There is a growing need for scaffold material with tissue-specific bioactivity for use in regenerative medicine, tissue engineering, and for surgical repair of structural defects. We developed a novel composite biomaterial by processing human cardiac extracellular matrix (ECM) into a hydrogel and combining it with cell-free amniotic membrane via a dry-coating procedure. Cardiac biocompatibility and immunogenicity were tested in vitro using human cardiac fibroblasts, epicardial progenitor cells, murine HL-1 cells, and human immune cells derived from buffy coat. Processing of the ECM preserved important matrix proteins as demonstrated by mass spectrometry. ECM coating did not alter the mechanical characteristics of decellularized amniotic membrane but did cause a clear increase in adhesion capacity, cell proliferation and viability. Activated monocytes secreted less pro-inflammatory cytokines, and both macrophage polarization towards the pro-inflammatory M1 type and T cell proliferation were prevented. We conclude that the incorporation of human cardiac ECM hydrogel shifts and enhances the bioactivity of decellularized amniotic membrane, facilitating its use in future cardiac applications.
Local pH is stated to acidify after bone fracture. However, the time course and degree of acidification remain unknown. Whether the acidification pattern within a fracture hematoma is applicable to adjacent muscle hematoma or is exclusive to this regenerative tissue has not been studied to date. Thus, in this study, we aimed to unravel the extent and pattern of acidification in vivo during the early phase post musculoskeletal injury. Local pH changes after fracture and muscle trauma were measured simultaneously in two pre-clinical animal models (sheep/rats) immediately after and up to 48 h post injury. The rat fracture hematoma was further analyzed histologically and metabolomically. In vivo pH measurements in bone and muscle hematoma revealed a local acidification in both animal models, yielding mean pH values in rats of 6.69 and 6.89, with pronounced intra- and inter-individual differences. The metabolomic analysis of the hematomas indicated a link between reduction in tricarboxylic acid cycle activity and pH, thus, metabolic activity within the injured tissues could be causative for the different pH values. The significant acidification within the early musculoskeletal hematoma could enable the employment of the pH for novel, sought-after treatments that allow for spatially and temporally controlled drug release.
Bone morphogenetic protein-2 (BMP-2) is a known key mediator of physiological bone regeneration and is clinically approved for selected musculoskeletal interventions. Yet, broad usage of this growth factor is impeded due to side effects that are majorly evoked by high dosages and burst release kinetics. In this study, mesoporous bioactive glass microspheres (MBGs), produced by an aerosol-assisted spray-drying scalable process, were loaded with BMP-2 resulting in prolonged, low-dose BMP-2 release without affecting the material characteristics. In vitro, MBGs were found to be cytocompatible and to induce a pro-osteogenic response in primary human mesenchymal stromal cells (MSCs). In a pre-clinical rodent model, BMP-2 loaded MBGs significantly enhanced bone formation and influenced the microarchitecture of newly formed bone. The MBG carriers alone performed equal to the untreated (empty) control in most parameters tested, while additionally exerting mild pro-angiogenic effects. Using MBGs as a biocompatible, pro-regenerative carrier for local and sustained low dose BMP-2 release could limit side effects, thus enabling a safer usage of BMP-2 as a potent pro-osteogenic growth factor.
Nutrient supply via a functional vasculature is essential during regenerative processes, tissue growth, and homeostasis. 3D bioprinting offers the opportunity to engineer vascularized constructs by combining cells and biocompatible materials in specifically designed fashions. However, the complexity of microvascular dynamic networks can hardly be recapitulated yet, even by sophisticated 3D manufacturing. Ideally, the natural organizational competences of endothelial cells will be harnessed such that engineered vascular networks self-assemble to form complex, controllable microvascular patterns. Here, a bioengineering approach is presented to control microvascular structure formation and to steer cellular self-assembly of endothelial and supporting cells within a multi-material stereolithographic 3D bioprinting concept. Bioengineered vascularized constructs are generated by controlled cell deposition in an enzymatically degradable or a non-degradable material. In vitro, the microvascular structures are regulated in distribution, network orientation, vessel length and branching behavior and developed lumen, signs of vascular stabilization and an interconnected vascular network including anastomosis. This novel biofabrication approach demonstrates the capability to control microvascular network formation by using cellular and spatial cues allowing the generation of distinctly yet precisely vascularized constructs. Such novel approach of controlled microvascular formation may play a fundamental role in the development of vascularized implants or in vitro screening models.
4Despite years of diligent research in fracture healing, an unmet clinical need for safe and effective 5 pharmacological treatments to improve bone regeneration persists with 10 -20 % of fracture cases 6 exhibiting impaired healing. Bone morphogenetic protein-2 (BMP-2) is a known key mediator of 7 physiological bone regeneration and is clinically approved for selected musculoskeletal interventions. Yet, 8 broad usage of this growth factor is impeded due to side effects that are majorly evoked by high dosages 9and burst release kinetics. 10
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