Optimization of fat grafting to attenuate radiation damage: a narrative review

Introduction

Radiation-induced fibrosis (RIF) is an untoward consequence of cancer therapy and remains a progressive and irreversible condition with no curative therapies, often resulting in chronic pain, capsular contracture, and compromised reconstructive outcomes (1-3). Autologous fat grafting (AFG) has been increasingly utilized as a therapeutic strategy to mitigate radiation-induced tissue damage during breast reconstruction following mastectomies (4). While AFG has demonstrated promising regenerative effects, clinical outcomes remain variable, in large part due to graft loss (5,6). This review examines emerging adjuvant strategies aimed at improving fat graft survival, including cellular therapy, pharmacologic treatments, and prophylactic approaches designed to address traditional research outcomes regarding ischemia, oxidative stress, and impaired tissue regeneration. Although the majority of AFG research has focused on graft retention, vascularization, dermal thickness, and tissue elasticity as primary endpoints (7), an emerging body of work is investigating application of AFG to specifically resolve secondary lymphedema (8), neuropathic pain (9,10), and delayed wound healing (DWH) (11). We present this article in accordance with the Narrative Review reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0230/rc).

Methods

A literature search on PubMed was performed using the search terms “fat graft” or “adipose” and “fibrosis” and “radiation”. Full-text articles with applicable abstracts were manually screened by the first author. Articles from the reference lists and the senior authors’ own reference libraries also formed part of the knowledge base. Search strategy summarized in Table 1.

Use of radiation therapy (RT) in breast cancer

Globally, breast cancer remains the leading cancer diagnosis and the primary cause of cancer-related death in women, with an estimated 2.3 million new cases in 2022 (12). High-development countries have the highest incidence rates owing to routine mammography screening and early detection yet sustain a lower mortality rate reflecting access to advanced treatment options after timely diagnosis. Specifically in the United States (US), breast cancer is the second leading cause of cancer-related death in women nationwide and remains the leading cause of cancer-related death in Black and Hispanic women, highlighting continued healthcare disparities (13). Depending on the type, receptor subtype, tumor properties, genetic mutations, and stage of cancer, treatment involves either breast conserving surgery (BCS) or mastectomy followed by adjuvant radiation, chemotherapy, and/or endocrine therapy.

Radiation can be delivered as whole breast irradiation (WBI), where the entire breast and nearby lymph nodes receive treatment or as accelerated partial breast irradiation (APBI) for early-stage cancers where the radiation is localized to the tumor bed using a higher radiation dose (14). Nearly 50% of patients undergoing BCS will receive whole breast radiation (15). Although post-mastectomy radiation therapy (PMRT) statistics are not reported in the US, one recent study has shown that overall, 22.5% of mastectomy patients have undergone PMRT with increasing rates from 2003 to 2012 (16).

If indicated, a sentinel lymph node biopsy (SLNB) is performed as part of the surgical procedure, where the draining lymph nodes from the tumor bed are removed to confirm the advancement of cancer. This results in disruption of the lymphatic pathways and increases patient risk of developing secondary lymphedema with increasing risk as the number of lymph nodes removed increases (17).

Approximately 20% of women develop lymphedema following surgery alone, increasing to 25% following RT alone, and approaching 60% in patients who undergo both interventions (18-20). As of 2025, there are nearly 4.3 million women who have survived breast cancer and projections are expected to increase to 5.3 million survivors by 2035 (15). As the survival outcomes improve for breast cancer patients, the late effects of RT, including pain, fibrosis, lymphedema, and poor aesthetic outcomes significantly impact patient quality of life (1,2). RIF of the soft tissue leads to patients experiencing post-mastectomy pain syndrome (PMPS) and complications in breast reconstruction including DWH, capsular contracture, and breast implant extrusion with extreme cases requiring additional interventions (2).

Pathophysiology of radiation damage

RT is commonly administered as external beam RT, delivering fractionated doses of radiation over multiple sessions to the breast tissue (21,22). At a clinical level, a standard fractionated dose of approximately 2 Gy is delivered for five weekdays over the course of 3–5 weeks until a total dose of 50 Gy is achieved (23). Concurrently, advances in radiation oncology continue to reshape treatment paradigms. Hypofractionated radiotherapy delivers higher doses of radiation up to 6 Gy over fewer treatment sessions and is increasingly supported with favorable clinical outcomes (23-25). Although fractionated and hypofractionated RT are designed to deliver a sufficient dose to eradicate residual tumor cells and minimize healthy tissue injury, it can nonetheless result in both acute and chronic radiation-induced damage (26).

Radiation causes DNA damage either directly from the ionizing radiation (IR) or indirectly from reactive oxygen species (ROS) generated intracellularly (27). Cancer cells are especially sensitive to radiation compared to healthy cells due to mutated DNA repair pathways. However, proliferative tumor cells are not the only cell types with radiosensitivity, as radiation also impacts other high-turnover cells such as keratinocytes and endothelial cells. This clinically manifests as radiodermatitis in the acute phase (28,29). The damaged and dying cells release damage-associated molecular patterns (DAMPs) that activate local macrophages to secrete tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-8, which promote inflammation and recruit circulating neutrophils. Activated neutrophils release proinflammatory cytokines such as TNF-α, IL-1, and IL-6, further exacerbating oxidative stress to local tissues and increasing inflammation (1,27).

Locally, the early inflammatory response also induces vascular thrombosis and vessel occlusion, leading to tissue hypoxia that compounds existing oxidative stress, sustaining a cycle of DNA damage and inflammation (1). The activated macrophages also secrete platelet-derived growth factor (PDGF) to recruit fibroblasts and transforming growth factor (TGF)-β to promote healing by differentiating recruited fibroblasts into collagen-producing myofibroblasts that attempt to isolate the damaged tissue (3).

As the stiffness of the extracellular matrix (ECM) increases with rising collagen content, the transient myofibroblasts switch into persistent myofibroblasts driven by mechanotransduction pathways in response to the stiff environment. Transient myofibroblasts can undergo apoptosis upon completion of wound healing, whereas persistent myofibroblasts persevere and drive fibrosis (30,31). Chronically, the overproduction of collagen and ECM proteins results in RIF where irradiated soft tissue becomes scar-like with characteristics such as loss of vascularization, reduced tensile strength, increased dermal thickness, and increased collagen content with stiff, non-pliable mechanical properties. These findings have been replicated in animal studies investigating attenuation of RIF (32-36).

In addition to topical steroids (3), investigated pharmaceutical approaches include the antioxidant Silymarin as a topical gel to prevent radiodermatitis (37), cytoprotective agent Amifostine administered subcutaneously as a radioprotectant (38), oral pentoxifylline (PTX) which may reduce fibroblast proliferation to attenuate RIF, and oral PTX combined with vitamin E (VE) although nausea impacts patient compliance (3,39). Physiotherapy (PT) represents one of the most widely utilized non-surgical approaches for managing radiation-induced tissue injury, including fibrosis and lymphedema (40). While PT is traditionally positioned as a symptomatic intervention that is aimed at reducing swelling, improving mobility, and alleviating discomfort, its therapeutic effects may extend beyond mechanical tissue remodeling (41,42). Manual techniques used in PT facilitate lymphatic drainage and interstitial fluid clearance, raising the possibility that improved lymphatic function attenuates the progression of RIF. While these therapies focus on delaying the onset of fibrosis, none have shown efficacy in preventing the onset of RIF. Fat grafting has the potential to mitigate radiation damage or to prevent fibrosis when utilized in a prophylactic approach.

Fat grafting history

Since 2012, the American Society of Plastic Surgeons (ASPS) has recognized AFG as a safe and effective therapy in mastectomy patients, having demonstrated improvement of patient-reported PMPS and quality of irradiated skin (4). The first successful transplant of autologous fat was performed by Neuber in 1893 to correct a depressed facial scar, marking the origin of fat grafting and setting the foundation for its numerous cosmetic applications over the following century (43). Key learnings from the first fat grafting case included use of small volumes of fat to support sufficient vascularization and to minimize necrosis or cyst formation, which are techniques that remain in use today. Specifically in breast reconstruction, the first use of AFG was completed in 1895 by Czerny for a mastectomy case (44).

As autologous fat became recognized as an ideal filler, continued development of the harvesting, processing, and grafting techniques have improved graft survival (45). Fat grafting now has therapeutic effects beyond volume filling, and surgeons note improvement to scar tissue and skin quality, specifically in cases with radiation damage. These observations were first reported in the early 2000’s which led to clinical trials and basic science research to understand the underlying mechanisms.

Although clinical trials over the next decade focused on reducing PMPS symptoms with reduced analgesic drug use, the outcomes also demonstrated potential efficacy to mitigate radiation damage as evidenced by decreased occurrence of capsular contraction of breast implants and reduced implant exposure rates (2,6,46-52) with replication of these results in more recent studies (53-55).

Coincidentally, researchers identified stem cells in lipoaspirate tissues in 2001, marking the inception of a new field of research involving adipose-derived stem cells (ADSCs) and providing context to the healing mechanisms of fat grafting (56). Another key component to adipose tissue is the stromal vascular fraction (SVF), composed of immune cells, pericytes, endothelial cells, pre-adipocytes, fibroblasts, and hematopoietic-lineage cells that support the paracrine effects required for wound healing and angiogenesis (57). Supplementing fat grafts with SVF or ADSC concentrated cell populations have been investigated but have shown no significant improvement to graft retention as compared to AFG alone (6,58,59).

Although fat grafting has demonstrated therapeutic benefit, substantial variability remains in clinical techniques and procedural protocols to ensure sufficient graft survival. This disparity frequently exposes patients to increased procedural risk and emotional burden due to the need for multiple interventions ranging from 1–9 sessions over a long period of time to achieve the desired volume restoration (46,49,52,58,60). Further understanding of the known biological mechanisms underlying tissue regeneration in fat grafting is therefore essential to identify adjuvant therapies that can result in more consistent clinical outcomes.

Regenerative potential of adipose tissue

One of the key processes that can be attributed to the beneficial effects of fat grafting is ECM remodeling which enables future neovascularization supporting both graft survival but also attenuates radiation damage (61,62). Adipose tissue holds incredible value acting as an endocrine organ, providing the necessary paracrine signaling and cellular constituents for neovascularization and soft tissue fibrosis remodeling. The cells responsible for generating these trophic factors are the non-adipocyte cells within the SVF, which include ADSC populations that secrete vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, PDGF, and hepatocyte growth factor (HGF) (7). Certain ADSC sub-populations can also differentiate into fibroblasts, keratinocytes, and endothelial cells.

The regenerative properties can be attributed to the high population of stem cells with an approximated 375 million up to 2 billion ADSCs per liter of adipose tissue (56,63,64). Consequently, due to the significant loss of ADSCs in the months following radiation (Figure 1A-1D) the regenerative potential is severely diminished within the adipose tissue (65-67).

Figure 1 Schematic of progressive development of radiation damage. (A) Acute damage to keratinocytes and endothelial cells initiates the early inflammatory response where macrophages produce TGF-β. (B) Fibroblasts migrate to the area of injury where TGF-β promotes the transition of fibroblasts to myofibroblasts while early stages of lymphatic dysfunction persist. (C) Myofibroblasts over-produce collagen in the dermis and adipose tissue resulting in RIF. (D) Long term, there is loss of adipose tissue and significant reduction of regenerative ADSCs. Created in BioRender.com. ADSC, adipose-derived stem cell; RIF, radiation-induced fibrosis; TGF, transforming growth factor.

Recent in vivo results in irradiated mice have shown significant depletion in ADSCs, atrophy of adipose tissue, and increased adipose tissue fibrosis at 12 months as compared to non-radiated groups where ADSC densities remain unaffected despite adipose tissue loss with aging (68). AFG may restore this reservoir of regenerative ADSCs and the pro-angiogenic SVF niche which are depleted following radiation exposure, although the cellular mechanisms for why these specific cell populations attenuate RIF are not yet fully understood.

The primary challenge of fat grafting is achieving reliable long-term survival of the transplanted adipose tissue, which remains the central focus of ongoing basic research. There is currently no standardized method for assessing graft survival, therefore, clinicians use either aesthetic outcomes or advanced methods such as magnetic resonance imaging (MRI) to calculate preserved breast volume post-operatively (2).

Historically, graft retention rates of 20% to 75% have been reported with high unpredictability though direct comparisons between irradiated and non-irradiated patients were not specified (5). Focusing on studies that incorporated MRI-based volume measurements, the average volume persistence of AFG alone in irradiated patients can range from only 16.3% (5) to up to 51.4% (6), which for radiated tissue, is believed to be attributed to the hostile, non-vascularized post-radiation environment.

However, even healthy tissues see similar volume retention rates as shown in a recent prospective study for patients undergoing breast augmentation, which achieved similar findings of 46% volume retention as measured by MRI (69). The problem of volume retention is a shared challenge for both cosmetic and reconstructive procedures within both healthy and irradiated tissues, highlighting that the variability may be attributed to non-standardized procedures and measurement methods. Measurement of attenuating radiation damage could be indirectly quantified by the Late-Effects of Normal Tissue/ Subjective, Objective, Management and Analytical (LENT-SOMA) scores and the percentage of patients that experienced late complications such as capsular contraction or implant exposure in clinic (2). As such, ongoing research is currently underway to improve graft survival in irradiated tissue.

Emerging experimental approaches to enhance fat grafting in breast tissue

ADSC enriched grafts

Recognition of a regenerative ADSC population within the SVF of adipose tissue provides a biological rationale for exploring ADSC-enriched fat grafting as a strategy to improve graft retention and regenerative outcomes. Over subsequent decades, multiple clinical investigations evaluated these strategies, although reported outcomes demonstrated substantial variability in graft survival. A commonly employed approach involves reserving a portion of the harvested lipoaspirate while processing the remaining volume via centrifugation and enzymatic digestion to isolate the SVF pellet. The isolated SVF is then recombined with centrifuged lipoaspirate, typically at a 1:1 ratio, to generate an SVF-enriched fat graft, widely referred to as cell-assisted lipotransfer (CAL) (70).

In a review of three studies comparing CAL with conventional AFG, reported fat retention rates ranged from approximately 60–69% for CAL versus 45–51% for AFG, suggesting improved graft survival with SVF enrichment (71). In a separate study, SVF enrichment at a 2:1 ratio increased fat survival to 78.9% compared with 51.4% in controls, although this difference did not reach statistical significance (6). Notably, this study also identified significant variability in ADSC subpopulations between patients, reflected by differential expression of CD31, CD73, CD90, and CD105 markers which are commonly used to characterize ADSCs. Such cellular heterogeneity within adipose tissue may contribute to variability in clinical outcomes and represent an important area for further investigation given the small cohort of patients studied.

In parallel, efforts to further isolate ADSCs from the SVF led to the development of automated cell-processing platforms, such as the Celution system (Cytori Therapeutics). This platform enables Good Manufacturing Practice (GMP) compliant isolation of ADSCs, as required by regulatory authorities due to the extensive cell manipulation, and was used specifically in support of the RESTORE-2 clinical trial (NCT00616135) to correct breast deformities following mastectomy or lumpectomy with ADSC-augmented fat grafts (58). However, patients with more severe LENT-SOMA scores were excluded from the study, limiting evaluation of efficacy in advanced radiation injury and did not demonstrate significant clinical improvement. In addition, concerns remain regarding the oncologic safety of ADSC enrichment. A small cohort study of nine patients treated with ADSC-enriched fat grafts using the Celution system reported a mean follow-up of 7.8±1.5 years with no evidence of cancer recurrence or metastatic disease (59).

Nonetheless, evidence supporting the safety and efficacy of isolated ADSC enrichment remains limited, so larger and more adequately powered clinical trials are needed. Despite variable outcomes with ADSC enrichment, emerging research suggests that distinct ADSC subpopulations may exert specialized regenerative functions, including antifibrotic (CD74⁺), vasculogenic (CD146⁺), adipogenic (BMPR1A⁺), and angiogenic (CD248⁺) phenotypes (7). Enrichment of CD146⁺ ADSCs has been associated with improved graft survival, enhanced vascularization, and partial attenuation of radiation-induced tissue damage in irradiated murine models (32). Given the regulatory and translational challenges associated with extensive cell manipulation in clinic, pharmacologic modulation of specific ADSC subpopulations at the harvest site prior to fat grafting may represent a more clinically feasible strategy and warrants further investigation.

Prophylactic AFG

In 2024, of the 162,579 breast reconstructive procedures performed by members of the ASPS, nearly 26% (41,616 patients) underwent delayed reconstruction following mastectomy, underscoring the prolonged and multistage nature of contemporary breast reconstruction (72). Reconstruction is often deferred due to multiple factors, including the completion of cancer therapy, the need for tissue recovery to reduce postoperative complications, and individual patient preference. Within this framework, fat grafting has traditionally been employed as a secondary corrective procedure to address contour irregularities and volume deficits following autologous reconstruction, permanent implants, or tissue expanders.

Specifically in expander-based reconstruction, a retrospective analysis including mastectomy patients treated with RT evaluated outcomes depending on timing of fat grafting relative to implant placement. Fat grafting performed concurrently with implant placement was associated with lower complication rates and fewer revision surgeries as compared to fat grafting performed in a subsequent procedure (73). These findings suggest that earlier incorporation of fat grafting within the reconstructive timeline may confer clinical benefit, raising the possibility of integration at earlier stages, including immediately following mastectomy or after completion of RT. Preclinical evidence supports this prophylactic paradigm. In a murine model of irradiated tissue, RIF was prevented in groups treated with fat grafting or SVF injections, whereas untreated controls developed significant fibrotic changes (11).

Deferoxamine (DFO)

DFO, an iron-chelating agent, binds free iron to limit ferroptosis and stabilizes hypoxia-inducible factor-1α (HIF-1α), thereby promoting neovascularization when applied topically (74). Initial animal studies demonstrated that both topical preconditioning of target tissue prior to irradiation followed by fat grafting, as well as concurrent DFO treatment during irradiation in the absence of fat grafting, resulted in improved outcomes with respect to fibrosis prevention and vascular preservation (75-77). Additional studies investigated DFO application for excisional wound healing in irradiated tissue which demonstrated accelerated healing rates as compared to vehicle treated cohorts (78,79). Of particular interest, a case report also documented a radiation-induced breast wound that remained unresolved after five months, was treated with a topical DFO intradermal delivery patch, and demonstrated complete closure after two weeks of DFO treatment (80). Thus, DFO shows promise as an adjunctive therapy to attenuate RIF and prepare graft sites for future transplantation following RT.

Vitamin D3

Both active and inactive forms of vitamin D3 have been investigated as postoperative adjuncts due to their effects on stromal cell survival and vascular remodeling. In a nude murine xenograft model, intraperitoneal injection of vitamin D3 preserved the ADSC phenotype under hypoxic conditions and significantly improved fat graft retention, with increased graft weight and volume observed at 12 weeks (81). Treated mice exhibited enhanced neovascularization, preserved adipocyte architecture, and an absence of oil cyst formation which is indicative of necrosis. This supports vitamin D3 as a safe and accessible strategy to improve fat graft integration, however intraperitoneal injection up to three times weekly may not be feasible for patients and would require further investigation into more practical administration methods.

Metformin

Metformin has also demonstrated radioprotective and anti-fibrotic effects by inhibiting TGF-β-mediated myofibroblast differentiation and reducing radiation-induced skin thickening and collagen accumulation through FOXO3-PIK3r1 signaling. Prophylactic administration of metformin, particularly when combined with ADSCs, attenuated inflammation and fibrosis, preserved vascular integrity, and provided enhanced protection against RIF in murine models surviving to 42 days (82). In this study, metformin was delivered via intraperitoneal injection three times weekly, necessitating further evaluation to establish a clinically relevant oral dosing strategy. Moreover, repurposing metformin outside its approved indication for type 2 diabetes introduces regulatory and safety considerations that must be addressed prior to clinical application.

VE and PTX

To leverage preventive strategies commonly used to delay or reduce radiodermatitis, antioxidant and anti-inflammatory agents have been evaluated as adjuncts to fat grafting. VE, which scavenges ROS, and anti-inflammatory PTX were applied directly to adipose tissue prior to grafting. VE demonstrated a greater therapeutic benefit than PTX, exhibiting improved fat graft survival and evidence of radiation damage attenuation at 8 weeks in mice (33). Although these agents are already clinically available, their application in combination with fat grafting highlights the potential for synergistic, pharmacologic approaches to improve outcomes in irradiated tissue but may have similar challenges of being used outside of the FDA-approved intended use.

Decellularized adipose matrix (DAM)

For patients who lack sufficient autologous adipose tissue, an alternative approach may involve the use of Renuva^®, an FDA-compliant DAM. DAM is derived from human adipose tissue processed to remove viable cells while preserving key ECM components, including collagen and elastin, as well as bioactive growth factors such as FGF-2, macrophage migration inhibitory factor (MIF), and PDGF, which are associated with antifibrotic and pro-angiogenic activity. In murine models of radiation injury, DAM treatment resulted in attenuation of radiation-associated tissue damage comparable to fat grafting, despite reduced graft volume retention (34,35). Mechanistically, DAM functions as a bioactive regulator, reducing inflammatory cytokine production from irradiated fibroblasts and promoting likely macrophage M2 polarization, thereby supporting angiogenic remodeling (35).

A new human-derived adipose material known as alloClae^TM is another option for patients with inadequate adipose tissue. alloClae^TM is minimally processed with a gentler detergent as compared to Renuva^®, maintaining the adipose structure that is ideal for volume replacement including the critical ECM proteins previously discussed (83). There are no known animal research studies or clinical trials evaluating alloClae^TM and RIF. A key distinction for both products is the regulation as a human cell, tissue, and cellular and tissue-based product (HCT/P) which requires FDA-compliance but not FDA-approval. To highlight, HCT/P’s meet the definition of minimal handling and are intended for homologous use in addition to other regulatory considerations per 21 CFR Part 1271.

Prophylactic DAM

The prophylactic application of DAM using Renuva^® was also evaluated in preclinical models, in which the biomaterial was placed subcutaneously prior to irradiation. Treated animals demonstrated improved skin elasticity approaching that of non-irradiated tissue, as well as enhanced perfusion, despite reduced volume retention (36). These findings were consistent with prior studies in which DAM was used to rescue radiation-injured tissue. Although DAM was not reported to be as effective as AFG, it represents a potential alternative for patients who are suboptimal candidates for fat grafting. However, this prophylactic strategy would introduce an additional procedure prior to RT, and further investigation may be required to ensure that radiation efficacy is not compromised. Moreover, while Renuva^® is available as an off-the-shelf product, its current indication does not include prophylactic use prior to radiation.

Platelet-rich plasma (PRP)

PRP has been utilized for decades in surgical and aesthetic applications with more recent exploration for use in irradiated tissues and to supplement fat grafts in breast reconstruction. In response to injury, platelets secrete critical growth factors that support neovascularization and angiogenesis (7,84). Another key component of PRP are immunomodulatory leukocytes that have the potential to release anti-inflammatory cytokines.

In vivo studies have evaluated the use of PRP in conjunction with fat grafting, demonstrating improved wound healing rates, and attenuated fibrosis in irradiated tissues at three months follow-up in a murine animal model (85). In a head-to-head comparison of fat grafting with PRP-enrichment or fat grafting alone, a randomized control trial was performed to assess the long-term outcomes of graft survival and aesthetic outcomes (86). Patients with PRP as an adjuvant had fewer procedures required, improved aesthetic outcomes, and fewer complications. Conversely, these findings were compared in a meta-analysis which highlighted increased adverse events such as tissue necrosis in irradiated patients within PRP supplemented fat grafts despite improved aesthetic results (87). Preparation, activation, and dosage of PRP varied significantly or were not reported within the four studies included. There are limited studies evaluating PRP alone for breast reconstruction, but within head and neck oncological surgery, a case report including three patients showed promise in attenuating radiation damage when applied to the surgical wound site and minimized post-surgical complications (88).

Fat grafting applications beyond aesthetic outcomes

Secondary lymphedema

The most common cause of secondary lymphedema is breast cancer treatment with increasing risk from 3% to 21% if the axillary and/or supraclavicular lymph nodes are irradiated as compared to the breast or chest wall alone (89). Historically regarded as resistant to radiation injury, the lymphatic vasculature is now recognized as vulnerable to radiation injury, resulting in accumulation of cytokines and pro-fibrotic growth factors such as TGF-β in the interstitial fluid (90,91). The pathophysiology of lymphedema involves pathways similar to those in RIF, driven by a dysregulated Th2 mediated response releasing IL-4 and IL-13, M2 macrophage activation that produce TGF- β, that ultimately promote fibrosis and impair lymphangiogenesis (92,93). As depicted in Figure 2A-2C, radiation induces lymphatic endothelial cell (LEC) apoptosis (91), down-regulation of pro-lymphangiogenic receptor VEGFR-3 (20,94,95), and eventual stenosis of collecting lymph nodes driven by sustained local elevation of TGF-β (96,97).

Figure 2 Lymphatic fate after radiation. (A) LECs undergo an apoptotic fate following radiation but does not contribute to lymphatic dysfunction. (B) Radiation causes down regulation of VEGFR-3 receptors on LECs which inhibits lymphangiogenesis and causes accumulation of VEGF-C in the interstitium leading to leaky vessels that further increase concentration of TGF-β. (C) Within the lymphatic collecting ducts, presence of TGF-β results in an EndMT where the endothelial cells acquire an α-SMA-positive mesenchymal phenotype within the duct resulting in an occluded and sclerosed lumen. Created in BioRender.com. EndMT, endothelial-to-mesenchymal transition; LEC, lymphatic endothelial cell; SMA, smooth muscle actin; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Interestingly, a case report was performed evaluating use of fat grafting combined with SVF in the axillary region to resolve secondary lymphedema (98). The stage of lymphedema was not reported but had shown promising results regarding reduction in volume of the affected arm and improved lymphedema symptoms although there was no confirmation regarding lymphatic function. Based on these promising results, a small clinical study (NCT02592213) was initiated with ten patients having stage 1 or 2 lymphedema using SVF-enriched fat grafts but did not show significant improvement in arm volume of the affected limb and no improved lymphatic function as confirmed by lymphoscintigraphy at one year follow-up (8). In general, there were improved lymphedema symptoms and 50% of patients no longer required compression garments. Although the sample size was limited, the two patients with stage 1 lymphedema demonstrated promising responses, suggesting that earlier-stage disease may represent a more favorable response to fat grafting for irradiated lymph nodes. The current gold standard for evaluating lymphedema is lymphoscintigraphy utilizing a radioactive marker to diagnose more advanced stages. Conversely, this method lacks the sensitivity required for stage 0 and 1 detection, is time-consuming, exposes patients to additional radiation, and lacks the ability to visualize smaller lymphatic vessels (99,100). Recent advances in near-infrared fluorescence (NIRF) imaging using intradermal indocyanine green (ICG) have enabled sensitive detection of early lymphatic dysfunction and objective monitoring of treatment outcomes (101-103). The high-resolution visualization of lymphatic flow patterns also provides an opportunity for intraoperative mapping, potentially informing precision fat graft placement in areas of compromised lymphatic drainage as well as providing improved methods to measure clinical endpoints for future trials.

Experimental studies have demonstrated that SVF isolated from adipose tissue contains LECs capable of forming lymphatic vessel-like structures within seven days following transplantation (104). Additionally, investigations focusing on CD146⁺ ADSCs have reported significantly lower levels of TGF-β compared with CD146⁻ cell populations and conventional fat graft cohorts (32). Notably, CD146 is known to support both angiogenesis through VEGF-A signaling and lymphangiogenesis by mediating VEGF-C dependent pathways (105). This dual functionality suggests that CD146⁺ ADSCs may be preferentially biased toward promoting lymphatic sprouting and repair in post-irradiated tissues, where VEGF-C signaling predominates during attempted lymphatic regeneration (20,106). Whether the observed reduction in TGF-β is a direct consequence of restored lymphatics remains an important unanswered question. Recent studies have demonstrated the regeneration of lymphatic vessels in irradiated tissue of a secondary lymphedema animal model following treatment with ADSCs and bioactive ADSC-derived exosomes (107).

Neuropathic pain

One of the more debilitating outcomes of RT is the risk of developing neuropathic pain, which can range in severity from persistent and tolerable with use of analgesics to excruciating and requiring surgical intervention. Nearly one third of women develop chronic pain in the months and years after oncologic surgery and/or radiation treatment (15). The pathophysiology of RIF in the dermal tissues has the same impact on the peripheral nerves and nerve plexus, causing fibrosis both outside and within the neurons. As depicted in Figure 3A-3C, radiation directly damages the neuronal Schwann cells, causes nerve ischemia due to microvascular damage, and eventual fibrosis within and around the nerve tissues resulting in nerve entrapment and dysfunction (108).

Figure 3 Neuron fate after radiation leading to neuron degeneration and dysfunction. (A) Schwann cells that protect the axon are damaged by radiation leading to demyelination of the neuron. (B) Radiation causes neuronal microvascular damage resulting in neuron ischemia. (C) RIF develops after chronic inflammation and excess collagen deposition from activated myofibroblasts both within and around the neurons. Created in BioRender.com. RIF, radiation-induced fibrosis.

While AFG has shown improvement in pain symptoms for irradiated PMPS patients as previously discussed, a recent systematic review has shown that there is no improvement in quality of life (9). Application of AFG in the treatment of neuropathic pain has gained traction in the last decade, however clinical trials to date are limited by small sample sizes, low levels of evidence, and insufficient follow-up durations (often only 3 and 6 months) (109). Mechanistically, AFG attenuates the fibrotic tissue surrounding the affected neurons and supports axonal regrowth and remyelination as demonstrated in murine animal models with nerve injury (9,10,110).

Another neuropathic condition with shared pathology to PMPS is radiation-induced brachial plexopathy (RIBP), which is a progressive disease, occurs in 1.0–1.2% of women, and historically has higher rates due to the larger radiation doses previously used in clinic (111). Late effects of RIBP are the most common with symptoms initiating as loss of sensation that over time progress to limb paralysis. There are no clinical studies evaluating fat grafting for RIBP, although AFG has been proposed as a future direction in treatment.

DWH

An accompanying complication for irradiated skin is DWH, which arises from RIF and can develop up to 10 years after radiation exposure (112). Approximately 5–18% of irradiated cancer patients develop chronic ulcers or wounds (113) increasing the risk of infection, pain, and the need for surgical intervention for non-healing or necrosed wounds with devastating cosmetic outcomes. In a retrospective study of mastectomy patients, nearly 8% developed radiation-induced chest wall ulcers at an average of 16 years after treatment (114). Within the referenced fat grafting clinical studies of this paper, the development of DWH or radiation-induced ulcers are not known beyond the 18–36-month follow-up. Therefore, it would be valuable to determine whether improved outcomes persist in patient groups that received AFG.

Recent studies have been performed to evaluate the impact of AFG on wound healing rates. In an irradiated murine model, AFG was delivered subcutaneously immediately following radiation as a prophylactic measure to prevent RIF. Wounds were then created 6 months after AFG transplantation (11). In the AFG-derived groups there was a significantly improved healing rate at 15 days as compared to the irradiated control group. Another study evaluated intraperitoneal and intravenous injection of ADSC’s at completion of radiation in a mouse model with wound generation following 6 months from time of engraftment (115). Animals treated with ADSC’s had faster epithelialization with an average of 17.8 days for wound closure as compared to 28 days in the vehicle treated groups. A previous study investigated pro-angiogenic CD248⁺ SVF cell population suspended in a hydrogel and applied to dermal wounds in non-irradiated mice (116). Treated animals had an increased wound healing rate of 13 days as compared to hydrogel alone which healed after 16 days.

Clinically, there are two case reports specifically using AFG to resolve chronic radiation-induced ulcers. A 79-year-old male developed a fluoroscopic radiation-induced ulcer over the right scapula after stent placement 11 years prior without resolution for 19 months following conventional care (117). The patient experienced frequent wound-related infections and neuropathic pain. Near-complete wound healing and pain relief was achieved 10 months after AFG. Another case involved a 67-year-old female with a radiation-induced dermatitis ulcer that failed to resolve after removal of a carcinoma followed by radiotherapy on her leg (118). AFG was delivered at the margins of the ulcer and beneath the ulcer with complete ulcer healing occurring within 2 months following the two AFG procedures. These two clinical cases demonstrate that even after establishment of RIF and compromised wound healing, AFG has the potential to close wounds after standard of care therapies have failed.

Conclusions

Emerging cellular therapy, pharmacologic, and prophylactic strategies to enhance fat graft survival remain in early stages of investigation, leaving patients with limited options for the prevention or attenuation of RIF in the current clinical setting. Historically, fat grafting has been employed as a delayed reconstructive intervention, often months to years after RT, when tissue fibrosis and functional impairment are symptomatic. While emerging approaches have explored earlier post-radiation applications, fat grafting is rarely implemented immediately after RT due to concerns of fat necrosis and graft survival. In this review, we propose that prophylactic application of AFG prior to establishment of RIF could interrupt the chronic TGF-β driven fibrotic cascade to prevent chronic excess collagen deposition. Furthermore, we present evidence in the literature that AFG treatment could also mitigate other RIF complications such as secondary lymphedema, neuropathic pain, and chronic wounds. A better understanding of the molecular, cellular, and tissue-effects of AFG will allow us to improve its efficacy and expand its applicability to a wide range of complications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sarah N. Bishop) for the series “Aesthetic Breast Reconstruction” published in Gland Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0230/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0230/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0230/coif). The series “Aesthetic Breast Reconstruction” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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