Acellular scaffolds from complex whole organs such as lung are being increasingly studied for ex vivo organ generation and for in vitro studies of cell-extracellular matrix interactions. We have established effective methods for efficient de- and recellularization of large animal and human lungs including techniques which allow multiple small segments (∼1–3cm3) to be excised that retain 3-dimensional lung structure. Coupled with the use of a synthetic pleural coating, cells can be selectively physiologically inoculated via preserved vascular and airway conduits. Inoculated segments can be further sliced for high throughput studies. Further, we demonstrate thermography as a powerful noninvasive technique for monitoring perfusion decellularization and for evaluating preservation of vascular and airway networks following human and porcine lung decellularization. Collectively, these techniques are a significant step forward as they allow high throughput in vitro studies from a single lung or lobe in a more biologically relevant, three-dimensional acellular scaffold.

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There is no technology available to support failing lung function for patients outside the hospital. An implantable lung assist device would augment lung function as a bridge to transplant or possible destination therapy. Utilizing biomimetic design principles, a microfluidic vascular network was developed for blood inflow from the pulmonary artery and blood return to the left atrium. Computational fluid dynamics analysis was used to optimize blood flow within the vascular network. A micro milled variable depth mold with 3D features was created to achieve both physiologic blood flow and shear stress. Gas exchange occurs across a thin silicone membrane between the vascular network and adjacent alveolar chamber with flowing oxygen. The device had a surface area of 23.1 cm(2) and respiratory membrane thickness of 8.7 ± 1.2 μm. Carbon dioxide transfer within the device was 156 ml min(-1) m(-2) and the oxygen transfer was 34 ml min(-1) m(-2). A lung assist device based on tissue engineering architecture achieves gas exchange comparable to hollow fiber oxygenators yet does so while maintaining physiologic blood flow. This device may be scaled up to create an implantable ambulatory lung assist device.

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Over the past two decades, great strides have been made in the field of tissue engineering. Many of the initial attempts to develop an engineered tissue construct were based on the concept of seeding cells onto an avascular scaffold. Using advanced manufacturing technologies, the creation of a preformed vascular scaffold has become a reality. This article discusses some of the issues surrounding the development of such a vascular scaffold. We then examine of the challenges associated with applying this scaffold technology to two vital organ constructs: liver and lung. I n 1985, we hypothesized that a living vital organ could be rationally designed and built for human therapy from cells and degradable polymer scaffolding. This was based on only two pieces of previous work: 1) an acellular artificial dermis by Yannas and Burke (1); and 2) a vascular conduit of contracted collagen and vascular cells (2).Our first reports described the formation of hepatic, intestinal, and pancreatic tissue (3,4). In the ensuing 22 y, the fields of Tissue Engineering and Regenerative Medicine have become established and several tissues are available for human trials or use. In 1998, to overcome the problem of sufficient functional mass for human therapy, we hypothesized that we could build a vasculature as part of the tissue-engineered organ which would provide immediate exchange of oxygenand nutrient-rich blood to the full volume of engineered tissue, much as a transplanted organ functions today. Summarized below are the most recent developments toward an engineered vascularized tissue with emphasis on liver and lung. VASCULARIZED SCAFFOLD FOR SOLID ORGAN TISSUE ENGINEERINGThe fundamental challenge of developing a tissue for therapeutic use is scaling up the growth of cells from a culture dish to a three-dimensional scaffold. Multilayer cellular constructs are achievable on flat sheets or thin porous scaffolds. However, the creation of tissues for solid organ transplantation must overcome the limited distance of oxygen diffusion.One approach is centered on angiogenesis, or the selfassembly of a vascular network within a scaffold by endothelial and smooth muscle cells. Although on a small scale this is achievable, this approach develops too slowly to support the mass of tissue that is required for an organ transplant, such as a liver. The Tissue Engineering and Organ Fabrication Laboratory at Massachusetts General Hospital proposed the creation of a scaffold with an integrated vascular network (5,6). A capillary-like vascular network within a three-dimensional scaffold can deliver oxygenated blood to within several hundred micrometers of all cells in the scaffold. These vascular networks are designed to replicate features of a capillary network within the bounds of what can be manufactured. Initial work centered on the utilization of photolithography techniques to create molds of capillary-like networks (7-12). The vascular networks of these original molds were designed to have arterial pressure drop across the network wit...

Pediatric patients bridged from ECMO to lung transplantation have poor results. An alternative method for longer term respiratory support was necessary as a bridge for these patients. The use of a paracorporeal lung assist device successfully supported 4 patients to recovery, lung transplantation, or past the average wait time for pediatric donor lungs (27 days). This therapy has the potential to bridge children with decompensated respiratory failure to lung transplantation.

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