Current extracellular matrix (ECM) derived scaffolds offer promising regenerative responses in many settings, however in some applications there may be a desire for more robust and long lasting mechanical properties. A biohybrid composite material that offers both strength and bioactivity for optimal healing towards native tissue behavior may offer a solution to this problem. A regionally distinct biocomposite scaffold composed of a biodegradable elastomer (poly(ester urethane)urea) and porcine dermal ECM gel was generated to meet this need by a concurrent polymer electrospinning/ECM gel electrospraying technique where the electrosprayed component was varied temporally during the processing. A sandwich structure was achieved with polymer fiber rich upper and lower layers for structural support and an ECM-rich inner layer to encourage cell ingrowth. Increasing the upper and lower layer fiber content predictably increased tensile strength. In a rat full thickness abdominal wall defect model, the sandwich scaffold design maintained its thickness whereas control biohybrid scaffolds lacking the upper and lower fiber-rich regions failed at 8 weeks. Sandwich scaffold implants also showed higher collagen content 4 and 8 weeks after implantation, exhibited an increased M2 macrophage phenotype response at later times and developed biaxial mechanical properties better approximating native tissue. By employing a processing approach that creates a sheet-form scaffold with regionally distinct zones, it was possible to improve biological outcomes in body wall repair and provide the means for further tuning scaffold mechanical parameters when targeting other applications. Copyright © 2013 John Wiley & Sons, Ltd.