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Gelatin methacrylate microspheres for controlled growth factor release.

ABSTRACT: Gelatin has been commonly used as a delivery vehicle for various biomolecules for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chemical cross-linking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel cross-linking. Here we examined the physical properties and growth factor delivery of gelatin methacrylate (GMA) microparticles (MPs) formulated with a wide range of different cross-linking densities (15-90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle cross-linking density and degradation was observed, with the lowest cross-linked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower cross-linking densities could be loaded with up to a 10-fold higher relative amount of growth factor than conventional GA cross-linked MPs, despite the GA MPs having an order of magnitude greater gelatin content. Moreover, a reduced GMA cross-linking density resulted in more complete release of bone morphogenic protein 4 and basic fibroblast growth factor and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degradation tunability, thereby offering a more potent controlled release system for growth factor delivery.

SUBMITTER: Nguyen AH

PROVIDER: S-EPMC4293288 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Gelatin methacrylate microspheres for controlled growth factor release.

Nguyen Anh H AH McKinney Jay J Miller Tobias T Bongiorno Tom T McDevitt Todd C TC

Acta biomaterialia 20141120

Gelatin has been commonly used as a delivery vehicle for various biomolecules for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chemical cross-linking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel cross-linking. Here we examined the physical ...[more]

PMID: 25463489

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Project description:Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatic crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was increased by 2.4-fold compared with that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed compared to the controls after being subcutaneously injected in the dorsal side of the mice for 2 weeks. Interestingly, even without the incorporation of VEGF, the heparin-modified gelatin derivative still had the capability to induce angiogenesis to a certain degree. Our results suggest that the gelatin derivative/VEGF is an excellent injectable delivery system for induced angiogenesis of soft tissue regeneration.

Dataset Information

Gelatin methacrylate microspheres for controlled growth factor release.

Publications

Gelatin methacrylate microspheres for controlled growth factor release.

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