Introduction

Osteoarthritis is a major cause of disability and is a source of substantial expense to the medical system. Due to early development of osteoarthritis in young athletes, and increased overall lifespan, early diagnosis and treatment of osteoarthritis is critical. Also critical is the need for therapies that can prolong functional joint health and perhaps eventually, therapies that can reverse the disease process. There has been great enthusiasm by many for othobiologics to fill this need. Orthobiologic therapies rely upon the actions of substances that are normally present in the body that aid in tissue repair.¹ Examples of orthobiologic therapies include platelet-rich plasma (PRP), autologous conditioned serum (ACS), autologous protein solution (APS), culture expanded stromal cells from a variety of tissue sources, and minimally manipulated cell-based therapies such as bone marrow aspirate concentrate (BMAC) and stromal vascular fraction (SVF). Evidence from basic science and animal model studies of various orthobiologics frequently support the rationale for the use of these modalities as a component of the treatment paradigm for osteoarthritis. However, these therapies are inherently more complex than traditional pharmaceuticals and there is wide variability that contributes to confusing and conflicting results in the scientific literature. A systematic approach is essential to determine, for each therapy: the constituents of each product, patient effects (ie. age, systemic health), administration factors (timing, frequency, dose, route), and confounding factors such as systemic drug effects on the behavior of cells and platelets.

Content

Platelet-rich plasma is prepared from blood and has an increased platelet concentration compared to whole blood. Growth factors in the alpha granules of platelets are credited as the bioactive factors of interest in PRP, however the leukocytes, plasma proteins, and red cells also play a role. Based on systematic review of the literature, in vitro studies consistently demonstrate PRPs ability to increase cell viability, proliferation and migration.² In this same study, in vivo animal model results were less consistent although there is evidence to support anti-inflammatory effects in osteoarthritic joints. An interesting recent study in dogs challenges the paradigm of non-steroidal anti-inflammatory avoidance prior to collection of blood for PRP preparation as no effect was found on platelet degranulation.³ Despite calls for consistency in reporting, the PRP literature continues to be plagued by incomplete characterization of the product used which has been detrimental to the progress of this promising therapy.²

The fundamental concept of BMAC is to gain the best of both worlds in one patient-side therapy: platelet growth factors and MSC. The basic scientific literature with respect to BMAC is still in its infancy and is outweighed by small clinical studies. In a recent equine cartilage defect model, defects grafted with BMAC were not different in repair quality compared to microfracture.⁴ In addition, MSC in BMAC underwent chondrogenic differentiation in vitro but not in vivo. However, in a goat osteoarthritis model, injection of BMAC had increases in measured growth factors, reduced inflammatory cytokines in joint fluid, and had less matrix loss compared to control.⁵ This may support the role of growth factors and paracrine effects of MSC to modulate inflammation and catabolism in osteoarthritis in the absence of the ability of MSC engraftment and differentiation. Multisite aspiration should theoretically increase the fraction of MSC, however Oliver et al. found no difference with single vs multisite aspiration.⁶ Given that preparation is similar to PRP, BMAC is troubled by many of the same variables as PRP necessitating standardization of reporting.⁷

Stromal vascular fraction is an attractive therapeutic because of ease and speed of collection and processing. As a cell-based therapy, it is heterogeneous in nature. The advantages and disadvantages of this heterogeneity have yet to be fully elucidated as is also true for the basic mechanism of action in osteoarthritis.⁸

Culture expanded MSC provide a more homogeneous cell population and greater cell numbers at the time of injection, but require greater time between harvest and delivery, expense, and complexity of regulatory control. Numerous questions remain to be answered including the best cell source, dose, timing of therapy, culture optimization including avoidance of xenogeneic proteins, specific indications, and safety of allogenic therapy. Culture expanded cells from a variety of sources have been studied for their immunomodulatory potential including bone marrow-derived, adipose-derived, amniotic, and peripheral blood MSC, among others.^9,10 An important discovery in the concept of MSC as a treatment for osteoarthritis was the anti-inflammatory and immunomodulatory phenotype adopted by the cells after exposure to synovial fluid from osteoarthritic joints or inflammatory cytokines prominent in the pathophysiology of osteoarthritis and recent work has demonstrated differences in the secretome of MSC exposed to synovial fluid from early vs late osteoarthritic joints.^11,12

Overall, the orthobiologics are generally considered safe for the purpose of joint injection and the rationale for the utility of many of these therapies is strong and supported by basic mechanistic evidence. However, many questions remain that can only be answered by well controlled studies with complete characterization of the therapy being used.

References

1. Huebner K and Getgood A. Ortho-biologics for osteoarthritis. Clin Sports Med. 38:123-141, 2019.

2. Fice MP, Miller JC, Christian R, et al. The role of platelet-rich plasma in cartilage pathology: An updated systematic review of the basic science evidence. Arthroscopy. 35(3):961-976, 2019.

3. Ludwig HC, Birdwhistell KE, Breainard BM, Franklin SP. Use of cyclooxygenase-2 inhibitor does not inhibit platelet activation or growth factor release from platelet-rich plasma. Am J Sports Med. 45(14):3351-3357, 2017.

4. Chu CR, Fortier LA, Williams A, et al. Minimally manipulated bone marrow concentrate compared with microfracture treatment of full-thickness chondral defects: A one year study in an equine model. J Bone Joint Surg Am. 100(2):138-146, 2018

5. Wang Z, Zhai C, Fei H, et al. Intraarticular injection autologous platelet-rich plasma and bone marrow concentrate in a goat osteoarthritis model. J Orthop Res. Feb 21, 2018. Doi: 10.1002 [epub ahead of print]

6. Oliver K, Awan T, Bayes M. Single- versus multiple-site harvesting techniques for bone marrow concentrate: Evaluation of aspirate quality and pain. Orthop J Sports Med. 5(8):2325967117724398, 2017.

7. Gaul F, Bugbee WD, Hoenecke HR, D’Lima DD. A review of commercially available point-of-care devices to concentrate bone marrow for the treatment of osteoarthritis and focal cartilage lesions. Cartilage. Apr 1, 2018:1947603518768080. [epub ahead of print]

8. Shimozono Y, Fortier LA, Brown, D, et al. Adipose-based therapies for knee pain-fat or fiction. J Knee Surg. 32(1):55-64, 2019.

9. de Girolamo L, Kon E, Filardo G, et al. Regenerative approaches for the treatment of early OA. Knee Surg Sports Traumatol Arthrosc. 24:1826-1835, 2016.

10. Longhini ALF, Salazar TE, Vieira C, et al. Peripheral blood-derived mesenchymal stem cells demonstrate immunomodulatory potential for therapeutic use in horse. PLoS One. 14(3):e0212642, 2019.

11. McKinney JM, Doan TN, Wang L, et al. Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis. 37:42-59, 2019.

12. Gomez-Aristizabal A, Sharma A, Bakooshli MA, et al. Stage-specific differences in secretory profile of mesenchymal stromal cells (MSCs) subjected to early- vs late-stage OA synovial fluid. Osteoarthritis Cartilage 25(5):737-741, 2017.