3D-printed dimethyloxallyl glycine delivery scaffolds to improve angiogenesis and osteogenesis

Abstract

Angiogenesis-osteogenesis coupling processes are vital in bone tissue engineering. Normal biomaterials implanted in bone defects have issues in the sufficient formation of blood vessels, especially in the central part. Single delivery of vascular endothelial growth factors (VEGF) to foci in previous studies did not show satisfactory results due to low loading doses, a short protein half-life and low efficiency. Development of a hypoxia-mimicking microenvironment for cells by local prolyl-4-hydroxylase inhibitor release, which can stabilize hypoxia-inducible factor 1α (HIF-1α) expression, is an alternative method. The aim of this study was to design a dimethyloxallyl glycine (DMOG) delivering scaffold composed of mesoporous bioactive glasses and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) polymers (MPHS scaffolds), so as to investigate whether the sustained release of DMOG promotes local angiogenesis and bone healing. The morphology and microstructure of composite scaffolds were characterized. The DMOG release patterns from scaffolds loaded with different DMOG dosages were evaluated, and the effects of DMOG delivery on human bone marrow stromal cell (hBMSC) adhesion, viability, proliferation, osteogenic differentiation and angiogenic-relative gene expressions with scaffolds were also investigated. In vivo studies were carried out to observe vascular formations and new bone ingrowth with DMOG-loaded scaffolds. The results showed that DMOG could be released in a sustained manner over 4 weeks from MPHS scaffolds and obviously enhance the angiogenesis and osteogenesis in the defects. Microfil perfusion showed a significantly increased formation of vessels in the defects with DMOG delivery. Furthermore, micro-CT imaging and fluorescence labeling indicated larger areas of bone formation for DMOG-loaded scaffolds. It is concluded that MPHS-DMOG scaffolds are promising for enhancing bone healing of osseous defects.

Microvalve-based bioprinting – process, bio-inks and applications

“…Cells encapsulated within the 3D bioprinted tissue-engineered constructs are required to undergo a maturation process prior to implantation; adequate perfusion of growth factors, oxygen and other nutrients to the cells is necessary during the maturation process. [93][94][95] The microvalve-based bioprinting approach has been used to design and fabricate intricate channels within the 3D bioprinted constructs; micro-channels were printed within a 3D collagen scaffold that enabled medium perfusion throughout the bioprinted construct. 35 Gelatin was used as a sacrificial material to fabricate microchannels (400 μm width and 100 μm height) that were subsequently removed to create perfusable channels.…”

Angiogenic and Osteogenic Coupling Effects of Deferoxamine-Loaded Poly(lactide-co-glycolide)-Poly(ethylene glycol)-Poly(lactide-co-glycolide) Nanoparticles

“…That is to say, angiogenesis is the fundamental requirement for skeletal regeneration. The underlying mechanisms are as follows: (1) newly formed blood vessels transport oxygen, nutrients and BMSCs that are indispensable for bone defect repair; (2) the vasculature could serve as a scaffold for bone-forming cells and new bone tissue; and (3) endothelial cells could affect bone formation indirectly via paracrine actions [2,3,[28][29][30]. Thus, to find a therapeutic method that has the dual effects of osteogenesis and angiogenesis is a promising choice to modulate bone defect healing.…”

“…Successful bone regeneration requires close coordination of various factors, such as cells, marrow stroma microenvironment and vascular networks [1]. Specifically, the neovascularization process mediated by ECs is crucial, because it not only facilitates mass exchanges, but also recruits requisite cell sources (e.g., BMSCs) for skeletal regeneration [2,3].…”

“…However, a growing body of evidence has revealed that after BMSC grafting in vivo, either in the form of cell suspension or in combination with biological scaffolds, they often undergo oxygen and nutrients deprivation, which impair their survival and functionality [6,7]. This phenomenon could be mainly attributed to the impaired circulating networks in the topical damaged area of the host or the postponent neoangiogenesis in the scaffolds [1]. Therefore, the development of strategies which not only promote the osteogenic differentiation of BMSCs but also upregulate their angiogenic factors expressions to realize a rapid revascularization is urgently needed.…”

Dose effects of beta-tricalcium phosphate nanoparticles on biocompatibility and bone conductive ability of three-dimensional collagen scaffolds

“…Application of a three-dimensional (3D) scaffold to the bone defect produces a regenerative space for tissue reconstruction and stimulates cell proliferation and differentiation, along with angiogenesis and extracellular matrix secretion 20) . Therefore, refining the specifications of the regenerative scaffold is required for clinical upregulation of bone structure and function.…”