Abstract
Divalent trace metals (TM), especially copper (Cu), cobalt (Co) and zinc (Zn), are recognized as essential microelements for tissue homeostasis and regeneration. To achieve a balance between therapeutic activity and safety of administered TMs, effective gel formulations of TMs with elucidated regenerative mechanisms are required. We studied in vitro and in vivo effects of biodegradable macroporous cryogels doped with Cu, Co or Zn in a controllable manner. The extracellular ROS generation by metal dopants was assessed and compared with the intracellular effect of soluble TMs. The stimulating ability of TMs in the cryogels for cell proliferation, differentiation and cytokine/growth factor biosynthesis was characterized using HSF and HUVEC primary human cells. Multiple responses of host tissues to the TM-doped cryogels upon subcutaneous implantation were characterized taking into account the rate of biodegradation, production of HIF-1α/matrix metalloproteinases and the appearance of immune cells. Cu and Zn dopants did not disturb the intact skin organization while inducing specific stimulating effects on different skin structures, including vasculature, whereas Co dopant caused a significant reorganization of skin layers, the appearance of multinucleated giant cells, along with intense angiogenesis in the dermis. The results specify and compare the prooxidant and regenerative potential of Cu, Co and Zn-doped biodegradable cryogels and are of particular interest for the development of advanced bioinductive hydrogel materials for controlling angiogenesis and soft tissue growth.
Highlights
Treatment of severe organ/tissue injuries generally requires the replacement of a post-traumatic defect with a scaffold such as an autologous/decellularized graft or preferably biomimetic biodegradable material capable of supporting cell growth and functional activity while overcoming the limitations of donor grafts mostly related to their scarcity and host immunogenic responses [1]
The metal content in the cryogels linearly depended on the concentration of trace metals (TM) in the gel-forming solution from 0.04 to 5 mM; the TM-doped cryogels were designated by these concentrations
For the upper 1 mM concentration used in this study, the TM content in cryogels was previously shown to amount to ca. 3 × 103 ppm (Zn, Cu) and 1 × 103 ppm (Co) [19]
Summary
Treatment of severe organ/tissue injuries generally requires the replacement of a post-traumatic defect with a scaffold such as an autologous/decellularized graft or preferably biomimetic biodegradable material capable of supporting cell growth and functional activity while overcoming the limitations of donor grafts mostly related to their scarcity and host immunogenic responses [1]. A number of biomimetic scaffolds composed of synthetic or/and naturally occurring biopolymers have been proposed, these materials by themselves are not able to provide sufficient regenerative responses without special bioactivation [2] Transplanted cells such as mesenchymal stem cells from different sources [3], skin fibroblasts [4], neural cells [5], as well as related products (e.g., platelets [6] and extracellular vesicles [7]), were proved to enhance tissue regeneration activity of biomaterials. These biological products unavoidably feature typical limitations of donor tissues, primarily, low availability, variability of characteristics, and health risks. More stable, reproducible and available active components of biomaterials are still demanded in tissue engineering and regeneration applications
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