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12 Articles in Volume 18, Issue #4
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention
Assessment of Patients with Rheumatoid Arthritis or Osteoarthritis
Biosimilars in Rheumatology: How Popular Will They Be?
Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis
Commentary: Make the Easy Choice for Care
Editorial: The Emergence of Trackable Pill Technology: Hype or Hope?
Editorial: The Practicality of Pain Acceptance
How to Avert Government Scrutiny When Prescribing Opioids
Letters to the Editor: DEA and Prescribing, the War on Statistics, Failing Treatments, Patients' Options
Meet the Migraine Game-Changers
Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain
With concerns over opioids, could novel receptors be useful?

Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis

The authors discuss patient outcome and pain relief after administering orthobiologic treatments using platelet-rich plasma and bone marrow aspirate concentrate.

Case #1: Advanced Tendinopathic Disease

A 29-year-old male recreational soccer player who still enjoys regular participation in league play, presents with progressive right knee pain for several years. The pain is anterior, worse with descending stairs and with running when accelerating. There is no history of significant injury. He participated in two physical therapy programs over the prior three years, as well as various courses of anti-inflammatories. At the time, each would provide modest relief and allow him to continue playing. However, symptoms have progressed to the point of preventing active participation. He now reports pain with daily activities, such as stair climbing, which can “make him wince.” He avoids long walks and deep bending. He rates his pain as high as 7/10 on the visual analog scale.

Physical examination demonstrated a well-developed, healthy male who entered the examination room without antalgic gait. On examination, the right knee was without effusion. Range of motion was full. There is no significant medial or lateral joint line tenderness, and ligamentous testing was stable in the anterior, posterior, and lateral planes. There was mild crepitus with knee extension. There was pain with resisted knee extension, but not flexion. Palpation at the inferior pole of the patella extending into the first 2 cm of the patella tendon reproduced his pain. There is mild local soft-tissue edema.

A musculoskeletal ultrasound evaluation was performed. The ultrasound images shown in Figures 1 and 2 demonstrate advanced tendinopathic disease. Note the considerable thickening, diffuse hypoechoic change, and central anechoic lesions signifying intrasubstance tearing.

Figure 1: Pre-treatment, Case #1: long and short axis views of the patella tendon demonstrating significant thickening, diffuse hypoechoic changes, and anechoic areas consistent with intrasubstance tearing.

Figure 2: Pre-treatment, Case #1: long and short axis views of the patella tendon demonstrating significant thickening, diffuse hypoechoic changes, and anechoic areas consistent with intrasubstance tearing.

As the patient had already engaged in two bouts of physical therapy, the last including an attempt at eccentric exercise, he presented to our facility to discuss available options. He had investigated platelet-rich plasma (PRP) and was rather well read on that treatment modality. He was not interested in a surgical consultation.

Tendinopathy Pathophysiology& Changing Treatment Paradigms

The term tendinitis denotes inflammation of a tendon, most commonly from overuse but also from infection or rheumatic disease. It was as early as 1976 that Paddu et al. recognized a lack of inflammatory cells, bringing into question inflammation as the underlying pathology of chronic tendon pain.1 Evidence mounted until the early 1990s when an editorial by Khan et al. pronounced it is time “to accept the irrefutable evidence that the term tendinitis must be abandoned to highlight a new perspective on tendon disorders."2 This tipping-point drove clinicians and therapists into a new era of thinking about the structural forces and mal-adaptations that lead to what is now properly termed tendinosis. Various pathologic theories arose including angiogenic, neural, biochemical, and structural alterations that led to new treatments aimed at these theoretical models, such as eccentric strengthening, sclerosing agents, blood products, and extra-corporeal shockwave therapy.3

Each of the treatments has demonstrated various levels of success without any option rising to clear superiority. The current models of pain generation in tendinosis accept contribution from all of these mechanisms, without favoring either as the priority pain generator. Recent publications have cited central sensitization as playing a role in recalcitrant tendinopathies.4

Phases of Healing

The healing cascade in tendon injury and repair has been well described and will be briefly summarized. There are three phases which overlap and are not independent of each other, not including hemostasis which occurs in the first few minutes after injury, and whose purpose is platelet aggregation, coagulation, and fibrin plug formation to stop bleeding.

The inflammatory phase typically spans the first one to three days. Inflammation is heralded by the presence of large quantities of red and white blood cells. Platelets are emptying alpha and dense granules, dispersing cytokines and growth factors. Macrophages are activated and digest necrotic debris, while tenocytes migrate and begin replication.

The second stage is the proliferative or repair stage, beginning roughly 48 to 72 hours after injury. Macrophages shift from catabolic or phagocytic to anabolic or reparative functions. Tenocytes attempt to provide early structural support and deposit a temporary, mechanically inferior matrix composed mostly of collagen III.5,6

Remodeling begins 30 to 60 days after injury and can last up to one year before tissue is matured. However, it is important to know that the original structure, metabolic, and biomechanical qualities may never be fully restored. Tendon modulus of elasticity and tensile strength are diminished, and an increased mechanical stiffness often remains. Both the extracellular matrix and native cellular metabolism may be decreased compared to the uninjured state. Compounded, these characteristics increase the chance of ultimate tendon failure.6,7

Considerations in PRP

As mentioned, platelets are known to contain alpha and dense granules, which release multiple growth factors and cytokines that promote wound healing. Authors of in vitro studies have reported an enhancement of the recruitment, proliferation, and differentiation of the cells involved in soft-tissue regeneration. When injecting platelet-rich plasma (PRP), most clinicians also fenestrate the tendon. The local trauma promotes bleeding and release of collagen fragments. Collagen is a potent platelet activator, and when the PRP is introduced, the concentrated platelets are activated and immediately release their growth factors and chemokines. This converts a stagnant, non-healing state in an active inflammatory environment with a renewed healing potential.8-10

Platelet-rich plasma is safe, accessible, and has limited downtime. A 2013 meta-analysis by Mautner et al. concluded most patients reported a moderate (ie, 50%) improvement in pain symptoms.11 Prior to the rise of PRP utilization, surgery had been considered the final option for recalcitrant tendinopathies despite highly variable clinical outcomes – satisfaction estimated at approximately 80% depending on the type of tendon surgery.12,13 An updated meta-analysis of randomized controlled trials by Fitzpatrick et al. concluded “there is good evidence to support the use of a single injection of LR-PRP [leukocyte-rich platelet-rich plasma] under ultrasound guidance in tendinopathy. The authors also noted that “both the preparation and intra-tendinous injection technique of PRP appear to be of great clinical significance."14

Treatment Impact

In this case, due to the size of the lesion, ultrasound-guided percutaneous tenotomy was introduced as the initial step in treatment (TenJet, HydroCision, North Billerica, MA). The rationale was to debride tendinopathic tissue, allow the natural healing response to begin, and then stimulate with regenerative therapy. There are currently no studies using these techniques in succession, however the authors’ experience has found this to be more effective when faced with advanced pathology.

Following the tenotomy, the extremity was protected with partial weight-bearing in a double hinge brace locked out at 30 degrees for the first week, and at 45 degrees for the second week. Two weeks post-tenotomy, the lesion was infiltrated with a total of 4 mL of leukocyte-rich PRP obtained in a single spin method. A rehabilitative protocol was initiated. At week four post-PRP, the patient reported 60% reduction in pain, and a notable improvement in ease of descending stairs. Improvement continued, and at 10 weeks, he was running with little discomfort. See Figures 3 and 4.

Figure 3: Post-treatment, Case #1: The tendon remains thickened, but internal architecture is improved with better fibrillar arrangement and partial filling of the anoechoic regions.

Figure 4: Post-treatment, Case #1: The tendon remains thickened, but internal architecture is improved with better fibrillar arrangement and partial filling of the anoechoic regions.

It has been nearly two decades since the shift in the diagnosis and treatment of tendon disorders. Histologic studies demonstrated chronically painful tendons lacked a presence of active inflammatory cells. Rather, tendon architecture itself had changed with ingrowth of vessels, disorganized collagen, mucoid deposition and ingrowth of small nerve fibers. Treatments have slowly transitioned from treating inflammation (eg, ice, anti-inflammatories, corticosteroids) toward improving the actual tendon architecture. PRP was first revealed as an effective treatment option through the landmark publication of Mishra and Pavelko in 2006.15 Since then, validation of PRP as an effective treatment has admittedly been slow, and utilization is outpacing the science. Although several negative studies for PRP have been published, the research has been bogged down by extreme variation in characterization of PRP, post-treatment protocols, and needling techniques, among others. Several attempts have been made to better describe PRP for research purposes. Organized efforts at biologic registries are underway. Despite this, there is much work to be done.

Case # 2: Lateral Osteoarthritis of the Knee

A 69-year-old otherwise healthy female presents with left knee pain. Pain is lateral with radiation into the calf. Her pain is worse with climbing stairs, and after long walks. There are no mechanical symptoms of catching or locking. Radiographs by her primary care physician were described as mild arthritis, and she was treated with oral anti-inflammatories without sufficient benefit. A corticosteroid injection provided three weeks of symptom improvement, but pain returned to baseline. She preferred not to attend physical therapy. Her primary care physician referred her for total knee arthroplasty (TKA) and she had a consultation. She then presented to our clinic to discuss biologic cellular therapy.

MSC as a New Treatment Modality

The need for TKA is expected to rise 600% by 2030 due to the aging demographic,16 and it is estimated that 20% of patients are not satisfied with the result of their surgery.17 Increasingly, patients are seeking nonsurgical options, and this demand is likely to grow in accordance with the prevalence of osteoarthritis (OA). Mesenchymal stem cell (MSC) therapy has largely been associated with repair of focal cartilage defects, but in the past decade has gained recognition as a potential treatment for generalized osteoarthritis of the knee. High-level studies are lacking to support its efficacy, but large case series and registry data are reporting favorable outcomes. As more patients seek advice and insight on this mode of treatment, it may be crucial for practitioners to unify the message and point out several important misperceptions about this therapy.

First, and perhaps most important, MSC therapy does not regenerate hyaline cartilage to a measurable degree. This misperception is perhaps the most common among patients seeking this modality. There are multiple biologic mechanisms that result in decreased pain, enhanced function, and improved joint homeostasis that are beyond the scope of this paper. Arnold Caplan, the scientist credited with discovering and ascribing the mesenchymal stem cell nomenclature, originally suggested that MSCs progressed through a lineage of differentiation into their terminal cell lines; including osteocyte, chondrocyte, adipocyte, etc.18 He has since rebranded MSC, imploring that it now be called a “medicinal signaling cell,” as its potent biologic activity results in immunologic modification and autocrine and paracrine signaling to induce the regenerative environment.19 Thus, the outcome of bone marrow-derived cellular therapy is not cartilage restoration through stem cell proliferation as the transplanted cells do not themselves measurably replicate. As potent modulators of signaling pathways, Loniewsky better described MSCs as the “conductors, not the carpenters” of the repair process.20

It is worth mentioning a rapidly growing interest in amniotic fluid and amniotic membrane derived therapies. While these products are rich in growth factors and cytokines, the sterilization and packaging process yields few if any living cells capable of regeneration in culture. There is no data yet to support the use of these products in osteoarthritis. Patients seeking amniotic products as a “stem cell” treatment would benefit from even this brief clarification, so they can be fully informed consumers of their healthcare.

Next, clinicians may remind patients that disease severity on radiographs do not always correlate with pain. As pain practitioners know, pain experienced with OA is not directly related to the quantity or quality of hyaline cartilage.21,22 When evaluating for knee OA, it is imperative to have standing radiographs to properly evaluate the joint space. A routine series may include at a minimum: standing anteroposterior (AP), posteroanterior (PA) 45-degree bent-knee, and lateral views.23 Sunrise or merchant views are optional as some feel the patellofemoral space can be adequately assessed in the lateral view.

The radiographs demonstrated in Figure 5 show the initial AP film read on the patient; the imaging could be interpreted as minimal degenerative change. Figure 6 shows the PA 45-degree bent-knee view in the same patient, underscoring the importance of obtaining the complete radiographic series to properly evaluate joint space. The 45-degree bent knee view brings the posterior weight-bearing surface of the condyles into view.24

Figure 5: Case #2: Anteroposterior weight bearing radiograph demonstrating minimal degenerative changes.

Figure 6: Case #2: The postanterior bent-knee view in the same patient reveals complete lateral compartment collapse.

Treatment Impact

In this case, the patient was treated with a single injection of bone marrow aspirate concentrate, prepared by the Emcyte Pure BMC system yielding 7 mL concentrated product (EmCyte Corporation, Fort Meyers, FL). Injection was followed by intra-articular injection of 7 mL of leukocyte-poor PRP one month later. Six months following the initial treatment, the patient’s reported Knee injury and Osteoarthritis Outcome Score subscales had each improved by a factor of three times the minimal clinically significant difference.25 One year following initial treatment, she remains clinically satisfied and is considering a PRP booster in three months. Repeat radiographs are not indicated. However, benchmarking this outcome remains elusive. The largest database reporting clinical outcomes is published by Centeno et al. and suggests that 76% of patients report greater than 50% improvement at 36 months.26

Conclusion

Orthobiologic therapy, admittedly, will need to continue to build upon research and clinical experience to realize the optimum preparations, therapeutic techniques, and patient selection. Meanwhile, the potential to truly heal tissue in novel ways, along with a favorable risk-benefit ratio of platelet-rich plasma and bone marrow aspirate preparations, remains a promising option. Serious adverse events are very rare with this therapy.27 The side effect profile has, for the most part, been limited to pain during infiltration due to volume expansion or the pH of the preparation. Infection has not been reported as the preparations themselves are potently antimicrobial. Costs may be variable and remain a primary impediment for patients seeking this therapy as it remains in the retail space and is not yet covered by most third-party payers.

Last updated on: April 12, 2019
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