The integration of bioengineering approaches with stem cell biology has the potential to substantially change the practice of medicine as we know it today. While hematopoietic cell transplantation therapies have been used in the clinic for more than a decade to resolve blood malignancies, most solid tissues are precluded from treatment with cell-based therapies to regenerate defects and restore function. Several complicated factors lend to this discrepancy, but the lack of suitable strategies to expand isolated aSCs or to robustly differentiate ES or iPS cells into a single tissue-specific lineage is a major limitation to the progress of cell-based therapies. Using two-dimensional or three-dimensional biomaterials approaches, it is realistic to imagine that in the near future we will identify simple strategies based on smart design principles to expand aSCs and direct ES and iPS cell fate, enabling cell-based regenerative therapeutics.
After injury, or as result of aging or disease, the homeostatic microenvironment can undergo substantial remodeling and reconstruction and, consequently, render the environment ill-instructive for resident tissue-specific aSCs. For example, it is hypothesized that extrinsic changes to the satellite cell microenvironment prevent effective skeletal muscle regeneration rather than intrinsic changes to the satellite cell itself during aging [66
]. As an alternative to cell based therapies, studies suggest that simply providing an instructive cell-free scaffold to artificially modify the microenvironment and direct the aSCs residing in tissue could prove useful to regenerate damaged tissue [67
]. This approach was first developed and utilized in the repair of critical sized defects in bone through the use of allogeneic demineralized bone matrix, a US Food and Drug Administration approved product, and has now been extended to many other tissue types [68
]. For example, cell-free scaffold-based strategies are already used in the clinic to repair open skin wounds on war victims [70
]. By focusing on biochemical and biophysical parameters governing stem cell fate decisions (that is, directed migration, proliferation, differentiation, and so on), materials impregnated with signaling molecules designed for release in a temporally and spatially regulated manner are a viable option to modulate cell fate and promote repair over time within the intact patient [71
Regenerative medicine using cell-free scaffolds relies on the patient's own cells to migrate into and repopulate the acellular scaffold (Figure ). To overcome this potential challenge, strategies combining synthetic or natural matrices repopulated with cell types required for long-term function of the replacement tissue are being developed. For example, large cartilage defects resulting from injury or aging are notoriously difficult to repair. Use of a nanofibrous scaffold seeded with human mesen-chymal stem cells (which evade the immune response) demonstrated the ability of a bioengineering approach to repair large cartilage defects in swine while restoring smooth cartilage at the surface and withstanding use-associated compression force [72
]. Similarly, corneal function was restored in patients afflicted by debilitating burns using autologous limbal stem cells embedded in fibrin gels [73
Figure 3 Alternative approaches to functional organ replacement. Organ transplant is plagued by lack of available tissue, the short window of tissue viability prior to transplant and graft rejection after transplant. A new bioengineering approach promises to overcome (more ...)
A major challenge in the clinic is the availability of donor tissue for transplantation into patients with critical organ failure. A tissue-engineering approach based upon the principle of designing stem cell microenvironments that incorporate the cell types, signaling cues and structure required for long-term physiological function and incorporation in a living patient has the potential to substantially reduce the current reliance on organ donors to provide tissues to patients in critical need. Though generation of functional three-dimensional organs is an extraordinary challenge, several research groups are actively pursuing this goal and the literature is already repleat with successes. To overcome the challenge of lost bladder function in young patients afflicted with disease rendering malfunction, researchers utilized a bioengineering approach to construct collagen scaffolds in the likeness of the human bladder. To ensure proper longterm function and to reduce the possibility of tissue rejection, the engineered bladders were seeded with urothelial and muscle cells isolated from the patient prior to transplantation. Follow-up studies 2 years following transplantation concluded that the bioengineered bladders had not only maintained architecture, but were also still fully functional in the patient recipients [74
]. Organ transplantation is typically accompanied by use of immune suppression treatment to reduce the incidence of immune rejection. To improve transplantation success, several researchers are adopting a bioengineering approach that entails decellularizing donor tissue (to remove the major histocompatibility complex (MHC) component) with a gentle, multistep detergent treatment that leaves the matrix scaffold intact and permits recolonization with patient derived cells. This approach has been used successfully to treat a patient suffering from bronchomalacia (loss of airway function). Transplant of a decellularized donor trachea repopulated with epithelial cells and chondrocytes from patient-derived mesenchymal stem cells led to successful long-term repair of the airway defect and restoration of mechanical properties [75
]. Finally, a recent study demonstrated the possibility of using a bioengineering approach to construct corporal tissue to facilitate penile reconstruction. In a multistep, dynamic process the three-dimensional corporal tissue was engineered from a naturally derived collagen matrix reseeded with autologous cells and transplanted into rabbits with excised corpora. Amazingly, the bioengineered phallus was structurally similar to the native tissue and function was demonstrated by successful impregnation of female rabbits with the engineered tissue [76
]. Together these examples exemplify the potential impact that material science will have on the treatment of human disease in the not so distant future.