Bio-instructive materials for musculoskeletal regeneration

Abstract

The prevalence and cost of disorders affecting the musculoskeletal system are predicted to rise significantly in the coming years due to the aging global population and the increase of associated risk factors. Despite being the second largest cause of disability, the clinical options for therapeutic intervention remain limited. The clinical translation of cell-based therapies for the treatment of musculoskeletal disorders faces many challenges including maintenance of cell survival in the harsh in vivo environment and the lack of control over regulating cell phenotype upon implantation. In order to address these challenges, the development of bio-instructive materials to modulate cell behavior has taken center stage as a strategy to increase the therapeutic potential of various cell populations. However, the determination of the necessary cues for a specific application and how these signals should be presented from a biomaterial remains elusive. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues. There is a particular emphasis on emerging efforts such as the engineering of immunomodulatory and antibacterial materials, as well as the incorporation of these strategies into biofabrication and organ-on-a-chip approaches. STATEMENT OF SIGNIFICANCE: Disorders affecting the musculoskeletal system affect individuals across the lifespan and have a profound effect on mobility and quality of life. While small defects in many tissues can heal successfully, larger defects are often unable to heal or instead heal with inferior quality fibrous tissue and require clinical intervention. Cell-based therapies are a promising option for clinical translation, yet challenges related to maintaining cell survival and instructing cell phenotype upon implantation have limited the success of this approach. Bio-instructive materials provide an exciting opportunity to modulate cell behavior and enhance the efficacy of cell-based approaches for musculoskeletal repair. However, the identification of critical instructive cues and how to present these stimuli is a focus of intense investigation. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues, while also considering exciting progress in the engineering of immunomodulatory and antibacterial materials.

Keywords: Biomineralization; Electroconductive; Musculoskeletal; Stem cell differentiation; Tissue engineering.

Figure 1.

Bio-instructive materials present physical and biochemical signals to associated cells at the meso-, micro-, and nanoscale.

Figure 2.

The cell niche is determined by intrinsic and external cues of physical (substrate mechanics, topography, external force and electric stimulation) and biochemical (substrate composition and soluble molecules) origin. This complex milieu determines cell behavior and differentiation.

Figure 3.

Substrate stiffness is an essential design parameter for the incorporation of physical cues into biomaterials to guide stem cell fate.

Figure 4.

Incorporation of calcium phosphate phases such as HA, dicalcium phosphate dihydrate (DCPD) or amorphous calcium phosphate (ACP) into biomaterials can provide a surface recognized by cells and biomacromolecules or act as a source of ions for the mineralization of incorporated or cell-produced ECM components. Both processes contribute to instructing stem cell phenotype towards de novo bone formation.

Figure 5.. Summary of physical and biochemical cues to enhance regeneration of specific musculoskeletal tissues.

While immunomodulatory and antimicrobial cues are common for the design of bio-instructive materials for musculoskeletal tissues, the necessary biochemical and physical cues are tissue specific. Softer and aligned substrates are preferred for muscle and cartilage, but bone requires stiff and randomly oriented materials to effectively guide cells toward the osteogenic lineage. Muscle regeneration is enhanced by the presentation of myogenic factors (e.g., IGF-1, SDF1α), cartilage by the presentation of members of the TGF-β superfamily (e.g., TGF-β1, TGF-β3) and the suppression of chondrocyte hypertrophy, and bone by other members of the TGF-β superfamily (e.g., BMP-2, BMP-4), angiogenic factors and the promotion of tissue biomineralization.