Biomaterials and Stem Cells

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Biomaterials are materials (synthetic and natural; solid and sometimes liquid) that are used in medical devices or in contact with biological systems. Biomaterials as a field has seen steady growth over its approximately half century of existence and uses ideas from medicine, biology, chemistry, materials science and engineering. There is also a powerful human side to biomaterials that considers ethics, law and the health care delivery system.

Biomaterials can be metals, ceramics, polymers, glasses, carbons, and composite materials. Such materials are used as molded or machined parts, coatings, fibers, films, foams and fabrics

Stem cells play increasingly prominent roles in tissue engineering and regenerative medicine. Pluripotent embryonic stem (ES) cells theoretically allow every cell type in the body to be regenerated. Adult stem cells have also been identified and isolated from every major tissue and organ, some possessing apparent pluripotency comparable to that of ES cells. However, a major limitation in the translation of stem cell technologies to clinical applications is the supply of cells. Advances in biomaterials engineering and scaffold fabrication enable the development of ex vivo cell expansion systems to address this limitation. Progress in biomaterial design has also allowed directed differentiation of stem cells into specific lineages. In addition to delivering biochemical cues, various technologies have been developed to introduce micro- and nano-scale features onto culture surfaces to enable the study of stem cell responses to topographical cues. Knowledge gained from these studies portends the alteration of stem cell fate in the absence of biological factors, which would be valuable in the engineering of complex organs comprising multiple cell types. Biomaterials may also play an immunoprotective role by minimizing host immunoreactivity toward transplanted cells or engineered grafts.

Summary and Future Perspectives

The field of TE has entered an exciting new chapter, where experimental technologies are being aggressively explored for clinical translation, signifying a veritable "coming of age" of the field. The convergence of two important disciplines, that of biomaterials engineering and stem cell research, promises to revolutionize regenerative medicine. With this merger, several concepts that would have been deemed far-fetched a few years ago are now being actively pursued. Among these concepts are brain reconstructive surgery, tailor-made autologous body replacement parts, and cybernetic prosthesis. The future of stem cell TE is undoubtedly technology driven. New applications and improvement upon current designs will depend heavily on innovations in biomaterials engineering. Concomitant with this, progress in stem cell biology will be imperative in dictating advances in stem cell TE. A better understanding of the molecular mechanisms by which substrate interactions impact stem cell self-renewal and differentiation is of paramount importance for targeted design of biomaterials. Discoveries in the fields of developmental biology and functional genomics should also be parlayed for broadening the repertoire of biological molecules that can be incorporated into biomaterials for fine-tuning stem cell activities. With the merger between the two powerful disciplines-biomaterials engineering and stem cell biology-a new drawing board now lies before us to develop therapies that could hopefully help the world population age more gracefully.

Biomaterials

Biomaterials are materials (synthetic and natural; solid and sometimes liquid) that are used in medical devices or in contact with biological systems. Biomaterials as a field has seen steady growth over its approximately half century of existence and uses ideas from medicine, biology, chemistry, materials science and engineering. There is also a powerful human side to biomaterials that considers ethics, law and the health care delivery system.

Biomaterials can be metals, ceramics, polymers, glasses, carbons, and composite materials. Such materials are used as molded or machined parts, coatings, fibers, films, foams and fabrics

What subjects are important to biomaterials science?

• Toxicology

• Biocompatibility

• Functional Tissue Structure and Pathobiology

• Healing

• Dependence on Specific Anatomical Sites of Implantation

• Mechanical and Performance Requirements

• Industrial Involvement

• Ethics

• Regulation

Biomaterials may be the most multidisciplinary of all fields. The impact to people and to commerce is huge. Because of this impact and multidisciplinarity, biomaterials is always an exciting area for study and application.

Biomaterials for biomedical applications - A market study!

The biomaterials market is defined and explained through the introduction of biotechnology and advances in the understanding of human tissue compatibility. Developing from bio-inert materials to biodegradable materials in contact with the living tissue, biomaterials are widely used in medical devices, tissue replacement, and surface coating applications. The major segments in biomaterials market are ceramics, metals, polymers, and composites. Biomaterials products are classified into orthopedic, cardiovascular, gastrointestinal, wound care, urology, plastic surgery, and others. Reconstructive surgery and orthobiologics are the dominant segments in orthopedic biomaterials market. 

Biomaterials Approach to Expand and Direct Differentiation of Stem Cells

Introduction

Stem cells, whether derived from embryos, fetuses, or adults, seem poised to dominate the next frontier of human regenerative medicine and cellular therapy. Over the last 15 years, major advances have been made in the isolation, culture, and the induction of differentiation of stem cells from various sources. Stem cells have now been identified in every major organ and tissue of the human body. Concomitant with these discoveries are intense efforts to understand the molecular mechanisms underlying the decision of stem cells to enter mitotic dormancy, undergo self-renewal, or differentiate terminally. Recent studies uncovered novel mechanisms by which stem cell fate is regulated, implicating the participation of stem cell-specific microRNAs and fate reprogramming factors that can act cell autonomously. Continued discoveries in the cell and molecular biology of stem cells will facilitate their application, the most exciting of which would be in regenerative medicine and cell therapy.

The chronic shortage of donor organs and tissues for transplantation has provided the impetus for intense research in the field of tissue engineering (TE). Unlike pharmacology and physiotherapies that are mainly palliative, TE and cellular therapy seek to augment, replace, or reconstruct damaged or diseased tissues. The advent of various enabling technologies coupled with paradigm shifts in biomaterial designs, promises to change the fundamental landscape of TE. In recent years, biomaterials design has evolved from the classical, first-generation material-biased approach that favored mechanical strength, durability, bioinertness, or biocompatibility to third-generation, biofunctional materials that seek to incorporate instructive signals into scaffolds to modulate cellular functions such as proliferation, differentiation, and morphogenesis. Advances in conjugation chemistries have now widened the options for modifying natural biopolymers or synthetic biomaterials. The development of smart biomaterials that can respond to specific stimuli such as temperature, pH, electrical signals, light, and metabolites such as glucose and adenosine triphosphate can be employed to control properties such as drug release, cell adhesiveness, phase behavior, and mechanical parameters such as permeability, volume, and electrical conductivity.

The Roles of Biomaterials in Stem Cell TE

With the possibility of therapeutic cloning becoming a reality, there is an urgency to develop technologies that can precisely control the behavior of stem cells in culture. Central to these technologies would be the probable inclusion of biomaterials as an important component. For instance, the recent report of the successful transplantation of a urinary bladder engineered from autologous urothelial and muscle cells in human patients, made possible by culturing these cells in a poly(D,L-lactide-co-glycolide) (PLGA) scaffold, heralds the arrival of the era of whole organ TE. Advances in biomaterial research will undoubtedly facilitate the transformation of this concept into reality. Biomaterial scaffolds can play a number of specific roles in TE applications using stem cells.

Biomaterials as defined systems for stem-cell derivation and expansion

A fundamental bottleneck that must be overcome to exploit stem cells for TE is the adequate supply of cells. This problem will become more critical when the engineering of bulk tissue or complex organs is contemplated, particularly when autologous tissue production is desired. Such goals would necessitate the maintenance of large quantities of undifferentiated cells to provide sufficient starting material. The long doubling time of most types of stem cell weighs directly on this problem. The doubling time of stem cells ranges from 36 h for human embryonic stem cells (ESCs) to an estimated 45 days for human hematopoietic stem cells (HSCs) Although it is generally believed that human ESCs can divide indefinitely, there is evidence to suggest that other stem cell types are subjugated to Hayflick's limit when cultured in vitro.

Although a number of commercially available cell culture matrices such as Matrigel and Cartrigel have produced encouraging results, the animal origin of these products renders them undefined and precludes their widespread use in human clinical applications. A recent trend favors the use of animal-free products, with recombinant human substitutes for such animal products emerging as an attractive alternative. Concerns about exposure of human tissues to xenogenic products have been substantiated experimentally. Besides the risk of contamination by adventitious infectious agents, there has been evidence to suggest that human cells could incorporate and express immunogenic molecules present in animal products. Human ESCs cultured with animal feeders or serum products could take up and express Neu5Gc, a non-human sialic acid, from the culture medium. Synthetic biomaterials could play a significant role in meeting the demands for well-defined systems for derivation and maintenance of ESCs.

Biomaterials for differentiation of stem cells

The plasticity of ESCs represents a proverbial double-edged sword for its use in clinical application. Although clearly a desirable property owing to the tremendous differentiation repertoire that it accords, it also poses a risk of tumorigenicity. Undifferentiated cells that retain pluripotency give rise to tumors known as teratomas. Hence, it is critical for any therapeutic strategy employing a stem cell-based approach to ensure complete and irreversible differentiation of stem cells into the desired progenitors or terminal target cell type. Different technologies have been developed to incorporate drug delivery function into a scaffold. Proteins, peptides, or plasmid DNA can be loaded into microspheres and uniformly dispersed in a macroporous polymeric scaffold, or they can be encapsulated in a fiber before forming a fibrous scaffold. This biomaterials-based approach to provide a local and sustained delivery of growth factors would be particularly valuable for the tissue development of ES-seeded scaffolds in vivo.

The mechanical properties of a scaffold or culture surface can also exert significant influence on the differentiation of the seeded stem cell. By exerting traction forces on a substrate, many mature cell types such as epithelial cells, fibroblasts, muscle cells, and neurons sense the stiffness of the substrate and show dissimilar morphology and adhesive characteristics. Highlighting the importance of matrix elasticity in dictating stem cell fate, this study also suggests an interesting biomaterial approach to influence the differentiation of stem cells.

Biomaterials as cell carriers for in vivo stem cell delivery

The loss of implanted cells can arise due to cytotoxicity or failure of the cells to integrate into host tissue, which presents a significant challenge to current approaches to tissue regeneration. Sites of injury or diseased organs often present hostile environments for healthy cells to establish and repopulate owing to the heightened immunological surveillance and the high concentration of inflammatory cytokines at these sites. Therefore, an additional role for TE scaffolds is to insulate their cellular cargos from the host immune system, obviating the need for a harsh immunosuppressive regime to promote the survival of grafts. Alginate-based biomaterials have been found to immunoprotect encapsulated cells and preliminary studies have demonstrated their feasible use as a vehicle for stem cell delivery. The incorporation of immuno-modulatory molecules into biomaterial designs may represent another strategy to tackle the issue of immunorejection.

Figure 1.

Multiple roles for biomaterials in stem cell TE. Biomaterials play different roles at various stages in the application of stem cells to TE. ESCs may be derived from blastocysts obtained by either fertilization or somatic cell nuclear transfer under xeno-free conditions on biomaterial substrates. Derived stem cells can be expanded in culture on biomaterial-based bioreactors. Tissue scaffolds can be tailored according to the specific goals of the intended therapy. (a) Expanded ESCs can be differentiated terminally into mature cell types before seeding into scaffolds to construct tissues or whole organs. Alternatively, expanded stem cells may be partially differentiated into committed tissue progenitors (proto-tissues) that undergo terminal differentiation in seeded scaffolds (b) before or (c) after implantation into the body. In the latter case, the progenitor cells may continue to proliferate and migrate outward from the implanted graft to repair lesioned areas. (d) Injectable grafts for both soft and hard tissue regeneration may be produced by encapsulating progenitor or fully differentiated cells in biodegradable hydrogels. Somatic stem cells isolated from pediatric or adult patients can similarly be expanded in a biomaterials-based culture system before being applied as described for ES-derived cells.

Emerging Trends in Stem Cell TE

The advent of micro- and nanofabrication technologies has made it possible to take apart and study independently the topographical and biochemical contribution to the cellular microenvironmental niche. Using technologies borrowed directly from the semiconductor and microelectronics industries, a plethora of techniques has been developed for creating patterned surfaces to investigate cellular behavior as diverse as cell-matrix and cell-cell interactions, polarized cell adhesion, cell differentiation in response to surface texture, cell migration, mechanotransduction, and cell response to gradient effects of surface-bound ligands.

The Development of Biomaterials for Stem Cell Expansion and Differentiation

ESCs

Expansion of ESCs. Until recently, the expansion of human ESCs was performed exclusively on feeder cell layers. However, recent reports of defined, feeder-free formulations for the derivation and maintenance of human ESCs promise to change this scenario. Biomaterials-based expansion of human ESCs has now become a distinct possibility, as has large-scale culture of human ESCs in bioreactors. This will hopefully lead to the alleviation, if not elimination, of the two major obstacles to the widespread implementation of ES technologies in the clinic, which are concerns about exposure to animal components as well as consistency in both the quality and quantity of cell supply.

Biomaterials-based expansion has been achieved with murine ESCs. A number of studies described the use of hydrogel polymers as a support substrate for the maintenance of murine ESCs and embryoid body (EB) formation. Alkali treatment of the substrate surface, which cleaves the polyester backbone to present carboxyl and hydroxyl groups, increases hydrophilicity and significantly increases the proliferation of mature ESCs. Murine ESCs cultured on electrospun nanofibrillar polyamide matrix (Ultra-Web) showed greatly enhanced proliferation and self-renewal compared to culture on two-dimensional tissue culture surfaces, highlighting the effects of 3D topography.

Human ESCs have been expanded in vitro as cell aggregates known as EBs. Culture of human ESCs in a slow-turning lateral vessel bioreactor yielded up to a threefold increase in EB formation compared to static dish cultures. Subsequently, the formation of human EBs within a 3D porous alginate scaffolds was reported. There is, however, a tendency for cultured human EBs to undergo spontaneous differentiation, particularly vasculogenesis. A good understanding of the factors affecting ESC self-renewal and maintenance and the underlying gene regulatory and signal transduction mechanisms will be instrumental in directing future designs of biomaterials for ES expansion.

Differentiation of ESCs. Achieving production of specific tissues from ESCs will require precise control of their differentiation. This would involve both physical and biochemical cues acting in concert. The versatility of such a concept was demonstrated by the induction of human with ESC differentiation into distinct embryonic tissue types within a biodegradable 3D polymer scaffold made from a 50:50 blend of PLGA and PLLA. Retinoic acid and transforming growth factor induced ESC differentiation into 3D structures with characteristics of developing neural tissues and cartilage, respectively, whereas activin-A or insulin-like growth factor induced liver-like tissues. It was therefore hypothesized that the mechanical stiffness conferred by the scaffold acted synergistically with the Matrigel or fibronectin to enhance human ESC differentiation and 3D organization. Furthermore, it was shown that tissue constructs made with the scaffolds integrated well into host tissues when transplanted into severe combined immunodeficiency (SCID) mice. Supplementation of retinoic acid, nerve growth factor, or neurotropin 3 induced neural rosette-like structures throughout the scaffolds. Nerve growth factor and neurotropin 3 induced the expression of nestin, a marker of neural precursor cells, as well as the formation of vascular structures. Pure PLLA scaffold was a suitable carrier for in vivo mineralization of human ESCs in SCID mice.

Challenges to Stem Cell TE

In spite of justified optimism, several major challenges remain to be met. Foremost is the problem of mass transport during scale-up of engineered tissue constructs. Any TE modality that aspires toward clinical translation must consider vascularization. This hurdle is currently viewed as the limiting factor to the size of tissue constructs that can realistically be achieved. Supply of nutrients and oxygen to cells located deep in bulk tissue or complex organs must be resolved in order for them to be maintained in the body for any meaningful duration. Thrombogenic occlusion of microconduits or micropores introduced into biomaterial constructs is a common problem faced in tackling this limitation. The incorporation of antithrombogenic molecules into biomaterials is one of the strategies employed to overcome the problem. Alternatively, angiogenic factors can be incorporated into biomaterials to induce de novo vasculogenesis and/or angiogenesis from tissues surrounding the implants. Spontaneous vasculogenesis observed under certain conditions, such as in human ESC EBs growing in suspension cultures, lends hope to surmounting this challenge.

The creation of relevant disease models to evaluate the efficacy of the engineered tissue constructs is as important as overcoming the engineering hurdles. Often, small rodent models with mechanically or pharmacologically induced lesions do not accurately recapitulate human disease conditions, causing disparate outcomes between preclinical and clinical trials. Non-human primate models may in theory, provide the most relevant animal models, but these are not readily available for practical and ethical reasons. The creation of non-human primate models for various human diseases by gene targeting and nuclear transfer has been proposed. However, cloning of monkeys remains unsuccessful to date. Success in this arena may positively impact stem cell TE.

Summary and Future Perspectives

The field of TE has entered an exciting new chapter, where experimental technologies are being aggressively explored for clinical translation, signifying a veritable "coming of age" of the field. The convergence of two important disciplines, that of biomaterials engineering and stem cell research, promises to revolutionize regenerative medicine. With this merger, several concepts that would have been deemed far-fetched a few years ago are now being actively pursued. Among these concepts are brain reconstructive surgery, tailor-made autologous body replacement parts, and cybernetic prosthesis. The future of stem cell TE is undoubtedly technology driven. New applications and improvement upon current designs will depend heavily on innovations in biomaterials engineering. Concomitant with this, progress in stem cell biology will be imperative in dictating advances in stem cell TE. A better understanding of the molecular mechanisms by which substrate interactions impact stem cell self-renewal and differentiation is of paramount importance for targeted design of biomaterials. Discoveries in the fields of developmental biology and functional genomics should also be parlayed for broadening the repertoire of biological molecules that can be incorporated into biomaterials for fine-tuning stem cell activities. With the merger between the two powerful disciplines-biomaterials engineering and stem cell biology-a new drawing board now lies before us to develop therapies that could hopefully help the world population age more gracefully.

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