Hydrogel based oxygen carriers are introduced as a novel type of hemoglobin based oxygen carrier that addresses the issues and challenges associated with the development of artificial blood substitutes, which are designed to replace loss volumes of blood and restore tissue oxygenation to normal. The research addresses the impending shortage in blood supply and will be useful in emergency medicine and military applications. An innovative formulation of hemoglobin cross-linked to the hydrogel core of nanoscale hydrogel particles via UV-induced free radical polymerization of an environment responsive polymer within liposomal reactors is described. This work is novel due to the chemical cross-linking of hemoglobin to the polymer matrix of non-biodegradable, nanoscale hydrogel particles. The biological activity (i.e. ability to bind and release oxygen) of the oxygen carrier is demonstrated and the physical properties (i.e. size, shape, hemoglobin encapsulation efficiency, methemoglobin level, colloidal osmotic pressure, zeta potential) of the oxygen carrier are characterized. The effect of the reaction pH on the physical properties and biological activity of hydrogel based oxygen carriers synthesized with the pH-responsive polymer, poly(acrylamide), is examined, and the temperature sensitivity of hydrogel based oxygen carriers formulated with the temperature-responsive polymer, poly(N-isopropylacrylamide), is investigated. Finally, numerical simulations of oxygen transport to the hamster retractor muscle are used to assess the efficacy of oxygen delivery and tissue oxygenation with hydrogel based oxygen carriers compared to current hemoglobin-based oxygen carriers under development. Ultimately, this research has led to a new class of artificial blood substitutes with unique physical properties.