Executive Summary : | Cardiovascular diseases are the number one cause of death world-wide. One of the most serious forms of heart disease is atherosclerosis, a process that causes narrowing of the arteries. Some of the surgical interventions attempted includes angioplasty, stenting and vascular bypass graft surgery. During the last decade, the interest of most laboratories has shifted towards the engineering of blood vessel substitutes. However, the challenge is to design a tubular structure with a diameter of 3-4 mm without inducing anastomotic hyperplasia, thus supporting the formation of a stable tissue. In recent years, there has been a focus on the problem of reduction of intimal hyperplasia especially in the use of small diameter synthetic grafts. This is where the role of all-trans retinoic acid has been seen to play a major role. It is understood that the mechanism behind the effect of atRA is the inhibition of the proliferation of vascular smooth muscle cells by upregulating the expression of Klf4 factor that directly transactivates downstream target genes by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) thereby maintaining the contractility phenotype of the VSMC. However, retinoic acid is insoluble in water and hence they have low effective administration and bioavailability. Hence the development of a platform enabling localized and controlled delivery of ATRA is a challenge wherein much smaller effective dosage will be possible. However this molecule is light sensitive and hence to preserve the stability and function, a proper delivery vehicle is required. Mesoporous silica nanoparticles (MSNP) particles have been proposed on the basis of their biocompatibility, high surface area, high pore volume and pore diameter. It has been shown that both small and large molecular drugs can be entrapped within the mesopores and liberated via a diffusion-controlled mechanism. Hence in this study we hypothesise that use of mesoporous silica with varied pore sizes to encapsulate the morphogen atRA and study the cell triggered release kinetics after loading these nanoparticles into electrospun Gelatin vinyl acetate-PCL as tissue engineered vascular grafts. The objective is to functionalize the external surface of the nanopores with stimuli responsive tethers acting as gatekeepers which can be removed by an external trigger so as to develop a controlled release mechanism. In vitro studies probing the differentiation of adipose derive mesenchymal stem cell to smooth muscle lineage and the preservation of the contractility function on the differentiated SMCs will be studied. The efficacy of the treatment will be evaluated using an ovine carotid artery graft model. Through this proposal we expect to find a solution to the long standing holy grail in the development of scaffold for tissue engineering of small diameter blood vessel and also a solution to the problem of neointimal hyperplasia by an atRA releasing graft treatment strategy. |
Co-PI: | Mr. Saurabh S Nair, Sree Chitra Tirunal Institute For Medical Sciences & Technology, Thiruvananthapuram, Kerala-695011, Dr. Sowmya V Remanan, Sree Chitra Tirunal Institute For Medical Sciences & Technology, Thiruvananthapuram, Kerala-695011, Dr. Umashankar PR, Sree Chitra Tirunal Institute For Medical Sciences & Technology, Thiruvananthapuram, Kerala-695011, Dr. Sachin Jayachandran Shenoy, Sree Chitra Tirunal Institute For Medical Sciences & Technology, Thiruvananthapuram, Kerala-695011 |