Regenerative Properties of Autologous Fat Grafting in a Complicated Radiation-Induced Wound

Radiotherapy is used either exclusively or in conjunction with chemotherapy and/or surgery for the treatment of many malignancies. Radiation is often very effective at reducing tumor size and/or recurrence but can have both short and long-term sequelae. The high proliferative capacity and metabolic requirements of basal epidermal cells makes them very sensitive to radiation. Radiated tissue manifests with hypodermal fibrosis, adiponecrosis, decreased and disrupted microvasculature density, and altered blood vessel morphology. Radiodermatitis occurs in more than 90% of patients receiving radiotherapy for cancer. Chronic soft tissue fibrosis may occur years or even decades after treatment. Radiated tissue also demonstrates epidermal thinning, eosinophilic sclerosis of dermal collagen, atypical fibroblasts, and fibrous thickening with luminal obliteration of vessels. Fibrosis is related to radiation-induced cytokine expression and reactive oxygen species resulting in cellular apoptosis. Radiated tissue is also particularly susceptible to infection because of the decreased blood supply to the tissue. 

Adipose tissue can promote angiogenesis by secreting growth factors and extracellular matrix and is also an important source of adipose stem cells. Adipose-derived stem cells (ADSCs) in adipose tissue can repair irradiated skin and soft-tissue damage, improve angiogenesis, secrete anti-apoptotic factors, mediate inflammation and mitigate anoxia, reduce fibrosis, stimulate epithelialization, and improve radiation fibrosis and other symptoms after radiotherapy.  

Few cases have been reported regarding the use of fat grafting to promote healing of radiation-induced skin damage in humans. In this case report, the authors present a patient with a chronic nonhealing, radiation-induced skin wound refractory to multiple interventions who achieved wound healing via fat grafting.

A 79-year-old male with history of medically complicated obesity, type 2 diabetes, hypertension, and coronary artery disease status presented to clinic with a chronic radiation-induced wound. Eleven years earlier, the patient had a non-ST-elevation myocardial infarction for which he received a total of 6 cardiac stents during 2 percutaneous transluminal coronary angiography procedures. Shortly after these procedures, the patient developed right scapular erythema diagnosed as radiation dermatitis. The erythema persisted with no change in severity but had recently been accompanied by pain in the same region of the patient’s right upper back. Physical examination showed a well-demarcated, rectangular, erythematous plaque measuring 4 cm x 4 cm with 2 inner areas of radiation-induced ulceration. Biopsy showed perivesical inflammation and edema with evidence of thinning of the skin associated with epidermal ulceration. The patient began receiving wound dressing changes 5 days per week and was offered a topical compound consisting of amitriptyline, ketamine, and lidocaine, but he continued to experience neuropathic pain. 

Over the next few months, the wound was complicated by 3 Pseudomonas infections and persistent pain despite repeated oral antibiotic courses, wound debridements, topical betamethasone, and weekly PuraPly AM antimicrobial wound matrix (Organogenesis Inc) applications. Recurrent Pseudomonas infections were confirmed via cultures of swab and biopsies of the wound. In consideration of potential surgical intervention, the patient was encouraged to lose weight to allow sufficient mobility to enable primary closure via fasciocutaneous flap; however, weight loss attempts did not prove to be significant for wide local resection and flap closure. The patient also commenced hyperbaric oxygen therapy (HBOT) sessions with the goal of re-establishing wound tissue oxygen gradients, which would thereby stimulate angiogenesis within areas of radiation-induced obliterative endarteritis and also provide a competent vascular foundation to support reconstructive procedures. After the completion of forty 90-minute HBOT sessions of 100% oxygen at 105 kPa, the patient experienced very minimal healing. 

On re-evaluation 19 months after the patient’s initial presentation, a plan was made to proceed with fat grafting to the radiated area using fat harvested from the patient’s lower back on the same side. In preparation for the procedure, selective sharp debridement was performed intermittently every few days for the next 6 months. Dressings included PuraPly membrane, Aquacel silicone foam (ConvaTec Inc, Berkshire, UK) into the open wound, and Mepilex border (Mölnlycke Health Care) to the radiated skin to prevent further breakdown. Preoperatively, the wound measured 1.5 cm x 1.1 cm x 2.2 cm (Figure 1). 

Fat grafting was performed as an outpatient procedure without complications. Conventional liposuction was used to harvest the fat into a Tissu-Trans device (Summit Medical). After processing and separation of microfat and nanofat, 112 cm³ of microfat was injected via a remote puncture wound into the deep subcutaneous area of the wound. Then, 18 cm³ of nanofat was injected in a more superficial plane. Xeroform gauze (Cardinal Health) was then applied to the wound. Two weeks postoperatively, the patient was counseled to apply over-the-counter moisturizing lotion and place a simple bandage over the wound daily. He otherwise did not require further treatments or procedures.

Three weeks after the procedure, the patient’s wound measured only 0.5 cm x 0.5 cm, extending less than 1 mm deep. The patient reported no associated pain. Figure 2 reflects the wound’s appearance at 3 months postoperatively. At 5 months, there were fewer associated telangiectasias; mobility of the soft tissue was increased. A small area of re-epithelialization with periodic breakdown of the area was also present. By 10 months after the procedure, the patient had near-complete healing and was pain-free (Figure 3). 

Applications of fat grafting in the treatment of radiation-induced wounds

After exposure to radiation, radiation- induced skin damage can manifest acutely or chronically. The acute manifestations of radiation-induced skin damage include a radiodermatitis-like reaction featuring localized thickening and desquamation of the epidermis. These changes are often the result of a radiation-induced inflammatory reaction precipitating hyperpermeability and progressive occlusion of dermal capillary vessels, which results in perivascular edema, erythema, and pruritus.^1,2 Proinflammatory cytokines such as interleukin (IL)-1 and IL-8 are increased and overexpression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß is seen. Stem cell proliferation mechanisms replace the lost functional cells slowly over time. 

However, even in the absence of acute manifestations, radiation exposure may cause later findings, such as increased vascular density of affected tissues, skin ulcers, or osteoradionecrosis as a result of chronic fibrotic processes that tend to worsen over time.³ Radiation disrupts the wound healing cascade as pro-inflammatory cytokines and fibrin infiltrate the tissue, collagen is deposited, and fibrogenesis is induced by chronic hypoxia, tissue ischemia and atrophy. Dysregulation of matrix metalloproteinases also cause fibroblast deposition of disorganized collagen into the wound bed. Release of reactive oxygen species and free radicals cause further damage to DNA. 

In cases of radiation exposure greater than 24 Sv, these pathologic changes can result in secondary skin ulceration that classically presents 6 weeks or more after radiation exposure.⁴ In these cases, one possible solution involves the use of fat grafting, which has been shown to reverse radiation-induced skin changes via processes thought to be mediated by multipotent adipose tissue-derived stem cells (ADSCs).⁵ These ADSCs have differentiation properties similar to those of bone marrow–derived mesenchymal stem cells, and they have been shown to secrete angiogenic and antiapoptotic factors and differentiate into endothelial cells and incorporate into vessels.^6,7 

The applications of fat grafting in reconstructive surgery have been well documented; breast cancer patients with radiotherapy-induced breast wounds who received fat grafting exhibit greater improvements in wound healing, clinical symptoms, and long-term aesthetic scores compared with patients who did not receive fat grafting.⁸ The use of fat grafting to promote healing in radiation-induced skin damage in murine models has also been documented. Animal models with radiation-induced skin damage who received fat grafting exhibit decreased epidermal thickening, collagen deposition, vascular density, and wound size in comparison to sham-grafted counterparts.^9,10 Moreover, immunoblot and histologic analyses of radiation-induced wounds treated with fat grafting have shown co-localization of ADSCs with endothelial cell markers in ulcerated tissues, again suggesting ADSCs as possible mediators of healing in these models.¹¹

Considerations involving the present case

The use of fat grafting to attenuate local vessel depletion and promote healing of radiation-induced skin damage has been well documented in murine models.^9,11-13 However, few reports to date have demonstrated its use in human models or detailed the efficacy of fat grafting in comparison with other treatment modalities, such as topical pharmacologic use, HBOT, repeated wound debridement, or surgery.¹⁴ The patient detailed in this report developed a radiation-induced skin wound refractory to multiple interventions, including more than 30 visits to dermatology for debridement and over 40 visits for HBOT. The goals of HBOT were to re-establish wound tissue oxygen gradients and thereby stimulate angiogenesis within areas of radiation-induced obliterative endarteritis, and also to provide a competent vascular foundation to support the ensuing reconstructive procedure. Wound healing was achieved after his fat grafting procedure, which was performed 19 months after initial presentation. During the procedure, harvested adipose fat was separated into microfat and nanofat, with microfat injected in a deep subcutaneous plane and nanofat injected into a more superficial plane. Due to their diminutive size, the overlying nanofat particles may lack important components for structural support of adipocytes, such as fibroblasts, blood vessels, and connective tissue. Although the nanofat particles may not contain adipocytes with long-term viability, they may retain a rich supply of ADSCs that are thought to offer improved skin quality postoperatively.¹⁵ In fact, a number of studies have demonstrated superior effects of cell-assisted lipotransfer over standard fat grafting. In C cell-assisted lipotransfer, fat grafts are enriched with the stromal vascular fraction of the lipoaspirate, or with ADSCs expanded in culture. In both animal and human experimental models, cell-assisted lipotransfer increased the volume of fat retained in irradiated skin and enhanced the ability of fat to attenuate radiation-induced dermal thickening.^16-20

Complications of fat grafting are rare but may include fat necrosis, infection, hematoma, oil cysts, calcifications and theoretical risk of cancer recurrence. Infection may be related to limited T lymphocyte activity in fat-grafted areas due to anti-inflammatory properties of the lipoaspirates. In the months before our patient’s fat grafting procedure, he developed repeated Pseudomonas-associated wound infections as a result of his radiation-induced skin damage, so proceeding with fat grafting was thought to be a means of limiting future infections and complications. After the procedure, this patient was discharged with a 7-day course of trimethoprim-sulfamethoxazole (Bactrim) and did not experience any postsurgical complications. Other complications of fat grafting in resolving radiation-induced skin damage may include damage to veins or small arteries causing ecchymosis or hematomas. 

As this patient’s course reveals, chronic nonhealing wounds can provide a tremendous burden to the patient in terms of time and costs; earlier intervention with fat grafting may prove helpful to patients who do not show evidence of healing via other methods. The findings in this report represent the clinical course of only 1 patient; although promising, it shares the limitation of all single-patient case reports. Further studies are needed to further elucidate the application of fat grafting for radiation-induced skin wounds.

Authors: Krishna S. Vyas, MD, PhD, MHS¹; Elias Simon Saba, MD²; and Nho Tran, MD¹

Affiliations: ¹Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN; ²Mayo Clinic School of Medicine, Rochester, MN

Correspondence: Krishna S. Vyas, MD, PhD, MHS, Division of Plastic and Reconstructive Surgery, Mayo Clinic, 200 First Street SW Mayo 12-44W RES, Rochester, MN 55905; vyas.krishna@mayo.edu 

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