Combined Regenerative Approach for a Complex Lower Extremity Wound: A Case Report

More than 400 million patients worldwide are affected by diabetes; over their lifetime, at least 25% will develop foot ulcers that often result in high rates of nonhealing wounds and amputation. The authors present the case of a 43-year-old female patient with multiple comorbidities who presented with a large (8 cm x 4 cm), noninfected, hindfoot plantar ulcer that extended down to the bone and calcaneus. Over 2 weeks, the patient was successfully treated using a combination of an acellular dermal matrix, nanofat grafting, and negative pressure wound therapy, lessening the effects of the ulcer on the patient’s quality of life and achieving limb salvage. Utilizing the regenerative procedures described herein may improve patient care and decrease costs.

How Do I Cite This?

Piccinini PS, Sousa Rebelato MR, Masri M, Uebel CO, Stümpfle RL, Oliveira MP. Combined regenerative approach for a complex lower extremity wound: a case report. Wounds. 2021;33(5):E34–E38. doi:10.25270/wnds/2021.e3438

Introduction

A diabetic foot ulcer (DFU) is a multifactorial complication affecting patients with diabetes mellitus (DM). These ulcers have a lifetime prevalence of 25% in this population and represent a major cause of hospitalization.^1-4 Diabetic foot ulcers also generate an economic burden on the health care system and severely impact patient quality of life.^5,6 Standard of care (SOC) consists of management of comorbidities, evaluation of vascular status and debridement, and provision of daily dressings, pressure offloading, and infection control. However, a majority of DFUs do not heal completely, and some lead to infection and amputation.^3,7 Newer wound therapies have been shown to offer better alternatives by promoting angiogenesis to accelerate healing.^4-6 In this context, the authors present the case of a patient with multiple comorbidities who presented with a chronic nonhealing plantar wound; while multiple prior treatments failed, the wound was successfully treated with nanofat grafting, negative pressure wound therapy (NPWT), and an acellular dermal matrix (ADM).

Case Report

A 43-year-old female patient presented to the authors’ clinic in Porto Alegre, Brazil, with a large (8 cm x 4 cm) hindfoot plantar ulcer that extended down to the bone and calcaneus; no necrosis or signs of infection were noted. The patient had adult-onset type 1 DM diagnosed at age 20, chronic renal failure status following living donor renal transplant 3 years prior, diabetic retinopathy, factor V Leiden mutation, and rheumatoid arthritis diagnosed in their 20s, with biopsy-proven vasculitis. The foot ulcer, which had started as a plantar perforating ulcer 2 years before, had extended into the bone and tendon and was classified grade 2 per the Wagner Diabetic Foot Ulcer Grade Classification System (Figure 1).

Previous DFU care consisted of multiple topical hydrocolloid dressings, hyperbaric oxygen therapy, NPWT, and 2 skin grafts, but the wound worsened. Computed tomographic angiography showed significant lower extremity trivessel disease, multiple luminal irregularities from the aorta down to the foot, and microvascular angiopathy. A vascular surgery consultation determined that revascularization procedures would not be of benefit; a below-knee amputation was considered. Due to the poor vascularization to the lower extremity, flap coverage would potentially be at risk of ischemia.

Thus, the authors opted for a different approach. With the patient under conscious sedation, the wound first was debrided by curetting the wound base to bleeding wound edges. Next, the distal medial thigh was infiltrated using a Klein cannula with 100 mL of a solution containing 0.5 mg of epinephrine and 500 mL of 0.9% normal saline. Manual liposuction was performed with a 3-hole, 2 mm liposuction cannula; this yielded 50 mL of lipoaspirate, which was decanted for 10 minutes, then transferred to a 10 mL syringe connected to another 10 mL syringe by a female-to-female Luer lock connector. Fat then was shuffled from one syringe to the other 30 times at a rate of 10 mL/second; resultant nanofat then was transferred through the same connector to 1 mL syringes for injection. Subsequently, 10 mL of nanofat was injected in tunnels at the periphery of the plantar wound and placed topically over the wound with a 1.4 mm microcannula. Next, an Integra Dermal Regeneration Template (DRT; Integra LifeSciences Corporation) was placed over the wound bed in contact with granulation tissue and calcaneus bone. The ADM, an acellular bilayer matrix composed of cross-linked type I collagen of bovine origin, glycosaminoglycans, and chondroitin-6-sulfate, was fixed in place using simple 4-0 mononylon sutures at the periphery (Figure 2). At the end of the 45-minute procedure, an NPWT device (VAC Therapy) was placed over the DRT and set on intermittent mode at -100 mm Hg negative pressure. The device was left in place for 7 days (Figure 3), after which dressing change was performed and the NPWT device was left in place for an additional 7 days. An additional 2 weeks of dry gauze dressings were used. Of note, the patient was only in the hospital for the operation, totaling to less than 24 hours and subsequent discharge; continued care occurred in an outpatient setting.

After 14 days of treatment, the wound showed excellent granulation tissue, with complete resolution at 60 days (Figure 4). No skin grafting was performed. At 30 days, 90 days, and 1 year, the wound remained stable. An adequate amount of calcaneal soft tissue regeneration was obtained, with restoration of a functional hindfoot architecture, and the patient was able to transfer independently from their bed to a wheelchair and return to office work. Some hyperchromia was evident, but this was not of concern to the patient.

Discussion

The psychological, medical, and economic importance of avoiding lower extremity amputation cannot be overstated. Although free flap coverage ordinarily might be an option for large wounds,^8-10due to the multiple clinical conditions and multiple macrovascular and microvascular arterial stenoses, the authors considered this approach to potentially have decreased morbidity, with no need for intensive care monitoring and subsequent discharge after less than 24 hours in the hospital. The patient was treated in an outpatient setting after discharge.

Management of DFUs remains challenging, with healing rates with conventional treatment of only 31% at 20 weeks.^2,5 The use of alternative modalities is recommended, especially when the ulcer does not decrease in size by at least 40% after 4 weeks of standard therapy.^2,5 One of the most promising treatments of DFUs is ADM; it provides a scaffold for cellular and vascular tissue growth, promoting wound healing. In this case, the authors used DRT; it has been shown to provide shorter time to closure, improve quality of life, and is associated with a lower percentage of complications compared with SOC.^3,6,7 The advantages of using NPWT as an adjunctive treatment modality for DFUs include exudate removal, edema reduction, and stimulation of granulation tissue formation.^2,6 Tonnard et al¹¹and Chen et al¹² describe nanofat as an innovative simple method of obtaining adipose-derived stem cells (ADSC) and growth factors; the process comprises mechanical emulsification and filtering of fat by repeatedly shuffling lipoaspirate.¹³ After processing, the number of adipocytes is reduced but the emulsification provides a rich stromal vascular fraction that contains ADSCs and a large amount of growth factors, such as vascular endothelial growth factor, hepatocyte growth factor, transforming growth factor, platelet-derived growth factor, basic fibroblast growth factor, and insulin-like growth factor 1.^13,14 Consequently, nanofat represents an efficacious strategy, considering that ADSCs have an angiogenic cytokine property—they are able to induce tissue neovascularization, attenuate inflammatory response, promote wound epithelialization, and form microvascular frameworks.^13-16 As a result, nanofat grafting may have positive effects on diabetic foot wounds after 4 weeks to 12 weeks of treatment, accelerating wound healing.^11,12,17 Nanofat grafting has been used successfully in the treatment of burn wounds and scars and for the improvement of skin quality for facial rejuvenation and chronic ulcers, among other more promising, though experimental therapies. Potential regenerative effects of ADSCs may be facilitated by the lattice framework of ADM; ideally, a single treatment such as described in our patient would be preferred compared to multiple rounds of fat grafting. The beneficial wound healing effects of ADSCs may be mediated by extracellular vesicles (exosomes and microvesicles).^18,19 A 2020 study suggested that, even in patients with chronic, infected ulcers unresponsive to systemic antibiotics, nanofat grafting in association with platelet-rich plasma may improve healing rates.¹⁷ In addition, studies have shown that nanofat grafting in association with NPWT may improve wound healing rates as can the application of ADSCs combined with NPWT to promote an increase in neovascularization and the adherence rate of ADM to the recipient bed.^15,20

An essential aspect to be considered concerning the treatment of DFUs is the burden on public and private insurers, due to the fact that the relative cost of care of patients with this complication is up to 5.4 times greater than patients without it.⁴ Diabetic foot ulcers are responsible for an estimated cost of $4595 per ulcer episode, resulting in up to $35000 per patient annually, representing a total annual cost of $9.1 to $13.2 billion in the United States alone.^7,20 Further, on average, patients with DFUs miss more days of work, resulting in an indirect cost of $6311 per patient per year in the US; additional costs incurred are associated with reduced quality of life and premature mortality.^6,15,20

Avoiding amputation leads not only to a significant decrease in health care costs²¹ but also to decreased medical and psychological morbidity to patients, which cannot be underestimated. The present patient was treated as an outpatient in Brazil; used as a single sheet of dermal matrix used once (one episode), the DRT cost in Brazil is approximately $4000. This is significantly different when compared with the United States, where cost is estimated to be around $2522. In the present study, each 7-day treatment period with NPWT costs $375, while hospital costs were $500 and physician reimbursement was approximately $1000. Thus, total cost for treatment for this patient was $6250.

Cost-effectiveness is fundamental when considering novel medical treatments. Interventions are considered cost-effective when they avert one DALY (disability-adjusted life-year) and cost less than 3 to 4 times of a country’s gross national income per capita (GNI). Since the GNI for Brazil is approximately $15000, a treatment of up to $45000 to $60000 would be considered cost-effective. In the same manner, considering the annual cost per patient with a DFU in the US is approximately $35000 and the cost associated with SOC in the US for 20 weeks has been reported to be $2823, the use of advanced wound care products likely represents a cost-effective alternative.^22,23

Median time to closure of DFU with DRT was 43 days compared with 78 days with 0.9% normal saline gel in a large, randomized trial in the US²⁴; healing rates were also significantly higher. Although use of advanced wound care products may increase short-term expenditures, overall cost savings can be achieved through increased and faster healing rates and reduced incidence of complications, recurrence, hospital length of stay, and loss of productivity.^4,22

As an isolated treatment modality, nanofat grafting has the potential to further decrease costs; however, studies are needed to standardize the process for use in chronic wounds. Since harvesting for nanofat may be done under local anesthesia, with minimal morbidity and cost, wound nanofat grafting can feasibly be performed in the clinic, which could potentially further facilitate treatment of such wounds.

Limitations

The use of nanofat in association with ADM and NPWT is a promising future direction for non-healing wounds; however, limitations include the single patient reported and the variability with regard to processing and yield of nanofat. Additionally, the additive effect of each of these 3 treatment modalities on wound healing is one of the most important aspects that the authors are beginning to evaluate in an outpatient clinic setting, with nanofat grafting performed under local anesthesia. Although there is no documentation in the literature to date, to the authors’ knowledge, promising results with the isolated use of nanofat have been presented at conferences and there are ongoing studies exploring these effects.

Conclusions

Besides causing recurrent hospitalization, loss of productivity, and the devastating potential need for amputation, DFU also lead to economic consequences for individuals and health services. For this reason, effective management is essential to provide a better quality of life to patients and reduce the burden on the healthcare system through faster wound healing and decreased costs. Nanofat grafting, NPWT, and DRT are more recent steps on the classic reconstructive ladder, which can lead to increased and faster time to closure, decreased morbidity, and lower costs. The synergistic effects of these interventions need to be evaluated, and a stepwise approach may help improve care for affected patients. Further cost-benefit analyses are necessary for more widespread adoption of these newer treatments; however, the association of nanofat with ADM may be the way forward in the treatment of DFUs.

Acknowledgments

All authors contributed equally to this manuscript.

Authors: Pedro Salomão Piccinini, MD¹; Mariana Rodrigues de Sousa Rebelato²; Marwan Masri³; Carlos Oscar Uebel, MD, PhD⁴; Rubem Lang Stümpfle, MD⁵; and Milton Paulo de Oliveira, MD⁴

Affiliations: ¹Associate Member, Brazilian Society of Plastic Surgery. Clinical Associate, Plastic Surgery Division, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; ²Medical student, Lutheran University of Brazil, Canoas, Rio Grande do Sul, Brazil; ³Pre-medical student, University of California, Los Angeles, CA; ⁴Full Member, Brazilian Society of Plastic Surgery. Professor, Plastic Surgery Division, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; ⁵Full Member, Brazilian Society of Plastic Surgery. Hospital Blanc Medplex, Porto Alegre, Brazil

Correspondence: Pedro Salomão Piccinini, MD, Rua Hilário Ribeiro, 202 – 5th floor, Porto Alegre – RS, 90510-040, Brazil; pspiccinini@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.

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