Preparation Of Reactive Oxygen Species(ROS) Responsive Biodegradable Polyurethane Patches And Their Treatment Of Rat Myocardial Infarction In Vivo

Cardiovascular disease such as myocardial infarction(MI)is currently one of the most frequent causes of death in the world.Myocardial infarction is a type of acute coronary syndrome caused by the result of blockage of the coronary artery.MI being responsible for nearly 8.2 million deaths annually worldwide,and the number of people affected by MI increases at an alarming rate each year,remains a therapeutic challenge throughout the world.In the myocardial infarction(MI)zone,the supply of nutrient and oxygen is reduced,leading to massive death of cardiac cells and tissues,and adverse remodeling of infarcted left ventricle(LV),featured with dilation of LV chamber,and thinning of cardiac wall,which eventually progress into heart failure.Reactive oxygen species(ROS)have been considered as the pivotal signaling molecules in many physiological processes,and are usually overproduced in various inflammatory tissues.The role of ROS in MI is very complex,such as indirect damage of the heart through activating the pro-apoptotic pathways,and oxidization of the myofibrillar proteins,resulting in the cardiac fibrosis and contractile dysfunction.The cardiac patches are designed to restrain the MI area and subsequently reduce myocardium wall stress,preventing left ventricular dilation and remodeling.Furthermore,attenuation of oxidative stress and inflammation in MI microenvironment after MI are conducive to restore structures and functions of infarcted myocardium.Tissue microenvironmental stimuli-responsive biomaterials have been widely used in the tissue repair and regeneration because their physical/chemical properties can respond to changes of signals from physiological environments.Recently,ROS-responsive biomaterials have been identified as a promising therapeutic material to alleviate the oxidative stress in tissue microenvironment,reduce cell apoptosis,and alleviate inflammation,and thus are used as a vehicle triggered by inflammatory diseases to realize drug release under physiological oxidative microenvironments.In this study,ROS-responsive biodegradable polyurethanes are designed and further combined with drugs and amniotic epithelial cells to construct myocardial therapy patches for MI treatment in rat.First,a ROS-responsive biodegradable elastomeric polyurethane containing thioketal(PUTK)linkages was synthesized from polycaprolactone(PCL)diol,1,6-hexamethylene diisocyanate(HDI),and ROS-cleavable chain extender.The PUTK was electrospun into fibrous patches with the option to load methylprednisolone(MP),which were then used to treat MI of rats in vivo.The overall mechanical properties of these patches matched well with the myocardium.Both the PUTK and PUTK/MP fibrous patches showed good antioxidant property in an oxidative environment in vitro,and could greatly protect the myocardium from oxidative injury in vivo,leading to a higher survival rate of cardiomyocytes compared with the non ROS-responsive PU fibrous patch group after the infarction injury for 24 h.In long-term treatment at 28 days,the ROS-responsive biodegradable polyurethane fibrous cardiac patches,especially when loaded with the anti-inflammatory MP,had shown appealing comprehensive performance in rebuilding post infarcted cardiac functions and angiogenesis,and effectively reduced the fibrosis and negative cardiac remodeling in vivo,and thus possess the great promise for further optimization to promote their applications.Although the PUTK patches have shown appealing comprehensive performance,the structures and properties of the patches can be further improved.For example,the degradation rate of the ROS-responsive biodegradable polyurethanes should be accelerated by incorporating more sensitive and hydrophilic segments to enhance the anti-oxidant performance,promote cell adhesion and proliferation,and to match the rate of tissue regeneration.Therefore,an elastomeric polyurethane(PFTU)containing ROS-sensitive poly(thioketal)(PTK)and unsaturated poly(propylene fumarate)(PPF)segments was synthesized,which was further clicked with pro-angiogenic Arg-Glu-Asp-Val(REDV)peptides to obtain PFTU-g-REDV(PR),and was formulated into a macroporous patch containing rosuvastatin(PRR).The beneficial effects of PRR patches were confirmed in a rat MI model in vivo compared to patches with only mechanical support or partial coverage of LV remodeling,leading to reduced cell apoptosis,suppressed local inflammatory response,alleviated fibrosis,and induced angiogenesis.The mechanically robust,multifunctional cardiac patch integrating ROS-scavenging,anti-inflammatory,and pro-angiogenic capabilities was developed to demonstrate the advantages of the integrative and orchestrated treatment strategy in MI therapy.Stem cell-based therapy has shown good therapeutic effects for MI,however,the low retention and survival limit their applications due to the ROS microenvironment after MI.The cardiac patch strategy can drastically improve cell retention and also provide mechanical support for ventricles.Cardiac patches based on ROS-responsive biodegradable polyurethanes,especially the one containing unsaturated double bond,were used as a ROS-responsive delivery platform of drugs,showing desirable effects with respect to free radical scavenging,rebuilding structures,and improving functions of infarcted myocardium after implantation in MI rats.Here,PFTU was modified with RGD(PUR)and fabricated into a porous patch which integrated with human amniotic epithelial cells(PUR/h AEC)for therapeutic heart regeneration after MI.The transplanted patch could get nutrients from the heart while releasing the paracrine factors to repair the heart.In rat MI model study,the application of the PUR/h AEC patch effectively augmented cardiac functions and enhanced angiogenesis,and effectively reduced the fibrosis and negative cardiac remodeling in vivo.