Introduction

There is a large variety of musculoskeletal diseases and injuries that could benefit from developing new technologies in regenerative medicine. Regenerative engineering can be defined as the convergence of advanced materials science, stem cell science, developmental biology, and clinical translation [1]. Stem cells (SCs) treatment hold great repair potential through systemic and local delivery [2-4]. However, the major challenge is to improve therapeutic cells’ delivery and targeting using standard protocols easily scalable.

Content

Biomaterials are fundamental tools for several regenerative medicine approaches, and they can either being use alone or in combination with SCs. Scaffolds – natural, synthetic or hybrid - have shown substantial promise for maintaining an organized space for tissue growth, providing mechanical stability, and superior support for cells’ adhesion and migration efficiently mimicking all the desired features of a host extracellular matrix. However, during the implantation of scaffolds, an injury occurs generating complex processes that stimulate the host’s inflammatory response to the implanted material can negatively impact the environment ultimately resulting in fibrosis (foreign body reaction) and scar formation. Scars are areas of fibrous tissue characterized by disorganized collagen deposition that seals off the damaged tissue. Despite this primary function, scars prevent the process of functional tissue recovery. On the contrary, most of the processes of functional healing are scar-free. Understanding these processes would allow the development of new therapeutic strategies based on the driving molecular mechanisms that improve the regenerative process.

On this porpoise, the surface of the biomaterial can be chemically functionalized with bioactive signals to tune the implanted or the infiltrating cells’ response to trigger functional tissue regeneration rather than scar formation.

A tissue engineering approach based on tuning the immune-response is still lacking in clinic as a regenerative therapy. The chemistry and architecture of biomaterials can be manipulated to prevent a pro-inflammatory response as well as boost the immunosuppressive potential of SCs ensuring a promotion of tissue regeneration. We are able to bestow on the surface of biomaterials active signals to efficiently reduce the inflammatory response promoting tissue regeneration rather than unfunctional scar formation.

We used SCs from classic bone marrow and cartilage tissue resident SCs to study and improve their stemness and therapeutic characteristics. We developed treatments to improve their homing ability [5], and created functionalized biomimetic materials to increase their immune-suppressive potential and support in situ proliferation and differentiation [6], showing osteoinductive and chondroinductive properties both in vitro and in vivo [7, 8].

We believe these treatments to be the new direction in order to develop cellular therapies to treat musculoskeletal inflammatory conditions. The transient enhancing of SCs potential induced by different substrates could be a new tool for new therapies with limited side effects. There is a clinical need for biomaterials that will give another strategy to treat patients with defects in their weight bearing joints as well as for critical size defects in bone. Right now, it is still debating if cellular or acellular scaffolds are most likely to be successful. We want to focus the attention that no matter the strategy, rather the target should be tuning the inflammatory response to enhance reparative pathways that presently lead to scar formation, failure of integration, and failure to generate native tissue.

References

References.

1. Taraballi, F., et al., Concise Review: Biomimetic Functionalization of Biomaterials to Stimulate the Endogenous Healing Process of Cartilage and Bone Tissue. Stem cells translational medicine, 2017. 6(12): p. 2186-2196.

2. Fernandez-Moure, J.S., et al., Not all stem cells are created equal: a comparative analysis of osteogenic potential in compact bone and adipose-derived mesenchymal stem cells. Journal of the American College of Surgeons, 2013. 217(3): p. S99.

3. Corradetti, B., et al., Osteoprogenitor cells from bone marrow and cortical bone: understanding how the environment affects their fate. Stem cells and development, 2014. 24(9): p. 1112-1123.

4. Fernandez-Moure, J.S., et al., Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis. Stem cell research & therapy, 2015. 6(1): p. 203.

5. Corradetti, B., et al., Hyaluronic acid coatings as a simple and efficient approach to improve MSC homing toward the site of inflammation. Scientific reports, 2017. 7(1): p. 7991.

6. Corradetti, B., et al., heparan sulfate: a Potential candidate for the Development of Biomimetic immunomodulatory Membranes. Frontiers in bioengineering and biotechnology, 2017. 5: p. 54.

7. Corradetti, B., et al., Chondroitin sulfate immobilized on a biomimetic scaffold modulates inflammation while driving chondrogenesis. Stem cells translational medicine, 2016. 5(5): p. 670-682.

8. Minardi, S., et al., Evaluation of the osteoinductive potential of a bio-inspired scaffold mimicking the osteogenic niche for bone augmentation. Biomaterials, 2015. 62: p. 128-137.

9. Taraballi, F., et al., Biomimetic collagenous scaffold to tune inflammation by targeting macrophages. Journal of tissue engineering, 2016. 7: p. 2041731415624667.

10. Corradetti, B., et al., Immune tuning scaffold for the local induction of a pro-regenerative environment. Scientific reports, 2017. 7(1): p. 17030.

Acknowledgments

Authors would like to thank: Dr. D. Litner, D. Dong, H. Goble, Dr. B. Corradetti, Dr. S. Minardi, G. Bauza, A. Brozovich for their support and help to make our research great.