Magnetic Resonance Cartigram Sequencing in the Setting of Autologous Orthopedic Immunobiologics

T2 Wetmap CartiGram® sequences of osteoarthritic knee in a 62 year old tennis player with intractable knee pain.

 

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Abstract

Diffusion weighted MRI Sequencing (DWI) has the capability to diagnose arthritic joint disease and degenerative disk disease (DDD) earlier than any other imaging modality. These studies are ideal for the early detection of joint pathology due to arthritis and spondylosis. Earlier detection of biochemical and structural changes may lead the way to establishing more evidence-based treatment options that prevent disease progression and limit costs, particularly with the emergence of autologous biologic signaling cell treatments. This technology could also play a role in the validation of treatment techniques with modern autologous biologic applications in orthopedic surgery and neurosurgery, particularly spondylosis. We discuss the role of DWI in the setting of bone marrow aspirate/signaling cell concentrate techniques for orthopedic surgery and neurosurgery with applications to arthritis and spondylosis and demonstrate examples of patients with arthritic joint disease and DDD. Autologous biologics are a treatment for early stage disc and joint disease, which may change the natural history of both to a far more favorable outcome. Biologics should be considered part of the current standard of care in the management of bone and joint disease.

Introduction

In 2008 approximately 100 million adults were affected by chronic, noncancer pain attributed to joint pain. 1 Chronic pain costs the nation over $635 billion each year in medical treatment and lost productivity. 2 A large proportion of this pain and lost productivity comes from lumbar disk disease and arthritis. Understanding the immunologic signaling cascades underlying the inflammatory process are key to providing patients with their best potential biologic solutions. Radiology and imaging play major roles in orthopedic and neurosurgery disciplines as well as many others. Orthopedic surgeons, neurosurgeons and radiologists have continued to develop imaging algorithms to determine cartilage deep tissue health. 3 4 5 Diffusion weighted imaging MRI (DWI) sequences provide clinicians with the first indicators of joint disease without contrast, when intervention is likely to be most successful and prove most durable.6 (Figures 1-6)

Management Strategies

The Challenge in treating patients with arthritis and spondylosis is the early identification of patients at risk for chronicity and subsequently preventing the chronicity from occurring. DWI MR enables clinicians to establish an earlier, more accurate patient diagnosis, potentially limiting future disease. Identifying arthritis and degenerative disk disease at the earliest stages possible preserves tissues and cell matrices, making interventions easier on the patient and more cost effective. Decision-making may be affected drastically when information from DWI is taken into consideration, particularly in the setting of a spondyloarthropathy diagnosis.

Diffusion weighted MR imaging sequences contribute unique information without additional cost. The sequencing provides useful pre and postoperative information on disc degeneration and bone marrow changes for more accurate assessments of pathology and better treatment plans. 7 Similar findings on peripheral joint imaging with commercially available T2 mapping sequencing at 3T have been reported, underscoring the value of the study. 8 9 10 11

Identifying arthritis and degenerative disk disease at the earliest stage gives patients the benefit of understanding their prognosis and presents more opportunity for simple treatments. Identification of patients at earlier time points on the disease spectrum may facilitate patients taking responsibility for the consequences of their treatment decisions. DWI MR could play a major role in arthroplasty protocols that are likely to be forthcoming. Intense investigation has improved our understanding of the complex biomechanical and biochemical consequences of musculoskeletal disease, leading to a search for the best molecular therapeutic targets. Biochemical protein sequencing and magnetic resonance imaging have elaborated specific stages of disease, providing the opportunity to determine timing of intervention. The studies offer the capability to follow progression of disease versus response to treatment at the same cost as conventional MRI.

Biologic Therapeutics And Signaling Cell Therapies

Autologous biologic cellular technologies have emerged as safe, viable options for the treatment of arthritic joint pain and disk disease. These applications have become popular and use will continue to grow. An aging population that is more active than their predecessors are demanding autologous biologic-based arthritic joint pain solutions that, unlike bionic solutions, will not limit their recreational and vocational pursuits and are viewed as natural solutions.

Bone marrow stimulating procedures and bone marrow concentrates demonstrate clinical utility and disease modifying capability in human and other animal models of arthritis. 12 13 14 15 16 Bone marrow MSCs are a heterogenous population of adult stem cells with the ability to specialize along mesenchymal lines into cartilage, bone, fat, tendon and other mesodermal derivatives. 17 18 In spite of their clonal capability, it is their immune- modulating and anti-inflammatory effects that have been concluded to be responsible for their clinical efficacy. Environmental cues cause progenitor cells to respond heterogeneously through ligand-receptor binding mediated activation of nuclear second messengers that promote translation of functional proteins needed in response to the environmental cues. Soluble signaling proteins and platelet granules contain additional growth factors. Cellular communication at the molecular level is complex and spatiotemporally based. The mesenchymal stem cells function as “medicinal signaling cells” through the molecular immune-signaling pathways that are the basis of rheumatology.19 20

Autologous mesenchymal stem cell (MSC) transplantation is a safe, autologous procedure with proven clinical efficacy in relieving arthritic joint pain. The procedure is professionally completed in an hour and is essentially painless and bloodless when performed properly.21 22 23 Bone marrow aspirate concentrates have proven scientifically safe to use, reliable and viable cellular products. The procedure is reproducible and based on immunomodulatory signaling and anti-inflammatory principles. The high costs of the procedure may limit more widespread use currently. Patient demand continues to grow rapidly in some areas. 24 25

Advanced Imaging

There have been dramatic advances in targeted treatments enabling improved disease management and more efficient control of inflammation and joint disease. 26 27 The commercial availability of magnetic resonance imaging (MR) T2 wetmap and apparent diffusion coefficient (ADC) MR may signify the time for a paradigm shift in the management of orthopedic surgery and neurosurgery patients with arthritis and spondyloarthropathy. 28

By acquiring multiple echoes at different TE times at each slice location representing different T2 weighting, CartiGram® (General Electric) is T2 mapping sequence and processing utility software that detects changes in the collagen component of the extracellular cartilage matrix. The acquired data is processed to produce T2 color wetmaps that demonstrate subtle changes in cartilage ultrastructure that are not visible on gray scale images. The images are extremely easy to interpret, ideal for patient education and may play a major role in surgical decision-making.

ADC images are made using a series of different diffusion weighted images taken at different magnetic field strength gradients that show information on the relative speed at which water diffuses through tissues. ADC maps increase contrast and allow for better differentiation of annular clefts and protruding nuclei when compared to routinely acquired T2 images.

Quantitative MRI techniques can provide a metric by which to evaluate the efficacy of cartilage repair techniques and offer insight into the composition of cartilage and cartilage repair tissue.29 Studies comparing T2 mapping before and after bone marrow concentrate injections are lacking. These studies will yield important information when used as part of a controlled, routine, database driven protocol. No studies have been published where diffusion weighted sequences have been used in the setting of autologous biologic therapeutics. DWI and T2 wetmapping studies may perfectly compliment the screening process in orthopedic and neurosurgical patients who could be candidates for signaling cell procedures. The imaging provides advantages defining patient options and treatment planning and may prove useful in qualifying or eliminating patients as candidates for treatment with autologous biologics.

Future Direction

The predictable molecular consequences that are closely intertwined with maladaptive physical joint changes may be reversed with autologous biologic treatments. (Figure 7) Orthopedic and neurosurgeons must have a working knowledge of the immunological basis for treatment using biologics. Patient demand for the less invasive procedures with now proven efficacy is certain to increase particularly with the evolution of this technology that is still in its infancy. New biologics and biosimilars with diverse cellular effects continue to be produced using DNA recombinant technology for rheumatoid arthritis with excellent safety, efficacy, tolerability and immunogenicity.30

Orthopedic surgery and neurosurgery, like the majority of medical and surgical subspecialties, are practiced and taught based on a clinically reactive strategy. Until now, preventative maintenance of the musculoskeletal system has been limited. Advanced imaging technology is now widely available that provides a distant early warning in the setting of organic joint disease. There are no added costs for the complete ADC or T2 wetmaps imaging study compared to standard MRI sequences. The clinical information derived from diffusion-weighted images reliably improves diagnostic accuracy and helps guide patients to more completely understand their options. In this context and acting on in the best interest of the patient, physicians and surgeons must adapt a more proactive approach to the musculoskeletal disease condition. Biological science has now provided us with the knowledge and ability to naturally optimize the human experience at the endurance limits of the physical machine.

Conclusion

Arthritis, spondylosis and facet arthropathy cause pain globally and cause great disability. These predictably progressive diseases are typically detected at late stages, when results from treatment have been less successful, more invasive and more complicated. Reports have demonstrated that most patients have been able to defer or forego joint replacement or lumbar fusion when appropriately selected. Most patients currently undergoing joint replacement could be candidates for autologous biologics and should be made aware of the techniques in the setting of informed consent for joint replacement. Diffusion weighted imaging provides early insight into organic joint disease and arthritis that specifically directs clinical treatment and may help patients avoid late or salvage interventions like surgery. Applications of available and future biologic products will likely continue to enjoy larger roles in all medical specialties. With clinical application of available technology, knowing the patient and the specific recreational and vocational pursuits they intend to return to is vital to avoiding expectation/result.

We initially used bone marrow concentrates in the setting of chondral defects in 2005 and have experienced no significant complications in over a decade of safely performing the procedure. These molecular strategies have led to more significant and more durable clinical pain relief than initially expected. 31 Earlier diagnosis and treatment will likely continue to have a profound effect on patient outcomes. DWI MR combined with currently available and future autologous and pharmacologic disease modifying biologics represent the future of orthopedic and neurosurgical management of arthritis and spondylosis. Further study should focus on determining the long term success and cost- effectiveness of signaling cell biologic procedures in multiple controlled settings.

 

 

Bibliography

1. https://meps.ahrq.gov/mepsweb/data_stats/MEPS_topics.jsp?topicid=5Z-1

2. DJ Gaskin, P Richard. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. Appendix C. The economic costs of pain in the United States.

3. Ramappa A, Steadman JR, Gill TJ, Bradford C, Briggs KK, Ho CP.MRI of microfractured chondral defects. J Knee Surg. 2007;20:228-34.

4. F Su, JF Hilton, L Nardo, S Wu, F Liang, TM Link, CB Ma, X Li. Cartilage Morpholog and T1rho and T2 Quantificaiton in ACL Reconstructed Knees: A two year follow up . Osteoarthritis Cartilage 2013 21(8): 1058-67.

5. CR Chu, AA Williams, RV West, Y Qian, FH Fu, BH Do, S Bruno. Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Menisucs Healing after Anatomic Anterior Cruciate Ligament Reconstruction. Am J Sports Medicine 2014; 42(8): 1847-56.

6. HJ Yu, S Bahri, V Gardner, LT Muftuler. In Vivo Quantification of Lumbar Disk Degeneration : Assessment of ADC Value Using a Degenerative System Based on Pfirrmann Framework. Eur Sine J. 2015; 24(11): 2442-8.

7. Gunnar Andersson (Ed.) New Imaging Technique to Improv Assesment of Surgical Patients with Lumbar Degeneration. Spinal News International. 2017 Dec; 17(45): 1-2.

8. R Kijowski, D Blankenbaker, AD Smet, G Baer, B Graf. T2 Mapping Sequence for Detecting Cartilage Lesion within the Knee Joint at 3.0T: Diagnostic Performance in 114 Patients with Surgical Correlation. Proc Intl Soc Mag Reson Me. 20 (2012)

9. TJ Mosher, BJ Dardzinski. Semin Musculoskeletal Radiology 2004 Dec 8(4): 355- 68.

10. J Pan, JB Pialat, T Joseph, D Kuo, GB Joseph, MC Nevitt, TM Link. Knee Cartilage T2 Characteristics and Evolution in Relation to Morphologic Abnormalities Detected at 3T MR Imaging. Radiology 2011 Nov; 261(2): 507-515.

11. TJ Mosher, Y Liu, CM Torok. Functional Cartilage MR T2 Mapping: Evaluating the effect of age and training on knee cartilage response to running. Osteoarthritis Cartilage 2010 March; 18(3): 358-364.

12. Frisbie DD, Trotter GW, Powers BE, Rodkey WG, Steadman JR, Howard RD, et al. Arthroscopic subchondral bone plate microfracture technique augments healing of large osteochondral defects in the radial carpal bone and medial femoral condyle of horses. J Vet Surg. 1999;28:242-55.

13. Frisbie DD, Morisset S, Ho CP, Rodkey WG, Steadman JR, McIlwraith CW. Effects of calcified cartilage on healing of chondral defects treated with microfracture in horses. Am J Sports Med. 2006;34:18t24-31.

14. WJ Shi, FP Tjoumakaris, M Lendner KB, Freedman. Biologic Injections for Osteoarthritis and Articular Cartilage Damage: Can we modify disease? Phys Sportsmed 2017 Sep 45(3): 203-223.

15. P Fernandez-Pemas, I Rodriguez-Lesende, A de la Fuente, J Mateos, I Fuentes, J DeToro, FJ Blanco, MC Arufe. CD105+ Mesenchymal Stem Cells Migrate into Osteorthrtic Joint in the Amimal Model. Plos One 2017 Nov; 12(11): 00188072.

16. SM Richardson, G Kalamegam, PN Pushparai, C Matta, A Memic, A Khademhosseini, R MObasheri, FL Poletti, JA Hoyland, A Mobasheri. Mesenchymal Stem Cells in Regenerative Medicine: Focus on Articular Cartilage and Intervertebral Disk Regeneration. Methods 2016 Apr; 99:69-80.

17. CA Sutton, K Brady, A Salerno, T Katopodi, RL Williams, CC West, D Evseenko, L Wu, S Pang, R Ferro de Godoy, AE Goodship, B Peault, AW Blom, W Kafienah, AP Hollander. The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchmal Stem Cells, with an Enhancd Capacity for Chondrogenic Differentiation. Stem Cells 2017 Nov; 35(1): 2280-2291.

18. CJ Xian, BK Foster. Repair of Injured Articular and Growth Plate Cartialge Using Mesencymal Stem Cells and Chondrogenic Gene Therapy. Curr Stem Cell Res Ther. 2006 May 1(2): 213-229.

19. A Caplan. Mesenchymal Stem Cells: Time to Chang the Name! Stem Cels Transl Med 2017 Jun; 6(6): 1445-1451.

20. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm57344 3.htm

21. M Yubo, L Yanyan, L Li, S Tao, L Bo, C Lin. Clinical Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Osteoarthritis Treatment: A meta analysis. Plos One 2017 Apr ;12(4): e0175449.

22. YS Kim, YJ Choi, DS Suh, DB Heo, Y Kim, JS Ryu, YG Koh. Mesenchymal Stem Cell Implantation in Osteoarthritic Knees: Is fibrin glue effective as a scaffold? Am J Sports Med 2015 Jan 43(1) 176-85.

23. A Goldberg, K Mitchell, J Soans, L Kim, R Zaidi. The Use of Mesenchymal Stem Cells for Cartilage Repair and Regeneration: A systematic review. J Orthop Surg Res 2017 9(12): 39.

24. SA Shapiro, SE Kazmerchak, MG Heckman AC Zubair, MI O’Connor. A Prospective, Single-Blind, Placebo Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am J Sports Med 2017 Jan 45(1): 82-90.

25. E Kon, L Engebretsten, P Verdonk, S Nehrer, G Filardo. Clinical Outcomes of Knee Osteoarthrtitis Treated With Autologous Protein Injection: A 1-Year Pilot Double Blinded Randomized Controlled Trial. Am J Sports Med 2018 Jan; 46(1): 171-80.

26. FP Luyten, RJ Lories, P Verschueren et al. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Practices. Res Clin Rheumatol 2006; 20: 829-848.

27. S Bajada, J Mazakova, JB Richardson, N Ashammakhi. Updates on Stem Cells and Their Applications in Regenerative Medicine. 2008 Jun 2(4): 169-83.

28. E Belykh, AA Kalinin, AA Patel, EJ Miller , MA Bohl, LA Bardonova, IA Stepanov, T Kerimbaev, AO Asantsev, MB Giers, MC Preul, VA Byvaltsev. Apparent Diffusion Coefficient Maps in the Assessment of Surgical Patients with Lumbar Spine Degeneration. Plos One 2017 Aug 12(8): Published Online e0183697, 15 pp.

29. EC Argentieri, AJ Burge, HG Potter. Magnetic Resonance Imaging of Articular Cartilage within the Knee. J Knee Surg 2018 Jan Epub ahead of print.

30. E Pelechas, PV Voulgari, AA Drosos. ABP 501 for the Treatment of Rheumatoid Arthritis. Expert Opin Biol Ther 2018 Jan: Epub ahead of print.

31. T Turajane, U Chaveewanakorn, W Fongsarun, J Apajanepong, KI Papadopoulos. Stem Cells. Avoidance of Total Knee Arthroplasty in Early Osteoarthritis of the Knee with Intra-articular Implantation of Autologous Activtaed Peripheral Blood Stem Cels versus Hyaluronic Acid: A Randomized Controlled Trial with Differential Effects of Growth Factor Addition. Stem Cells Int 2017; 8925132.

Author
S. Austin Yeargan III, MD Orthopedic Surgeon Molecular Immunobiologist

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