The synthesis of microspheres for tissue regeneration requires good control over the particle size and size distribution. This is particularly important when considering the immune response that may be triggered by the presence of particles in tissue. This report outlines the design of an injectable microsphere system using a low-inflammatory， degradable-polar-hydrophobic-ionic polyurethane， termed D-PHI， and investigates the system's performance in vitro and in vivo. Crosslinked polyurethane microspheres were prepared via a rapid and controlled process based on membrane emulsion and subsequent photopolymerization. The fabrication process efficiently generated microspheres with a narrow size distribution (12?±?2?μm， PDI?=?0.03). The D-PHI microspheres exhibited a slow and controlled degradation and a high capacity for water uptake. Water within the particles existed primarily within the pores of the particles and to a lesser degree within the polymer matrix itself. D-PHI microspheres supported human endothelial and fibroblast cell growth， and they maintained human blood-derived monocytes in a low-inflammatory state. Sub-acute toxicity was assessed for the particles after being administered via intramuscular injection in the gastrocnemius muscle of rats. Cellular infiltration and vascularization into the tissue region where the particles were deposited were observed along with an absence of a fibrous capsule around the particles. The microspheres did not cause elevated human monocyte induced inflammatory character， and supported tissue integration without a prolonged inflammatory response in the rat muscle. These injectable， degradable and low-inflammatory microspheres provide an attractive system for potential drug delivery and tissue regeneration applications in future studies. STATEMENT OF SIGNIFICANCE: Biodegradable， synthetic polymers are attractive candidates for generating tailored drug delivery vehicles and tissue scaffolds owing to their diverse chemical and physical properties that can be customised for delivering defined macromolecules at specific sites in the body. The past two decades have yielded interesting work exploring the fabrication of polymer microspheres with a narrow size distribution. However， the markedly low number of synthetic polymer chemistries currently used for microsphere production exhibit elevated proinflammatory character， both acute and chronic. Furthermore， a limited number of studies have explored the biocompatibility and immune response of polymeric microspheres with human primary cells and in vivo. In the current study， a method was conceived for efficiently generating low-activating polyurethane microspheres with respect to in vitro monocytes and in vivo macrophages. The biodegradable polyurethane， which contained multiple chemistry function and which has previously demonstrated anti-inflammatory properties in film and mm scale scaffold form， was selected as the base material. In this work we undertook the use of a room temperature membrane emulsification photopolymerization approach to avoid the need for high temperature cures and the use of solvents. The response of immune cells to the microspheres was studied with human primary cells and in the rat gastrocnemius muscle. The present work reveals important progress in the design of microspheres， with well-characterized low monocyte-activating properties and the translational advantages of a synthetic polyurethane which could be investigated in future studies for potential macromolecule delivery and tissue regeneration applications.