) (P = 0.027, P = 0.026, respectively). The postoperative BV in the NTF group was increased compared with the preoperative BV (P = 0.006). There were significant differences in relative BV, relative mean transit time, and ST between the two groups before and after surgery, and the postoperative BV in the NTF group and ST values in the two groups were increased compared with the preoperative values. The BV in the NTF group and the ST values in the two groups were effective indicators in evaluating the changes between preoperative and postoperative perfusion. These results indicate that TTT could increase plantar tissue perfusion as assessed by BV and ST; this increase was among the reasons for the surface healing of severe DF ulcers. Preoperative CT perfusion evaluation can provide relevant information of blood vessels and microcirculation for clinical operation, and postoperative CT perfusion evaluation can provide postoperative efficacy evaluation for clinical operation. All patients received information about the study and signed a specific informed consent. Approval for this study was granted by the regional ethics committee [Regional Ethics Committee of the First Affiliated Hospital of Guangxi Medical University, China [(2018-(KY-E-069].

Purpose: Microinjury can trigger in situ tissue repair. Bone transport consists of continuous microinjuries/microfracture and induces bone formation and angiogenesis. Tibial cortex transverse transport (TTT) was found to promote angiogenesis at the foot and the healing of diabetic foot ulcers (DFUs). However, the underlying mechanism remains largely unknown. Methods: We divided 72 Sprague-Dawley rats with DFUs into the control, sham, and TTT groups. Wound measurement and histology were performed to evaluate the wound healing processes. Enzyme-linked immunosorbent assay, flow cytometry, immunohistochemistry, and Western Blot were used to assess angiogenesis and the activity of endothelial progenitor cells (EPCs) and the Ras/Raf/MEK/ERK signaling pathway. Results: We found accelerated wound healing, improved epidermal continuity, and increased dermal thickness in the TTT group than the control and the sham groups. Higher levels of serum TGF-β 1, PDGF-BB, and VEGF were detected in the TTT group. These changes were in parallel with the expression of TGF-β 1, PDGF-BB, and VEGF in the foot wounds and the frequency of EPCs in both bone marrow and peripheral circulation, which implied that the secreted TGF-β 1, PDGF-BB, and VEGF promote proliferation and migration of EPCs to the foot wounds. The expression of CD31⁺ cells, SMA-α⁺ cells, and the Ras/Raf/MEK/ERK pathway was higher in the TTT group than in the control and sham groups. Conclusion: The findings showed that TTT enhanced the production of growth factors that in turn activated EPC proliferation and migration through the Ras/Raf/MEK/ERK pathway, ultimately contributing to angiogenesis and DFU healing. Based on these findings, we proposed a theory that remote continuous microinjuries can trigger the repair of target tissues (ie, microinjury-induced remote repair, MIRR). Future studies are needed to validate this theory.