Root-system-inspired core–shell microneedles enable spatiotemporal sequential therapy via ROS scavenging, angiogenesis, and capillary-driven lipid removal for enhanced fat graft survival

Abstract

Background: Autologous fat grafting is widely used in reconstructive and esthetic surgery, but its clinical outcomes are limited by early ischemia–hypoxia, oxidative stress, delayed vascularization, and subsequent lipid accumulation-induced inflammation. Current therapeutic strategies generally focus on single-stage regulation and lack temporal coordination with the dynamic pathological evolution of transplanted adipose tissue. Here, we developed a root system-inspired core–shell microneedle (MN) platform capable of sequentially regulating the graft microenvironment through early vascular promotion and later lipid removal. Methods: Vascular endothelial growth factor-loaded modified silk fibroin methacryloyl/grooved poly(lactic-co-glycolic acid) core–shell MNs (VEGF@mSF/gPLGA–MNs) were fabricated by integrating a reactive oxygen species (ROS)-responsive mSF shell with a lipid-adsorbing gPLGA core. The physicochemical properties, ROS scavenging ability, VEGF release behavior, and lipid adsorption capacity of the MNs were systematically characterized. Their biological effects were evaluated using in vitro cellular assays and a mouse autologous fat grafting model. Graft survival, vascularization, inflammatory regulation, and adipose remodeling and the underlying molecular mechanisms were assessed by imaging, histological analyses, immunofluorescence staining, ribonucleic acid sequencing, and western blotting. Results: The mSF shell rapidly responded to oxidative stress and degraded during the early stage after implantation, enabling localized VEGF release while alleviating ROS-induced cellular damage. Following shell degradation, the exposed gPLGA core facilitated directional lipid adsorption owing to its lipophilic properties and groove-mediated capillary transport. In vitro studies demonstrated improved endothelial migration, angiogenesis, ROS clearance, and mitochondrial protection. In a mouse fat graft model, VEGF@mSF/gPLGA–MNs significantly improved graft retention, reduced cystic degeneration and fibrosis, increased vascularization, and promoted adipose tissue remodeling. Transcriptomic and protein analyses revealed that lipid metabolism-related pathways, including PPAR signaling, were activated, and that inflammatory pathways, such as the NF-κB, TNF, IL-17, and toll-like receptor signaling pathways, were suppressed. Conclusions: The root system-inspired VEGF@mSF/gPLGA–MN platform enables spatiotemporally sequential regulation of the fat graft microenvironment by coordinating early vascular reconstruction with subsequent lipid clearance. This strategy provides a promising approach for improving fat graft survival and may offer a generalizable paradigm for regenerative therapies involving dynamic pathological transitions.

Keywords

Superficial fat transplantation / Core–shell microneedle / Ischemic–hypoxic microenvironment / Inflammation regulation / Lipid adsorption / VEGF / Fat graft survival

References

[1] Shim YH, Zhang RH. Literature review to optimize the autologous fat transplantation procedure and recent technologies to improve graft viability and overall outcome: a systematic and retrospective analytic approach. Aesth Plast Surg 2017; 41:815-31. https://doi.org/10.1007/s00266-017-0793-3.

[2] Fredman R, Katz AJ, Hultman CS. Fat grafting for burn, traumatic, and surgical scars. Clin Plast Surg 2017; 44:781-91. https://doi.org/10.1016/j.cps.2017.05.009.

[3] Saint-Cyr M, Rojas K, Colohan S, Brown S. The role of fat grafting in reconstructive and cosmetic breast surgery: a review of the literature. J Reconstr Microsurg 2011; 28:099-110. https://doi.org/10.1055/s-0031-1287675.

[4] Evans BGA, Gronet EM, Saint-Cyr MH. How fat grafting works. Plast Reconstr Surg Glob Open 2020; 8:e2705. https://doi.org/10.1097/gox.0000000000002705.

[5] Major GS, Simcock JW, Woodfield TBF, Lim KS. Overcoming functional challenges in autologous and engineered fat grafting trends. Trends Biotechnol 2022; 40:77-92. https://doi.org/10.1016/j.tibtech.2021.04.006.

[6] Xu S, Wang X, Xu Y, Yang H, Liao Y, Chang Q, et al. Lipophagy enhances fat graft retention by stimulating dedifferentiation of mature adipocytes and modulating inflammation. Plast Reconstr Surg 2024; 156:63-73. https://doi.org/10.1097/prs.0000000000011903.

[7] Chen X, Chen W, Xu H, Tian Y, Wang X, Chen X, et al. Disulfiram improves fat graft retention by modulating macrophage polarization with inhibition of NLRP3 inflammasome-mediated pyroptosis. Aesthet Surg J 2024; 44:NP501-18. https://doi.org/10.1093/asj/sjae075.

[8] Bhullar H, Hunter-Smith DJ, Rozen WM. Fat necrosis after DIEP flap breast reconstruction: a review of perfusion-related causes. Aesth Plast Surg 2020; 44:1454-61. https://doi.org/10.1007/s00266-020-01784-1.

[9] Irawati N, Every J, Dawson R, Leinkram D, Elliott M, et al. Effect of operative time on complications associated with free flap reconstruction of the head and neck. Clin Otolaryngol 2022; 48:175-81. https://doi.org/10.1111/coa.14000.

[10] Liu K, Cai J, Li H, Feng J, Feng C, Lu F. The disturbed function of neutrophils at the early stage of fat grafting impairs long-term fat graft retention. Plast Reconstr Surg 2018; 142:1229-38. https://doi.org/10.1097/prs.0000000000004882.

[11] Niu X, Zhang Y, Lai Z, Huang X, Guo L, Lu F, et al. Lipolysis inhibition improves the survival of fat grafts through ameliorating lipotoxicity and inflammation. FASEB J 2024; 38:e23520. https://doi.org/10.1096/fj.202302090r.

[12] Liu X, Yao Y, Zhu Y, Lu F, Chen X. Inhibition of adipocyte necroptosis alleviates fat necrosis and fibrosis after grafting in a murine model. Aesthet Surg J 2024; 44:NP585-605. https://doi.org/10.1093/asj/sjae108.

[13] Eto H, Kato H, Suga H, Aoi N, Doi K, Kuno S, et al. The fate of adipocytes after nonvascularized fat grafting: evidence of early death and replacement of adipocytes. Plast Reconstr Surg 2012; 129:1081-92. https://doi.org/10.1097/PRS.0b013e31824a2b19.

[14] Chen X, Deng Z, Feng J, Chang Q, Lu F, Yuan Y. Necroptosis in macrophage foam cells promotes fat graft fibrosis in mice. Front Cell Dev Biol 2021; 9:651360. https://doi.org/10.3389/fcell.2021.651360.

[15] Mineda K, Kuno S, Kato H, Kinoshita K, Doi K, Hashimoto I, et al. Chronic inflammation and progressive calcification as a result of fat necrosis: the worst outcome in fat grafting. Plast Reconstr Surg 2014; 133:1064-72. https://doi.org/10.1097/PRS.0000000000000097.

[16] Zhang Y, Cai J, Zhou T, Yao Y, Dong Z, Lu F. Improved long-term volume retention of stromal vascular fraction gel grafting with enhanced angiogenesis and adipogenesis. Plast Reconstr Surg 2018; 141:676e-86. https://doi.org/10.1097/prs.0000000000004312.

[17] Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 2019; 129:3990-4000. https://doi.org/10.1172/jci129187.

[18] Shin DW. Lipophagy: molecular mechanisms and implications in metabolic disorders. Mol Cells 2020; 43:686-93. https://doi.org/10.14348/molcells.2020.0046.

[19] Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol 2018; 68:280-95. https://doi.org/10.1016/j.jhep.2017.11.014.

[20] Gengatharan JM, Handzlik MK, Chih ZY, Ruchhoeft ML, Secrest P, Ashley EL, et al. Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis. Cell Metab 2025; 37:274-290.e9. https://doi.org/10.1016/j.cmet.2024.10.016.

[21] Tan Y, Huang Z, Jin Y, Wang J, Fan H, Liu Y, et al. Lipid droplets sequester palmitic acid to disrupt endothelial ciliation and exacerbate atherosclerosis in male mice. Nat Commun 2024; 15:8273. https://doi.org/10.1038/s41467-024-52621-x.

[22] Huang X, Xie M, Wang Y, Lu X, Mei F, Zhang K, et al. Porphyromonas gingivalis aggravates atherosclerotic plaque instability by promoting lipid-laden macrophage necroptosis. Signal Transduct Target Ther 2025; 10:171. https://doi.org/10.1038/s41392-025-02251-6.

[23] Zhang Q, Shen X, Yuan X, Huang J, Zhu Y, Zhu T, et al. Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis. Nat Commun 2024; 15:3213. https://doi.org/10.1038/s41467-024-47553-5.

[24] Shi S, Lu K, Tao Y, Zhang Y, Zhang L, Liu G, et al. Targeting ApoA5-associated hypertriglyceridemia to ameliorate acute pancreatitis: insights from a knockout hamster model. MedComm 2025; 6:e70555. https://doi.org/10.1002/mco2.70555.

[25] Zhao Q, Li J, Feng J, Wang X, Liu Y, Wang F, et al. Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke. Nat Metab 2025; 7:2099-116. https://doi.org/10.1038/s42255-025-01379-7.

[26] Singhal A, Russo S, Dhawan UK, Bhutia K, Bell CG, Hayat H, et al. TRIB3 links endoplasmic reticulum stress to impaired efferocytosis in atherosclerosis. Circ Res 2025; 137:1422-42. https://doi.org/10.1161/circresaha.125.326839.

[27] Soundararajan R, Maurin MM, Rodriguez-Silva J, Upadhyay G, Alden AJ, Gowda SGB, et al. Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer. Gut 2024; 74:586-602. https://doi.org/10.1136/gutjnl-2024-332535.

[28] Zhao L, Zhang C, Luo X, Wang P, Zhou W, Zhong S, et al. CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis. J Hepatol 2018; 69:705-17. https://doi.org/10.1016/j.jhep.2018.04.006.

[29] Yagyu H, Kiuchi M, Sasaki A, Itakura E, Kokubo K, Iwamura C, et al. Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity. Sci Immunol 2025; 10:eadp0849. https://doi.org/10.1126/sciimmunol.adp0849.

[30] Wu R, Zeng Y, Han J, Li L, Xiong QM, Li S, et al. Circulating FABP5 released by dying macrophages function as a DAMP to exacerbate septic inflammation. Cell Rep 2025; 44:116497. https://doi.org/10.1016/j.celrep.2025.116497.

[31] Zhang X, Lin Y, Li H, Wang Q, Mu D. Enhancing fat graft survival: thymosin beta-4 facilitates mitochondrial transfer from ADSCs via tunneling nanotubes by upregulating the Rac/F-actin pathway. Free Radic Biol Med 2025; 228:281-98. https://doi.org/10.1016/j.freeradbiomed.2024.12.061.

[32] Mohamed HJ, Jeong W, Son J, Kang HW. Bioprinting of adipose tissue graft with enhanced neo-vessel formation in vivo. Adv Healthc Mater 2025; 14:e2500627. https://doi.org/10.1002/adhm.202500627.

[33] Dong X, Suo Y, Yu J, Yu F, Li F, Zheng J, et al. Biomimetic nanoparticles simultaneously targeting modulation of lipid metabolism and phenotype of macrophages for programmed atherosclerosis management. ACS Nano 2025; 19:25628-44. https://doi.org/10.1021/acsnano.5c00216.

[34] Tang S, Cui Y, Xiao Y, Li W, Zhou Y, Li C, et al. Targeted lipid transfer nanoshuttle via lipid-specific transcytosis induces atherosclerotic plaque regression. Adv Mater 2026; 38:e11606. https://doi.org/10.1002/adma.202511606.

[35] Kim S, Kim Y, Paudel S, Kang IY, Kim S, Kim J, et al. LDI, a lipid droplet inhibitor, disrupts lipid accumulation and modulates hepatic lipid profiles in fatty liver. Adv Mater 2026; 38:e72127. https://doi.org/10.1002/adma.72127.

[36] Lin D, Li M, Wang L, Cheng J, Yang Y, Wang H, et al. Multifunctional hydrogel based on silk fibroin promotes tissue repair and regeneration. Adv Funct Mater 2024; 34:2405255. https://doi.org/10.1002/adfm.202405255.

[37] Jiang Z, Wu W, Chen T, Hu W, Zhang X, Zhou C, et al. Barrier-disrupting microneedle technology: overcoming physical, physiological, and pathological skin defenses to enhance therapeutic efficacy. Bioact Mater 2026; 57:400-29. https://doi.org/10.1016/j.bioactmat.2025.11.005.

[38] Yang Y, Sun H, Sun X, Wang Y, Xu F, Xia W, et al. From mechanism to applications: advanced microneedles for clinical medicine. Bioact Mater 2025; 51:1-45. https://doi.org/10.1016/j.bioactmat.2025.04.025.

[39] Zhou R, Yu H, Sheng T, Wu Y, Chen Y, You J, et al. Grooved microneedle patch augments adoptive T cell therapy against solid tumors via diverting regulatory T cells. Adv Mater 2024; 36:2401667. https://doi.org/10.1002/adma.202401667.

[40] Cheon H, Choi H, Kim S, Kim JH, Kim B, Kim J, et al. Surface fluidic microneedle patches for lymphatic delivery of diagnostic and therapeutic agents. Adv Funct Mater 2025; 35:e13324. https://doi.org/10.1002/adfm.202513324.

[41] Pagels RF, Prud’homme RK. Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics. J Control Release 2015; 219:519-35. https://doi.org/10.1016/j.jconrel.2015.09.001.

[42] Starmann J, Fälth M, Spindelböck W, Lanz KL, Lackner C, Zatloukal K, et al. Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis. PLoS One 2012; 7:e46584. https://doi.org/10.1371/journal.pone.0046584.

[43] Steenman M, Espitia O, Maurel B, Guyomarch B, Heymann MF, Pistorius MA, et al. Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries. Sci Rep 2018; 8:3940-12. https://doi.org/10.1038/s41598-018-22292-y.

[44] Nesvaderani M, Dhillon BK, Chew T, Tang B, Baghela A, Hancock RE, et al. Gene expression profiling: identification of novel pathways and potential biomarkers in severe acute pancreatitis. J Am Coll Surg 2022; 234:803-15. https://doi.org/10.1097/xcs.0000000000000115.

[45] Lee K, Jeong W, Choi J, Kim J, Son D, Jo T. Fat graft survival requires metabolic reprogramming toward the glycolytic pathway. J Plast Reconstr Aesthet Surg 2023; 83:23-31. https://doi.org/10.1016/j.bjps.2023.04.010.

[46] Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15:550. https://doi.org/10.1186/s13059-014-0550-8.

[47] Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43:e47-7. https://doi.org/10.1093/nar/gkv007.

[48] Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 2013; 14:7. https://doi.org/10.1186/1471-2105-14-7.

[49] Ru B, Wong CN, Tong Y, Zhong JY, Zhong SSW, Wu WC, et al. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics 2019; 35:4200-2. https://doi.org/10.1093/bioinformatics/btz210.

[50] Strong AL, Rohrich RJ, Tonnard PL, Vargo JD, Cederna PS. Technical precision with autologous fat grafting for facial rejuvenation: a review of the evolving science. Plast Reconstr Surg 2023; 153:360-77. https://doi.org/10.1097/prs.0000000000010643.

[51] Sun Y, Liu Q, Zhu J, Hu H, Lu L, Ying J, et al. Optimal strategies for autologous fat grafting in breast augmentation and reconstruction: a systematic review and network meta-analysis. Plast Reconstr Surg 2024; 155:243e-55. https://doi.org/10.1097/prs.0000000000011653.

[52] Zhu C, Huang Z, Zhou H, Han X, Li L, Yin N. Purified adipose tissue-derived extracellular vesicles facilitate adipose organoid vascularization through coordinating adipogenesis and angiogenesis. Biofabrication 2025; 17:025014. https://doi.org/10.1088/1758-5090/adb2e7.

[53] Ugusman A, Hisam NSN, Othman NS, Anuar NNM, Hamid AA, Kumar J, et al. Pharmacological interventions for intraplaque neovascularization in atherosclerosis. Pharmacol Ther 2024; 261:108685. https://doi.org/10.1016/j.pharmthera.2024.108685.

[54] Offer S, Menard JA, Pérez JE, de Oliveira KG, Indira Chandran V, Johansson MC, et al. Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration. J Exp Clin Cancer Res 2019; 38:241. https://doi.org/10.1186/s13046-019-1228-6.

[55] Kaveh A, Salazar-Martin AG, Dai W, Kithcart AP, Pan E, et al. Flow-mediated endothelial remodeling and inflammation drive developmental vascular susceptibility in ldlr loss of function. Nat Commun 2026; 17:6926. https://doi.org/10.1038/s41467-026-72756-3.

[56] Yang P, Lu Y, Gou W, Qin Y, Zhang X, Li J, et al. Andrias davidianus derived glycosaminoglycans direct diabetic wound repair by reprogramming reparative macrophage glucolipid metabolism. Adv Mater 2025; 37:2417801. https://doi.org/10.1002/adma.202417801.

[57] Zarubova J, Hasani-Sadrabadi MM, Ardehali R, Li S. Immunoengineering strategies to enhance vascularization and tissue regeneration. Adv Drug Deliv Rev 2022; 184:114233. https://doi.org/10.1016/j.addr.2022.114233.

[58] Zhang Z, Shi H, Chen J, Gu R, Li Y, Huai S, et al. Highly efficient intrastromal dual-drug delivery by a dissolving bilayer microneedle for synergistic therapy against corneal neovascularization. ACS Nano 2025; 19:37065-81. https://doi.org/10.1021/acsnano.5c10610.

[59] Ding YW, Li Y, Zhang ZW, Dao JW, Wei DX. Hydrogel forming microneedles loaded with VEGF and Ritlecitinib/polyhydroxyalkanoates nanoparticles for mini-invasive androgenetic alopecia treatment. Bioact Mater 2024; 38:95-108. https://doi.org/10.1016/j.bioactmat.2024.04.020.

[60] Tang S, Huang J, Du S, Feng W, Wang X, Cheng C, et al. Multifunctional NGF-loaded PLGA microsphere-PCL/GelMA scaffold enables coordinated osteo-neuro-vascular regeneration via PI3K/AKT pathway activation. Chem Eng J 2025; 520:165993. https://doi.org/10.1016/j.cej.2025.165993.

[61] Shan B, Wu F. Hydrogel-based growth factor delivery platforms: strategies and recent advances. Adv Mater 2024; 36:2210707. https://doi.org/10.1002/adma.202210707.

[62] Lan T, Li Q, Yu M, Duan X, Ming T, Li S et al. Dual-targeted siRubicon delivery strategy triggers hepatocellular lipophagy for mitigating liver steatosis. Nat Commun 2025; 16:7455. https://doi.org/10.1038/s41467-025-61965-x.

[63] Li MY, Wu LM, Xie HQ, Shen B. A self-assembled nano micelle-exosome with high selectivity and penetrability achieves precise intracartilage lipid delivery. Sci Adv 2025; 11:eadv8999. https://doi.org/10.1126/sciadv.adv8999.

[64] Li Y, Munoz-Mayorga D, Nie Y, Kang N, Tao Y, Lagerwall J, et al. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab 2024; 36:1351-1370.e8. https://doi.org/10.1016/j.cmet.2024.03.014.

[65] Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci 2020; 23:194-208. https://doi.org/10.1038/s41593-019-0566-1.

[66] Chen Q, Liu S, Cao L, Yu M, Wang H. Effects of macrophage regulation on fat grafting survival: improvement, mechanisms, and potential application-a review. J Cosmet Dermatol 2022; 21:54-61. https://doi.org/10.1111/jocd.14295.

[67] Ribatti D. Interleukins as modulators of angiogenesis and anti-angiogenesis in tumors. Cytokine 2019; 118:3-7. https://doi.org/10.1016/j.cyto.2018.10.022.

[68] Cai J, Feng J, Liu K, Zhou S, Lu F. Early macrophage infiltration improves fat graft survival by inducing angiogenesis and hematopoietic stem cell recruitment. Plast Reconstr Surg 2018; 141:376-86. https://doi.org/10.1097/prs.0000000000004028.

[69] Qiu H, Wang H, Ji Q, Wu D. Enhancing fat graft retention through adipose tissue browning: a systematic review. Stem Cell Res Ther 2025; 16:344. https://doi.org/10.1186/s13287-025-04473-5.

[70] Zhang Y, Li F, Dong Y, Xie W, Wang H. PPAR-γ regulates the polarization of M2 macrophages to improve the microenvironment for autologous fat grafting. FASEB J 2024; 38:e23613. https://doi.org/10.1096/fj.202400126R.

[71] Luo Z, Chen Z, Hu J, Ding G. Interplay of lipid metabolism and inflammation in podocyte injury. Metabolism 2024; 150:155718. https://doi.org/10.1016/j.metabol.2023.155718.

[72] Kim IK, Hong KY, Ju UI, Choi BG, Jin US, Chun YS, et al. Compact fat grafting: a novel method to improve graft retention through modulation of adipocyte size. Aesthet Surg J 2020; 41:NP653-61. https://doi.org/10.1093/asj/sjaa401.

[73] Dang J, Yang J, Yu Z, Chen L, Zhang Z, Wang K, et al. Bone marrow mesenchymal stem cells enhance angiogenesis and promote fat retention in fat grafting via polarized macrophages. Stem Cell Res Ther 2022; 13:52. https://doi.org/10.1186/s13287-022-02709-2.

[74] Henn D, Fischer KS, Chen K, Greco AH, Martin RA, Sivaraj D, et al. Enrichment of nanofiber hydrogel composite with fractionated fat promotes regenerative macrophage polarization and vascularization for soft-tissue engineering. Plast Reconstr Surg 2022; 149:433e-44. https://doi.org/10.1097/prs.0000000000008872.

[75] Song M, Wang L, Tian J, Qin Y, Zhang W, Chen S, et al. Photosensitive biomimetic nanomedicine-mediated recombination of adipose microenvironments for antiobesity therapy. Adv Mater 2025; 37:2417377. https://doi.org/10.1002/adma.202417377.

[76] Han J, Kanelli M, Liu Y, Daristotle JL, Pardeshi A, Forster TA, et al. On-patient medical record and mRNA therapeutics using intradermal microneedles. Nat Mater 2025; 24:794-803. https://doi.org/10.1038/s41563-024-02115-4.

[77] Han Y, Qin X, Lin W, Wang C, Yin X, Wu J, et al. Microneedle-based approaches for skin disease treatment. Nano Micro Lett 2025; 17:132. https://doi.org/10.1007/s40820-025-01662-y.

[78] Chang CS, Lanni MA, Mirzabeigi MN, Bucky LP. Large-volume fat grafting: identifying risk factors for fat necrosis. Plast Reconstr Surg 2022; 150:941e-9. https://doi.org/10.1097/prs.0000000000009655.

[79] Xining Z, Sai L. The evolving function of vasculature and pro-angiogenic therapy in fat grafting. Cell Transplant 2024; 33:09636897241264976. https://doi.org/10.1177/09636897241264976.

[80] Liu J, Wang J, Zhang Q, Lu F, Cai J. Clinical, histologic, and transcriptomic evaluation of sequential fat grafting for morphea: a nonrandomized controlled trial. JAMA Dermatol 2024; 160:425. https://doi.org/10.1001/jamadermatol.2023.5908.

[81] Zhou Q, Zhuang Y, Deng X, Jiang W, Wang X, Yuan C, et al. Hydrogel-based ROS-regulating strategy: reprogramming the oxidative stress imbalance in advanced diabetic wound repair. Adv Mater 2026; 38:e12719. https://doi.org/10.1002/adma.202512719.

[82] Xue L, Thatte AS, Mai D, Haley RM, Gong N, Han X, et al. Responsive biomaterials: optimizing control of cancer immunotherapy. Nat Rev Mater 2023; 9:100-18. https://doi.org/10.1038/s41578-023-00617-2.