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Histologic picture of a popliteal lymph node after 43 daily subcutaneous injections of bacterial cells. Depletion of paracortical areas and germinal centers, thickening of lymph node capsule, and formation of fibrous tissue around lymphatic sinuses and blood vessels could be observed (left panel) in comparison with control lymph nodes (right panel). HE staining, magnification 200.
Source publication
The mechanical injury of soft tissues and bones of lower extremities is frequently followed by long-lasting edema at the site of trauma and distally. The pathomechanism of this complication remains unclear. Venous thrombosis and interruption of lymphatics are considered to be the main etiologic factors. We propose a concept that protracted healing...
Context in source publication
Context 1
... simulans injections, no significant changes could be observed besides separation of collagen bundles by accumulating fluid and some minor infiltrates. Popliteal LN showed cellular depletion of the paracortical spaces and ger- minal centers. Moreover, thickening of node capsule and formation of fibrous tissue in the node parenchyma were seen (Fig. 3). Cultures of lymphocytes isolated from popliteal LN after subcutaneous injections of bacteria with mitogens showed increased responsiveness to PHA, ConA, and PWM over controls. The indexes were as follows: for PHA, 2 g/mL 38.5 22.5 vs control 18.0 21.2; for ConA, 2 g/mL 73.4 51.7 vs 38.9 46.2 in controls; and for PWM, 5 g/mL 46.1 43.7 ...
Citations
... Impaired lymphatic draining function and enlarged draining lymph nodes in the fractured hindlimb LDI with dilatation of the draining collecting lymphatics occurs after fractures 12,13 , but little is known about its onset and duration. To investigate the pathophysiological changes in lymphatic dysfunction at different phases of fracture healing, we performed an open tibial fracture surgery or sham surgery on 6-8 week-old C57/BL6 male mice. ...
In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice. Sufficient lymphatic drainage facilitates fracture healing in male mice. Furthermore, we identify that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, causes LDI, and inhibits fracture healing in male mice, which can be rescued by a blood thinner. Moreover, unblocked lymphatic drainage decreases neutrophils and increases M2-type macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs) in male rats. Lymphatic platelet thrombolysis also benefits senile fracture healing in female mice. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a way forward in the treatment of bone repair.
... Chronic lymphedema caused by B. atrox was previously reported in an elder male patient, after 5 years of envenomation, with extensive edema and skin thickening accompanied by pain, paresthesia and itching in the affected limb [5]. Tissue damage caused directly by the toxins or by microvascular alterations and secondary bacterial infection can cause changes in the venous and lymphatic system conducive to chronic edema [35,36]. Chronic edema of the lower limbs is a debilitating and progressive condition that can cause daily difficulties, life-long physical, psychological and social problems [37][38][39]. ...
Snakebites caused by Bothrops snakes are the most prevalent in the Amazon region, causing local and systemic complications. Local complications are mostly represented by necrosis, secondary bacterial infection and compartment syndrome. There are reports of long-term disabilities, but their burden is poorly investigated. This study aims to describe and estimate the frequency of physical and sensory long-term disabilities from Bothrops snakebites in the Manaus Region, in the western Brazilian Amazon region. Participants were >18-years individuals that accepted to return to the hospital 3-12 months (average follow-up time of 195 days) after the discharge for neuromusculoskeletal, chronic pain and sensory assessments. Assessment of disability was also performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with summary disability using WHODAS 2.0 were identified. Fifty participants were enrolled. A frequency of 20% of the participants reported difficulty in moving the affected limb (20%), and 23.7% reported difficulty in walking. Limitations of daily activities were reported by 26% of the patients. Decreased strength of the affected limb was observed in 22% of the patients. Decreased range of joint motion was seen in 20% of the patients. Chronic pain was reported in 48% of the patients. Tactile sensibility was decreased in 30%, thermal sensibility in 14%, painful sensibility (hypoalgesia) in 12%, kinetic-postural sensibility (hypokinesthesia) in 4% and vibratory sensibility was decreased or abolished in 16% of the participants. Cognition and mobility domains were those with the highest frequencies of participants with any degree of disability, each with 57%. The summary WHODAS 2.0 disability rate was 59%. Age > 59 years (p = 0.02)] was associated with protection against disability. Difficulty in moving the limb (p = 0.05), pain at the affected limb (p < 0.01), limitations of daily activities (p < 0.01) and decreased thermal sensibility (p = 0.05) were significantly associated with disability. Citation: Fernández, E.M.G.; Oliveira, D.N.; Silva-Neto, A.V.; Dávila, R.N.; Lengler, L.; Sartim, M.A.; Farias, A.S.; Ferreira, L.C.L.; da Silva Carvalho, É.; Wen, F.H.; et al. Physical and Sensory Long-Term Disabilities from Bothrops Snakebite Envenomings in the Manaus, Western Brazilian Amazon. Toxins 2025, 17, 22. https://doi.org/ 10.3390/toxins17010022 Copyright: © 2025 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/). Toxins 2025, 17, 22 2 of 17 The present study consists of the first follow-up investigation involving Bothrops snakebite patients related to long-term disabilities. These findings represent important data on Bothrops snakebites causing clinically significant long-term neuromusculoskeletal and sensory disabilities, resulting in reduced quality of life of the patients. Key Contribution: This study provides critical insights into the clinical and epidemiological findings and the impact of neuromusculoskeletal and sensory disabilities in Bothrops snakebites in the Brazilian Amazon, emphasizing the importance of targeted public health interventions to treat and rehabilitate the patients in a timely manner.
... P ost traumatic lymphedema (PTL) is a known complication of traumatic extremity injury that can result in poor wound healing and functional impairment, and 20%-55% of patients who undergo surgical treatment for traumatic injury have persistent postoperative edema. [1][2][3] Microsurgical techniques for PTL include vascularized lymph node transfer (VLNT), lymphovenous bypass (LVB), or prophylactic LIFT (lymph interpositional flap transfer) and SCIP-LV (superficial circumflex iliac artery perforator lymphatic vessels) flaps. [4][5][6][7] Cases of successfully treated PTL after limb salvage are limited, but one study showed LVB after flap coverage of limited soft tissue injury resulted in 55.93% reduction in excess volume. ...
Post traumatic lymphedema (PTL) is a known complication of extremity trauma that is detrimental to limb form and function, healing, and quality of life. In cases of complex lower extremity trauma with vascular and extensive soft tissue injury, the risk of PTL is increased. However, many trauma patients are lost to follow-up, making the risk and potential management of these patients’ lymphedema difficult to characterize. The purpose of this report is to describe the successful surgical management of PTL secondary to significant lower extremity trauma requiring complex limb salvage reconstruction. A 43-year-old woman involved in a motorcycle accident presented with a Gustilo IIIB right tibial fracture and single-vessel leg. She underwent successful limb salvage with serial debridement, bony fixation, creation of an arteriovenous loop with a contralateral saphenous vein graft, and a chimeric latissimus dorsi-serratus anterior muscle flap. At the 5-month follow-up, she presented with significant right lower extremity lymphedema. She underwent lymphovenous bypass surgery guided by preoperative indocyanine green lymphography, which resulted in a 62% improvement in functional outcome measures, eliminated her prior need for compression garments and inability to wear regular shoes, and sustained improvement at two years follow-up. This case illustrates a near circumferential traumatic defect reconstructed with a muscle flap and successful delayed lymphatic reconstruction with lymphovenous bypass in the same patient.
... The musculoskeletal system, especially that in the skin, muscle and periosteum, contains an extensive network of LVs [3][4][5]. Previous work by Grzegorz Szczesny and colleagues on the changes of the lymphatic system in response to bone fractures [6][7][8][9], has inspired much of our work. They found that decreased lymph flow with dilatation of the draining collecting lymphatics occurs after traumatic fractures [6,7]. ...
... Previous work by Grzegorz Szczesny and colleagues on the changes of the lymphatic system in response to bone fractures [6][7][8][9], has inspired much of our work. They found that decreased lymph flow with dilatation of the draining collecting lymphatics occurs after traumatic fractures [6,7]. In addition, enlarged superficial LVs and draining lymph nodes were found in limbs with healed bone fractures, while reduced draining lymph nodes were seen in the majority of patients with nonhealing fractures [8,9]. ...
Background
The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear.
Methods
To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above.
Results
Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41⁺ platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus.
Conclusions
Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing.
The translational potential of this article
(1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.
... Despite precise presurgical planning, the inherent laxity of native tissue in foot and distal lower extremity is often inadequate to facilitate primary closure of the pedicle [12]. This is mostly due to tissue edema that is exacerbated in lower extremity surgery secondary to underlying renal status, inflammation of the injury itself, prolonged surgery, and lymphatic disruption [13][14][15]. Such conditions are more often encountered in revision surgeries caused by vascular complications requiring microsurgical re-exploration. ...
Lower extremity reconstruction is challenging because of its intricate anatomy and dynamic biomechanics. Although microsurgical free tissue transfer offers pivotal solutions to limited local tissue availability, vascular pedicle exposure after free tissue transfer is common. We evaluated a novel method of managing pedicle exposure after free tissue transfer using a reprocessed micronized dermal substitute. Ten patients who underwent lower-extremity reconstruction using free tissue transfer and micronized dermal substitute between January and December 2023 were retrospectively reviewed. When native tissue could not be closed over the pedicle, reprocessed micronized artificial dermal matrix (rmADM) was cut and stacked to protect and stabilize it. Epithelialization was achieved by secondary skin grafting or healing by secondary intention. Flap dimensions, recipient artery and vein, ADM size, time required for granulation tissue maturation and complete epithelialization, and flap outcomes were analyzed. The mean age was 55.80 ± 20.70 years, and six patients (60%) were diabetic. The mean rmADM coverage area was 8.70 ± 8.41 cm2, and the average time required for complete epithelialization was 50.89 ± 14.21 days. Except for one total necrosis due to bypass graft failure, nine limbs were successfully salvaged. Application of rmADM offers numerous advantages, including vascular collapse prevention, moisture maintenance, granulation tissue growth promotion, and pedicle stabilization.
... Impaired lymphatic draining function and enlarged draining lymph nodes in the fractured hindlimb LDI with dilatation of the draining collecting lymphatics occurs after fractures 11,12 , but little is known about its onset and duration. To investigate the pathophysiological changes in lymphatic dysfunction at different phases of fracture healing, we performed open tibial fracture surgery or sham surgery on 6-8 week-old C57/BL6 male mice. ...
Lymphatic vessels (LVs) interdigitated with blood vessels, travel and form an extensive transport network in the musculoskeletal system. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, by near infrared indocyanine green lymphatic imaging (NIR-ICG), we examined lymphatic draining function at the tibial fracture sites and found lymphatic drainage insufficiency (LDI) occurred as early as two weeks after fracture. Sufficient lymphatic drainage facilitates fracture healing. In addition, we identified that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, caused LDI and then inhibited fracture healing, which can be rescued by a pharmacological approach. Moreover, unblocked lymphatic drainage decreased neutrophils and increased M2-like macrophages of hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs). These findings demonstrate that LPT limits bone regeneration by blocking lymphatic drainage from transporting DAMPs. Together, these findings represent a novel way forward in the treatment of bone repair.
... 22 The persistence of high protein concentrations in the interstitium maintains high oncotic pressure, resulting in a vicious cycle of further edema development. 54,56,57 Therefore, in the treatment of persistent edema, a phytochemical product that can minimize stagnant protein excess and fluid congestion from the interstitium is of interest. Benzopyrones (including diosmin and coumarin) are a group of drugs that have been successful in treating lymphedema and chronic venous disease. ...
... Benzopyrones (including diosmin and coumarin) are a group of drugs that have been successful in treating lymphedema and chronic venous disease. 6,11,13,15,54,55,57 Linfadren (OMEGA PHARMA Srl, Cantù (CO), Italy) is a phytochemical product containing 200 mg of diosmin, 30.6 mg of coumarin, and 3.7 mg of arbutin, and although it has not been approved for use in USA by the FDA but is available in other countries, it has been shown to reduce breast cancer-related lymphedema 10 as well as posttraumatic/postsurgery persistent hand edema. 9 In brief, coumarin (alpha-benzopyrones) promotes the removal of surplus stagnant proteins from interstitium by increasing macrophage activity and proteolysis, resulting in less edema and chronic inflammation, [11][12][13][14][15]42 diosmin (gammabenzopyrones) is mainly a vascular-protecting agent, improving venous tone, protecting capillary bed microcirculation, reducing capillary permeability, 4,[11][12][13][14][15] and acts on the lymphatic system by increasing lymph flow and lymph oncotic pressure, 40 but being an inhibitor of inflammatory mediators as prostaglandin E2 (PGE2) and thromboxane A2 (TxA2), it also exhibits anti-inflammatory properties 27 ; arbutin has diuretic properties that help to reduce water tissue retention. ...
... Our results would seem to confirm that besides the venous system, the lymphatic system is also involved in the pathogenesis of persistent edema, as suggested by previous studies. 33,52,[54][55][56][57][58] The efficacy of Linfadren in our patients may explain, at least in part, why many of the strategies used until now to manage persistent edema have not produced the expected results. The mechanism by which the 2 main components of Linfadren, coumarin and diosmin, act to improve the function of the lymphatic system are still poorly understood. ...
Background
Persistent posttraumatic/postsurgery ankle edema (PPAE) is edema that persists from 2 weeks to 3 months after injury or surgery. PPAE has negative effects on the healing process and quality of life. This study aimed to evaluate the efficacy of a phytochemical product containing diosmin, coumarin, and arbutin (Linfadren) in addition to the conventional treatment, in patients with PPAE.
Methods
Between October 2018 and February 2020, 60 outpatients with PPAE (42 with ankle fractures and 18 with ankle sprains) were enrolled and randomized (1:1 ratio) to receive either 6-week conventional treatment plus Linfadren (study group) or conventional treatment alone (control group). Primary outcome was ankle edema as measured by the “figure-of-8-20” method. Secondary outcomes were ankle function measured by the Lower Extremity Functional Scale (LEFS), and patient’s overall perceived treatment efficacy. Tolerability of Linfadren was also evaluated. Assessments were performed at baseline, at end of treatment (6 weeks after baseline), and 3 months after the end of treatment (follow-up). A subgroup analysis was also conducted for the injury type (fracture/sprain) to identify if this factor affected the results of the primary outcome measure.
Results
At the end of treatment, the study group had a significantly greater improvement in ankle edema, improved ankle function, and more patients who considered this treatment effective compared with the control group. The measured difference in circumference by the figure-of-8-20 method averaged 4% at 6 weeks and 5% at 3 months. No difference between groups was seen in rescue medication. No adverse events were recorded. Subgroup analysis revealed no significant influence of the injury type on the primary outcome measure.
Conclusion
Linfadren in addition to conventional treatment was more effective than conventional treatment alone in patients with PPAE.
Level of Evidence
Level I, randomized controlled trial.
... Persistent edema of the limbs after trauma is estimated up to 20 to 25%; however, available evidence is focused on posttraumatic edema of the limbs and does not necessarily involve an injury of the lymphatic system. 1 The lymphatic system has a delicate balance, and under normal conditions, a functional system can match transport capacity and lymphatic load. Over time, if the load presented is higher than the transport capacity, either because of additional lymphatic load or a damaged, attenuated lymphatic system, lymphedema will occur. ...
Background Posttraumatic lymphedema (PTL) is sparsely described in the literature. The aim of this study is to propose a comprehensive approach for prevention and treatment of PTL using lymphovenous anastomosis (LVA) and lymphatic vessels free flap, reporting our experience in the management of early-stage lymphedema.
Methods A retrospective observational study was performed between October 2017 and July 2022. Functional assessment with magnetic resonance lymphangiography and indocyanine green lymphography was performed. Patients with lymphedema and functional lymphatic channels were included. Cases with limited soft tissue damage were proposed for LVA, and those with acute or prior soft tissue damage needing skin reconstruction were proposed for superficial circumflex iliac artery perforator lymphatic vessels free flap (SCIP-LV) to treat or prevent lymphedema. Primary and secondary outcomes were limb volume reduction and quality of life (QoL) improvement, respectively. Follow-up was at least 1 year.
Results Twenty-eight patients were operated using this approach during the study period. LVA were performed in 12 patients; mean reduction of excess volume (REV) was 58.82% and the improvement in QoL was 49.25%. SCIP-LV was performed in seven patients with no flap failure; mean REV was 58.77% and the improvement QoL was 50.9%. Nine patients with acute injury in lymphatic critical areas were reconstructed with SCIP-LV as a preventive approach and no lymphedema was detected.
Conclusion Our comprehensive approach provides an organized way to treat patients with PTL, or at risk of developing it, to have satisfactory results and improve their QoL.
... Primary lymphedema caused by a malformation or repair defect of the lymphatic system is rare, with an estimated prevalence of 1 in 100,000 [3] . The population frequency of PTL has not been studied but uses persistent limb swelling after trauma as a proxy, and the incidence may be as high as 20% [4,5] . ...
... Stage III denotes a markedly enlarged limb with hardened, fibrotic tissue, which can become unusually tender to touch. Patients with persistent PTL in particular often suffer from chronic sequelae such as hyperpigmentation, hyperkeratosis, delayed wound and bone healing, and frequent bouts of cellulitis [4,7] . ...
... Critical lymphatic areas have been identified in the upper and lower extremities. In these regions, the increased density of lymphatic vessels creates susceptibility to lymphatic disturbances in the event of trauma [4] . These critical lymphatic areas include the anteromedial leg, medial aspect of the arm and thigh, and medial aspect of the elbow and knee. ...
Post-traumatic lymphedema (PTL) is a complex, debilitating, and potentially common disease which has received limited attention to date. The available literature is reviewed to identify injury patterns and critical lymphatic areas associated with the disease. A deeper understanding of these critical anatomic regions allows the reconstructive surgeon to potentially identify PTL patients earlier in order to apply surgical and nonsurgical interventions in the acute phase, improving lymphatic physiology and, ultimately, patient outcomes. Current diagnostic and treatment approaches are discussed in detail, with a focus on lymphatic microsurgical techniques developed and applied to PTL within the last decade.
... cases following traumatic bone fractures. 1 Due to irreversible alterations in the lymphatic system, obtaining optimal results when restoring the physiologic lymphatic flow may be problematic. Therefore, from an anatomophysiological standpoint, a comprehensive reconstruction of the lymphatic system may be necessary beyond solely restoring the flow of lymphatic fluid. ...
... As described by Szczesny et al, alterations in the lymphatic drainage have a main role in the incidence of posttraumatic edema, as even with preservation of the superficial lymphatic system, edema can occur in virtually all cases due to decreased lymphatic flow and increased production of lymphatic fluid, secondary to inflammatory mechanisms and irritation by heme-containing compounds. 1,2,11 Alterations in the venous outflow were initially thought to be the main pathophysiologic mechanism; however, venous thromboembolism was only recognized in 24% of the subjects developing posttraumatic edema. 1,2 In these cases, lymphoscintigraphy gains an important value during the evaluation of posttraumatic edema, in which an increase in lymphatic outflow and contrast in lymph nodes, and extravasation of contrast into the skin can confirm the diagnosis of lymphedema. ...
... 1,2,11 Alterations in the venous outflow were initially thought to be the main pathophysiologic mechanism; however, venous thromboembolism was only recognized in 24% of the subjects developing posttraumatic edema. 1,2 In these cases, lymphoscintigraphy gains an important value during the evaluation of posttraumatic edema, in which an increase in lymphatic outflow and contrast in lymph nodes, and extravasation of contrast into the skin can confirm the diagnosis of lymphedema. 12 CDT is the first line of treatment for lymphedema. ...
Background Posttraumatic lymphedema develops more frequently than expected and reports on its management are scarce in the literature. We aimed to report the clinical outcomes of a case series of posttraumatic lymphedema patients treated with different vascularized lymph node transfers (VLNTs).
Patients and Methods Five patients with secondary posttraumatic lower limb lymphedema treated with VLNT were included in this report. The groin-VLNT (n = 1), supraclavicular-VLNT (n = 2), and gastroepiploic-VLNT (n = 2) were implemented. The average flap area was 69.8 cm2. Patients underwent postoperative complex decompressive therapy for an average of 10.0 months.
Results The average mean circumference reduction rate was 24.4% (range, 10.2–37.6%). Postsurgical reduction in the number of infection episodes per year was observed in all patients. The mean follow-up was 34.2 months.
Conclusions VLNT is a promising surgical treatment for posttraumatic lymphedema patients. In our report, VLNT has demonstrated to reduce the volume and number of infections per year in posttraumatic lymphedema.