Orthobiologics: A New Frontier of Orthopaedics (OrthoPrenuer)
The past 20 years of medicine has been defined by an unprecedented rate of expansion and scientific discovery, opening discussions about chronic diseases and treatment protocols that have never before been addressed. Our understanding of science in many areas of medicine has flourished in these years, bursting wide the floodgates of possibility. With greater understanding of disease processes and pathology, a new area of medicine, coined orthobiologics, has emerged as the frontier for disease treatment with the potential to revolutionize medicine.
Orthobiologics have a specific emphasis on tissue healing and restoration by harnessing regenerative potential within the body’s own cells and redirecting their use for accelerated healing in damaged or diseased parts of the body. Orthobiologics have been used in a variety of different areas of medicine, such as cardiothoracic surgery, wound healing, ophthalmology, sports medicine, orthopaedic surgery, urology, cosmetic surgery, maxillofacial surgery and dentistry, and their applications continue to expand.1
The emergence of orthobiologics in the area of sports medicine and musculoskeletal injuries in particular has spawned a paradigm shift amongst clinicians, altering the treatment mindset from one of temporary and symptomatic relief to that of delaying or preventing onset of disease by modifying cell signals within the biologic environment. Cellular therapies are evolving as a middle ground between conservative treatments, such as physical therapy and pharmaceutical pain management and invasive surgical options. Thus far, orthobiologics have experienced three generations of evolution, starting with viscosupplementation as hyaluronic acid (HA), progressing to platelet-rich plasma (PRP), and now emerging are cellular therapies such as bone marrow concentrate and specific growth factors such as BMP 7.2
Although orthobiologic therapies have illustrated applications in a variety of medical fields, their use in the area of degenerative joint diseases such as osteoarthritis (OA) has exhibited an evolution unlike any other area. First-generation biologics consisted of viscosupplementation for joint arthritis, in the form of HA. Viscosupplementation involves the intra-articular injection of HA, a sticky viscous glycosaminoglycan, which can provide lubrication and shock absorbency for a damaged joint, 3 as well as pain reduction and functional improvements.4 This form of biologic therapy has illustrated significant results for patients experiencing painful OA.2 Given the better safety profile than continuous NSAID use for pain control, especially in older populations with more susceptibility to systemic effects, HA is viewed as a viable treatment alternative in OA.5 Furthermore, HA was shown to exhibit therapeutic effects at four weeks, peak efficacy at eight weeks and even illustrated residual therapeutic results at 24 weeks in a large meta-analysis conducted by Bannuru et al.6 However, this first-generation biologic represented a non-native form of cellular therapy, as the injectable forms of HA on the market are produced from sources outside of the body, such as bacteria, avian and synthetic origins.7
PRP emerged as the second generation of orthobiologics, and the first orthobiologic of the autologous form. The origin of PRP can be traced through the application of autologous blood products to facilitate healing. As scientists started examining the process of wound healing, and the role of platelets in hemostasis, it became clear that platelets were not solely involved in clotting. In fact, research would show that platelets contained several bioactive proteins and growth factors, which illustrated regenerative potential and healing properties for a variety of applications.8,9 Based upon this principle, the potent concentration of platelets are administered to stimulate a supra-physiologic response, comprising an undifferentiated cocktail of anti-inflammatory, pro-inflammatory, anabolic and catabolic mediators, in an attempt to jump start the body’s natural healing response.
First used by Ferrari et al in 1987 following open heart surgery,10 PRP has now been applied in a variety of areas such as ENT, wound healing, orthopaedics, maxillofacial surgery, ophthalmology, urology and dentistry, as well as cosmetic and neurosurgery. Although the majority of research comprises anecdotal evidence and small case series,2 larger randomized controlled trials have started to emerge in areas such as tendinopathies11-12 and knee OA.13 As a second generation of orthobiologic, PRP has not only exhibited a larger array of treatment applications, but has also been shown to be superior to the first generation biologic HA for patients with knee OA.14-17 With a growing volume of research and mainstream publicity from its use in professional athletes, PRP has become a mainstay in orthobiologic injectable therapy, although larger clinical trials are needed to fully understand the mechanisms and efficacy of the treatment.
In recent years, Bone Marrow Concentrate (BMC) has emerged as the third generation of orthobiologic therapy. Its potent mixture of mesenchymal stem cells, hematopoetic cells, platelets and cytokines have been shown to possess anti-inflammatory, immunomodulatory and chondrogenic properties, which act as the foundation for its regenerative potential.18 Although the exact mechanism is unknown, it is hypothesized that the bone marrow concentrate cells either induce differentiation or proliferation of resident stem cells, or possess innate chondrogenic differentiation potential.18 Early experimental trials using BMC have illustrated positive results in OA patients. In fact, at The Orthobiologic Institute: TOBI symposium in 2013, unpublished data was presented comparing one-year follow up of OA patients who received BMC therapy vs. those who elected for arthroplasty. The data illustrated similar patient outcomes in function and range of motion, as well as higher activity in the BMC group.19 Spine will be a focus at the upcoming Orthobiologic Institute Symposium in June 2014, including data from a randomized controlled trial of intra-disc PRP from Gregory Lutz, M.D., of the Hospital For Special Surgery (HSS) in New York. It has also been postulated that BMC therapy may have a potential use as an adjunct treatment post-operatively for procedures such as arthroscopic debridement, meniscal transplantation and subchondroplasty. Improved surgical results have been reported when a patient undergoes BMC treatment two to three weeks postoperatively.18 However, to date, there is a paucity of high quality research studies examining the therapeutic efficacy of BMC, as many of the studies are not randomized, lack a control and present anecdotal results. Larger clinical trials and clinician collaboration is needed to further expand BMC as the third generation of orthobiologics.
As with any new frontier, it takes a group of pioneers to forge the way, which is why it is imperative that clinicians and scientists from different fields collaborate to promote evidence-based medicine and advancements in the field of orthobiologics. The Orthobiologic Institute (TOBI): Platelet Rich Plasma and Regenerate Medicine Symposium, now in its fifth year, brings together clinicians from around the world, creating a platform for discussion and research in orthobiologic therapy. With all the many challenges for funding and conducting randomized clinical trials, symposiums such as TOBI are crucial for establishing treatment protocols and pushing the evolution of new generations of biologic therapies. Even as orthobiologics has evolved from first-generation HA to autologous PRP and now BMC, the field always keeps its eyes on the future. The Orthobiologic Institute (TOBI) symposium is scheduled to feature many pioneers from all over the world discussing the most cutting edge advancements in orthobiologics, which have the potential to revolutionize medicine and change the way we approach disease.
References
1. Adam Weglein, S.S., Danielle Aufiero, Platelet Rich Plasma: Practical Use in non surgical musculoskeletal patholgy, in Platelet Rich Plasma: Lecture Notes in Bioengineering. 2014, Springer. p. 187-201.
2. Sampson, S., M. Gerhardt, and B. Mandelbaum, Platelet rich plasma injection grafts for musculoskeletal injuries: a review. Current Reviews in Musculoskeletal Medicine, 2008. 1(3-4): p. 165-174.
3. Filardo, G., et al., Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskeletal Disorders, 2012. 13(1): p. 229.
4. Colen, S., et al., Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products. BioDrugs, 2012. 26(4): p. 257-68.
5. Bannuru, R.R., et al. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: A systematic review and meta-analysis. in Seminars in arthritis and rheumatism. 2013. Elsevier.
6. Bannuru, R., et al., Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and Cartilage, 2011. 19(6): p. 611-619.
7. inc, D.M. Comparison of Viscosupplements. Available from: http://orthoviscline.com/about-orthovisc/hyaluronic-acid-comparison.
8. Anitua, E., et al., New insights into and novel applications for platelet-rich fibrin therapies. Trends in Biotechnology, 2006. 24(5): p. 227-234.
9. Werner, S. and R. Grose, Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003. 83(3): p. 835-70.
10. Ferrari, M., et al., A new technique for hemodilution, preparation of autologous platelet-rich plasma and intraoperative blood salvage in cardiac surgery. Int J Artif Organs, 1987. 10(1): p. 47-50.
11. Mishra, A.K., et al., Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med, 2014. 42(2): p. 463-71.
12. Rha, D.W., et al., Comparison of the therapeutic effects of ultrasound-guided platelet-rich plasma injection and dry needling in rotator cuff disease: a randomized controlled trial. Clin Rehabil, 2013. 27(2): p. 113-22.
13. Patel, S., et al., Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med, 2013. 41(2): p. 356-64.