Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren–Lawrence II–IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects, and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols.

Autologous biologics, defined as platelet-rich plasma (PRP)and bone marrow aspirate concentrate (BMC), are cell-based therapy treatment options in regenerative medicine practices, and have been increasingly used in orthopedics, sports medicine, and spinal disorders. These biological products are produced at point-of-care; thereby, avoiding expensive and cumbersome culturing and expansion techniques. Numerous commercial PRP and BMC systems are available but reports and knowledge of bio-cellular formulations produced by these systems are limited. This limited information hinders evaluating clinical and research outcomes and thus making conclusions about their biological effectiveness. Some of their important cellular and protein properties have not been characterized, which is critical for understanding the mechanisms of actions involved in tissue regenerative processes. The presence and role of red blood cells (RBCs)in any biologic has not been addressed extensively. Furthermore, some of the pathophysiological effects and phenomena related to RBCs have not been studied. A lack of a complete understanding of all of the biological components and their functional consequences hampers the development of clinical standards for any biological preparation. This paper aims to review the clinical implications and pathophysiological effects of RBCs in PRP and BMC; emphasizes hemolysis, eryptosis, and the release of macrophage inhibitory factor; and explains several effects on the microenvironment, such as inflammation, oxidative stress, vasoconstriction, and impaired cell metabolism.

Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This study aimed to determine whether autologous orthobiologic tissue source affects pain and functional outcomes in patients with symptomatic knee osteoarthritis (OA) who received microfragmented adipose tissue (MFAT) or bone marrow aspirate concentrate (BMAC) injection. We retrospectively reviewed prospectively collected data from patients who received BMAC or MFAT injection for symptomatic knee OA. Patients completed baseline and follow-up surveys. Each survey included the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, Emory Quality of Life (EQOL) questionnaire, and Visual Analog Scale (VAS) for pain. The follow-up responses were compared with baseline for all patients and between BMAC and MFAT groups. A total of 110 patients met inclusion criteria, with 76 patients (BMAC 41, MFAT 35) and 106 knees (BMAC 58, MFAT 48) having appropriate follow-up data. The BMAC group included 17 females and 24 males, with a mean age of 59 ± 11 years. The MFAT group included 23 females and 12 males, with a mean age of 63 ± 11 years. Minimum follow-up time was 0.5 years. Mean follow-up time was 1.80 ± 0.88 years for BMAC and 1.09 ± 0.49 years for MFAT. Both groups had significant improvement in EQOL, VAS, and all KOOS parameters preprocedure versus postprocedure (p <.001). There was not a significant difference when comparing postprocedure scores between groups (p =.09,.38,.63,.94,.17,.15,.70, respectively). These data demonstrate significant improvement in pain and function with both MFAT and BMAC injections in patients with symptomatic knee OA without a significant difference in improvement when comparing the two autologous tissue sources. Stem Cells Translational Medicine 2019;8:1149–1156.

Orthobiologics is a subset of regenerative therapies consisting of biologic substances intended to treat or cure musculoskeletal conditions. They have grown in use and popularity, in part due to a growing evidence-base, but also a result of overexuberance related to a novel field. Numerous devices exist that make the minimal manipulation of autologous concentrated blood, bone marrow and fat derived ‘products’ accessible for clinical and surgical use in a manner compliant with many national regulatory frameworks. Except for limited surgical cartilage restoration products, however, the absence of formal regulatory ‘approved’ orthobiologic therapies has led to debate over their utility and subsequent reexamination of the marketing of such products and procedures. The American Medical Society for Sports Medicine has advocated for the responsible translation of orthobiologics into sports medicine practice.1 Their safe and effective use in clinical practice raises important questions including what level of evidence is needed and under what conditions should orthobiologics be offered to patients for their musculoskeletal maladies.

Autologous biological cellular preparations have materialized as a growing area of medical advancement in interventional (orthopedic) practices and surgical interventions to provide an optimal tissue healing environment, particularly in tissues where standard healing is disrupted and repair and ultimately restoration of function is at risk. These cellular therapies are often referred to as orthobiologics and are derived from patient’s own tissues to prepare point of care platelet-rich plasma (PRP), bone marrow concentrate (BMC), and adipose tissue concentrate (ATC). Orthobiological preparations are biological materials comprised of a wide variety of cell populations, cytokines, growth factors, molecules, and signaling cells. They can modulate and influence many other resident cells after they have been administered in specific diseased microenvironments. Jointly, the various orthobiological cell preparations are proficient to counteract persistent inflammation, respond to catabolic reactions, and reinstate tissue homeostasis. Ultimately, precisely delivered orthobiologics with a proper dose and bioformulation will contribute to tissue repair. Progress has been made in understanding orthobiological technologies where the safety and relatively easy manipulation of orthobiological treatment tools has been demonstrated in clinical applications. Although more positive than negative patient outcome results have been registered in the literature, definitive and accepted standards to prepare specific cellular orthobiologics are still lacking. To promote significant and consistent clinical outcomes, we will present a review of methods for implementing dosing strategies, using bioformulations tailored to the pathoanatomic process of the tissue, and adopting variable preparation and injection volume policies. By optimizing the dose and specificity of orthobiologics, local cellular synergistic behavior will increase, potentially leading to better pain killing effects, effective immunomodulation, control of inflammation, and (neo) angiogenesis, ultimately contributing to functionally restored body movement patterns.

The knee joint is one of the most frequently injured joints in the body, and the resulting injury may often lead to the presence of a bloody effusion, or hemarthrosis. The acute management of this condition can have long-lasting implications, and may ultimately result in the early onset of osteoarthritis in this population. Heme, a breakdown product of erythrocytes, and associated pro-inflammatory mediators, are known to have deleterious interactions with cartilage and synovium. The presence of blood in a joint following injury can precipitate these effects and accelerate the degenerative changes in the joint. Currently, there is no consensus on the optimal management of a traumatic knee joint injury with a hemarthrosis. Nontraumatic hemarthosis, seen most commonly in hemophilia patients, has a set of established guidelines that does not routinely recommend drainage of the joint. This article presents a rationale for joint aspiration to minimize the harmful effects of blood following traumatic hemarthrosis.