A　collagen-based　scaffold　carrying　poly(lactic-co-glycolic　acid)　(PLGA)　microspheres　(MPs)　delivery　system　has　been　developed　for　controlled　release　of　recombinant　human　epidermal　growth　factor　(rhEGF).　The　aim　of　this　study　was　to　incorporate　the　rhEGF-loaded　PLGA　MPs　into　a　collagen/　chitosan/silk　fibroin　scaffold　to　prepare　a　novel　MPs-scaffold　hybrid　system　for　drug　delivery　and　skin　tissue　engineering　application.　The　microstructure　of　the　obtained　scaffold　was　observed　by　scanning　electron　microscopy,　and　was　found　that　there　were　uniformly　distributed　spherical　MPs　in　the　scaffold　with　an　interconnected　porous　structure.　The　characteristics　of　the　obtained　scaffolds　were　evaluated　in　vitro,　including　swelling,　degradation,　cytotoxicity　and　drug　release.　These　results　showed　that　the　scaffold　could　control　release　of　rhEGF　in　vitro,　as　well　as　efficient　water　absorption　and　retention　capacities.　In　addition,　in　vitro　biocompatibility　of　the　scaffold　was　established　using　fibroblast　cells.　Histological　and　morphological　studies　showed　that　implantation　of　the　scaffolds　in　wounds　created　in　rat　skin　induced　progressive　regeneration　of　skin　tissue　without　signs　of　inflammation　or　infection　6　weeks　after　implantation.　These　results　indicated　that　the　as-prepared　collagen-based　scaffold　has　an　immense　potential　in　the　field　of　skin　tissue　regeneration.　©　2017　American　Scientific　Publishers　All　rights　reserved.