At a Glance
Researchers at Colorado State University have patented surface treatments and methods for modifying the surfaces of vascular stents and orthopedic devices to introduce multiple biological functions to the surface. Its use can be extended to other blood contacting devices (e.g. heart valves, biosensors and extracorporeal devices), and other orthopedic materials (internal fixation devices and intraosseous transcutaneous amputation prostheses).
The invention is a surface treatment for materials that includes the formation of metal oxide (e.g. titania) nanotubes, and their modification with nanostructured polyelectrolyte complexes (nanoparticles, nanofibers, and porous foams) that introduce multiple biological functions to the surface. The polyelectrolyte complexes contain chitosan and/or chitosan modified with a nitrous oxide donating group (NO-chitosan) as the polycation, and glycosaminoglycans, such as heparin, heparan sulfate, and chondroitin sulfate, as the polyanion. These surfaces are further modified with potent growth factors, such as vascular endothelial growth factor (VEGF), members of the fibroblast growth factor family (e.g. FGF-2), or the transforming growth factor beta superfamily (e.g. BMP-2) bound and stabilized by the glycosaminoglycans. The titania nanotubes provide tunable nanotopographical features, and the polyelectrolyte complexes introduce a number of biochemical functions to the surface.
The beneficial effects of the surface nanotopography introduced by the nanotubes have been demonstrated on a number of cell types. Surface nanotopographical features promote surface endothelialization and osteoblast attachment and differentiation. These effects would promote healing in both orthopedic and vascular applications. Furthermore, the nanotopography has been shown to prevent smooth muscle cell proliferation and increase their differentiation, and to reduce both platelet adhesion and macrophage activation. These effects reduce the potential for blood clotting, inflammation, and foreign body reaction to the surface.
With respect to growth factor delivery. Heparin and other glycosaminoglycans bind many growth factors and stabilize them in the extracellular matrix. Glycosaminoglycans also bind growth factor receptors and thereby regulate growth factor signaling. By modifying the surfaces with these glycosaminoglycans, growth factors are stabilized and presented to cells in a context that mimics their biochemical presentation in the native extracellular matrix. This enhances growth factor stability and signaling.
We have delivered FGF-2 from nanostructured glycosaminoglycan-based surfaces, using physiologically relevant growth factor doses (ng/cm2) rather than costly and potentially dangerous superphysiologic doses. Mitogenic activity of FGF-2 with respect to mesenchymal stem cells was maintained for more than 30 days. Chitosan promoted the induction of cytokine profiles that led to the waning of inflammation and healthy integration with the host tissue.
Heparin and other glycosaminoglycans bind VEGF and its two primary receptors, VEGF-R1 and VEGF-R2. This VEGF and VEGF-R binding helps promote endothelialization, by stimulating endothelial cell proliferation, without inducing smooth muscle cell proliferation. Heparin also potentiates the activity of antithrombin III and inhibits blood coagulation. Nitrous oxide (NO) released from the surfaces improve resistance to thrombosis by preventing platelet activation and adhesion, promoting vasorelaxation, and inhibiting neointimal hyperplasia.
Nanotexturing Provides Unique Geometries:
Geometries include nanofibers, porous foam, nanotubes, nanopillars or nanowires, which each can be tuned using polysaccharide chemistries, nitrous oxide-releasing polymers, and growth factors.
- Nanotopography promotes endothelial cell attachment and inhibits thrombus formation
- Chitosan has antimicrobial activity.
- Heparin interacts favorably with enzymes in the coagulation cascade to prevent coagulation.
- Nitrous oxide prevents platelet activation and acts as a vasodilator.
- Growth factors stabilized by binding to sulfated polysaccharides promote cell proliferation, differentiation, and extracellular matrix production at the surface.
- Combinations of multiple growth factors can be used, e.g. TGFB growth factors to promote bone healing and VEGF to promote angiogenesis.
- Scalable and conformal over surfaces with large (cm-scale) to very small (10-100 nm) features
- Surfaces can be applied to many surface types (e.g., flat polymers, medical-grade titanium and stainless steel, glass, nanostructured surfaces, and cortical bone)
- Can be automated and modified to precisely tune the composition, amount, and location of growth factors
- Specific binding sequences stabilize proteins of interest in the native extracellular matrix (e.g., VEGF, parathyroid hormone, members of the FGF family, the TGF-β superfamily, etc.)
- Stabilizing sequences reduce the amount of bound protein required to achieve the desired biological response
- Coatings have broad spectrum antimicrobial activity
- Tissue healing around implants having coating is characterized by waning of the inflammation response, good tissue integration, and lack of chronic inflammation
- Modifying the surfaces of vascular stents and orthopedic devices (for the introduction multiple biological functions)
- Application can be extended to other blood contacting devices (e.g. heart valves, biosensors and extracorporeal devices)
- Application in other orthopedic materials (internal fixation devices and intraosseous transcutaneous amputation prostheses)
J.R. Vlcek, et al. (2021) Enzymatic degradation of glycosaminoglycans and proteoglycan-mimetic materials in solution and on polyelectrolyte multilayer surfaces. Biomacromolecules. DOI: 10.1021/acs.biomac.1c00720.
J.R. Vlcek, et al. (2021) Blood-Compatible Materials: Vascular Endothelium-Mimetic Surfaces that Mitigate Multiple Cell-Material Interactions. Advanced Healthcare Materials. DOI:10.1002/adhm.202001748.
M. Hedayati, et al. (2018) Nanostructured Surfaces that Mimic the Vascular Endothelial Glycocalyx Reduce Blood Protein Adsorption and Prevent Fibrin Network Formation. ACS Applied Materials and Interfaces. DOI: 10.1021/acsami.8b09435.
V Leszczak, et al. (2014) Nanostructured biomaterials from electrospun demineralized bone matrix: a survey of processing and crosslinking strategies. ACS Appl Mater Interfaces. doi: 10.1021/am501700e.
F Zomer Volpato, et al. (2012) Preservation of FGF-2 bioactivity using heparin-based nanoparticles, and their delivery from electrospun chitosan fibers. Acta Biomater. doi: 10.1016/j.actbio.2011.12.023
Last updated: April 2022