Scar tissue: what is it?

If you have arthrofibrosis you’ve probably heard a lot about scar tissue. But what, exactly, is scar tissue? It’s an important question, and the answer has real implications for arthrofibrosis treatment (more on this below). You may be surprised to learn that, far from being inert, “dead” tissue, scars are highly dynamic, metabolically active and contractile tissues that are constantly changing [1, 2]. Scar tissue is composed of active cells attached to a collagen network that has glycoproteins [3] and growth factors incorporated into it. In addition, new blood vessels and nerves form within scar tissue in the early stages of healing, and become part of it [2, 4]. As the collagen continues to form it can compress and trap both nerves and blood vessels, increasing pain and decreasing blood flow.

The old concept of scars as inert, non-living fibrillar collagen has been replaced as we apply modern molecular and imaging techniques [2].

The main cells types within scars are immune cells and myofibroblasts, the cells that produce the collagen network and maintain fibrosis. These cells “talk” and react to each other with signalling molecules called cytokines and growth factors such as TGF-β [5]. As the collagen component of scar tissue matures cross-links form and stiffen it [5], changing the mechanical properties and altering the survival, proliferation and function of the cells within it [1]. This important knowledge comes from organ and skin fibrosis research - the scar tissue found in arthrofibrosis is biologically the same as these [6].

Figure from Whyte et.al. 2022 [7] showing collagen (a type of protein) in scar tissue using polarised light microscopy.

This dynamic nature of scar tissue means that its makeup and mechanical properties change over time [8] and with the degree of inflammation, and symptoms may also change. In healthy healing the myofibroblasts and immune cells eventually become quiescent or die, and scars in this residual phase contain relatively few cells, and have a reduced number of blood vessels [9, 10] But there is still plenty of biological action as the collagen fibrils continue to be made and remodelled [2], allowing ROM to gradually increase. In this residual phase scars typically reduce in size but never completely disappear.

Unfortunately, for some of us low grade inflammation persists, resulting in chronic active fibrosis (see blog Active and Residual Arthrofibrosis) and more reactive scar tissue. In this pathological state myofibroblasts and immune cells remain activated, but usually at a reduced level compared to the immediate post-operative period [2]. Collagen and inflammatory and fibrotic signalling molecules continue to be produced [2, 11], causing contractions and adhesions.

Figure from Fertala et.al. 2023 [12] showing bleeding (Bv = blood vessel) and immune cells activating myofibroblasts resulting om contractions and the formation of scar tissue. Collagen fibrils are shown in blue and double ended arrows indicate contraction caused by myofibroblasts. Scar tissue is also referred to as extracellular matrix (ECM), however this term is not specific to scar tissue.

This changing nature of scar tissue has created confusion about what arthrofibrosis is. Different names are sometimes applied to the same pathology at different phases. For example, the label Adhesive Capsulitis is often given to the highly inflammatory phase typical of earlier shoulder arthrofibrosis that is characterised by large numbers of immune cells and blood vessels [4]. The name Frozen Shoulder is often applied to the less inflammatory, residual phase of shoulder arthrofibrosis, although the two names are used interchangeably [13].

Implications. So, what are the implications of scar tissue being highly reactive, living tissue? Anybody with arthrofibrosis who has suffered even a minor bleed in the affected joint will likely remember the immediate, strong increase in their symptoms. So it seems clear that we need to be cautious and not use traditional overpressure techniques that force ROM and tears tissues, and avoid increasing inflammation in other ways, including aggressive exercise. In addition, sufferers may need to continue with gentle daily passive stretching, such as continuous passive motion, to maintain their limited ROM because of the ongoing contractions and adhesions of active arthrofibrosis. Research shows that regular, non-traumatic cyclic stretching that applies low magnitude dynamic loading has anti-inflammatory and anti-fibrotic effects [7] - which is, perhaps, a good topic for another blog.

References

1. Tracy, L. E., Minasian, R. A. & Caterson, E. J. Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound. Adv Wound Care (New Rochelle) 5, 119-136 (2016). https://doi.org/10.1089/wound.2014.0561

2. Sun, Y. & Weber, K. T. Infarct scar: a dynamic tissue. Cardiovascular Research 46, 250-256 (2000). https://doi.org/10.1016/s0008-6363(00)00032-8

3. Mostaco-Guidolin, L., Rosin, N. L. & Hackett, T. L. Imaging Collagen in Scar Tissue: Developments in Second Harmonic Generation Microscopy for Biomedical Applications. Int J Mol Sci 18 (2017). https://doi.org/10.3390/ijms18081772

4. Le, H. V., Lee, S. J., Nazarian, A. & Rodriguez, E. K. Adhesive capsulitis of the shoulder: review of pathophysiology and current clinical treatments. Shoulder Elbow 9, 75-84 (2017). https://doi.org/10.1177/1758573216676786

5. Ricard-Blum, S., Baffet, G. & Theret, N. Molecular and tissue alterations of collagens in fibrosis. Matrix Biol 68-69, 122-149 (2018). https://doi.org/10.1016/j.matbio.2018.02.004

6. Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7 (2019). https://doi.org/10.1038/s41413-019-0047-x

7. Whyte, W. et al. Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform. Nat Commun 13, 4496 (2022). https://doi.org/10.1038/s41467-022-32147-w

8. Karsdal, M. A. et al. The good and the bad collagens of fibrosis–their role in signaling and organ function. Advanced drug delivery reviews 121, 43-56 (2017).

9. Hildebrand, K. A. & Frank, C. B. Scar formation and ligament healing. Can J Surg 41, 425-429 (1998).

10. Frank, C. B., Hart, D. A. & Shrive, N. G. Molecular biology and biomechanics of normal and healing ligaments—a review. Osteoarthr. Cartil. 7, 130-140 (1999).

11. Eming, S. A., Murray, P. J. & Pearce, E. J. Metabolic orchestration of the wound healing response. Cell Metab 33, 1726-1743 (2021). https://doi.org/10.1016/j.cmet.2021.07.017

12. Fertala, J. et al. Extracellular Targets to Reduce Excessive Scarring in Response to Tissue Injury. Biomolecules 13 (2023). https://doi.org/10.3390/biom13050758

13. Harris, G., Bou-Haidar, P. & Harris, C. Adhesive capsulitis: review of imaging and treatment. J Med Imaging Radiat Oncol 57, 633-643 (2013). https://doi.org/10.1111/1754-9485.12111