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Orthobiologics

Orthobiologics are organic and biosynthetic materials utilized to treat various orthopedic conditions that can delay or prevent surgery (Moreno 2022, Rosen 2019, Turajane 2017). These materials include, but are not limited to Bone Marrow Aspirate Concentrate (BMAC), Microfractionated Adipose Tissue (MFAT), Platelet Rich Plasma (PRP), Hyaluronic Acid (HA), and Alpha 2 Macroglobulin (A2M). In cases where surgery is necessary, orthobiologics have been demonstrated to positively improve outcomes when used to augment surgical procedures as well (Malhotra 2015, Shottel 2017).

The efficacy of these substances varies widely if improperly harvested, processed, delivered, or indiscriminately applied to inappropriate pathologies or patients without proper training. As an example, it is well known that organic orthobiologics are negatively affected by anti-inflammatory medications such as ibuprofen and Advil, but additionally, BMAC shows decreased efficacy with even inhaled steroids as well as fluoroquinolone antibiotics and statins (Izadpanah et al 2015. Stephenson 2013).

Contrastingly, the efficacy of MFAT is strongly affected by increasing body mass index, diabetes, radiotherapy exposure, and tamoxifen while high blood pressure, kidney disease, exercise, peripheral vascular disease, and total cholesterol were shown not to have a statistically significant effect (Varghese et al 2017). Furthermore, MFAT shows decreased osteogenic potential and increased senescent features in elderly patients (Choudhery 2014) and is shown to be most efficacious when harvested from the abdomen above Scarpa’s fascia (Jurgens 2008, Iyyanki 2015, Schipper 2008). Contrastingly, in the elderly, MFAT has the highest amount of PPAR gamma activity, which plays an important role in adipogenesis, when harvested from the thighs and arms (Schipper 2008).

Hyaluronic acids’ efficacy varies by molecular weight and culturing process such that high molecular weight and bacterial-derived products are most efficacious and have a better safety profile (Altman et al 2016, Vincent et al 2019). Comparatively, a systemic review meta-analysis from Belk et al in 2023 demonstrates that BMAC or PRP alone, both outperform HA. Additionally, a prospective study by Pabinger et al in February of 2024 demonstrated that BMAC when used in patients with severe (stage III-IV) osteoarthritis of the knees had a 95% success rate and significant improvement in walking distance at 4-year follow-up.

Interestingly, combinations of biosynthetic and organic compounds have been show to have a synergistic effect on the treatment of more severe disease in certain conditions. In 2016, A randomized control trial by Lana et al demonstrated a combination of PRP and HA showed better outcomes at 3 months compared to PRP alone and at 1 year compared to HA alone. Another promising study by Chen et al 2016 demonstrated decreased pain scores, improved functional outcomes and increased joint width space on radiographs with a combination of HA and PRP in the treatment of knee OA in a review of three case studies.

Alpha-2-Macroglobulin (A2M) is a protease inhibitor prduced by the liver, chondrocytes, and synoviocytes that has strong anti-inflammatory properties. A2M concentration in synovial (joint) fluid is a tenth of that of serum and too low to adequately inhibit enzymes responsibly for cartilage breakdown and inflammation (Sun et al 2023). A2M binds and inactivates proinflammatory (IL-1B/NF-kappa-beta pathway) and catabolic cytokines (TNF alpha), inhibits metalloproteinases (MMP13, ADAMTS 1, 4, 5, 7, and 12), and endoproteinases in a dose-dependent manner making a more favorable healing environment. (Tortorella et al 2004, Luan et al 2008, Sun et al 2023). A recent study by, Klein et al demonstated A2M was marginally better than PRP, both of which better than corticosteroid, at improvement of functional scores and arthritis symptoms between 6 and 12 weeks, but no long term follow up was reported. Armstrong et al 1999 and Wang et al 2014 reported that A2M can bind cytokines and growth factors (TGF-B1, FGF-2, MACFs, and TNF alpha) within 15 minutes acting as a transporter of hormones and enzymes, thereby potentially having not just an additive, but a synergistic effect in combination with the growth factors present in alpha granules of the platelets in PRP. For this reason, clinically A2M is commonly combined with PRP and early data is promising.

In short, yes, orthobiologics are efficacious when properly applied to the right patient and right pathology as well as utilizing the correct harvesting, processing, and delivery technique. Even more importantly, deciding which orthobiologic is right for each patient requires training in regenerative medicine to have the knowledge and experience to weigh a variety of factors including age, BMI, type of pathology, severity of disease, duration of disease, co-morbidities, and smoking status (Hurley et al 2024). Additionally, one must also account for estimated benefit versus costs, estimated recovery time, the patient’s sport or activity, competition schedule, social determinants of health and correct post-interventional rehab that can affect the patient’s ability to properly recover.

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References

Moreno-Garcia A, Rodriguez-Merchan EC. Orthobiologics: Current role in Orthopedic Surgery and Traumatology. Arch Bone Jt Surg. 2022 Jul;10(7):536-542. doi: 10.22038/ABJS.2021.52770.2614. PMID: 36032640; PMCID: PMC9382248.

Rosen J, Niazi F, Dysart S. Cost-effectiveness of treating early to moderate stage knee osteoarthritis with intra-articular hyaluronic acid compared to conservative interventions. Adv Ther . 2019.

Turajane T, Chaveewanakorn U, Fongsarun W, Aojanepong J, Papadopoulos K.I. Avoidance of total knee arthroplasty in early osteoarthritis of the knee with intra-articular implantation of autologous activated peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial with differential effects of growth factor addition. Stem Cells Int . 2017;2017:8925132.

Malhotra R, Kumar V, Garg B, Singh R, Jain V, Coshic P, et al. Role of autologous platelet-rich plasma in treatment of long-bone nonunions: a prospective study. Musculoskelet Surg. 2015;99(3)::243–8.

Schottel PC, Warner SJ. Role of bone marrow aspirate in orthopedic trauma. Orthop Clin North Am . 2017;48(3)::311–21.

Izadpanah R, Scha¨chtele DJ, Pfnu¨r AB, et al. The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleotropic beneficial and adverse clinical effects. Am J Physiol Cell Physiol 2015;309(8): C522–31.

Stephenson A.L, Wu W, Cortes D, Rochon P.A. Tendon injury and fluoroquinolone use: a systematic review. Drug Saf . 2013;36(9):709–721. doi: 10.1007/s40264-013-0089-8.

Varghese J, Griffin M, Mosahebi A, Butler P. Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Res Ther . 2017;8(1):45. doi: 10.1186/s13287-017-0483-8.

Choudhery M.S, Badowski M, Muise A, Pierce J, Harris D.T. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. J Transl Med . 2014;12:8. doi: 10.1186/1479-5876-12-8.

Jurgens W.J.F.M, Oedayrajsingh-Varma M.J, Helder M.N, et al. Effect of tissue-harvesting site on yield of stem cells derived from adipose tissue: implications for cell-based therapies. Cell Tissue Res . 2008;332(3):415–426. doi: 10.1007/s00441-007-0555-7.

Iyyanki T, Hubenak J, Liu J, Chang E.I, Beahm E.K, Zhang Q. Harvesting technique affects adipose-derived stem cell yield. Aesthetic Surg J . 2015;35(4):467. doi: 10.1093/ASJ/SJU055.

Schipper B.M, Marra K.G, Zhang W, Donnenberg A.D, Rubin J.P. Regional anatomic and age effects on cell function of human adipose-derived stem cells. In:. Annals of Plastic Surgery . Vol 60. 2008:538–544. doi: 10.1097/SAP.0b013e3181723bbe.

Altman R.D, Bedi A, Karlsson J, Sancheti P, Schemitsch E. Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee. Am J Sports Med . 2016;44(8):2158–2165.

Vincent P. Intra-articular hyaluronic acid in the symptomatic treatment of knee osteoarthritis: a meta-analysis of single-injection products. Curr Ther Res Clin Exp . 2019;90:39–51.

Belk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC, Frank RM, Kraeutler MJ. Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy. 2023 Jul;39(7):1714-1734. doi: 10.1016/j.arthro.2023.03.001. Epub 2023 Mar 11. PMID: 36913992.

Pabinger C, Lothaller H, Kobinia GS. Intra-articular injection of bone marrow aspirate concentrate (mesenchymal stem cells) in KL grade III and IV knee osteoarthritis: 4 year results of 37 knees. Sci Rep. 2024 Feb 1;14(1):2665. doi: 10.1038/s41598-024-51410-2. PMID: 38302491; PMCID: PMC10834500.

Lana JF, Weglein A, Sampson SE, Vicente EF, Huber SC, Souza CV, Ambach MA, Vincent H, Urban-Paffaro A, Onodera CM, Annichino-Bizzacchi JM, Santana MH, Belangero WD. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med. 2016 Nov 29;12(2):69-78. doi: 10.46582/jsrm.1202011. PMID: 28096631; PMCID: PMC5227106.

Chen SH, Kuan TS, Kao MJ, Wu WT, Chou LW. Clinical effectiveness in severe knee osteoarthritis after intra-articular platelet-rich plasma therapy in association with hyaluronic acid injection: three case reports. Clin Interv Aging. 2016 Sep 8;11:1213-1219. doi: 10.2147/CIA.S114795. PMID: 27660427; PMCID: PMC5019165.

Sun C, Cao C, Zhao T, Guo H, Fleming BC, Owens B, Beveridge J, McAllister S, Wei L. A2M inhibits inflammatory mediators of chondrocytes by blocking IL-1β/NF-κB pathway. J Orthop Res. 2023 Jan;41(1):241-248. doi: 10.1002/jor.25348. Epub 2022 May 4. PMID: 35451533.

Tortorella M.D, Arner E.C, Hills R, et al. α2-Macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes.  J Biol Chem . 2004;279(17):17554–17561. doi: 10.1074/jbc.m313041200.

Luan Y, Kong L, Howell DR, Ilalov K, Fajardo M, Bai XH, Di Cesare PE, Goldring MB, Abramson SB, Liu CJ. Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. Osteoarthritis Cartilage. 2008 Nov;16(11):1413-20. doi: 10.1016/j.joca.2008.03.017. Epub 2008 May 15. PMID: 18485748; PMCID: PMC2574789.

Armstrong PB, Quigley JP. Alpha2-Macroglobulin: An Evolutionarily Conserved Arm of the Innate Immune System. Dev Comp Immunol (1999) 23:375–90. doi: 10.1016/s0145-305x(99)00018-x

Wang S, Wei X, Zhou J, Zhang J, Li K, Chen Q, Terek R, Fleming BC, Goldring MB, Ehrlich MG, Zhang G, Wei L. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014 Jul;66(7):1843-53. doi: 10.1002/art.38576. PMID: 24578232; PMCID: PMC4187342.

Hurley ET, Sherman SL, Stokes DJ, Rodeo SA, Shapiro SA, Mautner K, Buford DA, Dragoo JL, Mandelbaum BR, Zaslav KR, Cole BJ, Frank RM; Members of the Biologics Association. Experts Achieve Consensus on a Majority of Statements Regarding Platelet-Rich Plasma Treatments for Treatment of Musculoskeletal Pathology. Arthroscopy. 2024 Feb;40(2):470-477.e1. doi: 10.1016/j.arthro.2023.08.020. Epub 2023 Aug 23. PMID: 37625660.