Joris van Dongen

299 Adipose ECM hydrogels to release paracrine factors which results in more crosslinks between proteins and therefore a high stability of the ECM proteins 14 . The major component of ECM is collagen type I and glucose-based AGEs may cause a high level of intramolecular Lys-Arg and Lys-Lys crosslinks that increase the molecule’s stiffness 41 . The glycation and crosslinking masks potential pepsin digestion sites and thus yields different, likely larger, fragments upon pepsin treatment. As it appeared these fragments did not yield hydrogels from diabetic ECM. Instead of adipose tissue, other sources of matrices with a higher stiffness might also suit to enhance wound healing. Our recent data show that ECM hydrogels from heart or aorta tissue have a higher viscoelasticity (to be published elsewhere). To date, most studies that evaluate decellularized adipose tissue focus on tissue engineering of a new subcutaneous fat layer rather than its use to augment wound healing 42-46 . Moreover, all these studies used adipose matrix derived hydrogels without incubation of paracrine factors. Without the use of additional paracrine factors and cytokines, the soft adipose matrix will most likely only regenerate a soft subcutaneous fat layer. Yet, to regenerate a dermal layer for wound healing purposes, the addition of factors released by ASC is warranted. A combination of factors released by ASC and a soft adipose matrix derived hydrogel might, therefore, be an ideal treatment modality for full thickness wounds. Both types of gel released functional factors over a longer time. However, a large inter donor variation remains regardless the origin of the ECM. The inter donor variation might be caused by the fact that ECM derived from different donors with different ‘pack years’ of diabetes. In this way, the amount of AGEs accumulation is different between donors. Moreover, liposuction procedures are performed on lean patients and patientswith obesity. However, obese patients frequently acquire diabetes mellitus type 2 with high levels of glucose prior to diagnosis. It is feasible that ECM derived from non-diabetic donors was exposed to high levels of glucose already. Finally, the medical history of the anonymous donations was unknown. We cannot exclude the influence of age, gender, BMI and other confounding factors on the donor variation 47-50 . This warrant to standardize the generation of factor-loaded ECM hydrogels with regard to both producing ASC as well as to source of the ECM. The low yield of adipose-derived ECM (w/v base) hampers clinical application of adipose tissue-derived hydrogels. In summary, this study shows that several important wound healing related processes i.e. angiogenesis, fibroblast migration and proliferation are stimulated by a sustained release of growth factors from ECM-derived hydrogels. Therefore, the use adipose tissue ECM-derived hydrogels incubated with released factors from ASCs become a promising new treatment modality to augment disturbed dermal wound healing e.g. diabetic ulcers. Animal studies are warranted as an essential prelude to clinical trials.