Technologies for Enhancing Tissue Engineering: Materials and Environments for Guiding Stem Cell Function

Stem cells are central to the future success of tissue engineering. They are a valuable cell source for regenerating or engineering tissues because they can be extensively expanded without losing their multipotency, and when given appropriate signals via their local microenvironment, they can be guided to differentiate into multiple phenotypes. Understanding and controlling the environmental cues that direct stem cell fate and function, however, remain difficult challenges. The strategic importance of these concepts was highlighted in two separate publications in 2007: “Strategic Directions in Tissue Engineering” by the editors of Tissue Engineering, and “Advancing Tissue Science and Engineering” by the Multi-Agency Tissue Engineering Science (MATES) Interagency Working Group. Both publications delineate stem cell science and biomaterials/environmental control of stem cells as critical research topics that must be significantly advanced for functional tissue engineering to progress and ultimately succeed as a field. The manuscripts assembled in this special issue of Tissue Engineering are excellent examples of the cutting-edge work being performed to address these gaps in our knowledge.

The review article that opens this special issue by Burdick and Vunjak-Novakovic describes the recent literature, and outlines the technical difficulties and opportunities in biomaterial and bioreactor design for controlling stem cell function. This comprehensive review paper is followed by primary research manuscripts that span stem cell sourcing, native extracellular matrix (ECM) signaling, engineered biomaterials, soluble bioactive factor delivery, dynamic bioreactor culture, and high-throughput screening. Identifying abundant stem cell sources and elucidating conditions that allow for extensive self-renewal will be necessary to implement these cell populations in regenerative strategies. Recognizing the first of these challenges, da Silva Meirelles et al. present evidence using equine adipose tissue that mesenchymal stem cells (MSCs) may be found in perivascular locations. This may explain the reported presence of MSC-like cells in several different tissues and organs throughout the body.

Biomaterials (i.e., naturally derived, synthetically fabricated, or hybrids of the two) have been shown to present powerful signals that can dictate the behavior of stem cells. Two manuscripts are focused on biomaterials for cartilage tissue engineering. The first by Cheng et al. demonstrates the capacity of devitalized cartilage to provide chondrogenic signals to adipose-derived stem cells, revealing that the inherent signaling capacity of native tissue ECM can be maintained even when cells are removed. Next, Chung and Burdick report on the ability of a photocrosslinked hyaluronic acid hydrogel to promote MSC chondrogenesis with further enhanced response upon the incorporation of chondrogenic growth factors, demonstrating the importance of interplay between multiple signal types. Chu et al. highlight the significance of cell adhesion ligand density in engineered hydrogels for control of stem cell behavior, and present one of the first applications of this concept to spermatogonial stem cell growth. Hsiong et al. reveal that the differential affinity cells exhibit for distinct adhesion ligand confirmations can be harnessed in biomaterial design to impact stem cell–based bone regeneration, and this concept may be broadly relevant to other applications. Kundu et al. report that the synthesis and deposition of ECM by MSCs on a surface serves to alter their own osteogenic fate, showing the downstream cellular events that can autoregulate ultimate cell phenotypes. Lastly, Usas et al. demonstrate that the type of naturally derived biomaterial utilized to deliver stem cells, which have been genetically engineered to drive osteogenic differentiation, has a strong influence on the quantity and quality of regenerated bone in vivo.

Leading a series of manuscripts highlighting soluble signal regulation of stem cells, Martins et al. discovered that certain hydrolytic enzymes found in human blood plasma can degrade synthetic scaffolds and positively influence the proliferation and osteogenic differentiation of MSCs. Willerth and Sakiyama-Elbert report on a kinetic analysis to determine the minimum concentration of neurotrophin NT-3 necessary to drive embryonic stem cell neuronal differentiation, which could be an important variable when engineering tissues for spinal cord injury. Gong et al. demonstrate the importance of media screening for MSC expansion and differentiation into smooth muscle cells, which are critical steps in the engineering of blood vessel grafts using this cell source. Addressing the potential use of embryonic stem cells in cardiac tissue engineering, Sargent et al. reveal a possible role for physical forces, such as fluid shear, in controlling cardiomyogenic differentiation of embryoid bodies in dynamic suspension culture. Finally, a manuscript by Jongpaiboonkit et al. describes a high-throughput system based on 3D hydrogel arrays for screening a variety of ECM parameters that can regulate MSC function, providing a strategy to accelerate the process of evaluating multiple ECM signals.

The primary literature provides the fundamental building blocks and scientific foundation that industry must draw from to bring these therapies to the broader market and impact tomorrow's healthcare. Many of the concepts presented in this special issue are shaping product and process development in the commercial sector to engineer the next-generation regenerative therapies. However, many technological and regulatory hurdles must be cleared to translate these technologies into commercial products. Not only will scale-up and manufacturing issues emerge, but also the innovative aspects of these often complex technologies that utilize combinations of cells, bioactive factors, and biomaterial matrices will challenge the FDA to regulate these novel therapies within an infrastructure designed for traditional drugs. It is anticipated, though, that academia and industry will be able to tackle these difficult problems to make the goal of stem cell–based regenerative medicine for improving human health a reality.