The concept of using cells to replace damaged or missing tissue based on their functional characteristics35,36
preceded the field of tissue engineering as it was described by Langer and Vacanti in 1993.2
The use of cells in bioengineering tissue has since undergone remarkable expansion and evolution with the development of and continuing advances in stem cell biology. The breadth of cell populations available for use in tissue engineering constructs has increased tremendously from early reports using adult differentiated cell types.37,38
Most recently embryonic stem cells,39,40
adult mesenchymal stem cells,41,42 and induced pluripotent stem cells (iPS)43,44
have been used in tissue engineering efforts.
Our laboratories have recently focused on adipose-derived stromal cells (ASCs) for tissue engineering.41,45–50
Research from the early 1960s described a stromal-vascular fraction (SVF) isolated from fat that contained fibroblast-like cells.51
Subsequent examination of this SVF cell type led scientists to believe that they represented an adipose progenitor cell whose fate was limited to adipose tissue.52
In 2001, the understanding of the potential of these SVF cells greatly changed as Zuk et al. demonstrated the ability of these cells to undergo adipogenic differentiation but also chondrogenic, myogenic and osteogenic differentiation.53
The potential multipotency of ASCs has expanded tremendously since these early studies as scientists continue to fine tune and improve the differentiation of each pathway.54–60
Cell surface receptors in ASCs have been shown to be similar to those of bone marrow-derived mesenchymal stem cells (BM-MSCs).60,61
However, ASCs hold several advantages over BM-MSCs in that they are readily available in large quantities and can be harvested with minimally invasive procedures, thus making them more amenable to clinical use. Like BM-MSCs, ASCs can also be safely and effectively transplanted into an autologous host.
Recent clinical studies have focused on the use of human adipose-derived stromal cells to replace bone loss.62
Specifically, hASCs seeded on a PLGA scaffold were recently used to treat a young girl after severe mandibular trauma. In small pilot studies, defects of the cranium,63
have shown accelerated healing with the use of hASCs.66
In these case reports, however, the method of hASC usage has varied dramatically, from the combination with bone chips to the use of recombinant proteins. Such reconstructions eliminate the need for alloplastic materials, and thus reduce the risk of infection, breakdown or rejection. In our laboratory, we have observed convincingly that ASCs, whether derived from mouse or human origin, contribute to osseous healing of mouse cranial defects.41,67
Despite these intriguing case reports and accumulating translational research, there is a paucity of data defining the mechanisms through which ASCs and other stem and progenitor cells contribute to regeneration of damaged tissue. Do cells directly form the tissue of interest to heal a defect? Do engrafted cells exhibit mainly paracrine functions to produce potent pro-regenerative cytokines? In the case of our calvarial defect model, careful examination of calvarial defects engrafted with ASCs yields some valuable insights into the potential derivation of healing. In this case, bone is often observed to mineralize from the edges of a cranial defect inwards, which suggests that the host calvarium is the prime contributor to the bone regenerate.
One exciting advance in tissue engineering is the recent discovery of the ability to transform adult somatic cells, back to an embryonic-like pluripotent cell that can differentiate into ectoderm, endoderm as well as mesodermal tissues creating “induced” pluripotent stem (iPS) cells.68,69
Considering the ease and reproducibility of generating iPS cells as well as the lack of ethical concerns, experts have raised the hope that iPS cells might fulfill much of the promise of human ES cells in regenerative medicine.70
These cells represent a potential mechanism by which to use readily available cells from a patient in need of an organ, transform them into iPS cells, expand them and design a tissue-engineered construct containing entirely autologous cells ().
Figure 3 Patient-specific tissue engineering. The recent discovery of iPS technology has offered the potential of patient-specific cell therapy. A small skin biopsy could be obtained from a patient in need of an organ or tissue replacement, from which dermal fibroblasts (more ...)
One of the primary obstacles in transitioning a cell-based tissue engineered construct to commercial production is the scale up of cultured cell populations.71
In an early report by Vacanti et al. taking tissue engineering to the bedside, a patient’s distal thumb was reconstructed using autologous periosteal cells.72
However, these autologous cells were grown in culture for nine weeks before they could be expanded enough to reimplant into the patient. In order to make a significant clinical impact, the ex vivo expansion of cells must be accelerated. While proliferation rates are cell-specific, the speed of autologous cell expansion will likely continue to be a rate-limiting step in the time to their therapeutic application. One potential means of avoiding the time-consuming process of in vitro cell expansion is to use ASCs for cell-based constructs. A small volume of lipoaspirate allows for the harvest of a large number of these cells thus negating the need for expansion in culture prior to implantation. Additionally, the automation of cell culture may provide a means to ensure the safety and efficiency of cell expansion for commercial production of bioengineered constructs.73,74