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A Biomimetic Approach toward Enhancing Angiogenesis: Recombinantly Expressed Domain V of Human Perlecan Is a Bioactive Molecule That Promotes Angiogenesis and Vascularization of Implanted Biomaterials

ABSTRACT: Abstract Angiogenic therapy involving delivery of pro?angiogenic growth factors to stimulate new blood vessel formation in ischemic disease is promising but has seen limited clinical success due to issues associated with the need to deliver supra?physiological growth factor concentrations. Bio?inspired growth factor delivery utilizing the native growth factor signaling roles of the extracellular matrix proteoglycans has the potential to overcome many of the drawbacks of angiogenic therapy. In this study, the potential of the recombinantly expressed domain V (rDV) of human perlecan is investigated as a means of promoting growth factor signaling toward enhanced angiogenesis and vascularization of implanted biomaterials. rDV is found to promote angiogenesis in established in vitro and in vivo angiogenesis assays by potentiating endogenous growth factor signaling via its glycosaminoglycan chains. Further, rDV is found to potentiate fibroblast growth factor 2 (FGF2) signaling at low concentrations that in the absence of rDV are not biologically active. Finally, rDV immobilized on 3D porous silk fibroin biomaterials promotes enhanced vascular ingrowth and integration of the implanted scaffolds with the surrounding tissue. Together, these studies demonstrate the important role of this biologically active perlecan fragment and its potential in the treatment of ischemia in both native and bioengineered tissues. A biomimetic growth factor delivery approach utilizing the native signaling roles of extracellular matrix is described. C?terminal region of perlecan (rDV) is shown to promote angiogenesis by signaling endogenous and exogenous growth factors at low concentrations in its soluble form and when immobilized on a biomaterial, making it a promising approach toward angiogenic therapy for the treatment of ischemic disease.

SUBMITTER: Lin X

PROVIDER: S-EPMC7507460 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Project description:Mitigation of the foreign body response (FBR) and successful tissue integration are essential to ensuring the longevity of implanted devices and biomaterials. The use of porous materials and coatings has been shown to have an impact, as the textured surfaces can mediate macrophage interactions with the implant and influence the FBR, and the pores can provide space for vascularization and tissue integration. In this study, we use a new class of implantable porous biomaterials templated from bicontinuous interfacially jammed emulsion gels (bijels), which offer a fully percolating, non-constricting porous network with a uniform pore diameter on the order of tens of micrometers, and surfaces with consistent curvature. We demonstrate that these unique morphological features, inherent to bijel-templated materials (BTMs), can enhance tissue integration and vascularization, and reduce the FBR. Cylindrical polyethylene glycol diacrylate (PEGDA) BTMs, along with PEGDA particle-templated materials (PTMs), and non-templated materials (NTMs), were implanted into the subcutaneous space of athymic nude mice. After 28 days, implants were retrieved and analyzed via histological techniques. Within BTMs, blood vessels of increased size and depth, changes in collagen deposition, and increased presence of pro-healing macrophages were observed compared to that of PTM and NTM implants. Bijel templating offers a new route to biomaterials that can improve the function and longevity of implantable devices. STATEMENT OF SIGNIFICANCE: All implanted biomaterials are subject to the foreign body response (FBR) which can have a detrimental effect on their efficacy. Altering the surface chemistry can decrease the FBR by limiting the amount of proteins adsorbed to the implant. This effect can be enhanced by including pores in the biomaterial to allow new tissue growth as the implant becomes integrated in the body. Here, we introduce a new class of self-assembled biomaterials comprising a fully penetrating, non-constricting pore phase with hyperbolic (saddle) surfaces for enhanced tissue integration. These unique morphological characteristics result in dense blood vessel formation and favorable tissue response properties demonstrated in a four-week implantation study.

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A Biomimetic Approach toward Enhancing Angiogenesis: Recombinantly Expressed Domain V of Human Perlecan Is a Bioactive Molecule That Promotes Angiogenesis and Vascularization of Implanted Biomaterials

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