Search

Radiotherapy puts bones at risk of developing osteonecrosis. Irradiation has an impact on the viability as well as the differentiation capacity of mesenchymal stem cells (MSC), which play a pivotal role in bone regeneration. To investigate the effect of irradiation on MSC, human bone-derived MSC were irradiated in vitro. With increasing doses the cells’ self-renewal capabilities were greatly reduced. Notably however, mitotically stalled cells were still capable of differentiating into osteoblasts and preadipocytes. Next the pigs mandibles were subjected to fractionized radiation of 2x9 Gy within one week. This treatment mimicks that of a standardized clinical treatment regimen of a head and neck cancer patient (30x2 Gy). Fractures, which had been deliberately generated and subsequently irradiated showed retarded osseous healing. When isolating MSC from irradiated sites at different time points post irradiation, no significant changes in comparison to cells derived from un-irradiated specimens regarding proliferation capacity and osteogenic differentiation potential became apparent. Therefore, pig mandibles were irradiated with 9 and 18 Gy in vivo, and MSC were isolated immediately afterwards. No significant differences between the untreated and 9 Gy -irradiated bone with respect to proliferation and osteogenic differentiation were unveiled. Yet, cells isolated from 18 Gy irradiated specimens exhibited a reduced osteogenic differentiation capacity, and during the first two weeks proliferation rates were greatly diminished. Thereafter, cells recovered and showed normal proliferation behaviour. These findings imply that MSC can cope with irradiation up to high doses in vivo, and could be implemented in future therapeutic concepts to protect from osteonecrosis.

Regeneration, tissue remodeling and organ repair after injury which rely on theregulated activity of tissue-borne stem cells become increasingly compromised withadvancing age.Mesenchymal stroma cells were isolated from bone of differently aged healthydonors. The rare population of mesenchymal stem cells (MSC) contained in theprimary cell isolates, barely declined in number, yet relative to the donor age thestem cells displayed diminished long-term proliferation potential. The expression ofvascular cell adhesion molecule 1 (CD106) was elevated on primary MSC. InCD106bright MSC, the abundance of a panel of stemness transcription factorsremained unchanged. As the CD106 level could be further enhanced by proinflammatorycytokines, we considered the rate of VCAM1 expression a goodreflection of an endogenous inflammatory milieu MSC are exposed to. Treatment ofMSC with increasing doses of interferon gamma exerted no immediate influence ontheir self-renewal capacity. It however impacted on the differentiation potentialtowards the adipogenic or osteogenic lineage. Moderately elevated levels ofinflammatory stimuli supported osteoblastogenesis while the same treatmentreduced adipogenic differentiation in MSC from young and intermediately ageddonors. In mesenchymal stem cells from elderly donors however,osteoblastogenesis was greatly diminished in an inflammatory environment whereasadipogenic differentiation remained unchanged.Conclusively, moderate levels of inflammatory stimuli are being interpreted bymesenchymal stem cells at young age as instructive signals for osteoblastogenesis,whereas at old age, an inflammatory milieu may effectively suppress boneremodeling and repair by tissue-borne mesenchymal stem cells while uninterruptedadipogenic differentiation may lead to adipose upgrowth.

Medical implants are increasingly often inserted into bone of frail patients, who are advanced in years. Due to age, severe trauma or pathology-related bone changes, osseous healing at the implant site is frequently limited. We were able to demonstrate that coating of endosseous implants with nanocrystalline diamond (NCD) allows stable functionalization by means of physisorption with BMP-2. Strong physisorption was shown to be directly related to the unique properties of NCD, and BMP-2 in its active form interacted strongest when NCD was oxygen-terminated. The binding of the protein was monitored under physiological conditions by single molecule force spectroscopy, and the respective adsorption energies were further substantiated by force-field-calculations. Implant surfaces refined in such a manner yielded enhanced osseointegration in vivo, when inserted into sheep calvaria. Our results further suggest that this technical advancement can be readily applied in clinical therapies with regard to bone healing, since primary human mesenchymal stromal cells strongly activated the expression of osteogenic markers when being cultivated on NCD physisorbed with physiological amounts of BMP-2.