Growth factor delivery using extracellular matrix-mimicking substrates for musculoskeletal tissue engineering and repair

Abstract

Therapeutic approaches for musculoskeletal tissue regeneration commonly employ growth factors (GFs) to influence neighboring cells and promote migration, proliferation, or differentiation. Despite promising results in preclinical models, the use of inductive biomacromolecules has achieved limited success in translation to the clinic. The field has yet to sufficiently overcome substantial hurdles such as poor spatiotemporal control and supraphysiological dosages, which commonly result in detrimental side effects. Physiological presentation and retention of biomacromolecules is regulated by the extracellular matrix (ECM), which acts as a reservoir for GFs via electrostatic interactions. Advances in the manipulation of extracellular proteins, decellularized tissues, and synthetic ECM-mimetic applications across a range of biomaterials have increased the ability to direct the presentation of GFs. Successful application of biomaterial technologies utilizing ECM mimetics increases tissue regeneration without the reliance on supraphysiological doses of inductive biomacromolecules. This review describes recent strategies to manage GF presentation using ECM-mimetic substrates for the regeneration of bone, cartilage, and muscle.

Keywords: Affinity; Extracellular matrix; Growth factor; Spatiotemporal control; Tissue engineering.

Graphical abstract

Fig. 1

(A) A sampling of methods for GF delivery used to influence transplanted or host cells for tissue engineering. Various biomaterials have been utilized for tissue engineering applications, driven by application or tissue type. ECM components are commonly utilized for their cell instructive nature and capacity for GF retention. Materials can be further altered to tune the presentation of GFs and increase their effectiveness. (B) Combinations of these biomaterials, either synthetic or naturally derived, coupled with an ECM component regulate spatiotemporal GF presentation. Inclusion of ECM improves molecular feedback between cells and the matrix by engaging integrin signaling which may potentiate GF signaling.

Fig. 2

Representative GF release profiles from monolithic, ionic, and ECM-based delivery systems. Monolithic carriers release GFs by diffusion, while ionic and ECM-based GF delivery leverage the interaction of positively charged proteins with negatively charged substrates for sustained presentation. Release profiles are drawn to reflect the relative release profile of each mechanism.

Fig. 3

The ECM acts as a reservoir for the retention of GFs necessary for musculoskeletal tissue repair. Endogenous GFs are commonly sequestered by heparan-binding proteoglycans within the ECM. Cells engage the surrounding ECM via integrin engagement with specific ligands present in matricellular proteins. This interaction may also enable GF receptor clustering on the cell surface, further promoting activation of the targeted cell signaling pathway and resultant changes in cell phenotype.