ABSTRACT
In this chapter we describe new biomaterial led approaches to immobilization, maintenance, programming and promotion of desirable stem cell responses while regenerating clinically acceptable human tissues. We also describe efforts to enhance survivability of human cell transplantation inside protective devices. Biostructures are being designed into functional scaffolds that can adapt (evolve) to changing in situ environment during regeneration, regulate cell responses at nanostructured surfaces, as modules for self-assembling by the patient’s own cells and as smart devices that possess tissue specific homing capabilities.One of the major shortcomings of current synthetic implants is their inability to adapt to the local tissue environment [3].Therefore new advanced bioactive materials are needed which can elicit re generative responses. A major key approach towards driving tissue regeneration is the use of biochemical factors to trigger cell proliferation and differentiation. Bone Morphogenic Proteins (BMP’s) are widely used in musculoskeletal tissue engineering to promote bone tis sue formation and gene expression [3]. Increased understanding of growth factor function and the interplay during regeneration has increased development of pharmaceutical grade growth factors for use in the clinic. Alternative biological factors with unique cel lular functions and activities are sought to establish more precise control of the regenerative response and simulate the sequential temporal and spatial secretion of secretory factors (proliferative, differentiation and growth). There is a clear and pertinent need for better tissue engineering scaffolds that possess more natural bio-responsive environments conducive to guiding the natural pro cesses of regeneration which can be highly intricate and dynamic in space and time. Thus scaffolds must have intelligent designs to meet this biological challenge. We are convinced that there needs to be a step change to scaffold environments that are responsive to bone and extracellular tissue to implant nano-interactions and adaptability to applied functional loadings. In biologic environment the synthesized biomatrix evolves in real-time to meet the demands and optimisations of adaptive growth and regeneration of human tissues.As cells proliferate and differentiate they alter their environ-ment. Future advanced biomimetic scaffolds must be able to adapt to these changes and meet the ever-changing needs of de veloping
tissues. We anticipate synthesizing biomaterial scaffolds with functional cross-links and pendant side groups that interact with surrounding integrated cell populations at three levels: at the surface, at the architectural and at a functional (e.g., mechanical enhancement).Development of modular self-assembling biomaterials is an attempt to harness the cell as the master-builder of its own extra-cellular matrix using tailored synthetic components [5]. Biomaterial structures that are designed and built by human cells and their cel lular components is only just being realized and is an important aim for future biomaterials for clinical applications. 38.2 Biomimetic Stem-Cell ScaffoldsUse of stem cells in regenerative medicine has increased the potential to restore a greater range of tissues in a more sustainable manner and for longer than with conventional tissue-specific differentiated cells. There is increasing awareness that the com-position of scaffolds is important to control stem cell activities as they are so reliant on the extracellular surroundings to survive and generate tissues [1, 13]. Technologies that harness and modulate stem cell activities therefore offer exciting new prospects for tissue engineering of self-renewing tissues and organs [2].They are pivotal for permanent reparation of self-renewing tissues such as skin and bone. Protocols that enhance the accession, processing, function and transplantation of conditioned cells to the patient are impera tive.Naturally derived polysaccharide hydrogels are ideal tem plates for organising cells in 3-dimensional configurations, directing tissue responses and delivering soluble factors to both embedded and co-cultured human cell populations [17].Chitosan and alginate are biodegradable, non-toxic materials that elicit minimal immunoreactivity and break down into chemical con stituents that can be completely metabolized and excreted (glu cosamine and mannose/glucoronic acids respectively). Mineralized polysaccharide constructs have the advantage of being more me chanically stable than unmineralized ones [20]. Adjustments in cap sule formation chemistry provide a programmable mechanism for controlling
the diffusion of soluble biological factors across the capsule wall. Mineral-polysaccharide capsules synthesized at a macroscopic scale have been investigated for their role in tissue regeneration, gene transfection and growth factor delivery [15].Our original hypothesis was to use self-assembled miner alized polysaccharide capsules with readily specifiable proper ties to encapsulate enriched mesenchymal cell populations in biomimetic microenvironments for the generation of a range of tissue types. We have been able to successfully demonstrate the ability to modulate capsule composition and the physico-chemical properties of polysaccharide capsules for enhancement of carti lage, bone and adipogenic tissue formation and augmentation of the capsule environment tailored for specific tissue types. We also demonstrated a wide range of other significant biological and physical functions that show clinical potential including gene de livery, growth factor delivery and spatial and temporal segrega tion of cell populations in nested capsules.Mineralized polysaccharide capsules are specially designed bioconstructs for tissue engineering applications [25].The production of polysaccharide capsules involves a unique one step self-assembling process carried out at room temperature and in aqueous media thus avoiding toxic chemicals and harsh physical treatments. The shell and core properties, such as shell thickness and core cellularity, diffusion potential and mineraliza tion can be modulated through simple adjustments to the chem istry of the forming solutions (Fig. 38.1). It was found that the shell thickness and cell loading deter-mined the potential to rupture and burst releasing the contents from the core. For example capsules with populations of cells be tween 500,000 and 800,000 dispersed encapsulated cells into the surrounding environment at 7 days due to rupturing of the shell (Fig. 38.2). Capsules with low mineralization burst. Modifications can also be made to generate capsules with different 3D shapes (rods, plates and spheres) and sizes ranging from 100 nm to 5 mm in diameter.We have harnessed recent innovations in mineralized alginate-chitosan technology for a range of therapeutic applica tions using primary human stem cells. Microcapsules, nanocap sules
have been newly developed that enable more effective targeted delivery of functional biological factors, lead to mature tissue formation and generate bio-responsive native extracellu lar matrix environments. This addresses existing limitations of using stem cells in therapies for tissue replacement and aug mentation, namely sourcing and obtaining enough stem cells from each sample, impaired differentiation potential and poor growth. We contend that such tailored polysaccharide microenvi ronments will directly address many of these issues, for example, by improving survival, initiating differentiation and enhancing proliferation.21.2. Bi mimetic Stem-cell Scaffolds 825
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