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Stimuli-Responsive Delivery of Growth Factors for Tissue Engineering

Growth factors (GFs) play a crucial role in directing stem cell behavior and transmitting information between different cell populations for tissue regeneration. However, their utility as therapeutics is limited by their short half-life within the physiological microenvironment and significant side effects caused by off-target effects or improper dosage. "Smart" materials that can not only sustain therapeutic delivery over a treatment period but also facilitate on-demand release upon activation are attracting significant interest in the field of GF delivery for tissue engineering. Three properties are essential in engineering these "smart" materials: 1) the cargo vehicle protects the encapsulated therapeutic; 2) release is targeted to the site of injury; 3) cargo release can be modulated by disease-specific stimuli. The aim of this review is to summarize the current research on stimuli-responsive materials as intelligent vehicles for controlled GF delivery; Five main subfields of tissue engineering are discussed: skin, bone and cartilage, muscle, blood vessel, and nerve. Challenges in achieving such "smart" materials and perspectives on future applications of stimuli-responsive GF delivery for tissue regeneration are also discussed.


A) Summary of the specific hallmarks and cellular activities associated with typical injuries and disorders of the human body. These hallmarks have the potential to be utilized as specific inducers in responsive or targeted drug delivery.

A) Summary of the specific hallmarks and cellular activities associated with typical injuries and disorders of the human body. These hallmarks have the potential to be utilized as specific inducers in responsive or targeted drug delivery.


Tissue engineering is a rapidly developing field aiming to regenerate or replace defective or diseased tissues through the application of biomaterials, cells, or bioactive molecules. For tissue regeneration, cellular function and behavior are modulated by interactions between a cell and its environment; other cells play an important role as communication occurs through either direct cell-cell contact or the secretion of small molecules, such as hormones and mediators. Growth factors (GFs) play an important role in the transmission of information between different cell populations. Within organ systems, these proteins control and regulate bioactivities of different cells, including regulation of cell proliferation, migration, and differentiation. GFs initiate their functions by binding to specific receptors which trigger a signaling cascade appropriate dosage or release kinetics of GF could result in distinct differentiation of stem cells and undesired side effects. For example, bone morpho-genic proteins (BMPs) are able to promote the osteogenic and chondrogenic differentiation of stem cells at different local concentrations. However, an overdose of BMP-2 may cause uncontrolled bone formation, soft tissue inflammation, and even carcinogenesis. To overcome such issues, controlled and sustained GF release systems have been extensively studied. One of the primary approaches is to encapsulate GFs within the polymeric matrix to protect them from degradation. Additionally, GF release kinetics can be controlled by adjusting the degradation rate of the polymeric matrix or facilitating physical and chemical interactions between GFs and the matrix. Apart from sustained release, “smart” materials with the ability to sense signals within the physiological environment and react correspondingly are gaining attention for applications in drug delivery, tissue engineering, and biomedical devices. As reported in previous studies, tissue injuries lead to site-dependent environmental changes and abnormal cellular activity. Multiple factors, including enzymes, reduction and oxidation (redox) reactions, hypoxia, pH, temperature, and other characteristics, become dysregulated at the onset of injury or during the progression of the healing. These hall-marks can be monitored to serve as a reference to evaluate the extent of the injury, stage of wound healing, and the necessity for treatment. For example, in the healing process for chronic wounds, the microenvironment is turned acidic early on to prevent bacterial infection and the pH returns to normal levels over time as therapeutic interventions are used and the wound heals. However, the pH of burn wound fluid is slightly basic and decreases with therapy and healing. While these changes in pH already enhance the wound healing potential, they can also be exploited by “smart” materials as potential stimuli for on-demand drug release. Stimuli-responsive GF delivery systems have been designed to tailor therapeutic release profiles based on the need of the injury. Microenvironmental triggers, such as enzymes, pH, redox gradients, and temperature can be used to passively tune drug release while external inducers such as ultrasound, magnetic fields, and light can be used to promote the on-demand release of bioactive molecules. In response to these inducers, “smart” materials can adjust therapeutic release by changing their physical or chemical properties like degradation, swelling/shrinking, sol–gel transition, hydrophobicity shift, and competitive binding. This responsiveness facilitates on-demand release when triggered, preventing improper and off-targeting release leading to serious side effects. In this review, they summarize the stimuli-responsive GF release strategies that can be tuned to respond to the dynamic microenvironment of injured tissues in five main fields of tissue engineering: i) skin; ii) bone and cartilage; iii) skeletal and cardiac muscle; iv) blood vessel and v) nerve. They will also discuss their perspectives on the future design requirements for stimuli-responsive GF delivery in tissue regeneration1.


  1. Qu, M., Jiang, X., Zhou, X., Wang, C., Wu, Q., Ren, L., Zhu, J., Zhu, S., Tebon, P., Sun, W., & Khademhosseini, A. (2020). Stimuli-Responsive Delivery of Growth Factors for Tissue Engineering. Advanced healthcare materials, 9(7), e1901714. https://doi.org/10.1002/adhm.201901714