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Enhancing the regeneration of bone defects in elderly: Rejuvenation of bone microenvironment

Periodic Reporting for period 1 - RejuvenateBone (Enhancing the regeneration of bone defects in elderly: Rejuvenation of bone microenvironment)

Reporting period: 2015-04-10 to 2017-04-09

Bone defects resulting from trauma, tumor resection and bone diseases represent one of the most pressing health problems in the aging European population. Annually, over 2 million surgical procedures are required to repair bone defects in traumatology, orthopaedics, neurosurgery and dentistry. Current treatments include the transplantation of the patient’s own bone tissue from another site in the body, donated bone tissue from bone banks or various bone substitute materials that support new bone formation. However, all these options are associated with significant drawbacks, limiting the success of treatments. More importantly, they depend on appropriate function of bone cells to complete the process of bone healing.
During aging, the regenerative capacity of cells in our body decreases due to a number of interacting cell-intrinsic and cell-extrinsic (microenvironmental) mechanisms. This means the success of bone therapies in elderly patients is in most cases limited. The treatments often require prolonged hospital stays and in many cases repeated surgeries, posing a high burden on the patients as well as extensive healthcare costs. Currently, there is only a limited number of treatments promoting the activity of bone forming cells.
The overall aim of our project was therefore to investigate a new multidisciplinary approach to enhance new bone formation, based on recent advances in cellular reprogramming and tissue engineering. Our first objective was to prepare and study the components synthesized by young bone cells (obtained by cellular reprogramming) on aged bone cells from trauma patients. Our second objective was to develop bone tissue substitutes containing the components synthesized by young cells for transplantation. Our third objective was to test the developed bone tissue substitutes in pre-clinical models to evaluate their safety and bone healing potential.
We based our studies on the hypothesis that microenvironment components released by young bone forming cells can stimulate the regenerative potential of elderly dysfunctional cells and that such components can be engineered into bone tissue substitutes which could be transplanted to improve the healing.
In Objective 1, we isolated and cultured bone cells from adult/elderly trauma patients and evaluated their functional potential. We also cultured reprogrammed young cells and expanded them to a larger cell stock, which was used to prepare soluble components and matrix components. We found that soluble components contain a number of different factors acting on immune response, stem cell maintenance and blood vessel growth. Extracellular matrix included major components of basal lamina and bone tissue matrix. These microenvironment components were then tested with primary bone cells from the patients. Notably, some of the cell lines from the eldest patients, that exhibited a severe loss of function, increased their growth and bone forming activity when cultured with young cell components. The extent of these responses was patient-specific, requiring further studies of underlying mechanisms.
In Objective 2, we conducted scale-up and tissue engineering studies. We scaled-up the reprogrammed young cell cultivation and the preparation of young cell components. We then developed three-dimensional bone substitutes containing young cell components within silk scaffolds. Remaining cells were removed from soluble fractions by processing and from matrix fractions by a combination of detergent and enzyme treatments for potential allogeneic use.
In Objective 3, the developed bone substitutes were tested in a preclinical model. We found that bone substitutes containing soluble young cell components did not elicit adverse reactions (inflammation, infection) two weeks after transplantation. Compared to controls, tissue substitutes containing young cell components exhibited increased tissue development. Future studies will involve the testing of bone regenerative ability of these developed bone tissue substitutes.
Taken together, our studies showed that young bone cell components have the ability to modulate the activity of aged bone cells from trauma patients and that they can be engineered into bone substitutes and transplanted to modulate tissue regeneration responses. Future studies will involve the testing of developed bone substitutes to enhance bone regeneration during aging.
The results of our project were/will be presented at international meetings of societies from the regenerative medicine field (TERMIS, ESAO, ISCT, EORS) and provide the basis for further investigations and development of these off-the-shelf bone substitutes toward clinical translation to enhance bone regeneration during aging.
On the one hand, the RejuvenateBone project allowed the re-integration of a female researcher within the European research community and the transfer of acquired know-how on stem cells and most advanced tissue engineering technologies to fortify the regenerative medicine sector in Europe. The use of reprogrammed cells, a novel cell source first reported outside Europe, as a source of regenerative components is highly innovative and has an unlimited potential for scale-up, thus realistically allowing clinical translation either as patient-specific or general source of regenerative components. As these cells can develop into any type of human tissue, the findings and materials developed within the project are likely to be applicable to other areas of tissue regeneration. Internationally, production and differentiation of reprogrammed cells has already been automated and translated to industrial scale.
On the other hand, the project was addressing a major unmet clinical need, regeneration of bone defects in the elderly population, where the number of the treatment complications and unwanted outcomes is the largest. The proportion of cases is expected to further grow due to the ageing of European population. Treatment solutions that would target the biological basis of limited bone regeneration during aging – dysfunctional cells - are practically non-existent, further underlining the importance of the RejuvenateBone approach and findings.
At this early stage of our new experimental approach, our findings are promising and might well lead to exploitable results in the near future. It is expected that the development and production activities arising from these results will contribute to the growth of industrial sector in Europe.
RejuvenateBone Project Concept