ABSTRACT
Organ transplantation is needed for patients suffering end-stage organ failure. In 2011 alone, over 50,000 patients were added to the waiting list to receive an organ for transplantation (Organ Procurement and Transplantation Network, accessed May 2012). Of these patients, close to 16,500 died, became too sick to transplant, or could not be matched to a donor. The demand for viable organs is far greater than the current supply. Currently, the only sources for transplant organs are from living donors and deceased donors. In 2011 living donors accounted for just over 6,000 transplanted organs, while deceased donor organs comprised the remaining 22,500; this sum accounts for far less than the 50,000 patients
added to the wait list that year (Organ Procurement and Transplantation Network, accessed May 2012). The remaining demand must be supplied by deceased donor organs. Since 1988, the total number of deceased donors has increased thanks to improved protocols for deceased donor organ harvest and transplantation (Perera and Bramhall, 2011; Goldstein et al., 2012; Pavlakis and Hanto, 2012; Ojo et al., 2004). However, in order to satisfy the needs of all patients requiring a transplant, whole organ fabrication approaches are required.The disparity between organ supply and demand led to emergence of the field of Tissue Engineering in the late 1980s (Vacanti et al., 1988). According to Langer and Vacanti, “tissue engineering is an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function” (Langer and Vacanti, 1993). Several engineered tissues have been designed in labs throughout the world and have been proven successful in clinical trials, including skin (Gómez et al., 2011), cartilage (Kreuz et al., 2009), and vascular grafts (McAllister et al., 2009). Significant growth in the tissue engineering and stem cell industry from 2007 reflects successful results from these academic research efforts (Jaklenec et al., 2012). Despite this progress, the goal of whole organ fabrication has yet to be realized. Certain fundamental limitations must be overcome in order to scale from engineered tissues up to whole organ replacement. 9.1.2 Mass Transport and Manufacturing Limitations
The first limitation to overcome arises from mass transport properties in engineered tissues. Aerobic respiration in these cells consumes oxygen and glucose and creates waste products such as carbon dioxide and urea. Mass transport of these molecules to and from the cell is accomplished through passive diffusion along concentration gradients. Oxygen has the highest metabolic rate and diffusional resistance of these molecules, and therefore can be considered as the limiting factor in mass transport (Malda et al., 2007). Consumption of oxygen during aerobic respiration occurs at an average rate of 4 × 1017 mol/cell-sec, depending on cell type (Chow et al., 2001a; Collins et al., 1998; Kunz-Schughart et al., 2000). Tissues without sufficient oxygen to support their metabolic needs
are in a state of hypoxia, which can lead to necrosis (Smith and Mooney, 2007).The cardiovascular system enables convective transport of oxygen and other molecules to each of the trillions of cells within the human body. Most cells are within 100-200 µm from a capillary lumen (Ishaug-Riley et al., 1998; Suzuki et al., 1998). The minimum distance between a cell and an oxygen source, the oxygen diffusion distance limit, is dependent upon (1) the rate of cellular oxygen consumption and (2) the diffusion rate of oxygen through tissue. Dimensional analysis of these quantities shows that the following relationship must be observed in order to avoid necrosis within a tissue (Muschler et al., 2004): ,O2 02Cell2[Cell] D CQ L (9.1) where [Cell] is the cellular concentration in the scaffold, DO2is the diffusion coefficient of oxygen, C0is the oxygen concentration at the surface of the tissue, Qcellis oxygen consumption rate of each cell, and L is the diffusion distance to the center of the tissue. DO2and C0are constants that have been measured experimentally (Chow et al., 2001b). An inverse square relationship is evident; [Cell] 1/L2.The implications for engineered tissues are evident; according to the relationship defined in Eq. 9.1, if the characteristic dimension of a tissue-engineered construct is scaled by a factor of N, the theoretical limit of cellular density is decreased by a factor of N2. An intrinsic vascular network is thus necessary in order to increase the size of engineered tissues while maintaining minimum oxygen diffusion distances. This concept has been recognized, and several attempts have been made to incorporate vascularization into scaffolds for cellular growth. As early as 2000, microfluidic devices were used as platforms for cell culture, manufactured using photolithography technology adapted from the semiconductor industry (Kaihara et al., 2000; Pimpin and Srituravanich, 2012). Typical designs contain two-dimensional microchannel arrays and can be theoretically adapted for whole organ scaffolds. However, organs are inherently three-dimensional, and their vascular organization must reflect this. The evolutionary development of capillary systems has favored specific vascular designs and fluidic properties for different organ functions. The emerging field of biomimetic vascular design utilizes these principles found in natural
vascular architectures to create models for tissue-engineered scaffolds of whole organs. Fabrication of such intricate networks would be challenging when using traditional photolithography techniques. Several microfabrication technologies have been developed that are capable of achieving the geometric complexity of organ capillary networks. 9.2 Biomimetic Vascular Design Principles
The field of biomimetic design has developed as an engineering approach that attempts to recapitulate the form and function of biological systems. Living organism structures have developed through years of evolution in order to survive in specific ecosystems; their adaptations to the environment can yield unique design solutions for engineering problems. For example, the hooked spines found on plant burs, which allow them to cling to animal fur and be dispersed, led to the development of Velcro products (Hagland, 2012). The self-cleaning and water-repellent surface of the lotus leaf inspired the creation of water-repellent paint (Barthlott and Neinhuis, 1997). The unique properties of the Gecko’s footpads, which allow the animal to traverse walls and ceilings, have spurred the creation of surgical bandages (Cho et al., 2012) and wall-climbing robots (Kim et al., 2008).
