Introduction

Knee pain effects 25% of individuals over age 55, and is most commonly due to osteoarthritis, although other etiologies can occur [1]. For many of these patients, their arthritis is too advanced for arthroscopy but too premature for arthroplasty. This leaves many patients in a grey zone where no good surgical treatments remain. Furthermore, even well indicated total knee arthroplasty outcomes result in persistent knee pain in 10-34% of cases [2]. Therefore, there is a large unmet need to help understand and treat knee pain outside of the structural abnormalities that is typically the focus for surgeons. Through collaborating with other medical fields and basic scientists, translational research can further our understanding, and eventually our treatment practices, of the knee in the future.

Content

The knee is a unique joint that may be better perceived as an organ due to its complexity and multiple tissue types and should be treated as such. When taking this approach, it becomes reasonable to focus treatments based on the different tissue types including the following: hyaline articular cartilage, bone, synovial fluid, meniscus, ligaments, and the synovial lining. Along with this, the contributions to pain can be significant when considering the bone and synovial lining as the cartilage is aneural. This was demonstrated by Dye et al. when he had an arthroscopy performed on his knee while awake and demonstrated that the most sensitive area was in fact the synovium [3]. Therefore, while treating structural abnormalities in the knee are important, treating the knee environment such as the synovial fluid and synovium itself can be just as relevant. These treatments can result from collaboration with the field of Rheumatology and have included treatments such as injections of steroids for post-traumatic osteoarthritis and IL1-Ra for ACL injury [4-5]. Novel injections are also being investigated, such as ABT-981, an immunoglobin that targets IL-1α and IL-1β and intraarticular injections of Etanercept [6].

Treatment options for patients with knee pathologies, both surgical and non-surgical, continue to evolve. This is largely in part due to a greater volume of basic and translational science literature of the knee, especially our understanding of the role of synovial fluid and the healing potential of cartilage. This understanding has led to a recent interest in the role of biologic treatments. Biologics, including adipose tissue, platelet-rich plasma, hyaluronic acid (HA), bone marrow aspiration (BMAC), and amniotic fluid, have been relatively understudied in the treatment of knee pain [7]. These compounds have the potential to alter the synovial fluid environment and may have a clinical benefit intraoperatively and postoperatively. Early evidence of their efficacy has been shown in some studies. For example, the AMELIA study, which investigated HA in knee arthritis, showed symptom improvement [8]. Other current clinical trials include the investigation of intraarticular BMAC for the treatment of early arthritis. As we continue researching these compounds, basic scientists must collaborate with physicians to understand the mechanism behind these interventions by testing the effects of biologics on an in vitro knee environment and exploring compounds, namely growth factors and cytokines, that likely play a role.

While different structures in the knee can cause pain, the nerves themselves can be the source of pain as well. For example, anesthesiologists have shown that the addition of cooled radiofrequency ablation with corticosteroid injection improves outcomes in patients with symptomatic osteoarthritis [9]. Furthermore, pain management physicians have shown that Botox can be used in the treatment of patellofemoral pain syndrome [10].

The components of the knee, from articular cartilage to synovium, create a unique environment that works as a synergistic unit. However, when parts of this system go awry, pain often ensues. Therefore, physicians from different specialties, researchers, physical therapists, and other healthcare personnel need to collaborate to understand and treat the pain of this complex joint.

References

[1] Peat, G., R. McCarney, and P. Croft. "Knee Pain and Osteoarthritis in Older Adults: A Review of Community Burden and Current Use of Primary Health Care." Ann Rheum Dis 60, no. 2 (Feb 2001): 91-7.

[2] Beswick, A. D., V. Wylde, R. Gooberman-Hill, A. Blom, and P. Dieppe. "What Proportion of Patients Report Long-Term Pain after Total Hip or Knee Replacement for Osteoarthritis? A Systematic Review of Prospective Studies in Unselected Patients." BMJ Open 2, no. 1 (2012): e000435.

[3] Dye, S. F., G. L. Vaupel, and C. C. Dye. "Conscious Neurosensory Mapping of the Internal Structures of the Human Knee without Intraarticular Anesthesia." Am J Sports Med 26, no. 6 (Nov-Dec 1998): 773-7.

[4] Kraus, V. B., J. Birmingham, T. V. Stabler, S. Feng, D. C. Taylor, C. T. Moorman, 3rd, W. E. Garrett, and A. P. Toth. "Effects of Intraarticular Il1-Ra for Acute Anterior Cruciate Ligament Knee Injury: A Randomized Controlled Pilot Trial (Nct00332254)." Osteoarthritis Cartilage 20, no. 4 (Apr 2012): 271-8.

[5] Lattermann, C., C. A. Jacobs, M. Proffitt Bunnell, L. J. Huston, L. G. Gammon, D. L. Johnson, E. K. Reinke, et al. "A Multicenter Study of Early Anti-Inflammatory Treatment in Patients with Acute Anterior Cruciate Ligament Tear." Am J Sports Med 45, no. 2 (Feb 2017): 325-33.

[6] Wang, S. X., S. B. Abramson, M. Attur, M. A. Karsdal, R. A. Preston, C. J. Lozada, M. P. Kosloski, et al. "Safety, Tolerability, and Pharmacodynamics of an Anti-Interleukin-1alpha/Beta Dual Variable Domain Immunoglobulin in Patients with Osteoarthritis of the Knee: A Randomized Phase 1 Study." Osteoarthritis Cartilage 25, no. 12 (Dec 2017): 1952-61.

[7] Devitt, B. M., S. W. Bell, K. E. Webster, J. A. Feller, and T. S. Whitehead. "Surgical Treatments of Cartilage Defects of the Knee: Systematic Review of Randomised Controlled Trials." Knee 24, no. 3 (Jun 2017): 508-17.

[8] Navarro-Sarabia, F., P. Coronel, E. Collantes, F. J. Navarro, A. R. de la Serna, A. Naranjo, M. Gimeno, G. Herrero-Beaumont, and Amelia study group. "A 40-Month Multicentre, Randomised Placebo-Controlled Study to Assess the Efficacy and Carry-over Effect of Repeated Intra-Articular Injections of Hyaluronic Acid in Knee Osteoarthritis: The Amelia Project." Ann Rheum Dis 70, no. 11 (Nov 2011): 1957-62.

[9] Davis, T., E. Loudermilk, M. DePalma, C. Hunter, D. Lindley, N. Patel, D. Choi, et al. "Prospective, Multicenter, Randomized, Crossover Clinical Trial Comparing the Safety and Effectiveness of Cooled Radiofrequency Ablation with Corticosteroid Injection in the Management of Knee Pain from Osteoarthritis." Reg Anesth Pain Med 43, no. 1 (Jan 2018): 84-91.

[10] Chen, J. T., A. C. Tang, S. C. Lin, and S. F. Tang. "Anterior Knee Pain Caused by Patellofemoral Pain Syndrome Can Be Relieved by Botulinum Toxin Type a Injection." Clin Neurol Neurosurg 129 Suppl 1 (Feb 2015): S27-9.

Introduction

It’s an exciting time for Orthoregeneration research. New tools and technologies have provided further insight into the biology and repair of joint tissues than ever before. Despite much progress in recent decades, the quest to achieve “perfect” joint restoration in patients with damaged cartilage has remained elusive. Perhaps the answer has been lost somewhere in translation. It is a long journey from bench to bedside, and this talk will explore why and how effective collaboration between basic scientists and physicians is essential to achieve our common goals.

Content

By definition, translational research leverages basic biology to create and implement practices which improve patient care [1]. Recent major advances in gene and cell therapy highlight how successful scientist-physician collaborations have resulted in ground-breaking therapies for patients [2, 3] and key examples exist in the cartilage repair field as well [4, 5]. A formidable obstacle to such partnerships is a perceived cultural divide between basic scientists and clinicians, which is not unique to the Orthoregeneration field [6]. This culture divide can often be attributed to communication barriers, and as highlighted by Restifo and Phelan, basic scientists and clinicians often do not speak the same language. [6] Lengthy and highly specialized training result in the creation of unique dialects including specific terminology and acronyms. These dialects separate not only the scientists and clinicians, but can alienate them from the general public as well. Where then, do we begin to bridge this divide? First, defining shared challenges and objectives is a critical step forward.

Fundamentally, both clinicians and basic scientists in our field are working to restore joint function. It is well understood from both perspectives that joints are complicated organs involving multiple tissues under varied stresses. However, there is less agreement regarding which specific challenges are the greatest in the field. At the bench, basic scientists have recently made great progress towards understanding signaling mechanisms required for maintenance of a healthy chrondrocyte phenotype [7]. We have new answers for long standing questions regarding the origin and fate of intrinsic joint progenitor cell populations [8-11]. If, how and when this information could be leveraged to develop new therapies for patients remains unknown. From a basic science perspective these are all intriguing areas of research – but which would be the highest priority for clinicians? Further communication is needed to develop a consensus.

Recent data suggests that the traditional linear pipeline from bench to bedside may not be the most efficient path forward [12]. Basic scientists in the Orthoregeneration field need a clear understanding of which issues clinicians view as the greatest challenges. Inversely, clinicians could benefit from information about the knowledge and tools available from the bench. A refined circular or iterative model of translational research which fosters greater reciprocal interaction between scientists and clinicians could be the most productive path forward towards these efforts [12]. Furthermore, this model should strive to include not only experts in the Orthoregeneration field, but interdisciplinary collaborations as well [13].

In summary, several key challenges exist for basic science – clinical collaborations. There is great strength in the diversity between scientists and clinicians. To leverage this strength, the Orthoregeneration field must work towards speaking a common language, collectively defining challenges so that we may work together to achieve shared goals.

References

1. Woolf, S.H., The meaning of translational research and why it matters. Jama, 2008. 299(2): p. 211-213.

2. Mendell, J.R., et al., Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med, 2017. 377(18): p. 1713-1722.

3. June, C.H., et al., CAR T cell immunotherapy for human cancer. Science, 2018. 359(6382): p. 1361-1365.

4. Grande, D.A., et al., The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. Journal of Orthopaedic Research, 1989. 7(2): p. 208-218.

5. Brittberg, M., et al., Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New england journal of medicine, 1994. 331(14): p. 889-895.

6. Restifo, L.L. and G.R. Phelan, The cultural divide: exploring communication barriers between scientists and clinicians. Disease models & mechanisms, 2011. 4(4): p. 423-426.

7. Sherwood, J., Osteoarthritis year in review 2018: biology. Osteoarthritis and Cartilage, 2019. 27(3): p. 365-370.

8. Li, L., et al., Superficial cells are self-renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice. The FASEB Journal, 2016. 31(3): p. 1067-1084.

9. Decker, R.S., et al., Cell origin, volume and arrangement are drivers of articular cartilage formation, morphogenesis and response to injury in mouse limbs. Developmental Biology, 2017. 426(1): p. 56-68.

10. Roelofs, A.J., et al., Joint morphogenetic cells in the adult mammalian synovium. Nature Communications, 2017. 8: p. 15040.

11. Fellows, C.R., et al., Characterisation of a divergent progenitor cell sub-populations in human osteoarthritic cartilage: the role of telomere erosion and replicative senescence. Scientific reports, 2017. 7: p. 41421.

12. Fudge, N., et al., Optimising Translational Research Opportunities: A Systematic Review and Narrative Synthesis of Basic and Clinician Scientists' Perspectives of Factors Which Enable or Hinder Translational Research. PloS one, 2016. 11(8): p. e0160475-e0160475.

13. Chao, H.-T., L. Liu, and H.J. Bellen, Building dialogues between clinical and biomedical research through cross-species collaborations. Seminars in cell & developmental biology, 2017. 70: p. 49-57.

Introduction

The cartilage repair field was the pioneer of biological approaches in the re-attainment of joint homeostasis, including the use of cells and tissue in joint surface repair. Why then are we still trying and failing to attain our goal whilst the rest of medicine surges ahead in harnessing the power of cells and genes in all areas of medicine from opthalmology to immunology and cancer? Was John Hunter correct in 1743?

Content

From the groundbreaking work of early pioneers in the cartilage repair field to the latest crop of therapies, we as a field are trying, and mostly not succeeding in our goal of repairing and regenerating cartilage. Cartilage repair pioneers led the way in understanding how cells and even tissues might be harvsted safely from living patients and stored or reused in the repair of cartilage defects.

This talk will explore the current state of the art in cell and gene therapies being developed globally for a variety of diseases and how the cartilage repair and joint preservation field might be able to learn from some of these developments and breakthroughs. The rapid expansion in the development of cell and gene therapies has allowed us to look at how therapies are developed and to make some fundamental changes to the way we think about collaboration between the various actors in this ecosystem. By starting with autologous products, we have brought the scientific, clinical and manufacturing steps much closer together with a common focus - the patient. This has allowed knowledge and experience to spill over from one group to the other, creating new ways of working to the benefit of our patients.

It is not just these groups that have had to change the way they work. Regulators, previously the keepers of the developmental and scientific application knowledge have had to lean into companies and academics in order to understand the rapidly developing field of Regenerative Medicine and the multitude of scientific adavnces being made at a blistering pace. By companies and academics assuming a new role of educators to the regulators, we have managed to build a much stronger relationship of trust with them and in so doing helped to advance their understanding, but also our ability to propose new approaches and therapies at a much faster rate with more uncertainties than previously before. By bringing the regulators on our journey of scientific discovery, we have empowered them to generally take a more risk balanced approach to regulation and review of advanced therapies, allowing patients to access them sooner than previously.

The relationship between academia and industry has also shifted thanks to the unique challenges of advanced therapies. No longer are the large pharma giants the masters of drug discovery and development. They have come to realise that the true innovation engines are in academia. Academia is the fertile ground of scientific breakthrough, but industry is the sunlight that allows it to blossom into therapies from which thousands of patients will benefit. Regen med has allowed industry and academia to find new ways of innovating in partnership. We will explore some of these examples and how patients have benefitted from this new found mutual understanding and respect.

Only by all players in the ecosystem working together to innovate for patients will we be able to improve how we address the challenges of repairing and regenerating the joint, and soon perhaps even preventing the degeneration occuring in the first place. This is an exciting time for our ecosystem and only by collaborating will we truly prove John Hunter wrong.