Biomaterials with persistent growth factor gradients in vivo accelerate vascularized tissue formation

Abstract

Gradients of soluble factors play an important role in many biological processes, including blood vessel assembly. Gradients can be studied in detail in vitro, but methods that enable the study of spatially distributed soluble factors and multi-cellular processes in vivo are limited. Here, we report on a method for the generation of persistent in vivo gradients of growth factors in a three-dimensional (3D) biomaterial system. Fibrin loaded porous poly (ethylene glycol) (PEG) scaffolds were generated using a particulate leaching method. Platelet derived growth factor BB (PDGF-BB) was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres which were placed distal to the tissue-material interface. PLGA provides sustained release of PDGF-BB and its diffusion through the porous structure results in gradient formation. Gradients within the scaffold were confirmed in vivo using near-infrared fluorescence imaging and gradients were present for more than 3 weeks. The diffusion of PDGF-BB was modeled and verified with in vivo imaging findings. The depth of tissue invasion and density of blood vessels formed in response to the biomaterial increased with magnitude of the gradient. This biomaterial system allows for generation of sustained growth factor gradients for the study of tissue response to gradients in vivo.

Effect of prevascularization on in vivo vascularization of poly(propylene fumarate)/fibrin scaffolds

“…In vitro prevascularization strategies have been shown to be effective in pre-therapeutic research for the establishment a vascular supply and for the subsequent formation, development and integration of bone neo-tissue [28, 49–51]. The following two main in vitro strategies have been used to vascularize an implant: 1) strategies to recruit/stimulate local vascularization [52, 53], 2) in vitro prevascularization to form de novo blood vessels inside the implant [48]. We use the second strategy in this study to form blood vessels inside the PPF/fibrin solid cured/hydrogel polymeric scaffold system.…”

Computational Model-Based Analysis of Strategies to Enhance Scaffold Vascularization

“…20 A layer of degradable hydrogel containing microspheres (distal layer) is placed on the surface of a porous fibrin/poly (ethylene glycol) (PEG) composite scaffold. PDGF-BB was encapsulated into degradable microspheres (poly (lactic-co-glycolic acid)) (PLGA) and microspheres and placed at the top of the scaffold within the degradable polymer.…”

“…The effective diffusion coefficient within the scaffold was calculated by fitting the model to experimental results to account for both steric effects of the scaffold structure and any binding to fibrin. The experimental release findings and details of the diffusion model were reported previously 20 …”

“…Spatial and temporal gradients of GF affect the direction, structure, rate of cell invasion, and vascularization. 20,21 …”

Accelerated wound healing in a diabetic rat model using decellularized dermal matrix and human umbilical cord perivascular cells

“…Therefore, incorporation of the cells into an appropriate polymeric or synthetic scaffold has shown promising results in the augmentation of cell engraftment [22]. Up to now, various biomaterials and multiple growth factors have been used to regenerate skin lesions, particularly in chronic wounds [23,24]. Considerable attention has been paid to biologic scaffolds derived from the extracellular matrix (ECM) of native tissues due to the safety and efficacy of such natural scaffolds [25,26].…”