Discussion of: decellularized adipose matrices can alleviate radiation-induced skin fibrosis; adv wound care (New Rochelle).

https://doi.org/10.58974/bjss/azbc019

With the advent of cellular targets and immunotherapy, cancer treatment has undergone significant improvement over the past several decades. While curative treatment of malignancy often relies on surgical excision, adjuvant modalities such as loco-regional irradiation remain important tools in comprehensive cancer care. Adjuvant radiotherapy (RT) is highly effective in reducing cancer burden, limiting the need for extensive surgery and decreasing the risk of local recurrence.^1-3 However, RT brings collateral damage to the healthy surrounding soft tissues. Exposure to ionizing radiation results in a series of tissue changes marked by erythema, ulceration and oedema in the acute phase, followed by chronic inflammation and skin fibrosis, which may persist after treatment ^4,5. As cancer survival rates continue to improve, an increasing number of patients are living with chronic morbidity related to RT.  

Autologous fat transfer (AFT) has emerged as a possible treatment to the harmful effects of irradiation.^6,7 Here, adipose tissue is suctioned from one part of the body, processed and then injected in small aliquots directly into the irradiated tissues.⁸ The mechanism through which lipoaspirate exerts a reparative effect is poorly understood but thought to be through direct and indirect actions: direct differentiation of transferred adipose-derived stem cells (ASCs) into new adipocytes, and paracrine signalling of cytokines and growth factors (HGF, TGF-ß, FGF-1,2, VEGF) that inhibit profibrotic signalling pathways and contribute to the recruitment of proangiogenic cells ⁹.

Like a skin graft, the adipose graft in AFT is dependent on the recipient tissue bed for nutrition and engraftment to achieve adequate ‘take.’ One of the challenges of fat grafting, in particular into a poorly perfused, irradiated tissue bed, is its unreliable retention rate, which is cited at between 30%-70%. Repeat procedures are often performed.^10,11 As an alternative to AFT, decellularized adipose matrices (DAM) derived from discarded lipoaspirate have been developed. The allografts are processed through physical, chemical, and enzymatic purification techniques to develop decellularized scaffolds that retain the complex macromolecular architecture of the adipose tissue, and potentially its paracrine function via key growth factors retained in the graft. In recent studies, DAMs have been shown to promote adipose tissue regeneration, and have become a promising alternative to traditional fat grafting for soft tissue defects. ¹² However, DAMs have not been studied in the context of radiation or a former tumour bed.

In the current study, Adem et al. compared the effectiveness of DAMs with autologous fat grafts in treating radiation injury in both murine and human tissue by analyzing the dermal architecture and vascular density of irradiated skin.¹³ First, immunocompromised mice were divided into several treatment conditions: radiation only, radiation with AFT, radiation with DAMs, and a control group that received neither radiation nor grafting. In grafted mice, volumetric analysis was conducted using micro-computed tomography (CT) at baseline and every two weeks for a total of eight weeks. Irradiated mice were sacrificed after twelve weeks, at which time the scalp skin and explanted fat were subjected to histological and mechanical analysis. Next, human skin samples (including nonirradiated, irradiated, and irradiated with grafting) were obtained from three women who had undergone grafting with autologous fat or DAM following breast cancer excision with radiation, during subsequent autologous breast reconstruction.

Both AFT and DAM grafts were found to have significant reparative effects on irradiated skin compared to controls in both murine and human tissue. However, AFT was superior to DAM in all metrics investigated. Tissue from mice injected with autologous fat had greater adipocyte integrity, greater vascularity, less inflammation, and less fibrosis compared to those grafted with DAMs. Both fat grafted and DAM grafted skin showed a decrease in dermal thickness, collagen density, and stiffness when compared to irradiated, non-grafted skin, though AFT showed significantly superior results to DAM. The authors observed high levels of factors known to regulate adipogenesis and increase angiogenesis such as FGF2, EGF2, and PDGF compared to the controls. Longitudinal CT analysis of graft retention in irradiated sites found a decrease in both AFT- and DAM-graft volume, though retention in DAM-injected mice was significantly lower. Analysis of human skin had similar findings. AFT and DAM significantly reduced dermal thickness and collagen density, with increasing tissue vascularity, when compared to irradiated, non-grafted skin.

The similar findings between the murine model and proof-of-concept human tissue lays a promising groundwork for necessary randomized control clinical trials. It remains unclear whether the decellularized matrix serves merely as an extracellular scaffold that becomes repopulated with native adipocytes, or whether the growth factors and cytokines embedded in the graft contribute to remodelling and angiogenesis observed. Previous studies suggest that it may be a combination of the two processes.¹⁴ As such, it will be critical to ascertain the oncogenic properties, if any, of the DAMs when delivered to a former tumour bed. Furthermore, given that chronic radiation effects can develop over the course of months to years after initial injury, a longer duration of study is required to substantiate the effects of DAM. Despite these drawbacks, this study provides encouraging evidence that DAM use in irradiated skin can improve and reverse several of the negative effects seen with RT, and provides a good translational model for future work in the field.

The study by Adem and colleagues has important implications for the use of DAM in clinical practice. Though it was found to be inferior to AFT, DAM showed a significant improvement in fibrosis, dermal thickness, and vascularity compared to non-grafted controls without the additional donor site or soft tissue requirement. This would have particular value in patients who may not have excess fat stores following oncological treatment. While there is much work to be done, this study provides encouraging evidence to support to the use of DAM in soft tissue reconstruction and offers a suitable translational model.