in the field of fat transplantation

Thank you very much for your detailed introduction, which gives me a more detailed understanding of your current research project. Your team has indeed done a lot of work in the field of fat transplantation, which makes me excited and a little bit stressful. Last week, I read your email and searched some relevant literatures according to the clues you gave, which also deepened my understanding in the field of fat transplantation. According to your comments and my work experience, I am very interested in the fourth topic “influence of senescence on lipograft/tSVF-augmented scar reversal/wound healing + 3D in vitro modelling (building on pilot data, new research). ” scar and wound healing Wound healing and scar treatment has always been a difficult problem in plastic surgery. Wound healing and scar formation mainly comprising three phases：（1）inflammation，（2）proliferation，（3）remodeling. Research on wounds and scars mainly focuses on the second phase, the proliferation of vascular endothelial cells and fibroblasts which plays an important role in wound contraction. Fibroblasts have an ability to differentiate to myofibroblasts. Myofibroblasts are characterized by a large amount of α-SMA. When the wound contraction stops and complete epithelialization, myofibroblasts will disappear. However, they persist in hypertrophic scars and lead to scar contraction. Myofibroblasts are encapsulated in the extracellular matrix they secrete, and they also secrete MMPs, TGF-β and TIMPs to regulate the degradation of extracellular matrix. Only exquisite balance between matrix degradation and synthesis can achieve ideal wound healing. Senescence cell and senescence-associated secretory phenotype(SASP) You mentioned in the email that you did two consecutive lipografts to augment dermal scars and showed that during scar reversal several senescence markers were upregulated (e. g. p16). And professor Marco Demarria, your colleague, has published papers that suggest that dermal senescence is promoting wound healing. This is novelty for me and I am very interested, so I read some literatures about that. Cell senescence is often accompanied by the generation of senescence-related secretory phenotypes (SASP). Professor Marco Demarria mentioned in the article that PDGF-AA is an early SASP factor induced during wound healing through myofibroblast differentiation. Another important SASP factor is MMP which could degradate ECM. These are closely related to wound healing and scar formation. Most senescent cells express the tumor suppressor P16, which prevent cell cycle progress. As we mentioned above, we can infer that lipografts may induce cell senescence. This hypothesis surprised me very much, as, most of the existing fat transplants in China are implemented for facial anti-aging treatments. So I carefully read the article published by Marco Demarria in 2014 again. There is another significant conclusion suggesting the time-dependent regulation of SASP factors might inpart explain the beneficial versus deleterious effects of senescent cells. In the process of tissue damage, senescent cells only appear transitorily, and the continuous appearance of senescent cells could lead to aging-related diseases. Lipograft Studies have pointed out that cells (including fat cells and ASCs) within 300 microns from the edge of the transplanted fat tissue can basically survive, and this area is called the "survival zone". The second area approaching inward is the "regeneration area". The survival of the tissue in this area depends on the degree of revascularization and its contaction with surrounding tissues. The fat cells in this area would die the first day after transplantation, but ASCs can survive and differentiate into new fat cells instead of dead fat cells. The core area is the "necrotic area". The fat cells and ASCs in this area die without fat regeneration. The necrotic fat suffers from liquefaction and absorptionand, then filled with fibrous connective tissue or forms calcification. That is to say, lipograft could form a microenvironment with ischemia, hypoxia and inflammation for a period of time. It may be that this microenvironment induces senescent cells to temporarily appear and secrete SASP factors (PDGF-AA, MMP), thereby affecting wound healing and scar reversal. This kind of microenvironment might induce the transient presence of senescent cell which secrete SASP factors（PDGF-AA，MMP）, and then affects wound healing and scar reversal. ECM-drived hydrogels I’m not so familiar with tissue engineering technology, but I attended a plastic surgery conference last year and one of the experts mentioned the application of hydrogel as scanfolds in plastic surgery. This technique is very attractive to me. Using ECM-derived hydrogel as a scaffold for tissue engineering can build a good three-dimensional growth environment, promoting the growth and differentiation of seed cells and secreting extracellular matrix, so it is very ideal to use ECM-derived hydrogel to construct tissues. I also want to try to use ECM-derived hydrogel as a platform to study the relationship between scar reversal/wound healing, fat transplantation and senescent. The above are some of my thoughts about this topic. Could I design a research proposal based on this hypothesis? Hope you could provide some suggestions and guidance.