Recently, there has been a growing interest in orthobiologics and their role in augmentation, regeneration, and healing of bone, cartilage, and soft tissues because of unmet clinical needs in bone and soft-tissue healing (eg, rotator cuff repair, fracture healing) and progression of arthritic change (eg, cartilage preservation/regeneration in early osteoarthritis). Orthobiologic products are derived from substances that naturally occur in the body, including human blood and tissue (bone marrow, adipose), extracellular matrix, placenta, and amniotic fluid. A recent survey of members of the American Orthopaedic Society for Sports Medicine revealed that 66% are using at least one orthobiologic in their practice and 72% are increasing their use,1
although regulatory and FDA approval for the various orthobiologic agents are at various stages. Although orthobiologics are perceived as less invasive than surgery with the potential to improve healing and recovery, the lack of high-quality evidence has slowed their widespread acceptance among all practitioners. Most published studies on this topic have small sample size, lack comparative effectiveness, and have high heterogeneity in both patient characteristics and follow-up duration, as well as inconsistency in dose and preparation of orthobiologic interventions.2
For instance, lack of standardization and high variability in the preparation, dose, frequency, and route of administration of platelet-rich plasma (PRP) have led to conflicting results and complicated the interpretation of the literature on this topic.3
Regulatory approval may also limit the use of certain intervention and, therefore, the ability to study treatment efficacy effectively. For example, mesenchymal stem cells are not FDA approved but do have approval for use in Europe, Canada, and Australia.4
One of the major determinants of evaluating quality in orthobiologic studies is the selection of appropriate outcome measures. The outcome measure is defined by the World Health Organization as the change in the health of an individual, group of people, or population that is attributable to an intervention or series of interventions. The measures vary from a simple question about patient’s pain level to a complex questionnaire that assigns a numeric value to patient’s health status. More generalized outcome measures (eg, Short Form [SF] 36) may focus on a patient’s general health status, whereas others can be specific to a disease process (eg, Western Ontario Rotator Cuff Index) or a joint in the body (eg, Constant score).5
Also, outcome measures can be patient or physician assessed.
Wilson and Cleary combined the biomedical and social science paradigms of health outcome and proposed a conceptual model for patient outcomes that includes five main categories:6
biologic and physiologic outcomes (eg, biomarkers), symptoms (eg, pain level), functioning (eg, return to sport), general health perception (eg, Veteran Rand 12), and overall quality of life (eg, quality-adjusted life year). One of the major attributes of good outcome measures is their relevance to patients and their experience, which explains the growing attention to patient-reported outcome measures (PROMs) in the orthopaedic literature,7
instruments that are now widely used and encompass four of the five categories highlighted in the conceptual model of Wilson and Cleary: symptoms, functioning, general health perception, and overall quality of life. PROMs are essential to understanding the benefit of orthobiologic interventions, in addition to biologic, imaging (structural), and objective functional (strength, range of motion [ROM]) outcomes after treatment.
Outcomes are increasingly assessed through standardized instruments. The most important attribute of an outcome instrument is to examine whether an intervention is effective in improving symptoms or function from a patient’s standpoint.8
An outcome instrument should be reliable, valid, and responsive to change in health status relevant to the procedure or intervention it assesses.9
Reliability refers to the extent an instrument yields the same results in repeated measurements in a cohort with stable health. This can be assessed through interrater, test-retest, and internal consistency reliability.10
Validity is an estimate of the extent to which an instrument measures what it is designed to measure. An instrument is valid if it has face validity (relevance), content validity (covering all domains), and construct validity (correlation to other instruments). Responsiveness refers to the ability of an instrument to reflect change in a cohort of patients over time. It is critical for a responsive instrument to detect any effect that is important to the patient, even if that effect is small, and the magnitude is often referred to as the minimum clinically important difference.11
The choice of outcome measure has important implications for all aspects of orthobiologic research, including sample size, patient compliance, feasibility, and the cost of data collection.12
It is important to review the different outcome measures used to evaluate orthobiologic interventions in the upper extremity, including those used to assess biologic, imaging (structural), functional outcomes (strength, ROM), and PROMs.
BIOLOGIC AND PHYSIOLOGIC OUTCOMES
Orthobiologic interventions aim to improve biologic aspects of tissue healing, such as regeneration of soft tissue and articular cartilage, and they hold promise for treatment of a variety of acute and chronic orthopaedic conditions. The rationale for the clinical application of orthobiologics is that they promote or enhance a healing response in tissues that have less inherent regenerative capacity and can optimize the inflammatory response following an injury.13
Most of the data on the biologic effects of orthobiologics are based on preclinical and in vitro laboratory studies. Clinical trials are designed with the hope that those results translate to improved outcomes for patients, but this has not always panned out because of the lack of high-quality studies and absence of true controls in many intervention studies,14
as well as the heterogeneity of included studies in most meta-analyses.15
Biologic outcomes such as the evaluation of tissue biopsies and the analysis of biomarkers from serum, urine, or synovial fluid have been used in orthobiologic studies. The advantage of tissue-based outcome variables is their high sensitivity to healing or the biologic process of interest. The disadvantage of tissue biopsies is that they may fail to yield enough tissue or only small quantities that may not be representative of the tissue of interest, and the process of obtaining and analyzing tissue biopsies can be invasive and destructive, which prohibits their application in longitudinal studies. Although biomarker analysis of systemic blood or urine is not destructive and commonly can be repeated over time, there is questionable specificity and relevance to patients’ local healing or inflammatory process.
Overall, the strength of the relationship between biologic outcomes and PROMs is not well understood, and the difficulty in procurement and interpretation of biologic outcome measures has limited their widespread application. Identifying prognostic biomarkers for both disease progression and response to treatment in various orthopaedic conditions would provide additional depth of assessment beyond what is captured by PROMs. For example, Carr et al16
reported the results of a randomized clinical trial of arthroscopic acromioplasty with and without injection of autologous PRP in 60 patients with chronic rotator cuff tendinopathy. They obtained tendon biopsies at the time of surgery and at 3-month follow-up using needle biopsy under ultrasound guidance. Their study showed significant improvement in patient-reported outcomes at up to 2 years of follow-up with acromioplasty, but the PRP group showed worse tissue characteristics at 3 months, including reduced cellularity and vascularity and increased apoptosis suggesting a potential deleterious effect of PRP injection on the healing response. This example depicts a rare but effective application of a biologic outcome in orthobiologic research that adds a new dimension to the growing knowledge of these interventions.
There is a growing body of literature on the role of biomarkers in diagnosis and treatment of common upper extremity diseases such as rotator cuff disease,17
and adhesive capsulitis.20
Although most novel biomarkers are in the early stages of preclinical validation, they are showing promising application in orthobiologic research. For example, biomarkers are able to provide information about tissue integrity by quantifying the molecular composition (such as the type and orientation of collagen fibers in tendon21
), cellular makeup (such as the number and differentiation of regenerative cells), and healing response (such as the concentration and type of biologic mediators) in the tissue.22
It is crucial to closely monitor the potential future application of these assays and biomarkers in orthobiologic research.
Imaging studies are one of the most commonly used surrogate outcome measures in orthopaedic research (Table 1
). They provide valuable structural data that can be used in formulating the diagnosis, assessing the severity of the disease, and monitoring disease progression and the response to treatment. Examples of imaging outcome measures include the degree of joint-space
narrowing measured on plain radiographs, the integrity of a rotator cuff repair on ultrasonography or MRI, and the amount of fatty infiltration and atrophy of the rotator cuff muscles seen on MRI. The advantages of imaging-based outcomes include the ability to assess structural changes in a noninvasive and nondestructive manner that allows for longitudinal assessment of tissues of interest, as well as their reliability and availability as outcome measures.
TABLE 1 Imaging Outcomes and Their Characteristics
Ubiquitous, low cost
Poor soft-tissue delineation
Short penetration, operator dependent
Three dimensional, fast, high resolution, best for bone
Radiation, poor soft-tissue delineation
Three dimensional, high resolution, best for soft tissue
Low resolution, radioactive probe
PET = positron emission tomography, SPECT = single photon emission CT
Reproduced with permission from Wallyn J, Anton N, Akram S, Vandamme TF: Biomedical imaging: Principles, technologies, clinical aspects, contrast agents, limitations and future trends in nanomedicines. Pharm Res 2019;36(6):78.
There are a few universal challenges in designing studies with primary imaging outcome measures. First, exposure to radiation may pose a concern when patients undergo repeated radiographs or CT, especially at a younger age. Second, depending on the type of tissue and the intervention, an imaging-based structural effect may not be observed. For instance, several studies on the efficiency of PRP injections in rotator cuff repair have failed to show any effect on the rate of retear based on MRI evaluation.23
This may be due to a lack of true benefit of the orthobiologic intervention, but also brings up the question of the sensitivity of imaging measures to detect change following these types of interventions, as well as the optimal timing of imaging measures to capture maximum healing response. Third, the cost of imaging studies, especially advanced imaging (eg, CT, MRI, and positron emission tomography), practically limits their use. Last, generally, there is a challenge interpreting imaging-based structural outcomes when they do not correlate with patients’ symptoms and function. A classic example of this is the weak correlation between MRI-based assessment of rotator cuff integrity and PROMs in the early (1-year or at most 2-year) follow-up period after rotator cuff repair when outcomes are assessed.24
Additional studies are needed to understand the relationship between poor short-term structural outcomes and longer term clinical outcomes when clinical declines are more likely to be manifest.
Plain radiography is one of the most basic and ubiquitous imaging modalities that provides useful information about bone and joint anatomy. The variables that can be assessed on radiographs include gross alignment of joints, presence and classification of fractures, fracture healing, joint space as a surrogate for cartilage height, overall bone density and cortical thickness as a crude measure of osteoporosis, and other arthritic changes, including the presence of osteophytes, joint line medialization, and bony erosion to assess the severity of osteoarthritic disease. Radiographic analysis generally has low sensitivity and long latency and provides limited data on soft tissue and its healing response while exposing patients to radiation. Although plain radiography has commonly been used as an imaging modality in cartilage restoration and osteoarthritis studies in the lower extremity, its utility in orthobiologic studies of soft tissues in the upper extremity has been limited.
Ultrasonography has dual applications both as an image guidance tool for targeted injections and a diagnostic modality for soft-tissue assessment. Ultrasound-guided injection has improved the precise and effective delivery of orthobiologics and image-guided injections have become more popular in recent years.26
In two recent meta-analyses of the effectiveness of PRP in rotator
cuff tendinopathy, almost all studies used ultrasound guidance for the injection of PRP in subacromial, intra-articular, or intratendinous applications.27
As an imaging modality, ultrasonography has the advantage of not exposing patients to radiation, having reasonable cost, and being able to assess soft tissues dynamically. The limitations of ultrasonography are its user dependency, low resolution, limited depth penetration, and the effect of swelling and body habitus on its accuracy. Ultrasonography has been applied in the assessment of lateral epicondylitis29
and rotator cuff tendinopathy and tears.30
CT is considered an advanced imaging study that can provide three-dimensional views of the body with high resolution, short acquisition time, and preferential visualization of bony structures. Although it is a diagnostic modality of choice in the assessment of fracture healing and has capability to quantify bone density, its application in orthobiologic studies has been limited mainly because of its decreased utility in the assessment of granular soft-tissue changes, risk of radiation exposure, and cost.
MRI is the most commonly used diagnostic imaging modality for high-resolution assessment of soft tissue, especially tendon quality, healing response, and progression of osteoarthritis. MRI has also been used frequently as an imaging outcome measure in orthobiologic studies.28
It has the advantage of not exposing patients to radiation while providing detailed information about water and fat content in soft tissue, and with the help of different signal sequences, it is able to assess tendons, ligaments, muscles, cartilage, and other soft-tissue structures. In addition, it offers an enduring imaging study that can be reviewed by many and for detailed assessments. With the increased application of scaffolds to deliver orthobiologic solutions, MRI has been able to show utility in the assessment of scaffold location, integration, and integrity over time. Potential limitations of MRI-based outcome measures include long acquisition time, interference of metallic objects, and high cost. Contrast-based functional CT or MRI modalities to assess tissue quality (eg, cartilage, meniscus, tendon) or healing response around a joint are being investigated and developed,32
but have not yet been routinely used in clinical studies to assess the benefit of orthobiologic interventions.
Positron emission tomography and single photon emission CT are advanced nuclear medicine imaging techniques that use radioactive tracers to identify areas of soft tissue and bone that are highly metabolically active.33
They are costly, have low resolution, and require a radioactive probe and exposure to radiation, but are highly specific and can have unique applications in detection of stress fracture and intense soft-tissue healing response, and although this has not been explored, they can potentially be used in orthobiologic studies.34
Assessment of function is one of the most relevant outcome measures for patients undergoing orthobiologic interventions. The functional outcome of an extremity or joint can be captured by measurement of patients’ ROM and strength and can be inferred by their return to a desired level of activity at work or sports. The patient’s assessment of their function is also an important part of any patient-reported outcome instrument. The advantage of functional outcomes is their objective nature and the fact that they can be quantified (eg, ROM and strength) or verified through registries or official records (eg, return to sports in professional sport leagues). The challenge in assessing functional outcomes, however, is that they are most commonly evaluated by an observer and require an in-person or virtual visit and are subjected to inaccuracies depending on the observer and the method of measurement. Although using blinded and trained observers who use standard protocols to examine and record functional outcomes can reduce the chance of error and bias, studies still show high interobserver and intraobserver variability in this setting.8
In addition, the cause of gain of function with regard to measures such as ROM and strength can be multifactorial in nature and may be affected by a variety of mental, emotional, and physical factors.
Functional outcome measures including ROM, strength, and return to work and sports have been used in orthobiologic studies. Randelli et al35
published a randomized controlled trial on the effect of intraoperative PRP injection after arthroscopic rotator cuff repair and showed not only better pain control in the first month and improved PROMs at 3 months, but patients’ external rotation strength measured by dynamometer was also significantly higher in the treatment group at 3 months, supporting a positive effect of PRP on rotator cuff healing in this study. In contrast, Kesikburun et al36
reported another randomized controlled trial on the effect of PRP injection on rotator cuff tendinopathy and showed at 1 year the PRP injection was no more effective than placebo in improving PROMs and pain level. In addition, no difference was found in patients’ ROM at 3, 6, 12, and 24 weeks and 1 year after the PRP injection, which added more depth to the assessment of function in this study. A study by Mills et al37
explored the ability to return to sport after PRP injection following elbow ulnar collateral ligaments injury in a cohort of 50 patients and found favorable results in type I, II, and III ulnar collateral ligament injuries, but not type IV with regard to return to sports, suggesting an effect modification by severity of the injury. As seen in these examples, functional outcomes are commonly used in orthobiologic studies and often add objectivity to the assessment of clinical outcomes.
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