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Induced pluripotent stem cell seeded active osteochondral nanofibrous scaffolds

Periodic Reporting for period 1 - iP-OSTEO (Induced pluripotent stem cell seeded active osteochondral nanofibrous scaffolds)

Período documentado: 2019-02-01 hasta 2021-01-31

Scientific objective of the project is the development of Induced Pluripotent Stem cells (iPSC)-based biodegradable implants for old patients affected by osteochondral defects. iPSCs are derived from terminally differentiated patient cells and re-programmed to pluripotent cells, which could be differentiated to range of cell types including osteogenic and chondrogenic lineage.
Osteochondral defect are formed in patient with osteoartritis. Specific scaffolds are being developed for patient with both fractures/osteochondral defect and osteoporosis. For this purpose, we have to develope scaffolds for both bone and cartlige. To control the regeneration, the scaffolds should be biocompatible, degradable, should allow cell ingowth from the adjacent tissues, mainly mesenchymal stem cells (MSCs) from bone marrow. Moreover they scaffolds should control MSCs or iPSC differentation into osteoblasts, which are present in bone and to chondrocytes which are present in cartilage.
In order to control cell differentiation, the scaffolds contain bioactive compound and release them for several days or weeks. These compounds involve small molecules, such as phosphates which are necessary for bone tissue formation, hormones and growth factors.
The scaffold structure should mimic natural extracellular matrix of the tissue therefore they have a porous nano or microstructure with high porosity and are combined with other matarials, mainly hydrogels. Thus they form three-dimensional scaffolds, wihichhave prositive effect on cell differentiation.

The impact of the new composite scaffold has on an older population where the older population whee the incidence of osteoarthitis and osteoporosis is inceased. The degeneration of cartilage in joints is associated with trauma or disease conditions like osteoarthritis and rheumatic arthritis. The disability of movement associated with joint impairment leads to decreased quality of life and socioeconomic loss. With ageing of western population the problem becomes more evident and is projected that 25% of adults will have problem with
joint disease (Hootman JR, 2006). Similarly, the number of osteoporotic patients (22 mio. woman and 5.5 mio. men in the EU) is rising and results in increased numbers of serious fractures. The effective therapy will decrease the number of reoperation of osteochondral or bone defects, will decrease the costs for surgery as well as indirect costs and will reduce the morbidity of patients. Subsequently the life quality of patient will be increased. Regeneration potential in older patients can be improved and can be close to the regeneration in young patients.

OBJECTIVES:
- Objective of the project is to develop an international, intersectorial and multidisciplinary network to solve the boost the boost progress in the regeneration of osteochondral defects
- Optimized isolation and differentiation protocols for iPSCs) for musculoskeletal use – protocols for iPSC source will be optimized to achieve reproducible reprogramming and regenerative potential with 90% reproducibility
(measured by differentiation potential and proliferation potential).
- Nanofibrous scaffolds with optimized biological and mechanical properties – iPSCs will show complete scaffold colonization, the scaffold will enable vascular ingrowth and mechanical properties respecting needs of particular tissues.
- Up-scaled and stabilized manufacturing of implants – technology will be up-scaled to form compliant with GMP manufacturing, the production rate will be at least 100 standard scaffold/day and standard-operational protocols (SOPs) will be delivered for commercialization.
-Decrease re-operation of complex bone fractures and osteoarticular injuries by 20% measured by regeneration outcomes of pre-clinical studies.
-Enhancement of healing of bone fractures and osteochondral defects in pre-clinical studies
-Development of a Business Plan. The Consortium will define the best strategy for future commercialization and exploitation, with special focus on the translational process for introduction of the new therapy into the European and world markets.
We have developed composite scaffold for bone regeneration based on biodegradable polycaprolactone nanofibres enriched with either hydroxyapatite or bioactive molecules. Scaffolds were optimized for the desired release of bioactive compounds and for enhancement of osteogenic differentiation of mesenchymal stem cells. Similarly, induced pluripotent stem cells (iPC) were studied for their osteogenic and chondrogenic differentiation.
Similarly, we have developed composite nanofibrous scaffolds for cartilage differentiation and were positively tested for chondrogenic differentiation, Different 3D scaffolds based on hydrogels were tested with bioactive supplements in order to control chondrogenic differentiation of mesenchmal stem cells. Moreover, xenohybrid organic grafts with bioactive peptides for bone regeneration were prepared. The in vitro testing showed that they stimulate osteogenic differentiation of mesennchymal stem cells. We prepared hybrid nanofibers functionalized with plasmonic TiN NPs. They led to slight variation in mass degradation initiation and phase change behaviour. They are promising for tissue engineering platforms and open up new avenues for theranostic applications.
We have developed a new 3D-printed chamber for a biorector for dynamic cell culture of 3D scaffolds.
We expect development od 3D composite scaffold delivering osteogenic and chondrogenic bioactive supplements or growth factors for osteochondral regeneration. We expect enhanced regeneration and formation of tissue specific matrix in the defect which may significantly prolong the positive effect of the therapy in older patients. Moreover, iPSC can be reprogrammed from an adult tissue and further can be differentiated into the desired cell type and then can stimulate the formation of either bone or cartilage.
The scaffold will be tested in vitro in a bioreactor and in vivo. In the first two years of the project we have developed drug delivery systems based on nanofibres, microfibres or microparticles. Moreover 3D scaffolds enhancing formation of cartilage have been prepared.
Spray dried microparticles for the delivery of proteins
Design of perfusion bioreactor for 3D cell culture developed in OSPIN