Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part II: Challenges on the Evolution from Single to Multiple Bioactive Factor Delivery

Abstract

The development of controlled release systems for the regeneration of bone, cartilage, and osteochondral interface is one of the hot topics in the field of tissue engineering and regenerative medicine. However, the majority of the developed systems consider only the release of a single growth factor, which is a limiting step for the success of the therapy. More recent studies have been focused on the design and tailoring of appropriate combinations of bioactive factors to match the desired goals regarding tissue regeneration. In fact, considering the complexity of extracellular matrix and the diversity of growth factors and cytokines involved in each biological response, it is expected that an appropriate combination of bioactive factors could lead to more successful outcomes in tissue regeneration. In this review, the evolution on the development of dual and multiple bioactive factor release systems for bone, cartilage, and osteochondral interface is overviewed, specifically the relevance of parameters such as dosage and spatiotemporal distribution of bioactive factors. A comprehensive collection of studies focused on the delivery of bioactive factors is also presented while highlighting the increasing impact of platelet-rich plasma as an autologous source of multiple growth factors.

Strategies to engineer tendon/ligament-to-bone interface: Biomaterials, cells and growth factors

“…Current challenges for engineering such biomimetic gradients are related to the difficulty of mimicking natural concentration gradients (micro-or nanoscale) and retaining long term gradient patterns due to the rapid diffusion of molecules. For extended and more detailed information on growth factor delivery strategies, readers are referred to the following reviews: [123,[127][128][129][130].…”

Liposomes in tissue engineering and regenerative medicine

“…For instance, bone morphogenetic protein 2 (BMP-2) is added to induce the osteogenic differentiation, whereas transforming growth factor b (TGF-b) is used to promote the chondrogenic differentiation. An adequate combination of signalling molecules should be provided by controlled release systems in order to promote the desired regenerative outcome [112,[157][158][159]. Therefore, liposomes can be used as carriers for the spatio-temporal controlled delivery of GFs, improving stem cell proliferation and differentiation in vitro [160,161].…”

Enhancing regenerative approaches with nanoparticles

“…Therefore, the development of 'smart' biomaterials with the ability to spatio-temporally control the dose, sequence and profile of release of several GFs and cytokines so as to regulate cellular fates during tissue regeneration represents one of the next steps within this field of research. There are several examples of carriers that allow for temporal controlled release of a few GFs using nanogels, cross-linked gelatin-polymer composites or gelatin-based coatings [67]. In these systems, the biomaterials are produced by incorporating different layers that serve as matrices enabling internal architecture with controlled release properties.…”