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Active and Residual Arthrofibrosis


Do you ever wonder if Frozen Shoulder and Adhesive Capsulitis are the same condition, or if Stiff Knee and Frozen Elbow are arthrofibrosis? If so, you aren’t alone – and the answer is yes they are, but they may be in different phases of healing. Despite widespread confusion about how these names should be applied, it’s evident that the presence of pain can differ significantly, but pain and inflammation are often overlooked in arthrofibrosis literature and discussions. Stiff Knee doesn’t sound like the painful joint condition that many of us are familiar with, so what is this all about?


We know that arthrofibrosis symptoms vary depending on which structures and tissues within the joint are affected, but there is a lot more to the story. It’s evident that the amount of pain and the speed and severity of adhesions and contractions that occur when the joint remains still (not in motion) changes with time, and shoulders are a good example of this. Shoulder arthrofibrosis begins with an inflamed, painful condition with restricted range of motion (ROM), and might be diagnosed as “Adhesive Capsulitis” [1]. If all goes well (unfortunately this doesn’t happen for everybody) over time the pain resolves but stiffness remains, and ROM slowly and gradually increases [1]. The name “Frozen Shoulder” may be used in this situation, but is also given to the painful condition. These painful and pain-free conditions are both shoulder arthrofibrosis, however the “pain-free but stiff” state is the resolving, residual phase [2]. Unfortunately, knee arthrofibrosis is more difficult to resolve, perhaps because knees and the Hoffa’s fat pad get a continual battering from walking. But for some the knee reaches a pain-free and stiff state that also “thaws” over time.


In our 2019 paper [2], I suggested that the arthrofibrosis occurs in two different phases,

  1. Active arthrofibrosis: an active inflammatory condition in which scar tissue formation, adhesions and contractions are ongoing processes driven by activated myofibroblasts (the cells that make fibrosis) and

  2. Residual arthrofibrosis: the joint is pain-free but has limited ROM due to mature scar tissue. The active inflammation and scar tissue production phase has resolved and myofibroblasts are no longer stimulated.


The crucial difference in these phases of shoulder arthrofibrosis appears to be how activated the myofibroblasts are. Fibrosis research demonstrates that the amount of inflammation and activation of myofibroblasts determines the severity of adhesions and contractions [3, 4]. However, it’s always difficult to put biology into neat “boxes” - inflammation and fibrosis are not on/off switches [4] but gradual changes as the body produces resolving factors. As fibrosis resolves there is a gradual progression from the active to residual, quiescent phase [4] and as this occurs it can be difficult to determine where on the disease spectrum a joint is. However, if the joint reacts with more discomfit or pain after use then it’s safe to assume that some level of inflammation and active fibrosis are present, and all care should be taken. The concept of active and residual phases in fibrosis is not new in organ fibrosis circles [5].


Figure from Hillsely et.al. 2022 Nature [4]. Fluorescence microscopy lights up the internal skeleton in a non-activated myofibroblast on the left, and an activated myofibroblast on the right.
Figure from Hillsely et.al. 2022 Nature [4]. Fluorescence microscopy lights up the internal skeleton in a non-activated myofibroblast on the left, and an activated myofibroblast on the right.

Myofibroblasts and immune cells communicate and both can produce inflammation and fibrotic growth factors that stimulate each other [6]. So the presence (or absence) of inflammation has important implications for individual treatment and also for research - we need to know what phase of the condition we’re actually studying. More research is needed, but from our experience the response to exercise is very different in joints with active and residual arthrofibrosis. In addition, Schiavone Panni et al [7]. report that painful, stiff knees do not respond well to arthroscopic surgery to lyse adhesions.


It’s important to understand that some joints don’t make the transition from active to residual arthrofibrosis; they remain chronically activated and painful.

Let’s talk about active arthrofibrosis first, because every joint with residual arthrofibrosis goes through this phase. Active arthrofibrosis often begins with an insult such as an injury or surgery, but in shoulders the insult often goes unnoticed. Blood and cell death creates a powerful inflammatory response [6] which is experienced as pain, heat and swelling, and causes the body to activate myofibroblasts. The myofibroblasts react by producing focal adhesion complexes (sticky sites) on their surface that adhere to nearby tissues, gluing together cells [8], scar tissue and joint structures that are necessary for movement [9]. When tissues have been stuck together by adhesions there can be intense pain as the joint is moved and the tissues are torn apart. The longer the joint has been immobile, the stronger the adhesions and the more intense the pain is likely to be.


In the early post-operative period when inflammation is high adhesions can form very rapidly, sometimes within minutes, and some knees need continuous passive movement continuously to prevent this from happening.

This sticking together of tissues (adhesions) is often overlooked in discussions about arthrofibrosis, and it’s an important reason why regular passive movement helps after arthrofibrosis surgery. In addition to adhesions, activated myofibroblasts produce scar tissue (collagen) and contract tissues, using the same sticky focal adhesion complexes on their surface to pull on scar tissue [5], creating traction force [10] and bringing essential joint structures like tendons, muscles and synovial membranes closer together and shortening them. Contractions occur because stress fibres form a kind of internal skeleton in myofibroblasts (see image above) which shortens, placing extreme forces on the scar tissue and cells attached to the myofibroblasts in a manner that is similar to muscle contraction [5, 11]. Another way in which passive stretching may reduce fibrosis is that after release from stretch the lengthened scar tissue (collagen) provides lower mechanical resistance, and theoretically reduces the stress stimulus on myofibroblasts. Surgical lysis of scar tissue can have a similar effect of reducing mechanical stress. The effects of collagen mechanical stress and stiffness on myofibroblasts are well known from organ fibrosis [4], but have not been studied in arthrofibrosis.


Figure: An insult results in hypoxia, bleeding, cell damage and inflammation. These trigger fibroblasts to transform into myofibroblasts which produce scar tissue, contractions and adhesions, and more inflammation.
Figure: An insult results in hypoxia, bleeding, cell damage and inflammation. These trigger fibroblasts to transform into myofibroblasts which produce scar tissue, contractions and adhesions, and more inflammation.

So, in the early post-operative period high levels of inflammation stimulates scar tissue production, adhesions and contractions resulting in pain and lack of ROM. As healing proceeds and inflammation resolves the length of time needed for the tissues to adhere and contract also increases. Myofibroblasts reduce the number of sticky adhesion complexes on their surface [4], but they remain tethered to stiff scar tissue and contractions continue while there is stiffness in the surrounding tissues [5, 11]. The pain from tissues adhering and tearing apart is usually only a problem in the early period after an insult, and should recede over time, however the length of time for resolution of these processes varies a lot. This activated phase can become persistent, so the fact that it’s been a long time since the insult is not a good indicator of which phase of fibrosis a joint is in.


If everything goes well the joint will reach a point at which inflammation is no longer activating myofibroblasts, and adhesions and contractions will no longer be an issue. The joint may lack ROM but it’s not swollen, warmer than usual or painful, it has hopefully reached the phase of residual arthrofibrosis. In the absence of inflammation many, but not all, of the myofibroblasts will die or revert back to their normal physiology, but the scar tissue will remain for some time, limiting ROM. This phase is always the aim of arthrofibrosis treatment but unfortunately sometimes it’s not reached leading to ongoing active arthrofibrosis with pain and limited ROM.


So, what are the practical outcomes of this? Attention should be focused on assessing levels of pain, inflammation and myofibroblast activation (adhesions and contractions). It is likely that patients with active arthrofibrosis have a higher risk of the return of severe symptoms following inflammatory stimuli such as aggressive exercise, surgical intervention or MUA compared to those with residual arthrofibrosis.


References
  1. Millar, N. L. et al. Frozen shoulder. Nat Rev Dis Primers 8, 59 (2022). https://doi.org/10.1038/s41572-022-00386-2

  2. 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

  3. Hu, Q. et al. A review of physiological and cellular mechanisms underlying fibrotic postoperative adhesion. Int J Biol Sci 17, 298-306 (2021). https://doi.org/10.7150/ijbs.54403

  4. Hillsley, A. et al. A strategy to quantify myofibroblast activation on a continuous spectrum. Sci Rep 12, 12239 (2022). https://doi.org/10.1038/s41598-022-16158-7

  5. Hinz, B., McCulloch, C. A. & Coelho, N. M. Mechanical regulation of myofibroblast phenoconversion and collagen contraction. Exp Cell Res 379, 119-128 (2019). https://doi.org/10.1016/j.yexcr.2019.03.027

  6. Hassanabad, A. F., Zarzycki, A. N., Jeon, K., Deniset, J. F. & Fedak, P. W. M. Post-operative adhesions: A comprehensive review of mechanisms. Biomedicines 9, 867 (2021). https://doi.org/10.3390/biomedicines9080867

  7. Panni, S. A., Cerciello, S., Vasso, M. & Tartarone, M. Stiffness in total knee arthroplasty. J Orthop Traumatol 10, 111-118 (2009). https://doi.org/10.1007/s10195-009-0054-6

  8. Gibb, A. A., Lazaropoulos, M. P. & Elrod, J. W. Myofibroblasts and Fibrosis: Mitochondrial and Metabolic Control of Cellular Differentiation. Circ Res 127, 427-447 (2020). https://doi.org/10.1161/CIRCRESAHA.120.316958

  9. Onoda, Y. et al. Joint haemorrhage partly accelerated immobilization-induced synovial adhesions and capsular shortening in rats. Knee Surgery, Sports Traumatology, Arthroscopy 22, 2874-2883 (2014). https://doi.org/10.1007/s00167-013-2659-9

  10. Burridge, K. & Guilluy, C. Focal adhesions, stress fibers and mechanical tension. Exp Cell Res 343, 14-20 (2016). https://doi.org/10.1016/j.yexcr.2015.10.029

  11. Vakhrusheva, A. V. et al. Role of actin-binding proteins in the regulation of cellular mechanics. Eur J Cell Biol 101, 151241 (2022). https://doi.org/10.1016/j.ejcb.2022.151241


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4 Comments


Kayley,


After watching Sebastiano's recent presentation and reading your post here, I was struck with the question of about what percentage of knees with AF do not progress from active to residual states. I expect that would be a difficult question to answer. Perhaps Dr. Noyes has seen enough to be able to make a decent guess.


Best,


Dan Vassilaros

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Replying to

Hi Dan,

That's an excellent question, hopefully we'll have some quality research to answer it at some point. The rate of healthy progression seems to be highly variable and likely depends on a lot of things such as surgical technique, physiotherapy methods and individual variables.

Kayley

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Hi Kayley,

Great Article! Your ability to explain a complex biological event into language a non-scientific person (like me) can fully understand is a gift. Arthrofibrosis has had a devastating effect on my life (and many others). I am truly grateful for your research.

Thank you

Greta Parker

Los Angeles

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Replying to

Hi Greta,

It's always nice to hear from you. Thank you so much for the feedback, I'm glad that we can help you to understand this devastating condition.

All the very best,

Kayley

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