Over the past 10 years, the field of Orthobiologics has grown rapidly and started to establish a foundation as a potentially safe and efficacious alternative for a variety of musculoskeletal injuries, including joint disorders such as osteoarthritis and chronic tendinopathy. With life expectancy on the rise, and an aging population of baby boomers, the demand for viable minimally invasive options is at an all-time high. The increased demand has led to scores of physicians attempting to integrate regenerative options into their practices. However, as the exponential growth of orthobiologics continues to skyrocket, coordinated research efforts haven’t been able to match the same trajectory, resulting in a paucity of high level of evidence studies. As the volume of physicians utilizing orthobiologics continues to rise, we have a duty as innovators in the field to strive for cohesiveness and standardization to provide the highest level of safety and therapeutic efficacy for patients. In order to satisfy this responsibility and progress the field of orthobiologics, it is important to establish a common definition and understanding of current orthobiologic options, as well as improve access to continuing education and facilitate research collaboration throughout the global medical community.

Orthobiologic treatments, as they pertain to the musculoskeletal field, are defined as any treatment modality that harnesses the healing potential within the body’s native cells, redirecting their use for accelerated healing in damaged or diseased tissues [1]. Most commonly, they are utilized as an injectable treatment for joints, tendons, or ligaments. Most orthobiologic injections are performed under image guidance, with either musculoskeletal ultrasound or fluoroscopic guidance [2]. However, arthroscopy may also be utilized to provide high-definition color visualization for accurate cellular deployment. Since the birth of the term, the field has continued to expand underneath this umbrella term; however the core of orthobiologic treatments can be classified by four generations: hyaluronic acid (HA), platelet-rich plasma (PRP), bone marrow concentrate (BMC), and adipose-derived tissue or lipoaspirate.

The first generation of orthobiologics is considered to be hyaluronic acid (HA), which has been used as an intra-articular lubricant to treat osteoarthritis since the late 1990s. Hyaluronic acid is a naturally occurring protein present in synovial fluid, which helps to decrease frictional forces within synovial joints [3]. Although HA is native to intra-articular synovial fluid, the injectable version does not currently exist in autologous form, and specific formulations can differ depending on manufacturer and production technique. HA has been shown to reduce painful symptoms of osteoarthritis and provided a superior safety profile when compared to continuous NSAID use for pain control [4–6]. It has also been shown to lengthen the time from diagnosis of OA to time of knee arthroplasty in Medicare (generally senior) patients [7]. Recent OARSI guidelines for the treatment of osteoarthritis suggest “good” level of evidence for the treatment of OA with intra-articular hyaluronic acid [8].

The second generation of orthobiologics, platelet-rich plasma, was the first autologous orthobiologic. Although platelet-rich plasma (PRP) didn’t appear in the sports medicine literature until 2006, it was first used by Ferrari et al. in 1987 following open-heart surgery [9] and has been used in many other medical fields including ENT, maxillofacial surgery, ophthalmology, urology, dentistry, cosmetic and neurosurgery, and wound healing for quite some time. Theoretically, the potent concentration of platelets are injected into soft tissue or intra-articularly to stimulate a supraphysiologic inflammatory response, as they are comprised of an undifferentiated cocktail of anti-inflammatory, pro-inflammatory, anabolic, and catabolic mediators in an attempt to elicit the body’s natural healing response. Platelet-rich plasma is created from a patient’s venous blood. Blood is drawn from a patient’s vein, spun in a centrifuge, and the buffy coat, which contains the highest concentration of platelets, [10] is extracted, and used as an injectable treatment.

To date, most of the literature on PRP consists of small case series; however, larger randomized controlled trials have demonstrated superior efficacy in areas such as chronic tendinopathies [11, 12] and knee osteoarthritis [13]. Research has also been published, suggesting therapeutic benefits of combining orthobiologic treatments [14], or utilizing multiple orthobiologics in a specific sequence or treatment protocol for musculoskeletal disorders [15]. Furthermore, protocols have been established for post-PRP recovery and rehabilitative exercises providing a preliminary framework for doctors and therapists to provide optimal treatment for return to sport [16].

Many researchers also emphasize that not all PRP is created equally. Currently, there are multiple cellular processing techniques for extracting PRP. Some practitioners utilize standardized PRP processing kits, which widely differ by manufacturer in regard to cellular composition and delivery methods. While, other practitioners perform more individualized techniques, utilizing single and double-spin centrifugation cycles and more precise laboratory procedure [16]. As of late, more clinicians are utilizing point of care cellular cytometry to analyze blood products and establish more cellular standardization of injectable PRP. In an attempt to facilitate uniform PRP classification, researchers have established the PLRA PRP classification, which classifies PRP based on the concentration of platelets, leukocyte concentration, red blood cells, and activation technique [17]. Routine classification usage will lead to more customized PRP formulations to maximize therapeutic efficacy for specific musculoskeletal disorders and aide when interpreting clinical trials. Initial research suggests that leukocyte-poor PRP may have stronger efficacy with intra-articular application [18, 19]. As research continues to expand in the area of PRP, the newest generations of orthobiologics are also beginning to establish a therapeutic framework.

Bone marrow concentrate (BMC) is considered the third generation of orthobiologic treatment. It has a potent mixture of mesenchymal stem cells (MSCs), hematopoetic cells, platelets, and cytokines noted for possessing anti-inflammatory, immunomodulatory, and chondrogenic properties, which act as the foundation for its regenerative potential [20]. Although the exact mechanism is unknown, it is hypothesized that the bone marrow concentrate milieu either induces differentiation and proliferation of resident stem cells or possesses innate chondrogenic potential [20]. Bone marrow is most commonly aspirated from the posterior iliac crest, utilizing ultrasound or fluoroscopic guidance. The bone marrow aspirate undergoes cellular processing via similar mechanisms as platelet-rich plasma. Physicians currently have multiple options for marrow concentration, either via standardized manufacturer kits or individualized laboratory techniques. Similar to PRP, the wide variability with bone marrow aspiration and concentration among physicians has added to the ambiguity with standardized treatments and research efforts. As one of the newer generations of orthobiologics, BMC has a paucity of high-level studies or randomized trials; however, early research has demonstrated significant patient safety and therapeutic efficacy with joint osteoarthritis [15, 20–23]. Select practitioners have started to utilize cell cytometry with BMC procedures, similar to the PLRA PRP classification; however no standardized classification exists currently.

As the field of orthobiologics continues to develop, research efforts continue to refine our scientific understanding, opening possibilities for future generations. Recent literature has suggested a perivascular origin of MSCs, in the form of pericytes [24], which has led to exploration of other autologous sources of mesenchymal stem cells, including the most recent fourth generation of orthobiologics: lipoaspirate/adipose-derived mesenchymal stem cells (or now termed “medicinal signaling cells”). Compared with BMC, processed lipoaspirate/adipose-derived MSCs (ADMSCs) has advantages in that it is procured in much larger quantities, and with less invasive techniques under local anesthesia and vacuum-assisted lipectomy. Similar to BMC, processed lipoaspirate has exhibited differentiation into chondrogenic, osteogenic, adipogenic, myogenic, and neurogenic lineages in the presence of lineage-specific induction factors [25, 26]. Although some research has illustrated that ADMSCs actually possess larger numbers of MSCs [24], data is mixed as to whether ADMSCs have equal osteogenic potential as BMC [27, 28]. Furthermore, preliminary research suggests that ADMSCs also exhibit an anti-inflammatory effect on chrondrocytes and synoviocytes in patients with osteoarthritis [29].

In addition, an emerging new allogenic orthobiologic option, amniotic tissue, has also been shown to be a source of MSCs [30, 31]. However, it has not been shown to possess the same resident cell volume as BMC and ADMSCs [24]. Few human trials exist for human amniotic membrane applications, but small case studies have shown efficacy for elbow tendinopathy [32] and plantar fasciitis [33], while preliminary animal studies have suggested potentially positive applications for tendon injuries [34] and osteoarthritis [35]. To date, this source of MSCs is the most under researched and one of the newest on the horizon.