Preterm premature rupture of membranes (pPROM) is a major cause of preterm birth. Recently, extracellular matrix-directed treatment is applied for wound healing. Here, we used a pregnant mouse model to test the efficacy of collagen type 1 gel for healing of the prematurely ruptured fetal membranes. Although injection of PBS into the ruptured fetal membranes resulted in 40% closure, injection of collagen type 1 improved closure rates to 90% within 72 h. Macrophages of the M2 wound healing phenotype were entrapped in the collagen layer. In primary human amnion mesenchymal cells, collagen type 1 gels activated collagen receptor discoidin domain receptor 2 (DDR2) to induce myosin light chain phosphorylation and migration of injured amnion mesenchymal cells. These findings define the mechanisms for matrix-directed therapeutics for pPROM.