NICHE-BASED PERSONALIZED CELL THERAPEUTICS IN BONE AND CARTILAGE REGENERATION

Unresolved musculoskeletal metabolic and traumatic damage, such as Osteoarthritis (OA) Osteoporosis (OP) or bone fracture non-union, is a clinical challenge that is increasing as the population ages. Theragnostic approaches combine personalized cellular and molecular candidates to deal with those chronic complex conditions. However, the absence of high-level verification and operational restrictions impede our understanding of stem cell (SC) theragnostic efficacy at nanoscale biomaterial-assisted regeneration. Stem cell exosome-nanocomposite based therapeutics require a niche-based, targeted bone-cartilage regeneration along with a high biocompatibility, an optimized vascularization and innervation. The niche refers to the microenvironment where stem cells reside and receive signals that regulate their self-renewal and differentiation capacities. In the context of hematopoietic and skeletal systems, the somatic stem cells involved are often referred to as hematopoietic (HSCs) and mesenchymal stem cells (MSCs). An effective translation of targeted nanoscale cell therapies might be possible by coupling the in vitro study data with preclinical and clinical trials. The output of three coupled experimental studies concerning allogeneic MSC exosome and growth factor-based therapies implemented by boron-containing nanoscale bone matrix mimicking hydroxyapatite composites (BNHap) presented an increase in the mineralization acting on Wnt, TGF-β signalling pathways and enhance in response to stress on human osteoblasts. Intramedullary application of BNHap increased new bone formation and mineralization in an OP rabbit model. Low dose rhBMP2 containing nHap-PEG/PLA stimulated proliferation and osteogenic differentiation of human BMMSCs in a tight therapeutic window. The novel nHap/PLA-PEG/BMP-2 was validated in a VR model by enabling efficient bone formation by BMP-2. Calcium deficient Hap-annexin-V bound allogeneic BMMSC exosomes induced proliferation and matrix mineralization of human osteoblasts (patents pending #TR201608109B and #TR021/002221). The new complex could have a regenerative potential in OP as a cellular tool after clinical validation. In conclusion these randomized controlled preclinical trials that have been published from our lab to date personalized niche-based platforms, bring new therapeutic ideas and directions to the clinical treatment of musculoskeletal conditions. High-quality translational theragnostic trials are needed to complement the existing clinical prescriptions.