What are Orthobiologics?

By Chris Centeno, MD /

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what are orthobiologics

You’ve probably seen me use the term “orthobiologics” quite a bit. So what are orthobiologics? Let’s dig in.

Let’s Break Down the Word “Orthobiologics”

To understand orthobiologics, let’s break down the word. The term, “orthobiologics” is a combination of ortho (referring to the bones, joints, muscles, and tendons) and biologics, which in this context means substances that are naturally derived and that can heal orthopedic tissues. It’s important to note that this use of the word “biologics” is different here than it’s used in pharma and in particular rheumatology, where it often refers to prescription drugs that are made by living organisms (recombinant DNA technology) or contain a component of a living organism.

What are Orthobiologics?

Common orthobiologics include platelet-rich plasma, bone marrow concentrate, certain fat grafts, and birth tissues. These are autologous or allogeneic substances that can help bones, joints, muscles, or tendons heal if they are injected or placed surgically. However, to really understand the scope of what’s meant by the term “orthobiologics”, let’s start breaking it all down into categories as these four natural substances are just the tip of the orthobiologics iceberg.

Categories of Orthbiologics

You can break orthobiologics down into two main categories:

  • Where does it come from?
  • What type of tissue is being used and how?

Where Does it Come From?

We have two categories here:

  • Autologous
  • Allogeneic

Autologous means that the orthobiologic comes from the same person in which it’s used. So for example, the doctor may take blood and then make platelet-rich plasma (PRP) and then re-inject that PRP into a damaged tendon in that same patient(1). Allogeneic means that the orthobiologic comes from another patient. For example, a product derived from birth tissues and used in an adult is a type of allogeneic orthobiologic.

What Type of Tissue is Being Used and How?

We can break orthobiologics into major tissue categories:

  • Blood derived
  • Stem cell containing products
  • Extra-cellular matrix
  • Conditioned media

In the blood-derived category, we have orthobiologics like a platelet-rich plasma which is made from concentrated platelets taken from the patients own blood. These platelets produce growth factors that can assist in healing. Also in this category would be serums and plasmas made from blood. For example, platelet-poor plasma (PPP) is PRP without many platelets, which also contains different cytokines and growth factors in the plasma which also may aid healing. For example, PPP has been shown to help muscles heal (2). Another orthobiologic here would be PPP with a specific cytokine that’s concentrated, like A2M. This is a large molecule found in the blood that is believed to inhibit cartilage breakdown (3).

Stem cell containing orthobiologics are those that likely work through their stem cell content. For example, Bone Marrow Concentrate is produced from bone marrow aspirate taken from the back of a patient’s pelvis. This is then centrifuged so that the stem cell fraction is concentrated (4). There’s a body of research that shows that BMC (also known as BMAC or Bone Marrow Aspirate Concentrate) works better if it has a higher stem cell content (5). Also in this category would be orthobiologics that have stem cells derived from another person (allogeneic). These would include isolating and culturing stem cells from bone marrow, fat, or birth tissues, which is not permitted in the United States at this time (6).

Extra-cellar matrices or ECMs are orthobiologics that can act as a scaffold. This means that they can fill voids in torn tissue so that cells can grow across that area. These can help because cells usually need something to grow on as they do their repair work. In addition, many ECM orthobiologics also contain growth factors which act like espresso shots for repair cells, meaning that these chemicals can make cells work harder. Examples of ECM orthobiologics include fat grafts like the popular “Lipogems” (7) or birth tissues derived from amniotic (8) or umbilical cords (9). Other examples include products like demineralized bone matrix (DBM), which is cadaver bone that has had the calcium removed and is often placed through injection or surgically into a non-healing fracture where there is a larger gap (10). Finally, some ECM orthobiologics are derived from animals. For example, pig bladder can be used to help your tendons or muscles heal (11).

You may be surprised that birth tissue products derived from umbilical cords aren’t in the “stem cell” orthobiologics category. Regrettably, despite what is often sold at seminars all over the U.S. promising that these tissues have millions of young and vital stem cells, multiple research studies have shown the opposite: these are dead cell products with NO live or functional stem cells (12-14). However, they do have some growth factors and as such may help tissue that way.

Finally, the “conditioned media” category of orthobiologics includes products currently being marketed as “exosomes”. These are tiny packets of cell to cell instructions which are usually purified from the media in which stem cells are grown in culture (12). They can have their own tissue repair effects, but since this product generally relies on tissue culture, these are not yet legal to use in the United States at this time (despite many companies floating the regulatory risk and marketing them illegally).

Examples of Orthobiologics

Here are some common examples of orthobiologics in daily medical practice:

  • You have a partial rotator cuff tear that doesn’t heal with physical therapy. The doctor takes blood and creates PRP which is precisely injected into the tear areas using ultrasound guidance.
  • You get into a car crash and injure the neck joints *facets” that won’t heal on their own. The doctor performs a bone marrow aspirate from the back of your pelvis and concentrates the stem cells to produce BMC and injects this using x-ray guidance into your damaged facet joints to assist in the healing of the cartilage.
  • You have a massive rotator cuff tear that needs surgery, so the doctor surgically implants an ECM orthobiologic which is a patch derived from an animal bladder to help the tendon heal.

The Promise of Orthobiologics

As orthobiologics get more sophisticated, it’s likely that we’ll see more invasive orthopedic surgeries move to less invasive injections. Why? Because when we have substances that can heal, less invasive injections can be used to place those substances into damaged tissue without surgery. This type of approach is often called “Interventional Orthobiologics” or “Interventional Orthopedics”.

Are Orthobiologics Covered by Insurance?

While a handful of orthobiologics can get insurance coverage as part of more invasive surgery, the less invasive orthobiologic injections to help tissue heal without surgery tend to still lack insurance coverage. In addition, most orthobiologics used in surgery are usually billed to the patient directly. One exception is Regenexx, who is a medical group that has been able to get a growing number of self-insured companies cover many orthobiologic injections.

The upshot? Orthobiologics are revolutionizing orthopedic care now. Despite this, many patients don’t realize that these substances exist and can help them recover from orthopedic injuries, often without surgery.

_________________________________________

References:

(1) Brossi PM, Moreira JJ, Machado TS, Baccarin RY. Platelet-rich plasma in orthopedic therapy: a comparative systematic review of clinical and experimental data in equine and human musculoskeletal lesions. BMC Vet Res. 2015;11:98. Published 2015 Apr 22. doi:10.1186/s12917-015-0403-z

(2) Dragoo JL. The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts: Implications for the Use of Autologous Blood Products for Muscle Regeneration. Orthop J Sports Med. 2016;4(7 suppl4):2325967116S00150. Published 2016 Jul 29. doi:10.1177/2325967116S00150

(3) Zhang Y, Wei X, Browning S, Scuderi G, Hanna LS, Wei L. Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection. Arthritis Res Ther. 2017;19(1):175. Published 2017 Jul 25. doi:10.1186/s13075-017-1363-4

(4) Gianakos AL, Sun L, Patel JN, Adams DM, Liporace FA. Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. World J Orthop. 2017;8(6):491–506. Published 2017 Jun 18. doi:10.5312/wjo.v8.i6.491

(5) Harrell DB, Caradonna E, Mazzucco L, et al. Non-Hematopoietic Essential Functions of Bone Marrow Cells: A Review of Scientific and Clinical Literature and Rationale for Treating Bone Defects. Orthop Rev (Pavia). 2015;7(4):5691. Published 2015 Dec 28. doi:10.4081/or.2015.5691

(6) Berebichez-Fridman R, Gómez-García R, Granados-Montiel J, et al. The Holy Grail of Orthopedic Surgery: Mesenchymal Stem Cells-Their Current Uses and Potential Applications. Stem Cells Int. 2017;2017:2638305. doi:10.1155/2017/2638305

(7) Russo A, Condello V, Madonna V, Guerriero M, Zorzi C. Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J Exp Orthop. 2017;4(1):33. Published 2017 Oct 3. doi:10.1186/s40634-017-0108-2

(8) Woodall BM, Elena N, Gamboa JT, et al. Anterior Cruciate Ligament Reconstruction With Amnion Biological Augmentation. Arthrosc Tech. 2018;7(4):e355–e360. Published 2018 Mar 19. doi:10.1016/j.eats.2017.10.002

(9) Jadalannagari S, Converse G, McFall C, et al. Decellularized Wharton’s Jelly from human umbilical cord as a novel 3D scaffolding material for tissue engineering applications [published correction appears in PLoS One. 2017 Mar 7;12 (3):e0173827]. PLoS One. 2017;12(2):e0172098. Published 2017 Feb 21. doi:10.1371/journal.pone.0172098

(10) Drosos GI, Touzopoulos P, Ververidis A, Tilkeridis K, Kazakos K. Use of demineralized bone matrix in the extremities. World J Orthop. 2015;6(2):269–277. Published 2015 Mar 18. doi:10.5312/wjo.v6.i2.269

(11) Sicari BM, Rubin JP, Dearth CL, et al. An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss. Sci Transl Med. 2014;6(234):234ra58. doi:10.1126/scitranslmed.3008085

(12) Burke J, Kolhe R, Hunter M, Isales C, Hamrick M, Fulzele S. Stem Cell-Derived Exosomes: A Potential Alternative Therapeutic Agent in Orthopaedics. Stem Cells Int. 2016;2016:5802529. doi:10.1155/2016/5802529

(13) Dustin R. Berger, Nicolette F. Lyons, and Neven J. Steinmetz. In Vitro Evaluation of Injectable, Placental Tissue-Derived Products for Interventional Orthopedics. Interventional Orthopedics Foundation Annual Meeting. Denver, 2015. https://interventionalorthopedics.org/wp-content/uploads/2017/08/AmnioProducts-Poster.pdf

(14) Liliya Becktell, Andrea Matuska, PhD, Stephanie Hon, DVM, Michelle L. Delco, DVM, PhD, Brian J. Cole, MD, Lisa A. Fortier, DVM, PhD. Proteomic analysis and cell viability of nine amnion-derived biologics. Orthopedic Research Society Annual Meeting, New Orleans, 2018. https://app.box.com/s/vcx7uw17gupg9ki06i57lno1tbjmzwaf

(15) Panero, A. J., Hirahara, A. M., Andersen, W. J., Rothenberg, J., & Fierro, F. (2019). Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine, 47(5), 1230–1235. https://doi.org/10.1177/0363546519829034

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Chris Centeno, MD

Regenexx Founder

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications.
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