Heparin modification of a biomimetic bone matrix for controlled release of VEGF

Abstract

Bone regeneration using tissue engineered constructs requires strategies to effectively stimulate vascularization within such a construct that is crucial for its supply and integration with the host tissue. In this work, porous scaffolds of a collagen/hydroxyapatite nanocomposite were modified with heparin to generate biomimetic bone matrices which are able to release angiogenic factors in a controlled manner. Heparin was either integrated during material synthesis (in situ) or added to the scaffolds after their fabrication (post). Both approaches resulted in stable incorporation of heparin into the matrix of mineralized collagen. Investigations of binding and release of the vascular endothelial growth factor (VEGF-A₁₆₅) loaded onto the scaffolds revealed an enhanced binding capacity as well as a sustained and nearly constant delivery of VEGF as result of both heparin modification methods. The release rate could be controlled by varying the quantity of incorporated heparin and the modification method. Although the biological activity of VEGF released after 7 days from the unmodified scaffolds was reduced in comparison to control VEGF, it was maintained after release from post or even enhanced after release from in situ modified scaffolds. In conclusion, the heparin-modified scaffolds of mineralized collagen exhibited favorable growth factor binding and release properties and may be beneficial to stimulate vascularization.

Heparin affects human bone marrow stromal cell fate: Promoting osteogenic and reducing adipogenic differentiation and conversion

“…Furthermore, heparin exerts a strong binding affinity towards VEGF, a signal molecule stimulating vasculogenesis and angiogenesis [58]. This might be a plausible cause for the adverse effects on the bone since Kusumbe and colleagues highlighted the connection between angiogenesis and osteogenesis in their recent study, demonstrating that different subtypes of blood vessels orchestrate bone formation in mice [45].…”

Two‐step stem cell therapy improves bone regeneration compared to concentrated bone marrow therapy

“…Cylindrical MCM‐scaffolds (Ø: 2 mm, length: 2 mm) with a mean pore‐size of around 200 μm were produced as described previously, functionalized with 10 mg heparin (heparin sodium salt, unfractionated, Sigma–Aldrich, St. Louis, MO) per 1 g mineralized collagen and gamma sterilized.…”

Controlled drug release for tissue engineering

“…It is a highly sulfated and a highly anionic linear polysaccharide 69 that has varying levels of binding affinity for peptides and proteins. Controlled release of a drug from a heparin based delivery system (HBDS) is dependent on the heparin binding affinity of the drug being released.…”

“…Researchers developed porous scaffolds made from collagen/hydroxyapatite nanocomposite, which were then modified with heparin and used to deliver VEGF for bone tissue engineering. 69 Using an in situ or a post scaffold fabrication modification approach, heparin was incorporated into the scaffold matrix or coated the scaffold surface. VEGF was loaded onto the heparin-modified scaffolds by physical adsorption.…”