Stem Cells on Biomaterials for Synthetic Grafts to Promote Vascular Healing

Abstract

This review is divided into two interconnected parts, namely a biological and a chemical one. The focus of the first part is on the biological background for constructing tissue-engineered vascular grafts to promote vascular healing. Various cell types, such as embryonic, mesenchymal and induced pluripotent stem cells, progenitor cells and endothelial- and smooth muscle cells will be discussed with respect to their specific markers. The in vitro and in vivo models and their potential to treat vascular diseases are also introduced. The chemical part focuses on strategies using either artificial or natural polymers for scaffold fabrication, including decellularized cardiovascular tissue. An overview will be given on scaffold fabrication including conventional methods and nanotechnologies. Special attention is given to 3D network formation via different chemical and physical cross-linking methods. In particular, electron beam treatment is introduced as a method to combine 3D network formation and surface modification. The review includes recently published scientific data and patents which have been registered within the last decade.

Keywords: biomaterial; biopolymer; blood vessel; collagen; cross-linking; endothelial cell; scaffold; smooth muscle cell; stem cell; surface modification.

Figure 1

Publications and patents broaching the issue of vascular healing. (A) Publications (88) and patents (108) in the time period between 2003 and 2012 broaching the issue of vascular healing have been evaluated. The number of publications and patents is increasing after 2006 showing the growing interest in treating vascular diseases with stem cells and biomaterial. Blue: publications, green: patents; (B) Cell types for vascular healing approaches described in publications in the last decade. Embryonic stem cells were prominent in publications at the beginning of the decade. Their number decreased when in the iPS came up in the middle of the decade. Since iPS have a similar potency but cause less ethical problems and provide in addition the possibility for the future application of autologous cells, this was to be expected. Interestingly, the use of MSCs seems not to be affected by the development of induced pluripotent stem cell (iPS) cells. On the contrary, the use of this specific adult stem cell type is increasing. The reason for this might be the still unsolved risk of teratoma formation if endothelial cells (ECs) or IPS are used. ECs and smooth muscle cell (SMCs) have been described on a regular basis. The use of stem cells seems not to influence their utilization. Blue: EC, green: SMC, yellow: ESC, brown: MSC, orange: EPC, black: iPS, grey: other primary cells; (C) Cell types for vascular healing approaches described in patents during the last decade. The suggested used of the various cell types in patents follows the picture which can be seen in publications: The application of ECs is declining while the utilization of mesenchymal stem cell (MSC) which is the most prominent cell type. Blue: EC, green: SMC, yellow: ESC, brown: MSC, orange: EPC, black: iPS, grey: other primary cells.

Figure 2

Cells used on grafts to promote vascular healing. The picture shows the different sources of cells used to promote vascular healing. Endothelial cells and smooth muscle cells can be obtained directly from primary tissue, e.g., arteries or umbilical cord or via differentiation of stem cells. Those stem cells can also be used directly on a graft. The cells can differentiate into the desired cell type and then be transplanted into animal models.

Figure 3

Scaffolds materials for stem cell engineering of vascular grafts. This scheme gives an overview about the materials discussed in this review with respect to the origin of the scaffold material. Synthetic and natural materials are addressed in the discussion as well as combined approaches to scaffold materials.

Figure 4

Cross-linking reactions. (A) Cross-linking via formaldehyde. In the first step amino groups of collagen (e.g., in lysine entities) react with formaldehyde to form an aminomethylol-derivative. In the second step, a diagonal cross-link is formed by reaction of the aminomethylol-derivative with an acid amide; (B) Cross-linking via glutaraldehyde. Reaction of amino groups of two collagen molecules (e.g., in lysine entities) with glutaraldehyde leads to diagonal crosslinking of collagen molecules; (C) Cross-linking via hexamethylene diisocyanate. Hexamethylene diisocyanate can react with amino groups to crosslink collagens; (D) Cross-linking via enzymes. During enzymatic cross-linking with transglutaminase an amide bond is generated via conversion of glutamine and lysine units.

Figure 5

Energy sources and their application for polymeric and biological systems. Chemical reaction, UV-light, gamma rays, electron beam or enzymatic processing are valuable tools for the modification of polymeric materials. Hereby, miscellaneous, partially contrary effects are observed including cross-linking reactions. For biological applications, sterilization, disinfection and pasteurizing effects are described.