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3D Printing of Cell Laden Biomimetic Materials and Biomolecules for Joint Regeneration

Periodic Reporting for period 4 - JointPrinting (3D Printing of Cell Laden Biomimetic Materials and Biomolecules for Joint Regeneration)

Reporting period: 2020-03-01 to 2020-08-31

Osteoarthritis (OA), the most common form of arthritis, is a serious disease of the joints affecting nearly 10% of the population worldwide. The disease represents a significant economic burden to patients and society in Europe, with the cost of OA per patient calculated to exceed €10,000 per annum. At present the treatment options for OA are limited to surgical replacement of the diseased joint with a prosthesis. While this procedure is well established, it is not without its limitations and failures are not uncommon. Joint replacement prostheses also have a finite lifespan, making them unsuitable for the growing population of younger and more active patients requiring treatment for OA. In recent years there has been increased interest in the use of cell based therapies for the treatment of small focal cartilage defects within synovial joints such as the knee. While significant progress has been made in this field, realising an efficacious therapeutic option for the treatment of OA remains elusive and is considered to be one of the greatest challenges in the field of orthopaedic medicine. The objective of this proposal was to use 3D bioprinting to generate anatomically accurate, mesenchymal stem cell (MSC) laden biological implants that can be used to regenerate an entire synovial joint such as the knee. As part of this project, we demonstrated that emerging biofabrication techniques such as 3D bioprinting could be used to generate implants with mechanical properties very similar to biological tissues such as the articular cartilage in synovial joints. Furthermore, we demonstrated how bioprinting can be used to develop implants capable of accelerating the regeneration of large bone defects. Together these developments have the potential to transform the future treatment of musculoskeletal injuries and diseases.
This project had three main aims. The first aim of the project was to use 3D printing to create mechanically reinforced, biological implants suitable for articular cartilage regeneration. To this end we developed a new class of printable material (termed a bioink) by combining different materials together. We used this technology to produce biological implants with mechanical properties comparable to soft tissues such as articular cartilage. This work was published in the journal ‘Biofabrication’. To improve the capacity of these constructs to support cartilage repair, we also developed a new class of cartilage extracellular matrix (cECM)‐functionalized alginate bioink for the bioprinting of cartilaginous tissues. This work as published in the journal ‘Advanced Healthcare Materials’.

The second aim of the project was to develop 3D printed composite implants for large bone defect repair and cartilage repair. To this end we 3D bioprinted implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration. This work was published in the journal ‘Science Advances’.

The third and final aim of the project was to scale-up the printed implants developed as part of aims 1 and 2 of the project to enable whole joint regeneration. To this end we have used computational tools to help inform the design of implants that would possess the necessary mechanical properties to perform this function. This work was published in the journal ‘Connective Tissue Research’. Furthermore, we used medical imaging data to produce biological implants that mimic the geometry of different synovial joints. The lessons learned in the pre-clinical evaluation of these implants has informed the development of new 3D bioprinting strategies targeting degenerative joint diseases such as osteoarthritis.
The progress beyond the state of the art includes:
1. Using 3D printing to develop fibre reinforced biomaterials that mimic the mechanical properties of articular cartilage.
2. The development of extracellular matrix (ECM) functionalised bioinks capable of supporting specific stem cell phenotypes.
3. The development of bioinks that can be used to control the release of regulatory factors from 3D printed implants.
4. The development of printed biomaterials containing gradients in regulatory factors that promote rapid vascularization in vivo.
5. The development of printed biological implants that can support vascularization and the regeneration of critically sized bone defects.
6. The development of computational tools to model the mechanical behavior of 3D printed implants.
7. The development of printed biological implants that can enhance the regeneration of osteochondral defects within synovial joints such as the knee.
Process of developing 3D bioprinted implants for joint regeneration