Chemotactic and Angiogenic Potential of Mineralized Collagen Scaffolds Functionalized with Naturally Occurring Bioactive Factor Mixtures to Stimulate Bone Regeneration

Abstract

To develop cost-effective and efficient bone substitutes for improved regeneration of bone defects, heparin-modified mineralized collagen scaffolds were functionalized with concentrated, naturally occurring bioactive factor mixtures derived from adipose tissue, platelet-rich plasma and conditioned medium from a hypoxia-treated human bone marrow-derived mesenchymal stem cell line. Besides the analysis of the release kinetics of functionalized scaffolds, the bioactivity of the released bioactive factors was tested with regard to chemotaxis and angiogenic tube formation. Additionally, functionalized scaffolds were seeded with human bone marrow-derived mesenchymal stromal cells (hBM-MSC) and their osteogenic and angiogenic potential was investigated. The release of bioactive factors from the scaffolds was highest within the first 3 days. Bioactivity of the released factors could be confirmed for all bioactive factor mixtures by successful chemoattraction of hBM-MSC in a transwell assay as well as by the formation of prevascular structures in a 2D co-culture system of hBM-MSC and human umbilical vein endothelial cells. The cells seeded directly onto the functionalized scaffolds were able to express osteogenic markers and form tubular networks. In conclusion, heparin-modified mineralized collagen scaffolds could be successfully functionalized with naturally occurring bioactive factor mixtures promoting cell migration and vascularization.

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

“…The gold standard for reconstructing bone defects is still represented by autologous grafts (also known as 'autografts' and 'autogenous graft') [146][147][148][149][150]. Autografts are harvested from the patient, being ideal in many situations [145].…”

“…Properties like osteoinduction, osteoconduction, and total histocompatibility of autografts make them suitable for bone regeneration, reducing the risk of immunogenic reaction and disease transmission [9,150]. However, intervening at healthy sites to collect autografts can produce donor-site morbidity, thus restricting this therapeutic approach [146,149,151]. Other drawbacks are represented by the limited amount of tissue that can be harvested, the need for additional surgery, and prolonged operative times [1,9,16].…”

“…The field of tissue engineering allows the creation of smart multifunctional bone substitutes that use a porous structure (called scaffold) serving as a template for cell attachment, differentiation, proliferation, and tissue regeneration [1,9,149].…”

“…The material should mimic the native extracellular matrix guiding resident stem cells to regenerate the functional tissue [16]. Thus, tissue-engineered scaffolds preserve the requirements of ideal synthetic bone substitutes plus the features needed for osteogenic differentiation and maturation of the included cells [9,149,175]. These bioscaffolds should be able to interact with the cellular component of the bone, have an adequate morphology for permitting vascular ingrowth and cellular transportation, and be biodegrade at a predictable rate [9,176,177].…”

“…Other factors that can be added to bioscaffolds are PDGF, fibroblast GFs, vascular endothelial GFs, insulin-like GFs, TGF-β, IL-1, IL-6, and macrophage colony-stimulating factor [161,188]. The functionalization of the bone replacement with factors is a promising approach for attracting and stimulating cells from the surrounding host tissue after implantation, promoting osteogenic cells' ingrowth, and forming a vascular network within the implant [149]. Growth factors for promoting osteogenesis and angiogenesis can be incorporated in scaffolds, while these structures can also act as stem cell carriers for accelerating bone repair [161].…”