Innovative Regenerative Treatment with Nanofat Injection for Hypertensive Ischemic Leg Ulcer: A Case Report

Introduction

Chronic wounds affect millions worldwide, leading to significant morbidity and reduced quality of life [1]. Traditional therapies, including skin grafts, often result in poor outcomes and high recurrence rates. Martorell’s ulcer, also known as hypertensive ischemic leg ulcer (HYTILU) or Martorell hypertensive ischemic ulcer, is a specific type of chronic wound characterized by severe pain and poor healing [2]. Nanofat, enriched in adipose-derived stromal cells (ADSCs), has emerged as a novel therapeutic option due to its regenerative potential [3]. In accordance with the CARE Checklist (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000547402), we present a case demonstrating the successful use of nanofat in healing a Martorell's ulcer.

Case Description

A 75-year-old female presented with a HYTILU on the medial interphalangeal region of the left foot. The ulcer measured 30.1 cm² (Fig. 1a) and had been refractory to conventional treatments for over 5 years, with two previous skin graft failures. The patient had a history of chronic hypertension, managed with amlodipine, enalapril, and hydrochlorothiazide, and type 2 diabetes mellitus treated with metformin for over 30 years. Her body mass index was 29 kg/m². Wound management consisted of standard moist dressings (Urgotul^®) changed every 2 days. Two prior attempts of split-thickness skin graft were performed, both of which failed. Due to ulcer-related pain and chronic discomfort, her mobility was significantly limited, and she required a walking aid for short distances (less than 30 m).

Fig. 1.

HYTILU of the right foot’s back. a Ulcer of 30.1 cm² before intervention. b Ulcer of 9.1 cm² 3 months after injection. c Total healing 6 months after the injection.

The diagnosis of HYTILU was confirmed after exclusion of other potential causes. The patient had normal Ankle-Brachial Index. The Doppler ultrasound showed no evidence of arterial or venous insufficiency. A skin biopsy was also performed and excluded vasculitis and malignancy, including pyoderma gangrenosum and squamous cell carcinoma. These negative findings supported the diagnosis of a hypertensive leg ulcer.

The ulcer exhibited necrotic tissue with well-defined margins and signs of ischemia. The patient reported severe pain with a VAS = 8/10 (Visual Analog Scale) and mobility restrictions, significantly impairing her quality of life. Nanofat preparation was done using the Tonnard technique [4] to obtain nanofat (Fig. 2):

Fig. 2.

Nanofat preparation. a Harvest of subcutaneous adipose tissue using a multi-perforated cannula and a syringe. b Three emulsifiers of different sizes: 2.4 mm, 1.4 mm, and 1.2 mm (Anaerobic and Sizing Transfers^TM, Tulip Medical Products). c NanoTransfer Generation I^TM featuring a disposable 500-µm filter.

The procedure began with an infiltration of 100 cm³ of 0.9% NaCl diluted with a solution containing 1% lidocaine hydrochloride (10 mg/mL) and adrenaline (0.005 mg/mL) at the donor site (periumbilical region). Fat was harvested using a Trivisonno MicroHarvester™ (Tulip Medical Products), a multiperforated cannula with 1-mm-diameter holes connected to a 10-mL Luer-Lock syringe under manual vacuum.

Decantation was performed on the collected adipose tissue in 10-mL syringes, resulting in three distinct layers: an upper oily layer (damaged adipocytes), a middle purified fat layer, and a lower aqueous layer consisting of blood and infiltration fluid. The lower layer was discarded, and the purified fat layer was transferred to a clean syringe. The fat was then emulsified by transferring the material between two 10-mL syringes connected via female-female Luer Lock connectors, starting with a 2.4-mm connector (30 passes), then repeated using 1.4-mm and 1.2-mm connectors. This process produced a uniform, whitish emulsion.

To purify this emulsion into nanofat, it was passed once through a NanoTransfer Generation I™ system using a 500-µm filter cartridge, removing connective tissue and adipocytes. The resulting nanofat was collected in 1-mL syringes. A total of 5 mL of nanofat was ready for injection.

Local anesthesia was then administered to the ulcer site. After surgical detersion and trimming of the wound edges, nanofat was injected intradermally at a rate of 0.1 mL every 2 cm using a 1-mL syringe and a 30-gauge needle, targeting the edges of the ulcer and the wound bed. A silicone interface dressing was applied and left in place for 3 days. Dressings were changed on day 3 and subsequently daily at home. No immobilization or offloading was required; the patient remained ambulatory post-procedure.

Standardized photographs of the wound were taken at each follow-up visit using a digital single-lens reflex camera equipped with a fixed 50-mm focal length lens. Image analysis was performed using ImageJ software (NIH, Bethesda, MD, USA).

At 3 months, the ulcer surface area had reduced to 9.1 cm², reflecting a 70% healing rate (Fig. 1b). Complete healing was observed at 6 months (Fig. 1c). Pain was eliminated within 7 days (VAS: 0/10), and the patient discontinued opioid analgesics within 2 weeks post-procedure. Scar quality was assessed using SCAR-Q (300/300) and Vancouver Scale (3/13), indicating excellent outcomes. Quality-of-life assessments revealed significant improvements, with mobility and pain no longer impacting daily activities.

Discussion

HYTILUs are primarily caused by hypertensive microangiopathy, leading to subcutaneous arteriolosclerosis, reduced capillary density, and chronic tissue ischemia. The resulting hypoperfusion contributes to progressive skin necrosis, pain, and poor wound healing [5].

Nanofat, which contains a high concentration of ADSCs, supports tissue repair by releasing signaling molecules that encourage new blood vessel formation, reduce inflammation, and improve the structure of damaged tissue [4, 6]. These effects directly address the core problems in HYTILU, which are poor blood flow and chronic tissue damage, helping to explain the successful healing observed in this case.

This case underscores the regenerative capacity of nanofat in successfully treating HYTILU. The treatment not only resulted in the complete healing of a chronic wound persisting for over 5 years, despite previous skin graft failures, but also significantly reduced pain and improved the patient’s quality of life. The surgical technique was adapted from Tonnard, who highlighted the potential of nanofat for skin rejuvenation and its applicability in improving the management of chronic wounds [4].

Necrosectomy followed by skin grafting is currently the gold standard treatment for HYTILU. The graft promotes epithelialization and reduces healing time by releasing growth factors and vasodilator peptides [7]. The failure rate of skin grafts is high. Studies have shown that in 30–40% of cases, multiple successive grafts are required. For example, in this retrospective series involving 31 patients with HYTILU, 26 out of 29 patients underwent a skin graft immediately after necrosectomy. Healing was achieved with a single skin graft in 14 patients, while the remaining 12 experienced recurrence despite the initial graft [8].

Pain in HYTILUs is intense and often far worse than expected for the size of the wound. It occurs because poor blood flow from damaged small arteries leads to tissue death. The pain is often severe, especially at night, and doesn’t respond well to typical painkillers, including opioids [9, 10]. In this case, the pain was severe, with a VAS of 8/10, associated with mobility restrictions and a significant impairment of her quality of life. After the nanofat treatment, the pain was eliminated within 7 days (VAS: 0/10), and the patient discontinued opioid analgesics within 2 weeks post-procedure. This effective pain control aligns with the findings of Jan et al. [11], who demonstrated in 2019 that nanofat is an effective solution for alleviating pain in postburn scars, suggesting the broad analgesic application of nanofat in various types of chronic wounds.

Harvesting skin grafts can cause pain for several weeks and leave a scar at the donor site [12]. A scar from a grafted ulcer often differs in color and elasticity from the surrounding skin. When skin grafts necrose, direct healing results in sclerotic, fibrous, hypo- and/or hyperpigmented scars, along with vascular abnormalities. ADSCs are typically collected under local anesthesia on an outpatient basis. Nanofat, which does not utilize healthy skin, leaves only a discreet scar in the liposuction area. Stem cells begin to proliferate between the first and fourth week after injection [13] Stimulating various wound healing agents through their paracrine, anti-inflammatory, and proangiogenic functions facilitates angiogenesis, modulates inflammation, and enhances tissue repair [4, 6].

The patient’s rapid recovery aligns with existing literature on ADSC-mediated wound healing. A prospective study by Chopinaud et al. [14], published in 2017, investigated autologous fat grafting for the treatment of hypertensive leg ulcers in 10 patients. Liposuction and fat grafting were performed under general anesthesia. They reported a significant decrease in the ulcer area, with complete healing in 1 patient at 3 months and in 3 other patients at 4 months.

Compared to skin grafts, nanofat offers superior outcomes with minimal invasiveness and enhanced patient satisfaction. Limitations include the single-case design and lack of long-term follow-up.

Conclusion

Nanofat is an innovative way to treat HYTILU, especially for cases that do not respond to standard therapies. It shows promise in speeding up healing, reducing pain, and improving quality of life. More research is needed to confirm these results and refine treatment protocols. Future studies could also investigate its use for other types of chronic wounds.

Acknowledgments

The author acknowledges the contributions of the clinical and nursing staff at the University Hospital of Dijon.

Statement of Ethics

This study protocol was reviewed, and the need for approval was waived by the Clinical Research and Innovation Department (DRCI) as it is a retrospective case report. Written informed consent was obtained from the patient for publication of the details of her medical case and any accompanying images.

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

No funding was received for this study.

Author Contributions

Mélodie Terrasa and Marwa Majzoub contributed equally to the conceptualization, formal analysis, investigation, and software. Mélodie Terrasa drafted the original manuscript. Alessio Stivala was involved in initial study conception, design and data acquisition. Subsequently, Geraldine Jeudy and Vivien Moris contributed equally to the resources, supervision, validation, and writing – review and editing.

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