11 Clinical Decision Making for Use of Biologics in Orthopaedic Practice

10.1055/b-0035-123582

11 Clinical Decision Making for Use of Biologics in Orthopaedic Practice

James L. Cook and James P. Stannard

11.1 Introduction

The use of biologics in orthopaedic practice is increasing at a tremendous rate. In 2014, estimates for the number of injections of platelet-rich plasma (PRP) topped 250,000, more than 50,000 cell-based orthopaedic treatments were performed, and approximately 1 million bone grafts were used in the United States alone. Orthobiologics are used in operative and nonoperative settings to treat a wide spectrum of pathology across the entire gamut of musculoskeletal tissues. The authors contributing to this book have done an excellent job in providing detailed information regarding the scientific evidence, rationale, regulatory considerations, and clinical applications for many of the major orthobiologics in use. This chapter aims to provide summary recommendations for clinical use of nonoperative biologics across the spectrum of orthopaedic disorders routinely treated. It is critical that the reader understands that our recommendations are solely about practical application of nonoperative orthobiologics once the decision has been made to include them in a comprehensive treatment plan for a given patient. It is beyond the scope of this chapter to discuss the spectrum of potential treatments for a given condition, provide therapeutic algorithms, or include details about regulatory or financial considerations. In addition, these recommendations are based on best current evidence in conjunction with our opinions and experiences.

11.2 Nonoperative Orthobiologics

11.2.1 Osteoarthritis

Currently, the most abundant and clear data regarding use of orthobiologics are for treatment of osteoarthritis (OA). Though some variation in the peer-reviewed literature exists, the preponderance of evidence supports the use of leukocyte-poor platelet-rich plasma (LP-PRP) for intra-articular injection therapy in OA. Systematic reviews, meta-analyses, and level 1 studies report significant benefits for LP-PRP over placebo and over hyaluronic acid injections for patients with moderate to severe OA. ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ ^, ⁷ ^, ⁸ ^, ⁹ ^, ¹⁰ ^, ¹¹ ^, ¹² As reviewed in Chapters s. Kap. and s. Kap., these studies provide evidence for the safety of PRP for intra-articular injection and consistently show a duration for clinical efficacy of at least 6 months.

Though the data are not nearly as extensive or definitive, supporting evidence for the use of autologous-conditioned serum (ACS) for intra-articular injection therapy for OA has been published in the peer-reviewed literature. ¹³ ^, ¹⁴ ^, ¹⁵ These data suggest that ACS is safe and can be effective in reducing pain and improving function in mild to moderate OA (see Chapter s. Kap.). ACS requires an incubation period, so it may not be as convenient or meet regulatory approval as readily as PRP.

Though evidence regarding use of cell-based orthobiologics—such as bone marrow–derived and adipose-derived mesenchymal stem cells (MSCs) and bone marrow aspirate concentrate (BMAC)—for intra-articular injection therapy in OA is growing, current data do not provide strong support for clinical use of any of these treatments for this indication (see Chapters s. Kap. and s. Kap.). Intra-articular injections of MSCs or BMAC have been associated with beneficial anti-inflammatory, analgesic, and immunomodulatory effects in patients with OA. ¹⁶ ^, ¹⁷ ^, ¹⁸ ^, ¹⁹ ^, ²⁰ ^, ²¹ However, placebo-controlled or cohort studies showing clear evidence for safety and superior, or even noninferior, efficacy have not been published in the peer-reviewed literature. Therefore, in conjunction with regulatory and financial considerations, as well as the relative invasiveness for harvest, cell-based orthobiologics are not recommended for intra-articular injection therapy in OA at this time.

11.2.2 Tendinopathy

Tendinopathies comprise another large-volume area of orthopaedics where nonoperative treatments are used in abundance and yet without consistent success. As such, effective biologics could have significant benefit for these patients as outlined in Chapters s. Kap., s. Kap., and s. Kap.. For this discussion, we divide tendinopathies into three categories:

Acute tear or defect
Chronic degenerative tendinosis
Tendon–bone interface pathology

When nonoperative treatment for acute tears or defects of tendons is deemed appropriate, the primary considerations for use of orthobiologics include PRP and MSCs. For these acute problems, we prefer leukocyte-poor PRP injected into the tear or defect under ultrasound guidance (Fig. 11.1). However, leukocyte-rich PRP may be equally or even more effective for treatment of acute tendinopathies, and current best evidence does not suggest clear differences between formulations. ²² ^, ²³ ^, ²⁴ Because acute tendon disorders are expected to be associated with inflammation, leukocytes in the PRP are not felt to be necessary or additive to healing.

**Fig. 11.1** Ultrasound-guided injection of an orthobiologic for treatment of a partial-thickness bursal-sided tear of the supraspinatus tendon.

Extensive evidence exists supporting the use of bone marrow–derived and adipose-derived MSCs for treatment of acute tendinopathies in animal models and clinical veterinary patients. ²⁵ ^, ²⁶ ^, ²⁷ ^, ²⁸ ^, ²⁹ ^, ³⁰ ^, ³¹ However, there is a paucity of data regarding the use of MSCs for these problems in human patients. ³² ^, ³³ Though concerns regarding local pain and swelling, potential for local and systemic inflammatory and immune responses, infection risk, ectopic tissue formation, and potentially even tumor formation associated with the use of MSCs have been raised, use of autogenous MSCs is considered safe in general. ³⁴ However, based on the lack of supporting evidence, regulatory and financial considerations, and the relative invasiveness for harvest, we do not use MSCs for treatment of tendon problems in patients currently.

Similarly, there is no current evidence to support the use of BMAC for treatment of acute tendinopathies. The same harvesting concerns hold true for BMAC, and in addition, the relative potential for calcification in association with this orthobiologic deters us from using it for this indication.

11.2.3 Chronic Tendinosis

Chronic degenerative tendinosis is a much different entity than an acute tendon tear or defect and, as such, should be approached differently with respect to nonoperative treatment with orthobiologics. ³⁵ ^, ³⁶ ^, ³⁷ Chronic degenerative tendinosis in broad terms involves a failure of effective healing with associated poor vascularity, extracellular matrix degeneration, and loss of cell viability and phenotype. As such, progress toward healing needs to be “restarted” with the processes of inflammation, neovascularization, and cell proliferation, chemotaxis, and synthesis. In our view, leukocyte-rich PRP may be more effective than leukocyte-poor PRP in promoting these processes. Further, MSCs may be an optimal orthobiologic for this indication, as animal model and veterinary clinical studies suggest, ²⁵ ^, ²⁶ ^, ²⁷ ^, ²⁸ ^, ²⁹ ^, ³⁰ ^, ³¹ and should be considered if financial, regulatory, and technical factors allow use. BMAC could also be considered for treatment of chronic degenerative tendinosis as it contains MSCs and PRP, but its relative potential for calcification causes some concern.